Clinical manifestations

Presentation and course

The signature clinical feature of the Ullrich congenital muscular dystrophy phenotype is congenital muscle weakness with proximal joint contractures and coexisting marked distal joint hyperlaxity. The 100th ENMC International Workshop diagnostic criteria for Ullrich congenital muscular dystrophy due to primary collagen type VI involvement are summarized in Table 1 (25).

Table 1. Diagnostic Criteria for Ullrich Congenital Muscular Dystrophy Due to Primary Collagen Type VI Involvement

Hypotonia, congenital hip dislocation, congenital torticollis, contractures, and distal laxity may be the neonatal findings. Notably, most of the patients have delayed motor milestones (with a subset of children never gaining the ability to walk), and generalized slowly progressive muscle weakness including mild facial weakness and high-arched palate. Contractures of proximal joints, particularly elbows and knees, are frequently present from birth. Distal joints of hands, ankles, toes, and fingers are hyperextensible lifelong. During the early follow-up, most contractures release spontaneously, and some return over the years, particularly contractures involving elbows, knees, and spinal joints. Patients usually have dry skin and protruded bulbs of hair follicles giving the appearance of dermatitis (keratosis pilaris). There may be excessive keloid formation at the sites of muscle biopsy. Protruded calcaneus and thickening of the subcutaneous tissue on the soles of the feet may be the additional key features. Intelligence and mental development remain unaffected.

Prognosis and complications

Collagen VI–related dystrophies are a set of slowly progressive diseases. The clinical features and prognosis of the patients vary; there are patients who never achieve independent walking, usually in the sclerotic form at the severe end of the spectrum, and there are also patients who have mild delay in motor milestones and can walk independently for years.

There is no correlation between the severity of motor impairment, age at onset of the symptoms, histologic findings and collagen VI status on muscle biopsy, or the severity of secondary complications (22; 13).

In the severe Ullrich form, failure to thrive, early tendency to recurrent respiratory tract infections, spinal deformities, or painful dislocated hip may be complications. Mercuri and colleagues reported that failure to thrive became more evident after 10 years of age, and five of their patients required gastrostomy (22). Forced vital capacity was always below 40% in all patients aged 5 years and older; nine out of 15 patients required nocturnal ventilation, and five of them also required scoliosis surgery. Echocardiography was normal in seven of 154 patients; one of their patients with partial absence of collagen VI died unexpectedly at 12 years of age, bringing up the possibility of sudden electromechanical dissociation.

The natural history of Ullrich congenital muscular dystrophy has been reported in a cohort of 13 patients followed up in a single center (26). In summary, decline in motor and respiratory function is more rapid in the first decade of life, and deterioration is not always correlated with age or severity at presentation. Management of respiratory functions and introduction of noninvasive ventilatory support are crucial in the follow-up of these patients. Failure to evaluate for nocturnal ventilation needs may lead to death in the teenage years (05).

Bethlem muscular dystrophy is at the milder end of the clinical spectrum of collagen VI–related dystrophies and is characterized by joint contractures and proximal muscle weakness. Intermediate COL6-RD clinical features are in the middle of the clinical spectrum between the Ullrich and Bethlem phenotypes. Because all the disorders are variations on the same underlying genetic disruptions, the subclassification is more for clinical utility in describing the condition and prognosis of a particular patient rather than defining a distinct clinical entity from within the cluster of collagen VI–related dystrophies (09).

Clinical vignette

A 3-year, 9-month-old boy presented with developmental delay at the age of 20 months. He was born at term with a birthweight of 3200 g by cesarean section (breech presentation) without a complicated delivery. He had congenital hip dislocation as well as neonatal hypotonia and stayed in the hospital for the first 25 days because of respiratory and feeding problems.

He had head control at 6 months of age and sat with and without support at the age of 9 months and 12 months, respectively. Mental development was normal. There was second-degree consanguinity. Physical examination revealed a round myopathic face, high arched palate, deep sunken eyes, and low-set prominent ears. He had hypotonia, absent deep tendon reflexes, distal laxity, hip dislocation, and proximal contractures.

Serum creatine kinase level was 150U/l (N < 200). Muscle biopsy showed variation in fiber size, internal nuclei, muscle fiber degeneration and regeneration, increase in perimysial and endomysial connective tissue, and fatty tissue infiltration. Immunohistochemical studies revealed a merosin positive congenital muscular dystrophy with total absence of collagen VI.

