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Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.

ABSTRACT: Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on ?-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing ?-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.

SUBMITTER: Meilleur KG

PROVIDER: S-EPMC5113964 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.

Meilleur Katherine G KG Zukosky Kristen K Medne Livija L Fequiere Pierre P Powell-Hamilton Nina N Winder Thomas L TL Alsaman Abdulaziz A El-Hattab Ayman W AW Dastgir Jahannaz J Hu Ying Y Donkervoort Sandra S Golden Jeffrey A JA Eagle Ralph R Finkel Richard R Scavina Mena M Hood Ian C IC Rorke-Adams Lucy B LB Bönnemann Carsten G CG

Journal of neuropathology and experimental neurology 20140501 5

Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic ...[more]

PMID: 24709677

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Project description:BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking.MethodsWe provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information.ResultsSHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems.ConclusionsHaploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.

Dataset Information

Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.

Publications

Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.

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