Bethlem muscular dystrophy (ORPHA:610)
A form of congenital muscular dystrophy characterized by a congenital to childhood onset of progressive proximal muscle weakness, joint contractures, and potential respiratory insufficiency in adulthood.
Epidemiology
A Northern England study of genetic muscle disease reported an estimated prevalence of Bethlem muscular dystrophy of 1/129,870 people.
Clinical description
Patients present with hypotonia and delayed motor milestones in early childhood; mild hypotonia and muscle weakness may be present at birth and slowly progresses during the patient's lifetime. Proximal muscle weakness and joint contractures of the elbows, Achilles tendons, and long finger flexors are evident by adulthood. More than 2/3rd of the patients aged >50 years require mobility aids outdoors. Respiratory involvement in some patients can result in respiratory insufficiency in aduldhood, necessitating nocturnal non-invasive ventilation (NIV).
Etiology
The disease is caused by mutations in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3) and can be inherited in an autosomal dominant or autosomal recessive manner.
Diagnostic methods
The diagnosis of Bethlem myopathy is established in a proband with characteristic clinical, muscle imaging, and muscle immunohistochemical features and the identification of a heterozygous or biallelic pathogenic variants (PVs) in COL6A1, COL6A2 or COL6A3 by molecular genetic testing. Muscle biopsy shows degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI. Muscle MRI can be an excellent diagnostic tool to identify characteristic patterns of abnormal muscle signaling.
Differential diagnosis
The differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome (including COL12A1-related myopathy), limb-girdle muscular dystrophies (LGMDs) including calpainopathy (also called LGMDR1 and LGMD2A) due to PVs in CAPN, Emery-Dreifuss muscular dystrophy due to PVs in EMD, FHL1, or LMNA, FHL1-related myopathy, LAMA2-related dystropy (the partial merosin deficiency subtype), and TTN-related myopathy (the «contractural» phenotype).
Antenatal diagnosis
Once PVs have been identified in an affected family member, prenatal diagnosis and preimplantation genetic testing are possible.
Genetic counseling
Bethlem muscular dystrophy is usually inherited by an autosomal dominant PV in COL6A1, COL6A2 or COL6A3; in these cases, each child of an affected individual has a 50% chance of inheriting a PV. Less commonly, Bethlem muscular dystrophy can be inherited in an autosomal recessive manner; if both parents are carriers of a disease-causing mutation, they should be informed that there is a 25% risk of having an affected child with each pregnancy. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in COL6-RDs and should be considered, given the implications for recurrence risk assessment.
Management and treatment
Currently, there is no curative treatment; however, careful pulmonary surveillance and proactive care improve the quality of life of affected individuals. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) may be necessary to support nocturnal ventilation during adulthood. Use of a mechanical insufflator-exsufflator promotes airway clearance. Physical therapy and occupational therapy are important for providing recommendations for joint stretching, swimming, and aquatherapy. Achilles tendon contractures should be managed with splints and/or tendon release surgery.
Prognosis
Proximal weakness and joint contractures develop by adulthood. The disease progression is slow with more than 2/3rd of patients aged >50 years old requiring mobility aids (crutches, canes, wheelchair) outdoors. In some patients, respiratory muscle weakness, particularly of the diaphragm, can result in respiratory insufficiency in aduldhood.

                            Last update: 
                            October 2023


                            - Expert reviewer(s): 
                            Dr Carsten G. BONNEMANN  - Dr A. Reghan FOLEY