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This article includes discussion of Ullrich congenital muscular dystrophy, collagen VI-related myopathy, UCMD, Ullrich disease, and Ullrich scleroatonic muscular dystrophy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the author discusses Ullrich congenital muscular dystrophy, a collagen VI–related myopathy, which is characterized by proximal joint contractures, distal hyperlaxity, and normal intelligence. Clinical findings are hypotonia, congenital hip dislocation, torticollis, contractures, arthrogryposis, distal laxity in the neonatal period, and generalized, slowly progressive muscle weakness, including mild facial weakness. Ullrich congenital muscular dystrophy and Bethlem myopathy represent 2 ends of a clinical spectrum of disease defined as collagen VI–related myopathies. Both recessive and dominant mutations in collagen VI genes COL6A1, COL6A2, and COL6A3 are responsible for the disease phenotype in these myopathic conditions.
• Ullrich congenital muscular dystrophy (UCMD) is the severe clinical manifestation of collagen VI–related myopathic disorders.
• Ullrich congenital muscular dystrophy patients may have dominant or recessive mutations in collagen VI genes, and dominant mutations are frequently de novo mutations.
• Early diagnosis of this disorder is important because supportive nocturnal ventilation can help patient survival.
In 1930, Ullrich described a peculiar form of congenital muscular dystrophy with an unusual combination of distal hyperextensibility and proximal contractures in 2 boys; he termed the disorder “congenital atonic-sclerotic muscular dystrophy” (57; 58). Additional clinical findings were onset in the neonatal period or early infancy, which included generalized muscle weakness, hyperhidrosis, high-arched palate, protruded calcanei, and normal intelligence.
Ullrich congenital muscular dystrophy (MIM 254090) and Bethlem myopathy (MIM 158810) were originally described as separate entities, but demonstration of collagen VI gene mutations led to the concept of “collagen VI-related myopathies” as a group of conditions covering a broad clinical spectrum (32).
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 (40).
• Autosomal recessive inheritance
• Neonatal features, which may include hypotonia, hip dislocation, contractures, and distal laxity
• Delayed motor milestones
• Generalized slowly progressive muscle weakness including mild facial muscles and high-arched palate
• Distal laxity (hand, foot, and finger)
• Contracture of proximal joints: torticollis, limited neck flexion, and kyphoscoliosis
• Protruded calcaneus
• Lack of ambulation (a proportion of patients never achieved the ability to walk)
• Early respiratory failure
• No central nervous system involvement with normal intelligence
• Serum CK: normal or mildly elevated
• Myopathic to dystrophic muscle pathology, with fiber size variation, interstitial fibrosis and, possibly, necrotic and regenerating process
• Collagen VI staining on muscle biopsy: complete to partial deficiency
• The diagnosis can be confirmed by COL6 gene mutations
Hypotonia, congenital hip dislocation, congenital torticollis, contractures, and distal laxity may be the neonatal findings. Notably, most of the patients have delayed motor milestones 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. 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. There is absence of severe mental retardation.
Cases of variable severity have been described; the most severe end of the disease is the sclerotic form with severe contractures and rigidity of the spine. Although the patients at the severe end of the spectrum never achieve independent walking, there are also patients with a more benign presentation who can walk independently (43; 11; 05).
Ullrich congenital muscular dystrophy is usually a slowly progressive disease. 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 (38; 19).
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 5 of their patients required gastrostomy (38). Forced vital capacity was always below 40% in all patients aged 5 years and older; 9 out of 15 patients required nocturnal ventilation, and 5 of them also required scoliosis surgery. Echocardiography was normal in 7 of 154 patients; 1 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 (41). 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 (06).
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.
The majority of patients with Ullrich congenital muscular dystrophy show mutations in one of the collagen VI genes: COL6A1, COL6A2, and COL6A3. Numerous studies using next generation sequencing continue to expand the list of known mutations in these genes, and genotype-phenotype comparisons continue to 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 (61).
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 (47; 10).
Ishikawa and colleagues identified compound heterozygosity in the COL6A2 gene and complete deficiency of collagen VI (23). The authors suggested that loss of anchoring between the basal lamina and the interstitium may be the molecular mechanism of muscular dystrophy.
