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Pseudo-Hurler polydystrophy(ML3)

MedGen UID:
10988
Concept ID:
C0033788
Disease or Syndrome
Synonyms: ML 3 A; ML III; ML III ALPHA/BETA; ML IIIA; ML3; Mucolipidosis III Alpha/Beta; Mucolipidosis type 3A; Type III Mucolipidosis
SNOMED CT: Pseudo-Hurler polydystrophy (65764006); Mucolipidosis III (65764006); Pseudo-Hurler disease (65764006); Pseudo-Hurler's disease (65764006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GNPTAB (12q23.2)
 
Monarch Initiative: MONDO:0018931
OMIM®: 252600
Orphanet: ORPHA423461

Disease characteristics

Excerpted from the GeneReview: GNPTAB-Related Disorders
GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIα/β (ML IIIα/β), and phenotypes intermediate between ML II and ML IIIα/β. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIα/β becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIα/β are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIα/β. [from GeneReviews]
Authors:
Jules G Leroy  |  Sara S Cathey  |  Michael J Friez   view full author information

Additional descriptions

From OMIM
Mucolipidosis type III alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically less severe than the allelic disorder mucolipidosis type II alpha/beta (summary by Paik et al., 2005).  http://www.omim.org/entry/252600
From MedlinePlus Genetics
Mucolipidosis III alpha/beta is a disorder that affects many parts of the body. Signs and symptoms of this condition typically appear around age 3 and worsen slowly over time.

Individuals with mucolipidosis III alpha/beta grow slowly and have short stature. They also have stiff joints and dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Many affected individuals develop low bone mineral density (osteoporosis), which weakens the bones and makes them prone to fracture. Osteoporosis and progressive joint problems also cause bone pain that becomes more severe over time in people with mucolipidosis III alpha/beta.

People with mucolipidosis III alpha/beta often have heart valve abnormalities and mild clouding of the clear covering of the eye (cornea). Their facial features become slightly thickened or "coarse" over time. Affected individuals may also develop frequent ear and respiratory infections. About half of people with this condition have mild intellectual disability or learning problems. Individuals with mucolipidosis III alpha/beta generally survive into adulthood, but they may have a shortened lifespan.  https://medlineplus.gov/genetics/condition/mucolipidosis-iii-alpha-beta

Clinical features

From HPO
Shallow acetabular fossae
MedGen UID:
344384
Concept ID:
C1854910
Finding
Soft tissue swelling of interphalangeal joints
MedGen UID:
340744
Concept ID:
C1854913
Finding
Carpal bone hypoplasia
MedGen UID:
355049
Concept ID:
C1863749
Finding
Underdevelopment of one or more carpal bones.
Split hand
MedGen UID:
397570
Concept ID:
C2699510
Congenital Abnormality
A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middel fingers as far as oligo- or monodactyl hands.
Irregular carpal bones
MedGen UID:
870939
Concept ID:
C4025401
Anatomical Abnormality
Carpal bones with irregular or fragmented margins.
Aortic regurgitation
MedGen UID:
8153
Concept ID:
C0003504
Disease or Syndrome
An insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Constrictive median neuropathy
MedGen UID:
868610
Concept ID:
C4023009
Anatomical Abnormality
Injury to the median nerve caused by its entrapment at the wrist as it traverses through the carpal tunnel. Clinically, constrictive median neuropathy is characterized by pain, paresthesia, and weakness in the median nerve distribution of the hand.
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Craniosynostosis syndrome
MedGen UID:
1163
Concept ID:
C0010278
Disease or Syndrome
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Hurler syndrome
MedGen UID:
39698
Concept ID:
C0086795
Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.
Short ribs
MedGen UID:
98094
Concept ID:
C0426817
Finding
Reduced rib length.
Broad ribs
MedGen UID:
336390
Concept ID:
C1848654
Finding
Increased width of ribs
J-shaped sella turcica
MedGen UID:
381480
Concept ID:
C1854718
Finding
A deformity of the sella turcica whereby the sella extends further anterior than normal such that the anterior clinoid process appears to overhang it, giving the appearance of the letter J on imaging of the skull.
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Increased serum beta-hexosaminidase
MedGen UID:
435911
Concept ID:
C2673361
Finding
Increased iduronate sulfatase level
MedGen UID:
892439
Concept ID:
C4025599
Finding
An increased level of iduronate-2-sulfatase activity in the blood.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Thickened skin
MedGen UID:
66024
Concept ID:
C0241165
Finding
Laminar thickening of skin.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Retinopathy
MedGen UID:
11209
Concept ID:
C0035309
Disease or Syndrome
Any noninflammatory disease of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Hyperopic astigmatism
MedGen UID:
376146
Concept ID:
C1847524
Disease or Syndrome
A form of astigmatism in which one meridian is hyperopic while the one at a right angle to it has no refractive error.
Deficiency of N-acetylglucosamine-1-phosphotransferase
MedGen UID:
43809
Concept ID:
C0020725
Disease or Syndrome
An inherited lysosomal storage disease characterized by the presence of dense intracytoplasmic inclusions in mesenchymal cells, especially fibroblasts. Signs and symptoms include developmental delay, psychomotor deterioration, and growth failure.

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Recent clinical studies

Etiology

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Clinical prediction guides

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