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Lissencephaly type 1 due to doublecortin gene mutation(LISX1)

MedGen UID:
1644310
Concept ID:
C4551968
Disease or Syndrome
Synonyms: DCX-Related Disorders; DCX-Related Lissencephaly; Lissencephaly and agenesis of corpus callosum; Lissencephaly, X-linked; LISSENCEPHALY, X-LINKED, 1
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): DCX (Xq23)
 
Monarch Initiative: MONDO:0010239
OMIM®: 300067
Orphanet: ORPHA2148

Disease characteristics

Excerpted from the GeneReview: DCX-Related Disorders
DCX-related disorders include the neuronal migration disorders: Classic thick lissencephaly (more severe anteriorly), usually in males. Subcortical band heterotopia (SBH), primarily in females. Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment. Seizures, which frequently are refractory to anti-seizure medication, may be either focal or generalized and behavioral problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates roughly with the degree of the underlying brain malformation as observed in cerebral imaging. [from GeneReviews]
Authors:
Ute Hehr  |  Gökhan Uyanik  |  Ludwig Aigner, et. al.   view full author information

Additional descriptions

From OMIM
Lissencephaly ('smooth brain') results from migrational arrest of cortical neurons short of their normal destination, and can result in profound mental retardation and seizures. In X-linked lissencephaly-1, affected males generally have more a severe phenotype compared to females. DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome (des Portes et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432). There are several X-linked loci that affect neuronal migration, including the Aicardi locus (304050).  http://www.omim.org/entry/300067
From MedlinePlus Genetics
Isolated lissencephaly sequence (ILS) is a condition that affects brain development before birth. Normally, the cells that make up the exterior of the brain (cerebral cortex) are well-organized, multi-layered, and arranged into many folds and grooves (gyri). In people with ILS, the cells of the cerebral cortex are disorganized, and the brain surface is abnormally smooth with an absence (agyria) or reduction (pachygyria) of folds and grooves. In most cases, these abnormalities impair brain growth, causing the brain to be smaller than normal (microcephaly). This underdevelopment of the brain causes severe intellectual disability, delayed development, and recurrent seizures (epilepsy) in individuals with ILS.

Infants with ILS may have poor muscle tone (hypotonia) and difficulty feeding, which leads to poor growth overall. Hypotonia also affects the muscles used for breathing, which often causes breathing problems that can lead to a life-threatening bacterial lung infection known as aspiration pneumonia. Children with ILS often develop muscle stiffness (spasticity) in their arms and legs and an abnormal side-to-side curvature of the spine (scoliosis). Rarely, the muscle stiffness will progress to paralysis (spastic paraplegia). Individuals with ILS cannot walk and rarely crawl. Most children with ILS do not develop communication skills.

More than 90 percent of individuals with ILS develop epilepsy, often within the first year of life. Up to 80 percent of infants with ILS have a type of seizure called infantile spasms, these seizures can be severe enough to cause brain dysfunction (epileptic encephalopathy). After the first months of life, most children with ILS develop a variety of seizure types, including persisting infantile spasms, short periods of loss of consciousness (absence seizures); sudden episodes of weak muscle tone (drop attacks); rapid, uncontrolled muscle jerks (myoclonic seizures); and episodes of muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures).  https://medlineplus.gov/genetics/condition/isolated-lissencephaly-sequence

Clinical features

From HPO
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Agyria
MedGen UID:
361827
Concept ID:
C1879312
Congenital Abnormality
A congenital abnormality of the cerebral hemisphere characterized by lack of gyrations (convolutions) of the cerebral cortex. Agyria is defined as cortical regions lacking gyration with sulci great than 3 cm apart and cerebral cortex thicker than 5 mm.
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.
Pachygyria
MedGen UID:
504794
Concept ID:
CN001193
Finding
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Recent clinical studies

