Ullrich congenital muscular dystrophy (ORPHA:75840)
A form of congenital muscular dystrophy characterized by congenital weakness, hypotonia, proximal joint contractures, marked hyperlaxity of the distal joints, with a loss of ambulation (if achieved) and uniform respiratory insufficiency during childhood.
Epidemiology
A Northern England study of genetic muscle disease reported an estimated prevalence of Ullrich congenital muscular dystrophy (UCMD) of 1/769,231.
Clinical description
The first signs noted are typically noted in utero with decreased fetal movement. Characteristic features at birth include hypotonia, torticollis, contractures of the proximal joints, hyperlaxity of the distal joints, kyphoscoliosis, abnormal positioning of the hands (wrist flexion) and feet (ankle dorsiflexion), hip dislocation, and prominent calcanei. Independent walking is not always achieved, and progression of muscle weakness and joint contractures result in loss of ambulation by 10-11 years old. Progressive, severe respiratory insufficiency occurs in all affected individuals by ~11 years old. Congenital kyphoscoliosis may occur. Spinal rigidity with concomitant scoliosis typically manifest at ~7 years, with scoliosis surgical repair performed at ~11 years. Skin manifestations include keratosis pilaris/follicular keratosis, prominently along the extensor surfaces of the arms and legs, keloid scars, and atrophic scars.
Etiology
UCMD is caused by heterozygous or biallelic pathogenic variants (PVs) in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3).
Diagnostic methods
The diagnosis is based on clinical signs, muscle imaging (MRI helps to identify characteristic patterns of abnormal muscle signaling), biopsy (revealing degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue), and muscle immunohistochemical features (ranging from absent collagen VI to mislocalized collagen VI) and the identification of a PV or PVs by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome, kyphoscoliotic Ehlers-Danlos syndrome, classic Ehlers-Danlos syndrome, Marfan syndrome, congenital contractural arachnodactyly, TTN-related myopathy, RYR1-related myopathy, SELENON-related myopathy, other forms of congenital muscular dystrophy, and spinal muscular atrophy.
Antenatal diagnosis
Once PV have been identified in an affected family member, prenatal diagnosis for a pregnancy and preimplantation genetic testing are possible.
Genetic counseling
UCMD is typically caused by a de novo autosomal dominant PV in COL6A1, COL6A2 or COL6A3, in which case, each child of an affected individual has a 50% chance of inheriting the PV. Less commonly, UCMD is 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. Careful pulmonary surveillance and proactive care dramatically improve the quality of life of affected individuals, however. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) is necessary by ~11 years. Use of a mechanical insufflator-exsufflator promotes airway clearance. Without adequate respiratory support with NIV, respiratory failure leads to early death in adolescence. Surveillance of the spine and surgical correction of scoliosis, if indicated, should be provided. Physical 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. Feeding and nutrition support should be provided for failure to thrive.
Prognosis
UCMD is a severe progressive disorder. Progressive respiratory insufficiency uniformly necessitates the initiation of nocturnal non-invasive ventilation by ~11 years of age. Most patients either are unable to walk or can walk for a period of time, with full-time wheelchair dependence by ~10-11 years of age.

                            Last update: 
                            October 2023


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