A number sign (#) is used with this entry because of evidence that distal myopathy-4 (MPD4), also known as Williams distal myopathy, is caused by heterozygous mutation in the FLNC gene (102565) on chromosome 7q32.

Williams distal myopathy is an autosomal dominant slowly progressive muscular disorder characterized by distal muscle weakness and atrophy affecting the upper and lower limbs. Onset occurs around the third to fourth decades of life, and patients remain ambulatory even after long disease duration. Muscle biopsy shows nonspecific changes with no evidence of rods, necrosis, or inflammation (summary by Duff et al., 2011).

Mutation in the FLNC gene can also cause myofibrillar myopathy-5 (MFM5; 609524), which shows a different pattern of muscle involvement and different histologic changes.

Williams et al. (2005) reported an Australian family in which at least 12 members had adult onset of a slowly progressive myopathy that first affected the distal muscles of the hand and leg. Patients reported insidious onset of muscle weakness before the fifth decade, with 5 having onset in their teenage years. There was a variable pattern of muscle weakness at onset, including wasting of the small muscles of the hand and weak grip strength or wasting of the posterior leg muscles. There was also weakness of the forearm muscles and ankle plantar flexors. Five had weakness of knee flexion, and 8 had weakness of hip flexion, resulting in abnormal gait. Three had late onset of facial muscle weakness. All reported muscle pain, which was worse after exercise, and most had hyporeflexia in the lower limbs. None had dysphagia, respiratory, or cardiac involvement, and all remained ambulatory. Serum creatine kinase was normal or mildly elevated. Sensory examination was normal. Muscle imaging in some patients was normal, others with longstanding disease had atrophy and fatty replacement. The anterior compartment of the legs was normal. Biopsy of 1 patient at age 75 years showed no dystrophic features, but did show some increased fiber size variation and increased numbers of type 1 fibers. There were no rimmed vacuoles and electron microscopy was normal. Linkage analysis excluded known distal myopathy genes, and Williams et al. (2005) concluded that the disorder in this family represented a novel type of autosomal dominant distal myopathy.

Duff et al. (2011) provided follow-up of the family reported by Williams et al. (2005), noting that disease most often started in the third decade of life in the hands and was characterized by thenar muscle weakness leading to reduced grip strength. This was followed by calf muscle weakness beginning around the fourth decade of life and leading to difficulties in running and jumping. Progression to proximal muscles was evident in the fifth decade of life and usually required a stick for walking by the sixth decade of life. Muscle biopsies showed a spectrum of findings, such as fiber size variation and atrophy, but no necrosis, vacuoles, inclusions, regeneration, or inflammation.

Duff et al. (2011) also reported an Italian family in which 4 individuals had a similar phenotype. Three living patients had onset of reduced finger skills and running performance at about 30 years of age. This was followed by slow progression to the proximal lower limb muscle over the next 20 years, with atrophy of the hand muscles, inability to squat, and use of a stick for walking by age 60. None had respiratory features, but 2 of the 4 patients had cardiomyopathy. Muscle biopsies were unremarkable and showed no protein aggregates.

Velardo et al. (2022) described individuals with MPD4 from 2 Italian families. The first was a 53-year-old man who noticed wasting of his hand and triceps brachii muscles without weakness at the age of 28. Beginning at age 31 years, he began to complain of fatigue and weakness in the legs and arms, impairing daily activities. Muscle cramps, mostly in the lower limbs, were present. Clinical examination at age 52 years showed severe muscle atrophy of lower and upper limbs, with moderate to severe muscle weakness more evident at distal upper than lower limbs. He also had mild facial weakness and mild dysphonia, but no cardiac or respiratory involvement. Creatine kinase levels were moderately increased, and electromyography showed chronic myopathic signs with distal neuropathic signs in the muscles of his upper and lower limbs. MRI of the muscles at age 47 years showed diffuse and severe muscle atrophy more evident in the posterior portion of the legs and signs of fatty substitution of the paravertebral muscles. No other family members were affected. In the second family, the proband was first seen at age 33 years with a clinical history of fatigue and progressive bilateral hypotrophy of the posterior thigh muscles and distal quadriceps, with associated foot plantar flexion weakness. Electromyography showed predominantly myopathic changes in the proximal muscles of 4 limbs. Neurologic exam revealed bilateral mild weakness of opponens pollicis and extensor digitorum, severe weakness of the gastrocnemius muscles, and bilateral wasting of the posterior thigh and leg muscles. Creatine kinase levels were moderately elevated. Echocardiogram showed no involvement. A lower limb muscle MRI showed discrete muscle wasting of the posterior region of the lower legs and mild atrophy of the distal portion of the quadriceps and hamstring muscles, with adipose replacement. The patient's affected father was clinically asymptomatic with normal creatinine kinase levels. Muscle MRI displayed the same pattern of adipose replacement that was seen in the proband. Two affected maternal uncles were also examined. The first, age 60 years, was unable to lift on his toes and had modestly increased creatinine kinase levels, while the second, age 57 years, had a dilated cardiomyopathy without apparent skeletal muscle involvement. The authors emphasized the extreme inter- and intrafamilial variability in clinical manifestations, necessitating testing of asymptomatic relatives.

The transmission pattern of MPD4 in the Australian family reported by Williams et al. (2005) and the Italian family reported by Duff et al. (2011) was consistent with autosomal dominant inheritance.

The heterozygous mutation in the FLNC gene identified in an individual with MPD4 by (Velardo et al. (2022)) occurred de novo.

By linkage analysis followed by candidate gene sequencing of the Australian family with distal myopathy reported by Williams et al. (2005), Duff et al. (2011) identified a heterozygous mutation in the FLNC gene (M251T; 102565.0003). A different heterozygous mutation (A193T; 102565.0004) was found in affected members of an Italian family with the same phenotype and linkage to the same region of chromosome 7q. Both mutations occurred in the actin-binding domain, and in vitro cellular expression studies showed that both mutations resulted in increased affinity for actin.

Using trio exome sequencing in 1 proband and sequencing with a panel of genes involved in muscle disorders in the other, Velardo et al. (2022) identified 2 novel variants in the FLNC gene in Italian patients with MPD4. Both patients carried de novo heterozygous missense mutations at evolutionarily conserved positions (M222T, 102565.0011 and V245M, 102565.0012, respectively). The V245M mutation in the second patient was inherited from the his 65-year-old clinically asymptomatic father, who on testing had abnormal muscle MRI findings. The proband also had 2 affected maternal uncles: one, age 60, was unable to lift on his toes, and the other, age 57, had a dilated cardiomyopathy without apparent skeletal muscle involvement. intrafamilial variability in clinical manifestations, necessitating testing of asymptomatic relatives.