A number sign (#) is used with this entry because the phenotype is caused by mutation in the FHL1 gene (300163).

X-linked myopathy with postural muscle atrophy (XMPMA) is a progressive muscular dystrophy with onset in adulthood. Affected individuals develop a proximal myopathy characterized by specific atrophy of postural muscles, limited neck flexion, bent spine, contractures of the Achilles tendon, respiratory problems, and cardiomyopathy. Patients may show muscle hypertrophy in the early stages of the disorder (Windpassinger et al., 2008).

The clinical features of Emery-Dreifuss muscular dystrophy (see EDMD1; 310300) classically include the triad of muscle weakness, joint contractures, and cardiac involvement, thus showing clinical overlap with XMPMA (Gueneau et al., 2009).

Schwartzmeier et al. (1971) described an affected male member of an Austrian family who showed a progressive muscular dystrophy of pelvicofemoral and scapulohumeral type that was distinct from known muscular dystrophies. Muscle pathology had some similarity to myotonic dystrophy-1 (160900), but no myotonic reaction was observed. Significantly lowered levels of magnesium-ATPase were found, but pathology did not suggest any known metabolic myopathy.

Windpassinger et al. (2008) described the extended family of the patient described by Schwartzmeier et al. (1971). In this Austrian family, during the early stages of the disease, affected members (all males) showed an athletic appearance; however, detailed examination revealed weakness and atrophy of postural muscles, whereas other muscles appeared hypertrophic. In general, muscles with predominantly type I fiber content were atrophic, whereas muscles with predominantly type II fibers were hypertrophic. A mild scapular winging was noted in all patients. All affected males had significant contractures of the Achilles tendon and hamstrings, short neck, and a mechanically limited range of neck flexion and extension analogous to bent spine syndrome. All affected individuals had scoliosis, back pain, gait problems, and elevated creatine kinase (CK) levels. Symptoms were first noted at approximately 30 years of age. Death occurred at a range of 45 to 72 years of age in 6 affected members. Typically, heart failure was the cause of death, although the mechanism was not known; hypertrophic cardiomyopathy was suspected from earlier echocardiograph investigations. Known X-linked myopathies were excluded by simple tandem-repeat polymorphism (STRP) analysis, direct gene sequencing, and immunohistochemical analysis. Windpassinger et al. (2008) also identified a second family of British origin in which 3 affected members had received a putative diagnosis of Becker muscular dystrophy (300376). The index patient presented initially with hip flexor weakness and elevated serum CK at age 35 years. At that time he was playing professional football and showed a very athletic habitus. Muscle hypertrophy was most prominent in shoulder girdle and arm muscles. Neck flexion was compromised by spinal rigidity. Nerve conduction studies and EMG were normal. The maternal grandfather of the index patient started to experience difficulties with walking at 42 years of age and used a wheelchair for the last years of his life. He died of respiratory failure at age 52 with the label of Becker muscular dystrophy.

Schoser et al. (2009) reported 7 unrelated probands with XLPMA, including 1 proband from a side branch of the previously reported Austrian family. Family history identified a total of 10 affected men and 3 mildly affected women from these 7 families. Age at onset of symptoms ranged between 8 and 45 years. All patients reported an initial pseudoathletic appearance with muscle hypertrophy. The disorder was characterized by early-onset neck rigidity and Achilles tendon shortening, progressive limb-girdle muscle weakness, postural muscle atrophy, rigid spine, scapular winging, gait abnormalities, and respiratory insufficiency. There was disease progression in the late thirties. Although there were 8 female mutation carriers, 5 had no symptoms, and 3 had very mild symptoms. There was no overt cardiomyopathy, but 2 men in the same family had a rare aneurysm of the sinus of Valsalva, and 1 woman without neuromuscular symptoms had rhythm changes later in life. Muscle biopsies showed dystrophic changes, rimmed vacuoles, and scattered cytoplasmic bodies on Gomori staining. About half of samples also contained small core-like lesions. No reducing bodies were identified. Electron microscopy showed mild Z-line streaming and granulofilamentous material, suggesting a link to myofibrillar myopathies. FHL1 isoform A was severely reduced. Schoser et al. (2009) postulated that the preserved isoform C may be responsible for the relatively moderate phenotype compared to other FHL1-related myopathies.