Etiology

Tsai MH, Kuo PW, Myers CT, Li SW, Lin WC, Fu TY, Chang HY, Mefford HC, Chang YC, Tsai JW
Eur J Paediatr Neurol 2016 Sep;20(5):788-94. Epub 2016 May 30 doi: 10.1016/j.ejpn.2016.05.010. PMID: 27292316
Haverfield EV, Whited AJ, Petras KS, Dobyns WB, Das S
Eur J Hum Genet 2009 Jul;17(7):911-8. Epub 2008 Dec 3 doi: 10.1038/ejhg.2008.213. PMID: 19050731Free PMC Article
Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N
Neurogenetics 2008 Oct;9(4):277-85. Epub 2008 Aug 7 doi: 10.1007/s10048-008-0141-5. PMID: 18685874

Diagnosis

Quélin C, Saillour Y, Souville I, Poirier K, N'guyen-Morel MA, Vercueil L, Millisher-Bellaiche AE, Boddaert N, Dubois F, Chelly J, Beldjord C, Bahi-Buisson N
Neurogenetics 2012 Nov;13(4):367-73. Epub 2012 Jul 26 doi: 10.1007/s10048-012-0339-4. PMID: 22833188
Friocourt G, Marcorelles P, Saugier-Veber P, Quille ML, Marret S, Laquerrière A
Acta Neuropathol 2011 Feb;121(2):149-70. Epub 2010 Nov 3 doi: 10.1007/s00401-010-0768-9. PMID: 21046408Free PMC Article
Ruggieri M, Roggini M, Spalice A, Addis M, Iannetti P
Pediatr Neurol 2009 May;40(5):383-6. doi: 10.1016/j.pediatrneurol.2008.11.006. PMID: 19380077
Haverfield EV, Whited AJ, Petras KS, Dobyns WB, Das S
Eur J Hum Genet 2009 Jul;17(7):911-8. Epub 2008 Dec 3 doi: 10.1038/ejhg.2008.213. PMID: 19050731Free PMC Article
Okazaki S, Ohsawa M, Kuki I, Kawawaki H, Koriyama T, Ri S, Ichiba H, Hai E, Inoue T, Nakamura H, Goto Y, Tomiwa K, Yamano T, Kitamura K, Itoh M
Acta Neuropathol 2008 Oct;116(4):453-62. Epub 2008 May 6 doi: 10.1007/s00401-008-0382-2. PMID: 18458920

Prognosis

Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, Barkovich AJ, Guerrini R, Dobyns WB
Am J Med Genet A 2017 Jun;173(6):1473-1488. Epub 2017 Apr 25 doi: 10.1002/ajmg.a.38245. PMID: 28440899Free PMC Article
Mokánszki A, Körhegyi I, Szabó N, Bereg E, Gergev G, Balogh E, Bessenyei B, Sümegi A, Morris-Rosendahl DJ, Sztriha L, Oláh E
J Child Neurol 2012 Dec;27(12):1534-40. Epub 2012 Mar 8 doi: 10.1177/0883073811436326. PMID: 22408144
Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N
Neurogenetics 2008 Oct;9(4):277-85. Epub 2008 Aug 7 doi: 10.1007/s10048-008-0141-5. PMID: 18685874

Clinical prediction guides

Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, Barkovich AJ, Guerrini R, Dobyns WB
Am J Med Genet A 2017 Jun;173(6):1473-1488. Epub 2017 Apr 25 doi: 10.1002/ajmg.a.38245. PMID: 28440899Free PMC Article
Mokánszki A, Körhegyi I, Szabó N, Bereg E, Gergev G, Balogh E, Bessenyei B, Sümegi A, Morris-Rosendahl DJ, Sztriha L, Oláh E
J Child Neurol 2012 Dec;27(12):1534-40. Epub 2012 Mar 8 doi: 10.1177/0883073811436326. PMID: 22408144
Ruggieri M, Roggini M, Spalice A, Addis M, Iannetti P
Pediatr Neurol 2009 May;40(5):383-6. doi: 10.1016/j.pediatrneurol.2008.11.006. PMID: 19380077
Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N
Neurogenetics 2008 Oct;9(4):277-85. Epub 2008 Aug 7 doi: 10.1007/s10048-008-0141-5. PMID: 18685874

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