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Optic disc pallor

MedGen UID:
108218
Concept ID:
C0554970
Finding
Synonyms: Disc pallor; Pale optic disc; Pale optic discs; Pale optic disks; Pallor of optic discs; Pallor of the optic discs; Pallor of the optic disk; Pallor of the optic disks
SNOMED CT: Pale optic disc (302200001); Optic disc pallor (302200001); Pallor of optic disc (302200001)
 
HPO: HP:0000543

Definition

A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression. [from HPO]

Conditions with this feature

Retinitis pigmentosa 1
MedGen UID:
67395
Concept ID:
C0220701
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the RP1 gene.
Cholestanol storage disease
MedGen UID:
116041
Concept ID:
C0238052
Disease or Syndrome
Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the third decade in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid.
Hereditary motor and sensory neuropathy with optic atrophy
MedGen UID:
140747
Concept ID:
C0393807
Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Hyperimmunoglobulin D with periodic fever
MedGen UID:
140768
Concept ID:
C0398691
Disease or Syndrome
Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.\n\nMevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).\n\nDuring episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.\n\nPeople with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.
Spinocerebellar ataxia type 1
MedGen UID:
155703
Concept ID:
C0752120
Disease or Syndrome
Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy.
Ramon syndrome
MedGen UID:
208669
Concept ID:
C0796133
Disease or Syndrome
A rare, genetic, primary bone dysplasia syndrome characterized by bilateral, painless swelling of the face extending from the mandible to the inferior orbital margins (cherubism), epilepsy, gingival fibromatosis (possibly obscuring teeth), and intellectual disability. Other associated variable features include hypertrichosis, stunted growth, juvenile rheumatoid arthritis, and development of ocular abnormalities (e.g. pigmentary retinopathy, optic disc pallor, Axenfeld anomaly). Radiological images typically show bilateral multifocal radiolucency involving the body, angle and ramus of the mandible and coronoid process.
Retinitis pigmentosa 28
MedGen UID:
244030
Concept ID:
C1419614
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the FAM161A gene.
Optic atrophy 3
MedGen UID:
371657
Concept ID:
C1833809
Disease or Syndrome
Autosomal dominant optic atrophy and cataract is an eye disorder that is characterized by impaired vision. Most affected individuals have decreased sharpness of vision (visual acuity) from birth, while others begin to experience vision problems in early childhood or later. In affected individuals, both eyes are usually affected equally. However, the severity of the vision loss varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness.\n\nSeveral abnormalities contribute to impaired vision in people with autosomal dominant optic atrophy and cataract. In the early stages of the condition, affected individuals experience a progressive loss of certain cells within the retina, which is a specialized light-sensitive tissue that lines the back of the eye. The loss of these cells (known as retinal ganglion cells) is followed by the degeneration (atrophy) of the nerves that relay visual information from the eyes to the brain (optic nerves), which contributes to vision loss. Atrophy of these nerves causes an abnormally pale appearance (pallor) of the optic nerves, which can be seen only during an eye examination. Most people with this disorder also have clouding of the lenses of the eyes (cataracts). This eye abnormality can develop anytime but typically appears in childhood. Other common eye problems in autosomal dominant optic atrophy and cataract include involuntary movements of the eyes (nystagmus), or problems with color vision (color vision deficiency) that make it difficult or impossible to distinguish between shades of blue and green.\n\nSome people with autosomal dominant optic atrophy and cataract develop disturbances in the function of other nerves (neuropathy) besides the optic nerves. These disturbances can lead to problems with balance and coordination (cerebellar ataxia), an unsteady style of walking (gait), prickling or tingling sensations (paresthesias) in the arms and legs, progressive muscle stiffness (spasticity), or rhythmic shaking (tremors). In some cases, affected individuals have hearing loss caused by abnormalities of the inner ear (sensorineural deafness).
Retinitis pigmentosa 33
MedGen UID:
332080
Concept ID:
C1835895
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the SNRNP200 gene.
Retinitis pigmentosa 32
MedGen UID:
322781
Concept ID:
C1835927
Disease or Syndrome
A retinitis pigmentosa that has material basis in variation in the chromosome region 1p21.3-p13.3.
Spastic paraplegia, optic atropy, and neuropathy
MedGen UID:
324411
Concept ID:
C1836010
Disease or Syndrome
Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by Melo et al., 2015).
Peripheral cone dystrophy
MedGen UID:
323031
Concept ID:
C1836946
Disease or Syndrome
Leber congenital amaurosis 9
MedGen UID:
325277
Concept ID:
C1837873
Disease or Syndrome
Early-onset neurodegeneration in the human retina can lead to Leber congenital amaurosis (LCA), the most severe human form of inherited photoreceptor-neuron degeneration resulting in congenital blindness, with an incidence of approximately 1 in 80,000 (summary by Koenekoop et al., 2012). NMNAT1 mutations have been observed to cause severe and rapidly progressive macular degeneration, leading to severe central atrophy with an appearance of congenital macular coloboma in the neonatal period, as well as an unusual early-onset atrophy of the optic nerve (Perrault et al., 2012). Some patients present with later onset and milder phenotype than typical LCA (Kumaran et al., 2021). For a general discussion of the phenotypic and genetic heterogeneity in Leber congenital amaurosis, see LCA1 (204000).
Retinitis pigmentosa 11
MedGen UID:
325055
Concept ID:
C1838601
Disease or Syndrome
Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment. For a discussion of genetic heterogeneity of RP, see 268000.
Retinitis pigmentosa 14
MedGen UID:
325056
Concept ID:
C1838603
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the TULP1 gene.
Retinitis pigmentosa 12
MedGen UID:
374019
Concept ID:
C1838647
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the CRB1 gene.
Mitochondrial complex I deficiency
MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).
Retinitis pigmentosa 26
MedGen UID:
333996
Concept ID:
C1842127
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the CERKL gene.
Pontocerebellar hypoplasia type 3
MedGen UID:
334225
Concept ID:
C1842687
Disease or Syndrome
Pontocerebellar hypoplasia (PCH) refers to a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Clinical features vary, but usually include severe developmental delay, dysmorphic features, seizures, and early death (summary by Durmaz et al., 2009). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Chromosome 1p36 deletion syndrome
MedGen UID:
334629
Concept ID:
C1842870
Disease or Syndrome
The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features.
X-linked cone-rod dystrophy 3
MedGen UID:
336932
Concept ID:
C1845407
Disease or Syndrome
Cone-rod dystrophy is a retinal disorder with predominantly cone involvement. Rod impairment may occur at the same time as the cone impairment or appear later. Patients with CORD usually have reduced visual acuity, photophobia, and color vision defects (summary by Huang et al., 2013). For a discussion of genetic heterogeneity of X-linked cone-rod dystrophy, see 304020.
Spondyloepimetaphyseal dysplasia, Bieganski type
MedGen UID:
335350
Concept ID:
C1846148
Disease or Syndrome