Biological basis

Etiology and pathogenesis

Numerous studies using next generation sequencing continue to expand the list of known mutations in these genes, and genotype-phenotype comparisons support that collagen VI-related myopathies are a clinical spectrum. The genetic mutations result in variable deficiency of collagen VI at the basal lamina, with an apparently preserved expression in the interstitial connective tissue, whereas a minority of patients shows complete deficiency in the protein (38).

Genetics. Collagen VI genes were first found to be associated with Bethlem myopathy, a milder childhood-onset disorder characterized by muscle weakness and later manifesting multiple joint contractures, indicating tissue-specific importance of collagen VI (30; 06).

Collagen VI mutations in Ullrich congenital muscular dystrophy reported to date are extremely heterogenous. It was once thought that recessive mutations in collagen VI genes resulted in Ullrich congenital muscular dystrophy and that dominant mutations in collagen VI genes resulted in Bethlem myopathy (17; 16). However, it is now known that both autosomal dominant and autosomal recessive mutations may result in Ullrich congenital muscular dystrophy (03; 20; 31), as well as Bethlem myopathy (07; 12) and intermediate COL6-RD.

Large genomic deletions were described in two families with Ullrich congenital muscular dystrophy (08). The authors reported in detail that this type of a mutation will not be detected by single-exon amplification and sequencing (unless done quantitatively), and a hemizygous change detected on a nondeleted allele will appear homozygous and obscure the true genotype of the patient's disease. On the other hand, clinically unaffected parents carrying large genomic deletions of COL6A1 and COL6A2 also provided evidence that haploinsufficiency for COL6A1 and COL6A2 is not a disease mechanism for Bethlem myopathy (08). These results have great translational importance, and therapeutic strategies directed at the elimination of a dominant negatively acting mutation are conceivable and would create a functional state of haploinsufficiency.

Pathophysiology. Collagen type VI is a ubiquitous connective tissue component primarily present in the stroma and close to the basement membrane of most tissues. It is a glycoprotein that consists of three separate chains, the alpha1, alpha2, and alpha3 collagen chains, encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Collagen type VI is distributed in the connective tissues and is particularly abundant around cells associated with interstitial collagen fibers types I, II, and III, with a possible role as substrate for the attachment of cells and in anchoring collagen fibers, nerves, and blood vessels to the surrounding connective tissue. Moesin has been shown to be produced by fibroblasts in Ullrich congenital muscular dystrophy and may provide a new target for intervention (32).

Skin abnormalities, including predisposition to keratosis pilaris and abnormal scarring were described in patients with Ullrich congenital muscular dystrophy and Bethlem myopathy. COL6A5, previously designated as COL29A1 was linked to atopic dermatitis.

A dystrophic mouse model where collagen VI synthesis was prevented by genetic ablation of the COL6A1 gene allowed investigation of pathogenesis, which revealed the existence of a calcium-mediated dysfunction of mitochondria and the sarcoplasmic reticulum (15). The critical point appears to be an inappropriate opening of the mitochondrial permeability transition pore, an inner membrane high conductance channel. Studies from fibroblasts of patients with Ullrich congenital muscular dystrophy and Bethlem myopathy showed the existence of a latent mitochondrial dysfunction irrespective of the genetic background (01). The permeability transition pore opening seems to be the final common pathway for skeletal muscle fiber death (04).

Defective activation of the autophagic machinery was described to be pathogenic, firstly, in the skeletal muscles of collagen VI–knockout mice, and then in muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy (11). Persistence of abnormal organelles and apoptosis are caused by defective autophagy.

There is some work showing that collagen VI is the most abundant collagen subtype in lung tissues, which raises the possibility that the respiratory issues associated with collagen VI disorders is a direct effect of the deficiency on lung function as opposed to the earlier belief that pulmonary function decreased secondary to muscle weakness (23).

Epidemiology

A detailed population study of patients with genetic muscle disease in Northern England, which included over 1100 patients in whom the authors molecularly characterized 31 muscle entities, showed that for the group of congenital muscular dystrophies point prevalence was 0.89 out of 100,000 (28). Ullrich congenital muscular dystrophy and Bethlem myopathy had a prevalence of 0.13 out of 100,000 and 0.77 out of 100,000, respectively.

Prevention

Pattern recognition for clinical diagnosis and pedigree information is essential. By using next-generation sequencing, haplotype analysis of DNA extracted from chorionic villus samples, or collagen VI immunohistochemistry, prenatal diagnosis of collagen VI muscular dystrophy is possible.

