Neurodevelopmental Disorder With Poor Language And Loss Of Hand Skills

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) is caused by heterozygous mutation in the GABBR2 gene (607340) on chromosome 9q22.

Description

NDPLHS is an autosomal dominant disorder characterized by developmental stagnation or regression apparent in the first years of life and manifest as loss of purposeful hand movements, loss of language, and intellectual disability. Additional features may include stereotypic movements, dystonia, gait abnormalities, sleep disturbances, and small hands and feet. The phenotype is reminiscent of Rett syndrome (RTT; 312750) (summary by Yoo et al., 2017).

Clinical Features

Lopes et al. (2016) reported a 19-year-old Portuguese woman (patient 9), born of unrelated parents, with a neurodevelopmental disorder reminiscent of atypical Rett syndrome. She was noted to have stagnation of psychomotor development around 7 months of age, followed by regression and lack of interest in the environment. She walked at age 24 months, but never achieved purposeful hand grasp, language, or sphincter control. She had severe intellectual disability with autistic features, agitation, bruxism, sleep disturbances, crying spells, and hyperventilation. Additional features included stereotypic movements, dystonia of the lower limbs, swallowing difficulties, small and cold hands and feet, and enlarged ventricles on brain imaging. She did not have seizures.

Yoo et al. (2017) reported 4 unrelated patients, ranging in age from 8 to 28 years, with NDPLHS. Two Korean patients were ascertained from a cohort of 34 patients with a Rett-like syndrome who did not carry mutations in the MECP2 gene (300005). Two additional European patients were found through the GeneMatcher database. All patients showed a period of neurodevelopmental regression in the first years of life, had partial or complete loss of acquired purposeful hand skills, and had stereotypic hand movements. Two patients had partial or complete loss of acquired language skills, and 3 had gait abnormalities, including inability to walk in 1 and dyspraxia in 2. Other more variable features included microcephaly, macrocephaly, sleep disturbances, abnormal breathing, bruxism, self-injurious behavior, autonomic dysfunction, and small and cold hands and feet. One patient developed generalized tonic-clonic seizures at age 9 years. Brain imaging, performed in 3 patients, was normal.

Vuillaume et al. (2018) reported a 12-year-old girl with profound intellectual disability, hand stereotypies, and sleep and breathing abnormalities, but no seizures. The phenotype was reminiscent of Rett syndrome.

Molecular Genetics

In a 19-year-old Portuguese woman (patient 9) with NDPLHS, Lopes et al. (2016) identified a de novo heterozygous missense mutation in the GABBR2 gene (A567T; 607340.0007). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 19 Portuguese patients with a clinical phenotype similar to Rett syndrome who underwent exome sequencing.

Yoo et al. (2017) identified a de novo heterozygous A567T mutation in 2 unrelated Korean patients (RTT01-1 and RTT02-1) with NDPLHS. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found in a study of 34 Korean patients with a Rett-like phenotype who did not carry mutations in the MECP2 gene (300005). A GeneMatcher search enabled the identification of 2 additional patients of European ancestry (RTT83-1 and RTT84-1) who also carried this de novo variant and had a similar disorder. In vitro functional expression studies in HEK293 cells showed that the A567T mutation significantly lowered agonist-induced activity (about 30% of wildtype), suggesting that the mutation exerts a hypomorphic effect through a dominant-negative mechanism.

In a 12-year-old girl with NDPLHS, Vuillaume et al. (2018) identified a de novo heterozygous missense mutation in transmembrane 6 of the GABBR2 gene (A707T; 607340.0007). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the A707T mutation resulted in increased basal activity but weakly (nonsignificant) decreased GABA agonist-induced signaling activity compared to wildtype. Similar results were obtained with studies of the A567T mutation. These findings suggested that the phenotype could result from constitutive activity of the mutant receptor.

Animal Model

Yoo et al. (2017) found that transfection of the A567T mutation into tadpoles resulted in abnormal swimming patterns and increased frequencies of seizure-like behavior compared to wildtype. The variant could not rescue the defect in tadpoles with morpholino knockdown of the Gabbr2 gene, consistent with a loss of function. The addition of baclofen to the water partially rescued the phenotype in animals, suggesting a potential therapeutic target in humans with GABBR2 mutations.