X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL) is an X-linked recessive developmental disorder characterized by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy (summary by Miyake et al., 2017).
Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction
MedGen UID:
376565
Concept ID:
C1849333
Disease or Syndrome
Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD) is characterized by onset of hearing impairment and reduced vision within the first 5 years of life. Renal dysfunction results in rickets-like skeletal changes, and death may occur in childhood or young adulthood due to renal failure (Beighton et al., 1993).
Optic atrophy 5
MedGen UID:
377837
Concept ID:
C1853139
Disease or Syndrome
OPA5 is an autosomal dominant form of nonsyndromic optic atrophy, manifest as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and color vision defects. The pathogenesis is related to defective mitochondrial fission (summary by Gerber et al., 2017). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).
Oculocerebrofacial syndrome, Kaufman type
MedGen UID:
343403
Concept ID:
C1855663
Disease or Syndrome
Kaufman oculocerebrofacial syndrome (KOS) is characterized by developmental delay, severe intellectual disability, and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, hypotonia, and growth deficiency. Feeding issues, ocular abnormalities, hearing impairment, and respiratory tract abnormalities are common. Ocular abnormalities can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Breathing problems can lead to prolonged hospitalization after birth in more than half of individuals. Less common findings include ectodermal abnormalities, cardiac manifestations, urogenital abnormalities, seizures, and skeletal abnormalities.
Leber congenital amaurosis 4
MedGen UID:
346808
Concept ID:
C1858386
Disease or Syndrome
Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Various intermediate phenotypes between LCA and retinitis pigmentosa are known and are sometimes described as 'early-onset severe rod-cone dystrophy' or 'early-onset retinal degeneration' (Booij et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000; for cone-rod dystrophy, see 120970.
Cone-rod dystrophy 3
MedGen UID:
349030
Concept ID:
C1858806
Disease or Syndrome
Cone-rod dystrophy-3 (CORD3) is an autosomal recessive, clinically heterogeneous retinal disorder with typical findings of reduced visual acuity, impairment of the central visual field, color vision deficits, and fundoscopic evidence of maculopathy, with no or few midperipheral retinal pigment deposits. Cone degeneration appears early in life with a central involvement of the retina, followed by a degeneration of rods several years later (summary by Klevering et al., 2002 and Ducroq et al., 2002). Both cone and rod a- and b-wave electroretinogram (ERG) amplitudes are reduced (Fishman et al., 2003). For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
Leber congenital amaurosis 2
MedGen UID:
348473
Concept ID:
C1859844
Disease or Syndrome
RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy (RPE65-LCA/EOSRD) is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and age five years. While central vision varies, the hallmark of this disorder is the presence of severe visual impairment with a deceptively preserved retinal structure. Vision is relatively stable in the first decade of life, but begins to decline in adolescence. Most affected individuals are legally blind (visual acuity 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, visual acuity declines further and by the fourth decade all affected individuals are legally blind and many have complete loss of vision (i.e., no light perception). Milder disease phenotypes have been described in individuals with hypomorphic alleles.
Triosephosphate isomerase deficiency
MedGen UID:
349893
Concept ID:
C1860808
Disease or Syndrome
Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).
Retinitis pigmentosa 25
MedGen UID:
350427
Concept ID:
C1864446
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the EYS gene.
Retinitis pigmentosa 36
MedGen UID:
351175
Concept ID:
C1864621
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRCD gene.
Retinitis pigmentosa 19
MedGen UID:
400996
Concept ID:
C1866422
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the ABCA4 gene.
Spastic paraplegia, optic atrophy, and dementia
MedGen UID:
356630
Concept ID:
C1866849
Disease or Syndrome
Retinitis pigmentosa 10
MedGen UID:
357247
Concept ID:
C1867299
Disease or Syndrome
Retinitis pigmentosa-10 (RP10) is characterized in most patients by early onset and rapid progression of ocular symptoms, beginning with night blindness in childhood, followed by visual field constriction. Some patients experience an eventual reduction in visual acuity. Funduscopy shows typical changes of RP, including optic disc pallor, retinal vascular attenuation, and bone-spicule pattern of pigmentary deposits in the retinal midperiphery. Electroretinography demonstrates equal reduction in rod and cone responses (Jordan et al., 1993; Bowne et al., 2002; Bowne et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Mevalonic aciduria
MedGen UID:
368373
Concept ID:
C1959626
Disease or Syndrome
Mevalonic aciduria (MEVA), the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).
Autosomal recessive osteopetrosis 5
MedGen UID:
409627
Concept ID:
C1968603
Disease or Syndrome
Autosomal recessive osteopetrosis-5 is a form of infantile malignant osteopetrosis, characterized by defective osteoclast function resulting in decreased bone resorption and generalized osteosclerosis. Defective resorption causes development of densely sclerotic fragile bones and progressive obliteration of the marrow spaces and cranial foramina. Marrow obliteration is associated with extramedullary hematopoiesis and hepatosplenomegaly, and results in anemia and thrombocytopenia, whereas nerve entrapment accounts for progressive blindness and hearing loss. Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate. Most affected children succumb to severe bone marrow failure and overwhelming infection in the first few years of life (Quarello et al., 2004).
Autosomal recessive osteopetrosis 4
MedGen UID:
370598
Concept ID:
C1969106
Disease or Syndrome
The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease). ARO. Onset is at birth. Findings may include: fractures; reduced growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. IAO. Onset is in childhood. Findings may include: fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. ADOII. Onset is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.
Isolated microphthalmia 5
MedGen UID:
410021
Concept ID:
C1970236
Disease or Syndrome
Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by the association of posterior microphthalmia, retinal dystrophy compatible with retinitis pigmentosa, localized foveal schisis and optic disc drusen. Patients present high hyperopia, usually adult-onset progressive nyctalopia and reduced visual acuity, and, on occasion, acute-angle glaucoma.
Leber congenital amaurosis 13
MedGen UID:
382544
Concept ID:
C2675186
Disease or Syndrome
Leber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.\n\nA specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.\n\nLeber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.\n\nAt least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.\n\nIn very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.
Retinitis pigmentosa 46
MedGen UID:
382614
Concept ID:
C2675496
Disease or Syndrome
Retinitis pigmentosa-46 (RP46) is characterized by night blindness, loss of peripheral vision, and reduced visual acuity. Funduscopic findings are typical of RP, including pale optic discs, attenuated retinal vessels, and intraretinal pigment deposits. Electroretinography shows substantial loss of rod and cone photoreceptor function (Hartong et al., 2008). For a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Joubert syndrome 8
MedGen UID:
436772
Concept ID:
