Laing distal myopathy (ORPHA:59135)
A rare autosomal dominant distal myopathy characterized by preferential weakness of the great toe, ankle dorsiflexor, finger extensor and neck flexor. Progression is slow with variations in age of onset, severity, weakness, cardiac, and respiratory involvement.
Epidemiology
Worldwide prevalence is unknown. A founder variant in La Safor region (Spain) causes a local prevalence of 1/5,000. De novo variants cause 30% of cases.
Clinical description
Onset is usually from 4-5 years to the early 20s but may be in the 50s. The disease initially involves the dorsiflexors of the ankles and great toes, with foot drop causing high step walking and tripping, then spreads to finger extensors. Some patients present with neck flexion weakness. Mild involvement of the face (particularly the orbicularis oculi and oris) is frequent. Proximal and axial weakness may develop with variable severity and progression ranging from loss of ambulation in the 4th decade to symptomless old age. Exercise myalgia and backpain are occasional complaints. Atypical congenital or childhood forms with spinal rigidity, bent spine, dropped head or scapuloperoneal distribution may occur. Cleft palate, scoliosis, pes cavus, tendon contractions and calf hypertrophy may present. Cardiopathy occurs in one third of patients. Respiratory involvement is less common.
Etiology
The disease is caused by missense, deletion and insertion pathogenic variants (PVs) of the MYH7 gene (14q11), in the beta-myosin heavy chain rod domain. PVs alter the heptad amino acid repeat forming the coiled coil tail, or change its charge, hindering thick filament assembly and perturbing interaction with other sarcomeric proteins. Recent findings indicate altered myosin head function despite the PVs being in the myosin tail.
Diagnostic methods
Diagnosis is based on molecular genetic testing (exome, gene panel or Sanger sequencing). Serum creatine kinase concentration is normal to mildly increased. Electromyography demonstrates myopathy but occasional neurogenic features may mislead diagnosis. Muscle MRI grades muscle impairment and confirms the pattern of involvement with constant fatty replacement of anterior lower leg muscles and variable extension to other muscles independent of disease duration. Muscle pathology includes nonspecific myopathic/dystrophic features, type I fiber predominance and atrophy, cores or minicores, sarcoplasmic inclusions, occasional rimmed vacuoles and ragged-red fibres. Abundant fibers express both fast and slow myosin. Electron-microscopy shows focal sarcomeric disorganization, granular electrodense deposits like reducing bodies or lipofuscin material, aberrant mitochondria, and disorganized triads.
Differential diagnosis
Differential diagnosis is broad including: congenital myopathies and cardiomyopathies (RYR1 or MYH7-related); muscular dystrophies (due to PVs in LMNA/B, FHL1, SELENON, DUX4); Udd, Markesbery-Griggs, and Welander distal myopathies; GNE myopathy; distal nebulin myopathy; and neuropathy.
Antenatal diagnosis
Prenatal diagnosis may be performed using standard methods of preimplantation genetic testing or chorionic villus sampling and analysis.
Genetic counseling
Transmission is autosomal dominant. PV carriers have a 50% chance of transmitting it to their offspring.
Management and treatment
Management includes physiotherapy and lightweight ankle splinting for footdrop. Orthopedic and surgical management should be considered for scoliosis, rigid spine and tendon contractions. Annual neurologic evaluation, monitoring (electrocardiogram and echocardiogram) for cardiac involvement and spirometry for respiratory complications are recommended. There is no disease modifying therapy.
Prognosis
Life expectancy is normal for typical Laing distal myopathy. Patients with cardiac, spinal and respiratory complications should be evaluated accordingly.

                            Last update: 
                            June 2024


                            - Expert reviewer(s): 
                            Pr Nigel LAING  - Pr Phillipa LAMONT  - Dr Nuria MUELAS  - Pr Juan Jesús VILCHEZ PADILLA