G.P.207: Clinical and genetic spectrum in a large cohort of patients with a genetic diagnosis of congenital muscular dystrophies: Analysis of the UK diagnostic service 2001–2013

Abstract

Congenital muscular dystrophies (CMD) are a highly heterogeneous group of conditions clinically characterized by muscle weakness from birth, or shortly after, and variable involvement of eyes, heart and central nervous system. Some of these disorders are fatal in the first year of life, whereas others have a milder course and are compatible with survival into adulthood. The Dubowitz Neuromuscular Centre (DNC) is the National Specialist Commissioning Team (NSCT) referral centre for CMD in the UK. A few years ago we reported the relative frequency of CMD subtypes referred for clinical assessment to the DNC, with collagen VI related disorders being the most common diagnosis. This study reports the relative frequency and clinical and genetic spectrum of CMD in the entire cohort of UK patients in whom the genetic analysis for the CMD genes was requested between 2001 and 2013, including recently identified dystroglycanopathy genes. A total of 700 DNA samples were referred during this time interval and genetic diagnosis was reached in 366 of them. Detailed clinical information was available for 340 patients; 234 fulfilled a clinical diagnosis of CMD while the others had milder forms, such as LGMD. The most common type of genetically confirmed CMD was laminin α2 related dystrophy (MDC1A) accounting for about 44 % of cases, followed by dystroglycanopathies (26 %), Ullrich CMD (16 %) and Rigid Spine muscular dystrophy associated with SEPN1 gene mutations (14 %). Fifteen patients carried pathogenic mutations in the newly discovered ISPD, GMPPB and B3GALNT2 genes responsible for glycosylation defects in alpha-dystroglycan and here we also describe the associated phenotypes. Our results indicate MDC1A as the most common subtype of CMD in the UK and further expand the clinical and genetic spectrum of CMDs.