C2676771
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Retinitis pigmentosa 41
MedGen UID:
383126
Concept ID:
C2677516
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the PROM1 gene.
Syndromic X-linked intellectual disability Najm type
MedGen UID:
437070
Concept ID:
C2677903
Disease or Syndrome
CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.
Leber congenital amaurosis 14
MedGen UID:
442375
Concept ID:
C2750063
Disease or Syndrome
Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.
Retinitis pigmentosa 50
MedGen UID:
442563
Concept ID:
C2750789
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the BEST1 gene.
Autosomal recessive optic atrophy, OPA7 type
MedGen UID:
414112
Concept ID:
C2751812
Disease or Syndrome
A rare, syndromic, hereditary optic neuropathy disorder characterized by early-onset, severe, progressive visual impairment, optic disc pallor and central scotoma, variably associated with dyschromatopsia, auditory neuropathy (e.g. mild progressive sensorineural hearing loss), sensorimotor axonal neuropathy and, occasionally, moderate hypertrophic cardiomyopathy.
Hereditary spastic paraplegia 50
MedGen UID:
442869
Concept ID:
C2752008
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Retinitis pigmentosa 56
MedGen UID:
462169
Concept ID:
C3150819
Disease or Syndrome
Retinitis pigmentosa-56 (RP56) is an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity (Bandah-Rozenfeld et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa 57
MedGen UID:
462171
Concept ID:
C3150821
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the PDE6G gene.
Retinitis pigmentosa 58
MedGen UID:
462229
Concept ID:
C3150879
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the ZNF513 gene.
Porencephaly-microcephaly-bilateral congenital cataract syndrome
MedGen UID:
462350
Concept ID:
C3151000
Disease or Syndrome
HDBSCC is an autosomal recessive disorder with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy (summary by Akawi et al., 2013).
Retinitis pigmentosa 49
MedGen UID:
462409
Concept ID:
C3151059
Disease or Syndrome
Retinitis pigmentosa-49 (RP49) is characterized by onset of night blindness in childhood, followed by progressive loss of visual fields and reduced visual acuity. Typical fundus features are present, including pale optic disc, attenuated vasculature, and pigment deposits in the midperiphery (Zhang et al., 2004; Katagiri et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa 43
MedGen UID:
462489
Concept ID:
C3151139
Disease or Syndrome
Retinitis pigmentosa-43 (RP43) is characterized by night blindness in the first decade of life, with progressive loss of peripheral visual fields and reduction in visual acuity. Examination reveals typical features of RP, including waxy pallor of optic disc, attenuated retinal vessels, and bone-spicule pigment in midperipheral retina. Macular edema and/or atrophy has been observed in some patients. Electroretinographic responses are markedly reduced or absent (summary by Huang et al., 1995 and Corton et al., 2010).
Leber congenital amaurosis 15
MedGen UID:
462556
Concept ID:
C3151206
Disease or Syndrome
Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997). Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132). For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.
Retinitis pigmentosa 38
MedGen UID:
462578
Concept ID:
C3151228
Disease or Syndrome
Retinitis pigmentosa (RP) describes a group of disorders with progressive degeneration of rod and cone photoreceptors in a rod-cone pattern of dysfunction. RP has a prevalence of 1 in 3,500, and is genetically and phenotypically heterogeneous (summary by Mackay et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa 60
MedGen UID:
462784
Concept ID:
C3151434
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF6 gene.
Microcephaly and chorioretinopathy 1
MedGen UID:
480111
Concept ID:
C3278481
Disease or Syndrome
Microcephaly and chorioretinopathy is an autosomal recessive developmental disorder characterized by delayed psychomotor development and visual impairment, often accompanied by short stature (summary by Martin et al., 2014). Genetic Heterogeneity of Microcephaly and Chorioretinopathy See also MCCRP2 (616171), caused by mutation in the PLK4 gene (605031) on chromosome 4q27, and MCCRP3 (616335), caused by mutation in the TUBGCP4 gene (609610) on chromosome 15q15. An autosomal dominant form of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is caused by heterozygous mutation in the KIF11 gene (148760) on chromosome 10q23. See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive pigmentary retinopathy and mental retardation; 268050), which has been mapped to chromosome 8q21.3-q22.1.
Retinitis pigmentosa 62
MedGen UID:
481672
Concept ID:
C3280042
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the MAK gene.
Leber congenital amaurosis 16
MedGen UID:
481692
Concept ID:
C3280062
Disease or Syndrome
Leber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.\n\nA specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.\n\nLeber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.\n\nAt least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.\n\nIn very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.
Craniofacial anomalies and anterior segment dysgenesis syndrome
MedGen UID:
481729
Concept ID:
C3280099
Disease or Syndrome
Wolfram-like syndrome
MedGen UID:
481988
Concept ID:
C3280358
Disease or Syndrome
Autosomal dominant Wolfram-like syndrome (WFSL) is characterized by the clinical triad of congenital progressive hearing impairment, diabetes mellitus, and optic atrophy. The hearing impairment, which is usually diagnosed in the first decade of life, is relatively constant and alters mainly low- and middle-frequency ranges (summary by Valero et al., 2008). Wolfram syndrome (WFS1; 222300) is an autosomal recessive allelic disorder characterized by optic atrophy, diabetes mellitus, hearing loss, and diabetes insipidus, and is caused by homozygous or compound heterozygous mutation in the WFS1 gene. An autosomal dominant syndrome involving optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (125250), is caused by heterozygous mutation in the OPA1 gene (605290).
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
MedGen UID:
482290
Concept ID:
C3280660
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
Retinitis pigmentosa 63
MedGen UID:
482632
Concept ID:
C3281002
Disease or Syndrome
A retinitis pigmentosa that has material basis in variation in the chromosome region 6q23.
Cone-rod dystrophy 16
MedGen UID:
482675
Concept ID:
C3281045
Disease or Syndrome
Cone-rod dystrophy (CORD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (summary by Estrada-Cuzcano et al., 2012).
Usher syndrome type 3B
MedGen UID:
482696
Concept ID:
C3281066
Disease or Syndrome
Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (Karjalainen et al., 1983; Pakarinen et al., 1995). For a discussion of genetic heterogeneity of type III Usher syndrome, see USH3A (276902).
Jalili syndrome
MedGen UID:
501210
Concept ID:
C3495589
Disease or Syndrome
Jalili syndrome is an autosomal recessive disorder consisting of cone-rod dystrophy and amelogenesis imperfecta. Significant visual impairment with nystagmus and photophobia is present from infancy or early childhood and progresses with age. Enamel of primary and secondary dentitions is grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization (summary by Parry et al., 2009).
Linear skin defects with multiple congenital anomalies 2
MedGen UID:
763835
Concept ID:
C3550921
Disease or Syndrome
Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described.
Cone-rod dystrophy 17
MedGen UID:
767524
Concept ID:
C3554610
Disease or Syndrome
The first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).\n\nThere are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.\n\nCone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.