Emery-Dreifuss Muscular Dystrophy 6

Gueneau et al. (2009) reported 6 unrelated families and an isolated patient with a form of Emery-Dreifuss muscular dystrophy consistent with X-linked inheritance, but without mutations in the emerin gene (EMD; 300384). Skeletal muscle symptoms preceded cardiac involvement, and the disorder was progressive in all probands. The age at onset ranged from 4 to 14 years, except for 1 patient who had onset at age 48 years. Patients presented with joint contractures, neck stiffness, or muscle weakness. All patients were still ambulant after a disease duration ranging from 6 to 30 years. Muscle weakness and atrophy occurred in the pelvic, peroneal, and scapular regions. Additional axial muscle weakness and/or atrophy were observed in 4 patients, and facial involvement in 2. Other common features included rigid spine, joint contractures, and scoliosis. Serum creatine kinase levels were usually increased. Cardiac involvement became apparent between ages 10 to 48, and included arrhythmias and cardiac chamber hypertrophy; 2 patient had sudden death at ages 31 and 51 years, respectively. Two patients had severe respiratory insufficiency, with 1 dying at age 37. Unusual symptoms included swallowing difficulties (1), dysphonia due to vocal cord palsy (3), muscle hypertrophy (2), and ptosis (1). Skeletal muscle biopsy showed myopathic or dystrophic changes. Reducing bodies were not observed in the 3 samples tested. FHL1A protein expression was severely decreased. Among the relatives, 38 (15 males and 23 females) were found to carry FHL1 mutations. Among the males, 10 showed EDMD; 4 had isolated cardiac disease, and 1 had unknown clinical status. Sixteen female carriers were asymptomatic, 4 had isolated cardiac disease, and 3 had mild muscle involvement. Gueneau et al. (2009) noted the phenotypic overlap with the patients reported by Windpassinger et al. (2008).

Knoblauch et al. (2010) reported 9 affected male members of a large 4-generation German family with EDMD6. Age at onset was in the first or second decade, and all had contractures and rigid spine. Five had hypertrophic cardiomyopathy, 2 had left ventricular hypertrophy with fibrosis and hypertension, 1 had apical myocardial thinning, and 1 had normal cardiac findings. Only 1 had conduction abnormalities, and only 1 had clear muscle weakness; most appeared muscular but not athletic. Two female carriers of the mutation had rigid spine symptoms, and 1 had left ventricular hypertrophy with hypertension. None of the patients was or became wheelchair-bound. Skeletal muscle biopsy from 3 patients showed cytoplasmic bodies, but not reducing bodies, and dystrophic features. Western blot analysis showed decreased expression of FHL1. Genetic analysis identified a hemizygous mutation in the FHL1 gene (C209R; 300163.0011).

Using STRP analysis, Windpassinger et al. (2008) demonstrated linkage of the phenotype in the large Austrian family described by them to chromosome Xq25-q27.1. Haplotype analysis based on SNP microarray data from selected family members confirmed this linkage region on the distal arm of the X chromosome and narrowed the critical interval to 12 Mb.

In an Austrian family with postural muscle atrophy and generalized hypertrophy, Windpassinger et al. (2008) detected a missense mutation in the FHL1 gene (300163.0002) that putatively disrupted the fourth LIM domain of the protein. A British family with an almost identical phenotype carried 3-bp insertion mutation within the second LIM domain (300163.0003).

In affected members of 6 unrelated families with Emery-Dreifuss muscular dystrophy-6, Gueneau et al. (2009) identified 6 different mutations in the FHL1 gene (see, e.g., 300163.0010-300163.0012). A patient with sporadic disease also had an FHL1 mutation. The mutations were preferentially located in the most distal exons 5 to 8 of FHL1 and impaired the 3 isoforms to various degrees.

Schoser et al. (2009) identified mutations in the C terminus of the FHL1 gene in 7 additional families with XMPMA (see, e.g., 300163.0002; 300163.0013; 300163.0014). Muscle biopsies showed absence of the FHL1 A isoform.