Lissencephaly, X-Linked, 2 (LISX2)

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Disease Ontology 12 DOID:0112238 OMIM® 57 300215 OMIM Phenotypic Series 57 PS607432 MeSH 44 D054082 ICD10 via Orphanet 33 Q04.3

UMLS via Orphanet 71 C1846171 Orphanet 58 ORPHA452 MedGen 41 C1846171 C1846172 SNOMED-CT via HPO 68 128613002 204739008 204878001 21321009 221360009 224958001 228156007 23024003 246545002 247578003 249321001 253549006 263934009 267060006 271611007 27272007 276411001 30288003 313307000 32958008 33995003 34911001 359580009 367495003 37992001 397790002 398151007 398152000 45004005 47367009 5102002 60318001 62315008 81415000 83330001 84757009 86854008 91138005 91175000 95515009 more UMLS 70 C1846171 C3891556

GARD : ²⁰ The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 452 Definition X-linked lissencephaly with abnormal genitalia (XLAG) is a rare, genetic, central nervous system malformation disorder characterized, in males, by lissencephaly (with posterior predominance and moderately thickened cortex), complete absence of corpus callosum, neonatal-onset (mainly perinatal) intractable seizures, postnatal microcephaly, severe hypotonia, poor responsiveness and hypogonadism (micropenis, hypospadias, cryptorchidism, small scrotal sac). Defective temperature regulation and chronic diarrhea may be additionally observed. Clinical description XLAG differs considerably from classical lissencephaly, as the resulting cortical thickness is only 6-7 mm in XLAG, rather than 15-20 mm seen in classical lissencephaly due to mutations of the PAFAH1B1 or DCX genes. Etiology In 2002, mutations in the X-linked aristaless-related homeobox gene ( ARX ; Xp21.3) were identified in individuals with XLAG and in some of their female relatives. Mouse Arx and human ARX are highly expressed in both dorsal and ventral telencephalon, including the neocortical ventricular zone and germinal zone of the ganglionic eminence, with less intense signals in the subventricular zone, cortical plate, hippocampus, basal ganglia and ventral thalamus. Arx-deficient mice showed deficient tangential migration and abnormal differentiation of GABAergic interneurons in the ganglionic eminence and neocortex, as well as abnormal testicular differentiation. These characteristics include some of the clinical features of XLAG in humans. The ARX mutations in XLAG patients were predominantly premature termination mutations (large deletions, frameshift, nonsense mutations, splice site mutations) while the missense mutations were less common and located essentially in the homeobox domain. Patients carrying nonconservative missense mutations within the homeobox, showed less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome (ACC with abnormal genitalia). A non conservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. The ARX mutations are also associated with a spectrum of milder phenotypes, without macroscopic malformations of the brain, such as X-linked infantile spasms, a syndrome featuring mental retardation associated with distal dystonic movements (Partington syndrome; see this term), autistic features and nonsyndromicintellectual deficit.

MalaCards based summary : Lissencephaly, X-Linked, 2, also known as hydranencephaly with abnormal genitalia, is related to mental retardation, x-linked, with or without seizures, arx-related and partington x-linked mental retardation syndrome, and has symptoms including snoring and thick skin. An important gene associated with Lissencephaly, X-Linked, 2 is ARX (Aristaless Related Homeobox). Affiliated tissues include brain, testes and cortex, and related phenotypes are intellectual disability and agenesis of corpus callosum

Disease Ontology : ¹² A lissencephaly characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia that has material basis in mutation in ARX on chromosome Xp21.3.

MedlinePlus Genetics : ⁴³ X-linked lissencephaly with abnormal genitalia (XLAG) is a condition that affects the development of the brain and genitalia. It occurs most often in males.XLAG is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Individuals without any folds in the brain (agyria) typically have more severe symptoms than people with reduced folds and grooves (pachygyria). Individuals with XLAG may also have a lack of development (agenesis) of the tissue connecting the left and right halves of the brain (corpus callosum). The brain abnormalities can cause severe intellectual disability and developmental delay, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. Starting soon after birth, babies with XLAG have frequent and recurrent seizures (epilepsy). Most children with XLAG do not survive past early childhood.Another key feature of XLAG in males is abnormal genitalia that can include an unusually small penis (micropenis), undescended testes (cryptorchidism), or external genitalia that do not look clearly male or clearly female (ambiguous genitalia).Additional signs and symptoms of XLAG include chronic diarrhea, periods of increased blood sugar (transient hyperglycemia), and problems with body temperature regulation.

OMIM® : ⁵⁷ X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (Bonneau et al., 2002). LISX2 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432). (300215) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : ⁷² Lissencephaly, X-linked 2: A classic type lissencephaly associated with abnormal genitalia. Patients have severe congenital or postnatal microcephaly, lissencephaly, agenesis of the corpus callosum, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and ambiguous or underdeveloped genitalia.

Clinical features from OMIM®:

300215 (Updated 05-Apr-2021)

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