Retinitis pigmentosa 66
MedGen UID:
811638
Concept ID:
C3715216
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the RBP3 gene.
Bosch-Boonstra-Schaaf optic atrophy syndrome
MedGen UID:
816693
Concept ID:
C3810363
Disease or Syndrome
Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by delayed development, moderately impaired intellectual development, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific (summary by Bosch et al., 2014).
Hermansky-Pudlak syndrome 8
MedGen UID:
854728
Concept ID:
C3888026
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Mitochondrial complex III deficiency nuclear type 8
MedGen UID:
862877
Concept ID:
C4014440
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Retinitis pigmentosa 70
MedGen UID:
863118
Concept ID:
C4014681
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF4 gene.
Cone-rod dystrophy 20
MedGen UID:
863293
Concept ID:
C4014856
Disease or Syndrome
Cone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.\n\nThere are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.\n\nThe first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).
Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies
MedGen UID:
863583
Concept ID:
C4015146
Disease or Syndrome
Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies is a rare, genetic, retinal dystrophy disorder characterized by decreased central retinal sensitivity associated with hyper-reflectivity of ganglion cells and nerve fiber layer with loss of optic nerve fibers manifesting with photophobia, optic disc pallor and progressive loss of central vision with preservation of peripheral visual field.
Macular dystrophy with central cone involvement
MedGen UID:
863808
Concept ID:
C4015371
Disease or Syndrome
Microcephaly and chorioretinopathy 2
MedGen UID:
863825
Concept ID:
C4015388
Disease or Syndrome
Microcephaly and chorioretinopathy-2 is an autosomal recessive developmental disorder characterized by delayed psychomotor development, visual impairment, and short stature (summary by Martin et al., 2014). For a discussion of genetic heterogeneity of microcephaly and chorioretinopathy, see MCCRP1 (251270).
Autosomal recessive spinocerebellar ataxia 18
MedGen UID:
863942
Concept ID:
C4015505
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by Hills et al., 2013).
Optic atrophy 10 with or without ataxia, intellectual disability, and seizures
MedGen UID:
905727
Concept ID:
C4225227
Disease or Syndrome
Retinitis pigmentosa 74
MedGen UID:
906896
Concept ID:
C4225281
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the BBS2 gene.
Retinitis pigmentosa 73
MedGen UID:
907690
Concept ID:
C4225287
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the HGSNAT gene.
Retinitis pigmentosa 72
MedGen UID:
895867
Concept ID:
C4225315
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the ZNF408 gene.
Retinitis pigmentosa 71
MedGen UID:
897209
Concept ID:
C4225342
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the IFT172 gene.
Congenital stationary night blindness 1G
MedGen UID:
906532
Concept ID:
C4225345
Disease or Syndrome
PPP2R5D-related intellectual disability is a neurological disorder characterized by moderate to severe developmental delay and intellectual disability. Affected individuals have weak muscle tone (hypotonia); delayed development of motor skills, such as sitting, standing, and walking; and delayed speech development. Recurrent seizures (epilepsy) and autism spectrum disorder, which is characterized by impaired communications and social interaction, can also occur in affected individuals. Most people with PPP2R5D-related intellectual disability have an unusually large head size (macrocephaly), and some have other unusual facial features, including a prominent forehead (frontal bossing), widely spaced eyes (hypertelorism), and eyes that slant downward (downslanting palpebral fissures).
Optic atrophy 9
MedGen UID:
898858
Concept ID:
C4225384
Disease or Syndrome
Optic atrophy-9 (OPA9) is characterized by onset of decreased visual acuity and optic disc pallor in the first decade of life, with severely reduced visual acuity and color vision deficits observed in the third decade. Although initially described as an autosomal recessive disease (Metodiev et al., 2014; Kelman et al., 2018; Gibson et al., 2020), autosomal dominant cases of OPA9 have also been reported (Charif et al., 2021). Mutation in the ACO2 gene also causes a neurodegenerative disorder, infantile cerebellar-retinal degeneration (ICRD; 614559), of which optic atrophy is a feature. Dominant and Recessive OPA9 From a cohort of approximately 1,000 patients with optic atrophy, Charif et al. (2021) identified 50 probands with dominant mutations in the ACO2 gene, and 11 patients with biallelic variants. There was no significant difference in distribution of mutation type, with two-thirds of all variants being missense mutations in both groups, and nonsense, frameshift, and splice site mutations comprising the remaining third. Age at onset of symptoms occurred during the first 2 decades, without significant difference between dominant and recessive cases. Visual acuity was significantly more affected in recessive cases than in dominant ones, with more than 60% of eyes from the recessive group having a visual acuity lower than 20/200, whereas more than 80% of eyes from the dominant group had a visual acuity above 20/200. Analysis of the optic disc as well as retinal nerve fiber layer thickness measurements indicated a preferential involvement of the temporal quadrant in both patient groups. Assessment of color vision revealed highly variable alterations, including protan, deutan, and tritan types of dyschromatopsia. Some patients had additional retinal changes, including macular microcysts as well as macular dystrophy in 1 case. Extraocular symptoms were observed in 6 (12%) of the dominant cases and in 3 (27%) of the recessive cases, including hearing impairment in 2 dominant cases, and late-onset cerebellar ataxia in 1 dominant case and in 1 recessive case.
Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
MedGen UID:
934601
Concept ID:
C4310634
Disease or Syndrome
MECR-related neurologic disorder is characterized by a progressive childhood-onset movement disorder and optic atrophy; intellect is often – but not always – preserved. The movement disorder typically presents between ages one and 6.5 years and is mainly dystonia that can be accompanied by chorea and/or ataxia. Over time some affected individuals require assistive devices for mobility. Speech fluency and intelligibility are progressively impaired due to dysarthria. Optic atrophy typically develops between ages four and 12 years and manifests as reduced visual acuity, which can include functional blindness (also known as legal blindness) in adulthood. Because only 13 affected individuals are known to the authors, and because nearly half of them were diagnosed retrospectively as adults, the natural history of disease progression and other aspects of the phenotype have not yet been completely defined.
Developmental and epileptic encephalopathy, 48
MedGen UID:
934604
Concept ID:
C4310637
Disease or Syndrome
Developmental and epileptic encephalopathy-48 (DEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech; poor, if any, motor development; and onset of seizures usually in the first year of life, although later onset has been reported. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by Assoum et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Myoclonus, intractable, neonatal
MedGen UID:
934625
Concept ID:
C4310658
Disease or Syndrome
Neonatal intractable myoclonus (NEIMY) is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. There is phenotypic and biochemical evidence of mitochondrial dysfunction (summary by Duis et al., 2016).
Periventricular nodular heterotopia 7
MedGen UID:
934636
Concept ID:
C4310669
Disease or Syndrome
