LIMB GIRDLE MUSCULAR DYSTROPHIES: P.135 The 7-year progression of proximodistal dysferlinopathy in another Acadian patient from the Maritimes

Abstract

Dysferlinopathies represent several pathologies caused by mutations in the DYSF gene. The two main phenotypes are Limb-girdle muscular dystrophy (LGMD) type 2B and distal Miyoshi's myopathy, but a proximodistal phenotype accounts for 6-35% of dysferlinopathies. The Acadians were French colonists who settled in the Canadian Maritimes and incurred the Great Deportation. Those who eluded capture remained mostly along the Maritime coastlines, preluding a higher regional prevalence of some recessive diseases. Dysferlinopathies are estimated to represent 35-45% of all LGMD's in the Acadian population. We report the case of a 19-year-old Acadian, who presented with substantially elevated serum creatine kinase levels at age 13, before the occurrence of rapidly declining distal posterior leg and limb-girdle myopathy during puberty. The patient has been followed for seven years providing clinical, imaging and laboratory documentation of disease progression. The absence of dysferlin, pathogenic homozygous DYSF mutations, and two homozygous TTN mutations were found. The parents were 3rd degree cousins and no extended family members were symptomatic. Finally, we compared the clinical phenotypes of nine unpublished cases of dysferlinopathy in Acadian patients from the Maritimes. Similar to previously reported cases of proximodistal dysferlinopathy, our patient showed macrophage infiltration on histology, and a fast disease progression supported by MRI series and clinical observations. The majority of Acadian cases, from three different DYSF mutations, also presented with a proximodistal phenotype. Modifier genes, environmental factors, or other unknown mutations have been proposed to explain phenotypic variability. Our patient had two homozygous mutations in A-band TTN, a gene region previously linked to distal myopathy. Proximodistal dysferlinopathy should be considered as a rare but plausible diagnosis in Acadian patients presenting with progressive distal and proximal myopathy.