Distal Myopathies

Clinical Phenotype

Symptoms of ankle stiffness are usually observed in infancy before the child starts to walk. However, ankle dorsiflexion weakness may be very mild and remain unnoticed until later. Weakness is marked in ankle dorsiflexor, toe extensor, and neck flexor muscles. Later in the disease course finger extensors and proximal limb muscles are also affected, but most patients remain ambulatory throughout their lifetime. Disease severity ranges from the “hanging big toe” sign in the 30s to the more generalized weakness in childhood with scoliosis and ankle contractures. Cardiomyopathy may occur in a minority of patients and some cardiac monitoring is advised. LDM is an autosomal dominant disorder, but many patients appear in clinic as sporadic cases. Since the first report in 1995, many families have been identified in different populations.

Serum creatine kinase (CK) level is normal or mildly elevated (up to three-fold). Electromyography (EMG) shows short, brief myopathic potentials, and muscle biopsy reveals moderate myopathy with fiber type disproportion. Vacuoles are rare but cores and core-like changes are frequent. Muscle MRI is very informative and shows fatty degeneration consistently in anterior compartment muscles of the lower legs. Later in the disease course, medial gastrocnemius and proximal thigh muscles may be involved.

The exact prevalence is not known; however, in some well-studied smaller populations such as Western Australia, Finland, Norway, and Valencia, three to four different mutations in each have been identified, which suggests that the overall prevalence may be 1–5 per 1 million.

Molecular Genetics

The disease was first linked to chromosome 14q11 in an Australian family and later the causative mutations in MYH7 were identified. The gene encodes slow beta myosin heavy chain, which is the main myosin isoform in type 1 slow skeletal muscle fibers and in cardiac muscle fibers. Myosin molecules are hexameres and consist of two large heavy chain and four small light chain subunits. To date some 30 different MYH7 mutations have been identified. Many of them are recurring hotspot mutations and many are de novo mutations in the sporadic patients. The vast majority of mutations are located in the tail region of the MYH7 molecule between amino acids 1500 and 1855. The mutations are predicted to break the regularity of the heptad coiled-coil structure of the rod domain. Mutations in other parts of the protein may cause cardiomyopathy or hyaline body myopathy.

Diagnostics

The key for diagnosis is the clinical and muscle imaging phenotype, although the disease is still confused with Charcot-Marie-Tooth. Lack of high amplitude motor unit potentials on EMG in the affected muscles, despite the chronic condition, should indicate a myopathic process. Final diagnosis requires molecular genetic verification of mutated MYH7.

Therapy

Ankle orthotic devices are useful in severe foot drop situations. Tendon release in the ankles and scoliosis surgery may be needed. For the disabled child, multidisciplinary rehabilitation measures should be provided.