Periventricular nodular heterotopia-7 (PVNH7) is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.
Developmental and epileptic encephalopathy, 47
MedGen UID:
934652
Concept ID:
C4310685
Disease or Syndrome
Developmental and epileptic encephalopathy-47 (DEE47) is a neurologic disorder characterized by onset of intractable seizures in the first days or weeks of life. EEG shows background slowing and multifocal epileptic spikes, and may show hypsarrhythmia. Most patients have developmental regression after seizure onset and show persistent intellectual disability and neurologic impairment, although the severity is variable. Treatment with phenytoin, a voltage-gated sodium channel blocker, may be beneficial (summary by Guella et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Joubert syndrome 28
MedGen UID:
934672
Concept ID:
C4310705
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
MedGen UID:
934692
Concept ID:
C4310725
Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Encephalopathy due to defective mitochondrial and peroxisomal fission 2
MedGen UID:
934693
Concept ID:
C4310726
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-2 (EMPF2) is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (summary by Koch et al., 2016). For a discussion of genetic heterogeneity of EMPF, see EMPF1 (614388).
Congenital disorder of glycosylation, type IAA
MedGen UID:
934694
Concept ID:
C4310727
Disease or Syndrome
Retinitis pigmentosa and erythrocytic microcytosis
MedGen UID:
934743
Concept ID:
C4310776
Disease or Syndrome
Features that occur less commonly in people with TRNT1 deficiency include hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss), recurrent seizures (epilepsy), and problems with the kidneys or heart.\n\nTRNT1 deficiency encompasses what was first thought to be two separate disorders, a severe disorder called sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and a milder disorder called retinitis pigmentosa with erythrocytic microcytosis (RPEM), each named for its most common features. SIFD begins in infancy, and affected individuals usually do not survive past childhood. RPEM, on the other hand, is recognized in early adulthood, and the microcytosis usually does not cause any health problems. However, it has since been recognized that some individuals have a combination of features that fall between these two ends of the severity spectrum. All of these cases are now considered part of TRNT1 deficiency.\n\nNeurological problems are also frequent in TRNT1 deficiency. Many affected individuals have delayed development of speech and motor skills, such as sitting, standing, and walking, and some have low muscle tone (hypotonia).\n\nEye abnormalities, often involving the light-sensing tissue at the back of the eye (the retina), can occur in people with TRNT1 deficiency. Some of these individuals have a condition called retinitis pigmentosa, in which the light-sensing cells of the retina gradually deteriorate. Eye problems in TRNT1 deficiency can lead to vision loss.\n\nIn addition, many individuals with TRNT1 deficiency have recurrent fevers that are not caused by an infection. These fever episodes are often one of the earliest recognized symptoms of TRNT1 deficiency, usually beginning in infancy. The fever episodes are typically accompanied by poor feeding, vomiting, and diarrhea, and can lead to hospitalization. In many affected individuals, the episodes occur regularly, arising approximately every 2 to 4 weeks and lasting 5 to 7 days, although the frequency can decrease with age.\n\nMany people with TRNT1 deficiency have an immune system disorder (immunodeficiency) that can lead to recurrent bacterial infections. Repeated infections can cause life-threatening damage to internal organs. The immunodeficiency is characterized by low numbers of immune system cells called B cells, which normally help fight infections by producing immune proteins called antibodies (or immunoglobulins). These proteins target foreign invaders such as bacteria and viruses and mark them for destruction. In many individuals with TRNT1 deficiency, the amount of immunoglobulins is also low (hypogammaglobulinemia).\n\nA common feature of TRNT1 deficiency is a blood condition called sideroblastic anemia, which is characterized by a shortage of red blood cells (anemia). In TRNT1 deficiency, the red blood cells that are present are unusually small (erythrocytic microcytosis). In addition, developing red blood cells in the bone marrow (erythroblasts) can have an abnormal buildup of iron that appears as a ring of blue staining in the cell after treatment in the lab with certain dyes. These abnormal cells are called ring sideroblasts.\n\nTRNT1 deficiency is a condition that affects many body systems. Its signs and symptoms can involve blood cells, the immune system, the eyes, and the nervous system. The severity of the signs and symptoms vary widely.
Retinitis pigmentosa 78
MedGen UID:
1378790
Concept ID:
C4479481
Disease or Syndrome
Retinitis pigmentosa-78 (RP78) is an autosomal recessive retinal dystrophy that presents in the third to fourth decade with central visual disturbance, visual field defects, and nyctalopia. Fundus examination reveals optic disc pallor, attenuated retinal vessels, and irregular midperipheral intraretinal pigment migration (Arno et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa 79
MedGen UID:
1386200
Concept ID:
C4479526
Disease or Syndrome
Neurodevelopmental disorder with midbrain and hindbrain malformations
MedGen UID:
1385580
Concept ID:
C4479613
Disease or Syndrome
Neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) is an autosomal recessive disorder comprising impaired intellectual development, speech delay, mild microcephaly, and midbrain-hindbrain malformation (Ravindran et al., 2017).
Alkaline ceramidase 3 deficiency
MedGen UID:
1622324
Concept ID:
C4540358
Disease or Syndrome
A rare genetic disorder with characteristics of infantile onset of stagnation and regression of motor and language development resulting in complete lack of communication and purposeful movement. Further neurological manifestations include truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy and neurogenic bladder. Patients also present multiple contractures, late-onset relative macrocephaly, short stature and facial dysmorphism (including coarse facial features, sloping forehead, thick eyebrows, low-set ears, prominent nose, flat philtrum, and prominent lower lip). Brain imaging at advanced stages shows diffuse abnormal white matter signal and severe atrophy. Sural nerve biopsy reveals decreased myelination.
Joubert syndrome 1
MedGen UID:
1644883
Concept ID:
C4551568
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Knobloch syndrome 1
MedGen UID:
1642123
Concept ID:
C4551775
Disease or Syndrome
Knobloch syndrome-1 (KNO1) is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011). Genetic Heterogeneity of Knobloch Syndrome KNO2 (618458) is caused by mutation in the PAK2 gene (605022) on chromosome 3q29.
Retinitis pigmentosa 81
MedGen UID:
1637738
Concept ID:
C4693443
Disease or Syndrome
Leukodystrophy, hypomyelinating, 16
MedGen UID:
1631337
Concept ID:
C4693779
Disease or Syndrome
Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum (summary by Simons et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
Combined oxidative phosphorylation defect type 15
MedGen UID:
1646555
Concept ID:
C4706313
Disease or Syndrome
A rare mitochondrial disease due to a defect in mitochondrial protein synthesis with onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported. Caused by homozygous or compound heterozygous mutation in the MTFMT gene on chromosome 15q22.
Peroxisome biogenesis disorder 1A (Zellweger)
MedGen UID:
1648474
Concept ID:
C4721541
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Retinitis pigmentosa with or without situs inversus
MedGen UID:
1658130
Concept ID:
C4747737
Disease or Syndrome