Differential diagnosis

Confusing conditions

Ullrich congenital muscular dystrophy lies at one end of a spectrum of disorders that also includes intermediate collagen VI–related myopathies and Bethlem myopathy (05). The disease phenotypes of these collagen VI–related myopathies are somewhat overlapping, and genetic distinctions do not completely distinguish between patient groups.

Other entities to consider on the differential diagnosis include rigid spine syndrome, merosin positive congenital muscular dystrophy, some forms of Ehlers-Danlos syndrome, congenital laxity of the ligaments, and connective tissue diseases.

Interestingly, ultrastructural evidence from skin biopsies, including alteration of collagen fibril morphology and increase in ground substance, resemble findings in Ehlers-Danlos syndrome. This similarity suggests a true connective tissue component as part of the phenotypic spectrum of Ullrich congenital muscular dystrophy, and it highlights a potential clinical and morphological overlap between these two groups of disorders (18).

A form of congenital muscular dystrophy with joint hyperlaxity and proximal contractures with a milder phenotype compared to Ullrich congenital muscular dystrophy was defined and mapped to chromosome 3p23-21 (34). Pathological and genetic studies excluded mutations in collagen VI subunits. All patients are from the southwestern part of Quebec, suggesting a new French-Canadian founder effect.

Diagnostic workup

Collagen VI disorders are often suspected on clinical grounds. Serum creatine kinase levels may be normal or mildly elevated. Electromyography is not of clinical value. An anteroposterior pelvic x-ray may be helpful to demonstrate hip dislocation.

When performed, magnetic resonance imaging (MRI) of the leg muscle may show selective involvement of various muscles correlating with the severity of these disorders on the spectrum (21). At the thigh and calf muscle levels respectively, Ullrich congenital muscular dystrophy is characterized by diffuse involvement with selective relative sparing of the anteromedial muscles and more diffuse changes than in Bethlem myopathy, but similar peripheral involvement of the gastrocnemii. Bethlem myopathy is characterized by peripheral involvement more obvious in vasti and internal signal in the rectus and peripheral involvement of the gastrocnemii.

Muscle biopsy shows severe myopathic changes with a positive staining for merosin. In a typical case, there is proliferation of the connective tissue around individual muscle fibers along with increased adipose tissue infiltrating the muscle. Fiber type predominance is not observed. There is total or partial absence of collagen VI immunostaining in muscle and fibroblasts in most of the patients. Small muscle fibers in the patients with Ullrich congenital muscular dystrophy show marked expression of desmin, neural cell adhesion molecule, and neonatal myosin heavy chain, which is a characteristic finding of regenerating fibers; however, they show poor expression of developmental myosin heavy chain and thrombomodulin. These additional findings suggest that abnormal regeneration or maturation processes are involved in the pathogenesis of dystrophic muscle changes in the advanced stages (14). Early in the disease there may not be any dystrophic changes, and only type 1 atrophy and type 1 predominance may be seen (33).

Targeted gene testing may be performed in cases in which a collagen VI disorder is suspected. Muscle-specific panels as well as whole exome or whole genome sequencing, sometimes with confirmatory Sanger sequencing, are other options for demonstrating the underlying mutations in collagen VI.

Management

Treatment is supportive and symptomatic. Physical rehabilitation programs, prevention of respiratory tract infections and respiratory insufficiency with noninvasive ventilatory interventions, and dietary support are essential. Nocturnal hypoxemia, left unsupported by overnight ventilation, can be fatal by the teenage years (23). It has been suggested that the evaluation of initial maximum motor ability can help in appropriately directing supportive and proactive care (27).

There has been only limited investigational study on pharmacologic treatment for patients diagnosed with Ullrich congenital muscular dystrophy. Cyclophilin inhibitors, including cyclosporin A, are under investigation because of their role in mitochondrial depolarization from cyclophilin-dependent permeability transition pore regulation (02; 29; 35). Another cyclophilin inhibitor, NIM811, shows promise in zebrafish models and in cell culture models as a potential therapeutic agent (39). There is still a need for development of alternative outcome measures or biomarkers using different platforms such as genomics and proteomics because randomized clinical trials are not feasible for this rare disorder (24).

Animal models, drug discovery, and therapeutic approaches are in early phases of investigation.

Special considerations

Pregnancy

There is no knowledge about the risks of pregnancy for the mother or the fetus.

Anesthesia

There was no defined complication due to anesthesia in five patients with Ullrich congenital muscular dystrophy phenotype who underwent scoliosis surgery (22). Because of micrognathism and contraction of the temporomandibular muscles, tracheal intubation may be difficult, but it is felt that halogenated agents may be used successfully in patients with Ullrich congenital muscular dystrophy (10).