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 (25; 24). However, it is now known that both autosomal dominant and autosomal recessive mutations may result in Ullrich congenital muscular dystrophy (03; 33; 48), as well as Bethlem myopathy (13; 18). In 3 families, a form of autosomal dominant limb girdle muscular dystrophy has also been attributed to heterozygous mutations in the COL6A1 and COL6A2 genes (51). In some patients with Ullrich congenital muscular dystrophy, the COL6A2 mRNA has been shown to be nearly absent because of nonsense-mediated mRNA decay (NMD) (62). It has been suggested that inhibition of NMD may be a therapeutic approach because knockdown of essential proteins for NMD causes the upregulation of the mutant triple-helical collagen VI, resulting in the formation of partially functional extracellular matrix (59).
As a general conclusion, de novo dominant mutations in severe Ullrich congenital muscular dystrophy occur relatively frequently in all 3 collagen VI chains, and severity of the phenotype depends on the ability of mutant chains to be incorporated in the multimeric structure of collagen VI (34). Genotype-phenotype correlation in 5 Ullrich congenital muscular dystrophy patients showed that heterozygous glycine substitutions in the triple helix domain of COL6A1 were dominant and resulted in a milder phenotype, whereas recessive mutations resulted in more severe clinical and biochemical phenotypes (15).
Large genomic deletions were described in 2 families with Ullrich congenital muscular dystrophy (14). 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 (14). 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.
In summary, 2 mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy: heterozygous dominant negatively acting mutations and recessively acting loss-of-function mutations. Still, there are patients with Ullrich congenital muscular dystrophy phenotype who have normal collagen VI expression on muscle biopsy or samples and are not linked to known collagen VI loci, indicating genetic heterogeneity of this condition (38; 19; 12).
Pathophysiology. Collagen type VI is a ubiquitous connective tissue component, present primarily in the stroma and also close to the basement membrane of most tissues. It is a glycoprotein that consists of 3 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 (49).
Biosynthetic consequences of the collagen VI mutations depend on their positions in the triple-helical domain (31; 30). The collagen VI network is anchored to the basement membrane by collagen type IV and perlecan (29). These results all indicate a critical role of collagen VI in the muscle basement membrane and suggest that mislocalization of collagen VI is a potential mechanism for the severe Ullrich congenital muscular dystrophy phenotype.
Genetic and clinical correlations in early-onset collagen VI myopathies (Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes) have been reported in a multicenter study (08).
As a whole, patients with a phenotype consistent with Ullrich congenital muscular dystrophy constitute the largest group of patients with merosin-positive congenital muscular dystrophy. Selective depletion of collagen VI in the muscle basal lamina compared to normal levels in the endomysium is not clear. Collagen microfibrils near the surface of muscle cells are reduced in patients with Ullrich congenital muscular dystrophy (23; 42), and interactions of collagen VI near the cell surface may be more sensitive to structural changes or less stable than the interactions with extracellular matrix proteins leading to mislocalization of collagen VI. Collagen VI turnover is regulated by signaling through integrins, and, as an additional mechanism, impaired binding between mutated collagen and VI and integrins may alter collagen composition of the basement membrane and endomysial connective tissue (20; 60). Synthesis, formation, and binding of collagen VI to the extracellular matrix were studied from fibroblast samples with p.G284R mutation in COL6A1 and showed decreased binding of collagen VI microfibrils to the extracellular matrix, resulting in sarcolemma-specific collagen VI deficiency (26). Secretion and assembly of type IV and VI collagens is demonstrated to depend on glycosylation of hydroxylysines, which are shown to be indispensable for the formation of basement membranes (53).
Skin abnormalities, including predisposition to keratosis pilaris and abnormal scarring were described in Ullrich congenital muscular dystrophy and Bethlem myopathy patients. COL6A5, previously designated as COL29A1 was linked to atopic dermatitis. To gain insight into the function of these 2 new chains, the authors studied expression of the collagen VI alpha5 and alpha6 chains in normal human skin and the skin of patients with collagen VI-related myopathies. They showed that localization of alpha5 and, to a lesser extent, alpha6 is restricted to the papillary dermis, where the protein mainly co-localizes with collagen fibrils (50). In Ullrich congenital muscular dystrophy patients with COL6A1 and COL6A2 mutations, immunolabeling for alpha5 and alpha6 was often altered, whereas in an Ullrich congenital muscular dystrophy and Bethlem myopathy patient with COL6A3 mutation, expression was unaffected, suggesting that these chains may substitute for alpha3 while forming heterotrimers.