Retinitis pigmentosa-82 with or without situs inversus (RP82) is an autosomal recessive form of retinal degeneration characterized by initial loss of rod photoreceptors, resulting in impaired night vision followed by progressive visual-field constriction as both rod and cone photoreceptors die. Some affected individuals have situs inversus (Davidson et al., 2013; Audo et al., 2017).
Intellectual developmental disorder and retinitis pigmentosa; IDDRP
MedGen UID:
1648358
Concept ID:
C4748658
Disease or Syndrome
Intellectual developmental disorder and retinitis pigmentosa (IDDRP) is characterized by mild to moderate intellectual disability and typical features of RP. Patients experience reduced night vision, constriction of visual fields, and reduced visual acuity; optic disc pallor, attenuated retinal blood vessels, and bone-spicule pigmentation are seen on funduscopy. Attention-deficit/hyperactivity disorder is observed in some patients (Tatour et al., 2017).
Mitochondrial complex 1 deficiency, nuclear type 6
MedGen UID:
1648496
Concept ID:
C4748759
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 8
MedGen UID:
1648411
Concept ID:
C4748766
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 18
MedGen UID:
1648321
Concept ID:
C4748790
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 18 (MC1DN18) is an autosomal recessive disorder of the oxidative phosphorylation (OXPHOS) system. Affected individuals present with lactic acidemia soon after birth. Clinical features may include hypertonia or hypotonia, poor feeding, respiratory problems, leukomalacia, and seizures. Death occurs by 6 months of age (Saada et al., 2009). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Mitochondrial complex 1 deficiency, nuclear type 28
MedGen UID:
1648493
Concept ID:
C4748827
Disease or Syndrome
Hypomyelination with brain stem and spinal cord involvement and leg spasticity
MedGen UID:
1667792
Concept ID:
C4755254
Disease or Syndrome
Hypomyelination with brainstem and spinal cord involvement and leg spasticity is an autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild mental retardation. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013).
Developmental and epileptic encephalopathy, 75
MedGen UID:
1684253
Concept ID:
C5193099
Disease or Syndrome
Developmental and epileptic encephalopathy-75 (DEE75) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by onset of severe refractory seizures in the first months of life. Patients often have global developmental delay before the onset of seizures, and thereafter achieve few milestones. EEG usually shows multifocal spikes and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. They have severely impaired intellectual development with inability to walk, absent speech, and hypotonia with axial hyperreflexia. Brain imaging shows progressive cerebral atrophy, frontal lobe atrophy, white matter abnormalities, and delayed myelination. Since the disorder is due to mitochondrial dysfunction, some patients may develop other organ involvement, including cardiomyopathy or liver and renal dysfunction. Death may occur in childhood (summary by Yin et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Neuropathy, hereditary motor and sensory, type VIc, with optic atrophy
MedGen UID:
1680245
Concept ID:
C5193137
Disease or Syndrome
Hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C) is an autosomal recessive axonal sensorimotor peripheral neuropathy characterized by progressive distal muscle weakness and atrophy primarily affecting the lower limbs. Onset of neuropathy is in the first decade, manifest by difficulty walking and running and followed by similar involvement of the upper limbs and hands. The disorder is associated with distal sensory impairment, particularly of position and vibration sense, as well as areflexia; individuals usually have pes cavus, hammertoes, and atrophy of the intrinsic hand muscles. In addition, progressive optic atrophy and visual impairment occur during adulthood. Treatment with pyridoxal 5-prime phosphate supplementation (vitamin B6) may result in amelioration of symptoms and slow progression of the disease (summary by Chelban et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).
Leber congenital amaurosis 19
MedGen UID:
1679297
Concept ID:
C5193139
Disease or Syndrome
Leber congenital amaurosis-19 (LCA19) is characterized by reduced vision in early childhood and severely reduced responses of both rods and cones on electroretinography (Yi et al., 2019). For a general description and a discussion of genetic heterogeneity of LCA, see 204000.
Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features
MedGen UID:
1682428
Concept ID:
C5193147
Disease or Syndrome
Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).
Developmental and epileptic encephalopathy, 80
MedGen UID:
1684779
Concept ID:
C5231418
Disease or Syndrome
Developmental and epileptic encephalopathy-80 (DEE80) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Retinitis pigmentosa 86
MedGen UID:
1684789
Concept ID:
C5231428
Disease or Syndrome
Retinitis pigmentosa-86 (RP86) is characterized by night blindness followed by progressive narrowing of visual fields and decline in visual acuity, with typical findings of RP on fundus examination, including attenuated retinal vessels, waxy pallor of the optic disc, and bone spicule-like pigmentation (de Bruijn et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Usher syndrome, type 1M
MedGen UID:
1684669
Concept ID:
C5231434
Disease or Syndrome
Usher syndrome type 1M (USH1M) is characterized by prelingual sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa (Ahmed et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of Usher syndrome, see USH1 (276900).
Mitochondrial complex 1 deficiency, nuclear type 34
MedGen UID:
1720533
Concept ID:
C5394053
Disease or Syndrome
Retinitis pigmentosa 88
MedGen UID:
1720448
Concept ID:
C5394208
Disease or Syndrome
Retinitis pigmentosa-88 (RP88) is characterized by night blindness and constriction of peripheral visual fields, with mildly reduced visual acuity. Examination shows typical findings of RP, including attenuated retinal vessels, pale optic discs, and pigment deposits in the peripheral retinal pigment epithelium (Zobor et al., 2018; Hu et al., 2019; Albarry et al., 2019). For a discussion of genetic heterogeneity of RP, see 268000.
Liberfarb syndrome
MedGen UID:
1709796
Concept ID:
C5394404
Disease or Syndrome
Liberfarb syndrome is a progressive disorder involving connective tissue, bone, retina, ear, and brain. Patients exhibit severe short stature and scoliosis with thoracic kyphosis and lumbar hyperlordosis. Severe joint laxity results in dislocations of elbows, hips, and knees. Eye findings are consistent with early-onset retinal degeneration, and there is moderate to severe early-onset hearing loss. Microcephaly is apparent by school age, and patients exhibit developmental delay and intellectual deficits (Peter et al., 2019). Clinical variability has been observed, with some patients presenting differences in the severity and location of skeletal dysplasia involvement as well as variation in other features of the syndrome (Girisha et al., 2019; Zhao et al., 2019).
COACH syndrome 1
MedGen UID:
1769861
Concept ID:
C5435651
Disease or Syndrome
Any COACH syndrome in which the cause of the disease is a variation in the TMEM67 gene.
Arthrogryposis multiplex congenita 5
MedGen UID:
1731112
Concept ID:
C5436453
Disease or Syndrome
Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).
Suleiman-El-Hattab syndrome
MedGen UID:
1738652
Concept ID:
C5436458
Disease or Syndrome
