G.P.312: Intrafamilial variability in GMPPB associated alpha-dystroglycanopathy and broadening of the clinical phenotype

Abstract

Alpha-dystroglycanopathies (αDGs) represent a heterogeneous group of muscular dystrophies. There are currently 18 known genes leading to forms of alphaDG, with mutations of GDP-mannose pyrophosphorylase B (GMPPB) being one of the most recently described in one case series. The spectrum of reported GMPPB patients spans from severe neonatal to a mild later onset limb-girdle muscular dystrophy (LGMD) phenotype with or without intellectual disability. GMPPB is important for synthesis of GDP-mannose, a mannosyl donor in 4 glycosylation pathways. We present a 3 affected siblings with compound heterozygous mutations (previously described p.Asp27His and novel p.Gln264TER) in GMPPB presenting as LGMD with variable degrees of muscle weakness but a broader spectrum of early intellectual impairment, epilepsy (1 of 3 patients), and ocular findings. Onset and degree of weakness was variable. Patient P1 has severe intellectual disability, cataracts, glaucoma, and a history of intractable epilepsy, but minimal weakness; while patient P2 has severe weakness with near full time wheelchair use since 16 years old. CK level was elevated in all patients (3015–18,685). Muscle biopsy in P2 revealed dystrophic changes with reduced αDG staining. Brain MRI showed mild posterior cortical thinning in P1. Neuropsychological testing revealed variable intellectual disability in all three patients. Muscle imaging revealed variable changes consistent with areas of fatty infiltration. These siblings further contribute to and expand the spectrum of patients with mutations of GMPPB highlighting that motor and cognitive phenotypes associated with GGMPPB related αDGpathy may not directly correlate. Cognitive deficits and epilepsy can precede recognition of muscle symptoms, thus delaying more targeted testing. Simple CK testing may identify a larger cohort of patients with αDGpathy presenting with minimal motor but more severe cognitive or seizure phenotype whose muscle disease had remained undetected.