EP.18Mutations in TRAPPC11 are associated with Rett-like syndrome in absence of significant muscle involvement

Abstract

Rett syndrome is a neurodevelopmental disorder characterized by loss of speech and stereotypic movements. The TRAPPC11 protein is a part of the transport protein particle complex involved in endoplasmic reticulum to Golgi transportation. As more individuals with limb-girdle muscular dystrophy are reported, the spectrum of neurological disorders associated with mutations in the TRAPPC11 gene is beginning to emerge. Infantile hyperkinetic movements, ataxia and intellectual disability have been previously published. To our knowledge this is the first case presenting as a Rett-like syndrome. The patient was a girl from non-consanguineous parents. During the first year of life she presented with cognitive and motor delay and developed loss of speech and stereotypic hand movements. A brain MRI showed global atrophy and an EEG was consistent with slow background activity. Extensive metabolic studies were within normal limits. Her CK levels were elevated (1000 UI/L). Nerve conduction study, electromyography and muscle MRI were unremarkable. A muscle biopsy showed preserved architecture with normal histochemical pattern and molecular study of mitochondrial DNA. Genetic testing by Whole-Exome-Sequencing (BGI) detected a mutation in homozygosis in the TRAPPC11 gene (c.1287+5G>A), confirmed by Sanger-sequencing. Mutations in TRAPPC11 gene in homozygosis have been previously described in patients suffering from limb-girdle muscular dystrophy 2S (LGMD2S), characterized by proximal muscle weakness with childhood onset. However, severe cognitive impairment resembling Rett-syndrome can be the main clinical feature, even in absence of significant clinical muscle involvement. This report suggests that girls with asymptomatic hyperCKemia and profound mental delay including Rett-like phenotype should be studied to rule out mutations in the TRAPPC11 gene.