Suleiman-El-Hattab syndrome (SULEHS) is an autosomal recessive multisystem developmental disorder characterized by hypotonia and feeding difficulties soon after birth, global developmental delay with impaired intellectual development and poor expressive speech, and a general happy demeanor. There is a distinctive facial appearance with microcephaly, thick arched eyebrows with synophrys, hypertelorism, epicanthal folds, low-set ears, broad nasal bridge, and thin upper lip. Additional more variable features include recurrent respiratory infections, cardiovascular malformations, cryptorchidism, seizures, and distal anomalies of the hands and feet (summary by Suleiman et al., 2019).
Cone-rod synaptic disorder syndrome, congenital nonprogressive
MedGen UID:
1773574
Concept ID:
C5436505
Disease or Syndrome
Congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS) is characterized by retinal and neurodevelopmental disease as well as occasional anomalies of glucose homeostasis. Patients exhibit low vision, photophobia, and nystagmus, and show an electronegative waveform in response to bright flash under dark adaptation on electroretinography, with severely reduced and delayed light-adapted responses. Neurodevelopmental features include poor to no language and autistic behaviors (Mechaussier et al., 2020).
Optic atrophy 12
MedGen UID:
1720703
Concept ID:
C5436534
Disease or Syndrome
Optic atrophy-12 (OPA12) is an autosomal dominant neurologic disorder characterized by slowly progressive visual impairment with onset usually in the first decade, although later onset has been reported. Affected individuals have impaired color vision, photophobia, pale optic discs, optic nerve atrophy, and decreased thickness of the retinal nerve fiber layer. Some patients may exhibit additional neurologic features, including impaired intellectual development, dystonia, movement disorders, or ataxia (summary by Caporali et al., 2020). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy
MedGen UID:
1755716
Concept ID:
C5436747
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy (NEDMISB) is an autosomal recessive disorder characterized by severe global developmental delay, developmental regression with loss of milestones, severe microcephaly, and brain abnormalities, primarily cerebral atrophy and hypoplasia of the corpus callosum. Affected individuals develop seizures in the first year of life; eventually they are unable to sit, feed, or communicate, and may be unresponsive to stimuli. Other features include muscle weakness, spasticity with hyperreflexia, irritability, and contractures (Coulter et al., 2020).
Mitochondrial complex 2 deficiency, nuclear type 3
MedGen UID:
1751884
Concept ID:
C5436934
Disease or Syndrome
Mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients may have an encephalomyopathic picture with episodic developmental regression, loss of motor skills, hypotonia, ataxia, dystonia, and seizures or myoclonus. Other patients present in infancy with hypertrophic cardiomyopathy, which may be fatal. Laboratory studies show increased serum lactate and mitochondrial complex II deficiency in muscle and fibroblasts (summary by Jackson et al., 2014 and Alston et al., 2015). For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011).
Mitochondrial complex 1 deficiency, nuclear type 36
MedGen UID:
1773965
Concept ID:
C5436935
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (Alahmad et al., 2020). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
MedGen UID:
1780157
Concept ID:
C5543257
Disease or Syndrome
SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (Bedoni et al., 2020).
Alzahrani-Kuwahara syndrome
MedGen UID:
1782127
Concept ID:
C5543274
Disease or Syndrome
Alzahrani-Kuwahara syndrome (ALKUS) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay with severely impaired intellectual function and poor or absent speech. Patients have poor overall growth and dysmorphic facial features. More variable findings include early-onset cataracts, hypotonia, congenital heart defects, lower limb spasticity, and hypospadias (summary by Alzahrani et al., 2020).
Leukodystrophy, hypomyelinating, 22
MedGen UID:
1787833
Concept ID:
C5543406
Disease or Syndrome
Hypomyelinating leukodystrophy-22 (HLD22) is a neurologic disorder characterized by global developmental delay with mildly impaired intellectual development and marked motor impairment with limited or no ability to walk and dysarthria. Affected individuals have limb spasticity with pyramidal signs, as well as nystagmus, hypermetropia, and astigmatism. Brain imaging shows hypomyelination and a delay in myelination, although serial imaging shows some progress in both the central and peripheral white matter regions (Riedhammer et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Spinocerebellar ataxia, autosomal recessive 29
MedGen UID:
1788435
Concept ID:
C5543595
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-29 (SCAR29) is a progressive neurodegenerative disorder characterized by delayed motor development in early infancy followed by difficulty walking due to an ataxic gait or inability to walk, hypotonia, and variably impaired intellectual development. Other features include dysarthria, nystagmus, peripheral spasticity, nystagmus, and visual impairment. Brain imaging typically shows atrophy of the cerebellar vermis, but other abnormalities may also be present. Some patients are wheelchair-bound and/or nonverbal (summary by Sanderson et al., 2021) In a review of the pathogenesis of disorders with prominent dystonia as a feature, Monfrini et al. (2021) classified SCAR29 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS41.
Retinal dystrophy and microvillus inclusion disease
MedGen UID:
1794153
Concept ID:
C5561943
Disease or Syndrome
Retinal dystrophy and microvillus inclusion disease (RDMVID) is characterized by early-onset severe retinal dystrophy in association with intractable congenital diarrhea requiring total parenteral nutrition (TPN). Intestinal biopsies show typical features of microvillus inclusion disease (MVID), including loss of microvilli, microvillus inclusions, and accumulation of subapical vesicles in epithelial cells (Janecke et al., 2021). Because STX3 isoform B (STX3B) predominates in the retina, mutations in the STX3 gene that affect both isoform A (STX3A) and STX3B cause both retinal and gastrointestinal disease (RDMVID), whereas mutations in STX3 affecting only the STX3A transcript cause only diarrhea (DIAR12; 619445).
Combined oxidative phosphorylation deficiency 54
MedGen UID:
1812715
Concept ID:
C5676912
Disease or Syndrome
Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurocardiofaciodigital syndrome
MedGen UID:
1804193
Concept ID:
C5677020
Disease or Syndrome
Neurocardiofaciodigital syndrome (NCFD) is characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with a supernumerary hypoplastic digit between the fourth and fifth digits of the hands and/or feet. Other features include eye abnormalities, hearing impairment, and electroencephalogram anomalies (summary by Horn et al., 2021).
Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects
MedGen UID:
1824008
Concept ID:
C5774235
Disease or Syndrome
Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (NEDCDS) is characterized by global developmental delay, severely impaired intellectual development with poor or absent speech, characteristic facial features, and variable skeletal abnormalities. Additional features include feeding difficulties, inability to walk or walking with an abnormal gait, and cerebellar or other abnormalities on brain imaging (Reichert et al., 2020).
Retinitis pigmentosa 95
MedGen UID:
1824017
Concept ID:
C5774244
Disease or Syndrome
Retinitis pigmentosa-95 (RP95) is characterized by pale optic discs, attenuation of retinal vessels, and atrophy of the retinal pigment epithelium with bone-spicule pigmentation. Patients experience night blindness, and visual fields are restricted to approximately 10 degrees, with visual acuity ranging from normal to hand movement only. Age at onset of symptoms varies from childhood to the fifth decade of life (Van de Sompele et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Professional guidelines

