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We investigated a large German family (n = 37) with male members who had contractures, rigid spine syndrome, and hypertrophic cardiomyopathy. Muscle weakness or atrophy was not prominent in affected individuals. Muscle biopsy disclosed a myopathic pattern with cytoplasmic bodies. We used microsatellite markers and found linkage to a locus at Xq26-28, a region harboring the FHL1 gene. We sequenced FHL1 and identified a new missense mutation within the third LIM domain that replaces a highly conserved cysteine by an arginine (c.625T>C; p.C209R). Our finding expands the phenotypic spectrum of the recently identified FHL1-associated myopathies and widens the differential diagnosis of Emery-Dreifuss-like syndromes.

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations., Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients., Results: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a "dropped head" syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers., Interpretation: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).