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 (22). 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 (17). Persistence of abnormal organelles and apoptosis are caused by defective autophagy.
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 (44). 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.
Pattern recognition for clinical diagnosis and pedigree information is essential. By using both haplotype analysis of DNA extracted from chorionic villus samples and collagen VI immunohistochemistry, prenatal diagnosis of Ullrich congenital muscular dystrophy is possible. In a consanguineous family with linkage to COL6A3 locus and negative immunostaining with collagen VI in the proband’s muscle tissue, haplotype analysis in combination with immunocytochemistry is presented as a rapid and a reliable method (09).
Genetic counseling in Ullrich congenital muscular dystrophy may be complex in families with homozygous or compound heterozygous null mutations in COL6A1, COL6A2, and COL6A3 (46).
Ullrich congenital muscular dystrophy lies at one end of a spectrum of disorders that also includes intermediate collagen VI–related myopathies and Bethlem myopathy (06). 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. As a whole, patients with a phenotype consistent with Ullrich congenital muscular dystrophy constitute the largest group of patients with merosin-positive congenital muscular dystrophy.
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 2 groups of disorders (28).
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 (55). 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.
Diagnosis of Ullrich congenital muscular dystrophy is made 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) may show selective involvement of the thigh muscles, ie, relative sparing of sartorius, gracilis, adductor longus, and rectus (35). At the calf level, a significant proportion of patients had a rim of abnormal signal at the periphery of soleus and gastrocnemii. The authors suggest that muscle MRI may be used as an additional tool for collagen VI-related disorders (37). Muscle MRI findings have also been reported to be highly suggestive in identifying specific patterns of involvement in muscular dystrophies with rigidity of spine (36). 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 (21). Early in the disease there may not be any dystrophic changes, and only type 1 atrophy and type 1 predominance may be seen (52).
Quantitative RT-PCR (08) and a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies (07) have been described as complementary diagnostic tools. Using the second method, a pure intronic mutation in COL6A genes was identified; the authors suggest using this technology especially in recessive forms of the disease when only 1 mutant allele is detected by standard sequencing (07). Pepe and colleagues demonstrated the presence of a minisatellite in COL6A1 intron 8 predisposing the defined area to multiexon deletions in collagen VI–related muscular dystrophies. Therefore, genomic DNA analysis and short-range RT-PCR may underestimate the multiexon deletions so long distance RT-PCR and protein analyses are necessary for the accurate molecular diagnosis (48).
Flow cytometric analysis on fibroblasts has been suggested as a timely and cost-effective method of screening for collagen VI deficiency (27).
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.
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; 45; 56). Another cyclophilin inhibitor, NIM811, shows promise in zebrafish models and in cell culture models as a potential therapeutic agent (63). 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 (39).
Progress on drug discovery is hindered in part by lack of an adequate animal model for Ullrich congenital muscular dystrophy; knockout mice have a relatively mild phenotype. Zebrafish models of collagen VI–related myopathies were generated using antisense morpholino technology (54). Morpholinos designed to exon 9 of Col6a1 produced a severe muscle disease reminiscent of Ullrich congenital muscular dystrophy, whereas morpholinos designed to exon 13 produced a milder phenotype similar to Bethlem myopathy. This is the first vertebrate model with a severe phenotype resembling Ullrich congenital muscular dystrophy, and zebrafish embryos with dominant-negative transcripts of Col6a1 result in severe morphologic, structural, and functional changes. Cyclosporin A improved motor deficits in Ullrich congenital muscular dystrophy-like zebrafish but failed to reverse the sarcolemmal membrane damage (54).
There is no knowledge about the risks of pregnancy for the mother or the fetus.
There was no defined complication due to anesthesia in 5 patients with Ullrich congenital muscular dystrophy phenotype who underwent scoliosis surgery (38). 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 (16).
Jennifer Baccon MD PhD
Dr. Baccon of Akron Children's Hospital and Northeast Ohio Medical University has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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