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.

Clinical Phenotype

Patients with a similar early-onset ankle dorsiflexion weakness but without a dominant family history should also be considered with respect to nebulin mutations. Anterior compartment muscles of the lower legs and, later, extensors of the fingers and hands are predominantly affected. Neck flexor and mild facial weakness may occur. The progression is very mild and adult patients do not have major disability. There are no respiratory difficulties, no dysphagia, and no cardiomyopathy with the disease.

Muscle MRI shows selective fatty degeneration in the anterior compartment muscles of the lower legs, first in the tibialis anterior. EMG is myopathic and CK is normal or mildly elevated. Muscle biopsy in the affected muscles may be confusing with scattered and grouped atrophic fibers, easily interpreted as neurogenic pathology. The biopsy findings in proximal muscles are very mild with nonspecific increase of fiber size variation. Electron microscopy may or may not show a few small dense rods associated with Z-disks.

Molecular Genetics

Mutations in the nebulin gene are known to cause autosomal recessive congenital nemaline myopathy. The distal phenotype without nemaline rod pathology on light microscopy is explained by the fact that nemaline myopathy patients have more disrupting mutations, and the distal phenotype without nemaline rods is caused by missense mutations on both chromosomes. Sequencing of the large nebulin gene has not been available for diagnostic purposes, but the introduction of next generation sequencing capacity for diagnostic use will probably increase the number of patients identified with this disease.

Clinical Phenotype

So far, only one dominant German family has been described. Symptoms started between ages 8 and 16 years with ankle dorsiflexion weakness, and patients developed ankle contractures. In the disease course, finger weakness and intrinsic hand muscles were affected. Distal sensory loss was also reported by clinical examination, and progression was slow.

Serum CK levels were elevated (200–1400 U/L). Nerve conduction studies were usually normal, although a few increased distal motor latencies were recorded and sural sensory action potential was absent in one. EMG findings were also confusing with fibrillations and neurogenic motor unit potentials in distal muscles. MRI of muscles showed degenerative atrophic changes of the tibialis anterior, gastrocnemius, and soleus muscles with relative preservation of the tibialis posterior and peroneus longus muscles. In the thigh, the semimembranosus and biceps femoris muscles as well as the vastus intermedius muscle were more severely affected. The lateral and medial vastus muscles, gracilis, and sartorius were preserved. Gastrocnemius muscle biopsy showed fiber size variation, internal nuclei, and increased connective tissue. Biopsy of the sural nerve did not show axon loss or demyelination.

Molecular Genetics

A missense mutation p.L95F in the KLHL9 gene encoding a kelch-like homolog 9 protein segregated with the disease phenotype. KLHL9 is involved in a ubiquitin ligase complex with Cul3, and the mutation is thought to impair crucial interactions.