Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation

Abstract

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.

Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

“…9,22,23 Although menadione-NBT staining was not performed in any of our patients and we cannot formally rule out the presence of RB, the clinical phenotype of our patients was not consistent with a diagnosis of RBM. In agreement with this finding, mutations affecting the LIM2 domain were reported also in three EDMD patients without RB, 17 suggesting that the different type of mutations observed in these patients (small or large in-frame or out-of-frame deletions/insertions) might be responsible for the possible absence of RB in these patients.…”

“…[9][10][11][12][13][14][15][16][17]21 The available genotype-phenotype data indicate that patients belonging to the 'RB subgroup' harbour missense mutations or short in-frame deletions affecting the second LIM domain, whereas mutations found in XMPMA and EDMD/ EDMD-like patients are either missense, in-frame or out-of-frame mutations localized in the more distal exons encoding the third and fourth LIM domains. 17,21 Histidine 123 and cysteine 224 appear as the main mutation hot spots for RBM and XMPMA, mutated in 7/15 and 5/9 families, respectively. The mutation found in the three British families results in the insertion of an isoleucine between Phe127 and Thr128, a two-amino-acid region (C-X2-C), linker between the two zinc-fingers of the second LIM domain and typically invariant in length.…”

“…9 Concurrently, FHL1 gene mutations have been detected in X-linked dominant scapuloperoneal myopathy, 10,11 and subsequently in a wide spectrum of partly overlapping conditions, such as reducing body myopathy (RBM), [12][13][14] rigid spine syndrome, 15 Emery-Dreifuss muscular dystrophy (EDMD), 16 and in a single family with contractures, rigid spine, and cardiomyopathy. 17 It has been suggested to classify FHL1-related disorders into two main groups, the 'reducing body (RB) subgroup' including RBM, X-linked dominant scapuloperoneal myopathy and rigid spine syndrome, all characterized by RB at histological examination, and a second subgroup, including the XMPMA and EDMD patients, characterized by later onset and absence of RB. 12,13,16 RBM may also be seen as a condition within a larger phenotypic spectrum of protein aggregate myopathies, such as the myofibrillar myopathies.…”

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

“…4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.Myofibrillar myopathies (MFMs) arise from primary degeneration of the muscle fibers and represent a morphologically distinct but genetically heterogeneous subset of muscular dystrophies. The unifying histologic findings are early disintegration of the Z-disk followed by myofibrillar disintegration, aggregation of degraded filaments into pleomorphic granular or hyaline inclusions, and ectopic expression of multiple Z-disk-related and other proteins in the affected muscle fibers.…”

“…4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.…”