Acute reversible muscle weakness in two infants with limb girdle muscular dystrophy (LGMD) 2I and identification of a novel missense mutation in the FKRP gene

Abstract

Mutations in the fukutin-related protein gene FKRP (MIM*606596) cause limb-girdle muscular dystrophy (LGMD2I) as well as a form of congenital muscular dystrophy (MDC1C). Considerable variability of age of onset concerning progression and cardiorespiratory symptoms in patients with LGMD2I has been reported. We describe the clinical course in two boys of healthy non-consanguineous parents. The children (P1=patient 1, P2=patient 2) had normal motor milestones and presented at the age of 3 (P1) and 1,5 (P2) years with a febrile viral respiratory infection, increasing muscle weakness and refusal to walk. Creatine kinase (CK) levels were highly elevated with 111µmol/lxs (P1) and 328µmol/lxs (P2) (NR <3µmol/lxs). Symptoms disappeared spontaneously after one week and CK levels declined within weeks to only mildly elevated levels 9,52µmol/lxs (P1); 10,94µmol/lxs (P2). Clinically a myositis was suspected. In the further course P1 showed a broad-based waddling gait, pseudohypertrophy of his calves and marked proximal leg weakness. The CK level at the age of 8 years was 71,29µmol/lxs and muscle biopsy revealed histological changes characteristic of a muscular dystrophy with normal expression of dystrophin (Dys 1–3). He presented with dilated cardiomyopathy at the age of 14 years. At the age of 6 years P2 exhibits mild proximal leg weakness and pseudohypertrophy of the calves but no restrictions in walking distance. Haplotype analysis in the family was consistent with linkage to the LGMD2I locus 19q13.3. Sequence analysis of the FKRP coding region identified compound heterozygosity for the common 826C>A (Leu276Ile) mutation and the novel missense mutation 962C>A (Ala321Glu) in both brothers. Rhabdomyolysis and myoglobinuria have been described as presenting symptoms in LGMD2I. Therefore the diagnostic work-up of patients with infection- associated CK elevation and muscle weakness should include analysis of the FKRP gene if CK levels remain elevated.