ClinVar Genomic variation as it relates to human health

Dysmorphic features (present) , slight intellectual disability (present) , hypotonia (present) , cerebellar ataxia (present) , autistic disturbances (present) , normal MRI (present) , Slight synophris (present) , distal ligamentous laxity (present) , delayed sitting (14 months old) (present) , delayed walking (18 months old) (present) , normal language (present) , Drugs-induced sleep disorders (present) , attention deficit (present) , Tourette's syndrome (present) , obsessive-compulsive disorder (present) (less)

In an adult mother and daughter with mildly impaired intellectual development, speech difficulties, and gait disturbances, Orrico et al. (2000) identified a 493C-T transition in the MECP2 gene, resulting in an ala140-to-val (A140V) substitution in a highly conserved region in the alpha helix of the methyl-CpG binding domain. Four of the mother's adult sons who inherited the mutation had severe mental retardation, impaired language development, and movement disorders with tremor and bradykinesia (MRXS13; 300055). The mutation was not present in the normal father or in 300 X chromosomes from normal individuals. The pattern of X-chromosome inactivation in the mother and daughter were close to random. The authors suggested that missense mutations such as A140V may correlate with milder disease than those resulting from truncating mutations, possibly through the presence of residual protein function. Dotti et al. (2002) reviewed the clinical findings of the family reported by Orrico et al. (2000) and noted that although the mental retardation and neurologic signs were more pronounced in the men than in the women, the women did demonstrate abnormalities. Features present in all 6 family members included slowly progressive spastic paraparesis/pyramidal signs, distal atrophy of the legs, and mild dysmorphic features. In 2 males with nonspecific sporadic mental retardation, Couvert et al. (2001) identified the A140V mutation. No other clinical details were provided. Winnepenninckx et al. (2002) identified the A140V mutation in 5 affected males from a large kindred with X-linked mental retardation, which the authors designated MRX79 (300055). Variable clinical features included delayed psychomotor development, tremor, mood instability, and hyperkinetic behavior. Four carrier females in the family appeared to be unaffected. Winnepenninckx et al. (2002) referred to several other reports of the A140V mutation and estimated that this mutation occurs in approximately 1% of all X-linked mental retardation families. Klauck et al. (2002) identified the A140V mutation in affected members of a pedigree with mental retardation associated with psychosis, pyramidal signs, and macroorchidism, designated PPMX, and consistent with MRXS13. They pointed out that there had been independent reports of 2 patients with familial mental retardation and 2 patients with sporadic mental retardation caused by this mutation in the MECP2 gene. They suggested that A140V is a hotspot for mutation, resulting in moderate to severe mental retardation in males. They designed a simple and reliable PCR approach for detection of the A140V mutation as a prescreen in unexplained cases of mental retardation before further extensive mutation analyses. Cohen et al. (2002) identified the A140V mutation in a boy with a developmental language disorder and onset of psychosis and childhood schizophrenia (see 300055) at age 12 years. His unaffected mother also carried the mutation. The report expanded the phenotypic spectrum of males with the A140V mutation. Villard (2007) stated that the A140V mutation had never been reported in a girl with classic Rett syndrome (312750), suggesting that it results in serious disorders only when present in male patients. (less)