G.P.121 X-linked recessive distal myopathy with hypertrophic cardiomyopathy caused by a novel mutation in the FHL1 gene

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<h2>Abstract</h2> The four and a half LIM domain protein 1 (<i>FHL1</i>) gene encodes FHL1, a LIM domain containing protein that regulates skeletal and cardiac muscle function. <i>FHL1</i> mutations are associated with variable phenotypes including reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy and Emery–Dreifuss muscular dystrophy. The <i>FHL1</i> gene encodes three FHL1 isoforms (FHL1A, FHL1B, FHL1C). Patients with <i>FHL1</i> mutations affecting all three isoforms exhibit a more severe phenotype, whereas mutations that affect only FHL1A are less severe. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 8 with exercise intolerance and was found to have pes cavus, distal wasting, weakness of ankle dorsiflexion and areflexia. There was no clinical evidence of cardiac involvement. The patient's brother had died suddenly from isolated hypertrophic cardiomyopathy some years prior. A maternal uncle had also died suddenly from complications of cardiomyopathy. In this subject, an echocardiogram at age 8 was normal, but by age 14 there was evidence of a hypertrophic cardiomyopathy. Muscle biopsy showed myopathic changes and prominent rimmed vacuoles. Sequencing of the <i>FHL1</i> gene revealed a novel hemizygous c.764G>C missense mutation in exon 8, causing a C255S substitution affecting one of the zinc binding cysteine residues in the fourth LIM domain of FHL1A. The patient's mother and maternal aunt were heterozygous for the mutation. No suitable samples could be identified for testing of the deceased sibling and maternal uncle. Over 26 <i>FHL1</i> mutations have been reported to date, many of which cause phenotypes with shared clinicopathological features. This first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an <i>FHL1</i> mutation further expands the clinical spectrum of <i>FHL1</i>-related myopathies.