PubMed

Han J, Li Y, You Y, Fan K, Lei B
BMC Ophthalmol 2022 Jul 26;22(1):322. doi: 10.1186/s12886-022-02546-0. PMID: 35883160Free PMC Article
Elder BD, Goodwin CR, Kosztowski TA, Radvany MG, Gailloud P, Moghekar A, Subramanian PS, Miller NR, Rigamonti D
J Clin Neurosci 2015 Apr;22(4):685-9. Epub 2015 Jan 8 doi: 10.1016/j.jocn.2014.10.012. PMID: 25579238

Recent clinical studies

Etiology

Gibbon S, Muniz-Terrera G, Yii FSL, Hamid C, Cox S, Maccormick IJC, Tatham AJ, Ritchie C, Trucco E, Dhillon B, MacGillivray TJ
Transl Vis Sci Technol 2024 May 1;13(5):20. doi: 10.1167/tvst.13.5.20. PMID: 38780955
Zhang Y, Kim J, Andrews C, Archer E, Bursztyn L, Grabe H, Margolin E, Sullivan S, Trobe J
J Neuroophthalmol 2021 Dec 1;41(4):e548-e559. doi: 10.1097/WNO.0000000000001205. PMID: 33870941
Leahy KE, Wright T, Grudzinska Pechhacker MK, Audo I, Tumber A, Tavares E, MacDonald H, Locke J, VandenHoven C, Zeitz C, Heon E, Buncic JR, Vincent A
Genes (Basel) 2021 Feb 25;12(3) doi: 10.3390/genes12030330. PMID: 33668843Free PMC Article
Rodenbeck SJ, Mackay DD
Curr Opin Neurol 2019 Feb;32(1):105-110. doi: 10.1097/WCO.0000000000000637. PMID: 30516640
Yang HK, Oh JE, Han SB, Kim KG, Hwang JM
Acta Ophthalmol 2019 Jun;97(4):e519-e525. Epub 2018 Nov 8 doi: 10.1111/aos.13970. PMID: 30407733

Diagnosis

Bhatti MT, Gilbert AL, Watson G, Waheed M, Spencer D
Surv Ophthalmol 2023 Jul-Aug;68(4):821-829. Epub 2022 Sep 21 doi: 10.1016/j.survophthal.2022.09.003. PMID: 36150481Free PMC Article
Zhang Y, Kim J, Andrews C, Archer E, Bursztyn L, Grabe H, Margolin E, Sullivan S, Trobe J
J Neuroophthalmol 2021 Dec 1;41(4):e548-e559. doi: 10.1097/WNO.0000000000001205. PMID: 33870941
Yang HK, Oh JE, Han SB, Kim KG, Hwang JM
Acta Ophthalmol 2019 Jun;97(4):e519-e525. Epub 2018 Nov 8 doi: 10.1111/aos.13970. PMID: 30407733
Chun BY, Rizzo JF 3rd
Curr Opin Ophthalmol 2016 Nov;27(6):475-480. doi: 10.1097/ICU.0000000000000314. PMID: 27585216
Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D
Orphanet J Rare Dis 2012 Jul 9;7:46. doi: 10.1186/1750-1172-7-46. PMID: 22776096Free PMC Article

Therapy

Bhatti MT, Gilbert AL, Watson G, Waheed M, Spencer D
Surv Ophthalmol 2023 Jul-Aug;68(4):821-829. Epub 2022 Sep 21 doi: 10.1016/j.survophthal.2022.09.003. PMID: 36150481Free PMC Article
Aksu-Ceylan N, Güner ME, Cebeci Z, Altınkurt E, Kır N, Oray M, Tugal-Tutkun İ
Turk J Ophthalmol 2022 Dec 28;52(6):405-411. doi: 10.4274/tjo.galenos.2021.58609. PMID: 36578219Free PMC Article
Wasinska-Borowiec W, Aghdam KA, Saari JM, Grzybowski A
Curr Pharm Des 2017;23(4):586-595. doi: 10.2174/1381612823666170124113826. PMID: 28120722
Javaid Z, Rehan SM, Al-Bermani A, Payne G
Scott Med J 2016 Aug;61(3):155-159. Epub 2015 Aug 4 doi: 10.1177/0036933015598124. PMID: 26246524
Kang S, Kim US
Korean J Ophthalmol 2014 Apr;28(2):164-9. Epub 2014 Mar 14 doi: 10.3341/kjo.2014.28.2.164. PMID: 24688260Free PMC Article

Prognosis

Aksu-Ceylan N, Güner ME, Cebeci Z, Altınkurt E, Kır N, Oray M, Tugal-Tutkun İ
Turk J Ophthalmol 2022 Dec 28;52(6):405-411. doi: 10.4274/tjo.galenos.2021.58609. PMID: 36578219Free PMC Article
Zhang Y, Kim J, Andrews C, Archer E, Bursztyn L, Grabe H, Margolin E, Sullivan S, Trobe J
J Neuroophthalmol 2021 Dec 1;41(4):e548-e559. doi: 10.1097/WNO.0000000000001205. PMID: 33870941
Averseng-Peaureaux D, Mizzi M, Colineaux H, Mahieu L, Pera MC, Brassat D, Chaix Y, Berard E, Deiva K, Cheuret E; Kidbiosep study group
Br J Ophthalmol 2018 Jun;102(6):808-813. Epub 2017 Sep 13 doi: 10.1136/bjophthalmol-2016-309978. PMID: 28903961
Majander A, Bowman R, Poulton J, Antcliff RJ, Reddy MA, Michaelides M, Webster AR, Chinnery PF, Votruba M, Moore AT, Yu-Wai-Man P
Br J Ophthalmol 2017 Nov;101(11):1505-1509. Epub 2017 Mar 17 doi: 10.1136/bjophthalmol-2016-310072. PMID: 28314831
Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D
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