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Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are inherited disorders of collagen VI characterized by progressive muscle weakness and a combination of joint hyperlaxity and joint contractures. Collagen VI is present at the interface of the basement membrane and the extracellular matrix where it plays an important role in muscle maintenance. Recently, a role for collagen VI has been demonstrated in the regulation of cellular homeostasis including stress responses mediated through the mitochondrial permeability transition pore (mPTP) and autophagy pathways. We hypothesize that fundamental cellular defects resulting from dysfunctional collagen VI will be reflected in patient derived dermal fibroblasts and approachable using a systems biological approach. In this study we used transcriptional profiling to identify key pathways mediating the cellular response to mutations in collagen VI. We used an RNA-Seq approach on the Illuminia, HiSeq platform to deeply sequence poly (A) purified transcripts from cultured fibroblast from UCMD patients and healthy controls. We quantified differential expression levels and assessed alternative splicing and isoform switching. Among the most significantly down-regulated genes in UCMD patients is ATG13, an important initiator of autophagy. In contrast, APAF1, an important initiator of apoptosis was among the most up-regulated transcripts in UCMD patients. These data are consistent with work in animal models suggesting the presence of dysregulated autophagy and apoptosis pathways in collagen VI deficiency. Furthermore transcriptome profiling including gene-set analysis and determination of differential expression and alternative splicing in fibroblasts will identify cellular pathways important in pathogenesis. Identification of differentially expressed and regulated genes in UCMD will provide new targets for development of therapies as well as potential biomarkers to assess the efficacy of treatments.

Objective: To evaluate the reliability and accuracy of skeletal muscle computed tomography to correctly identify different muscular dystrophies manifesting with limb girdle weakness. Four evaluators assessed scans from 118 patients with limb girdle muscular dystrophy caused by mutations in seven different genes and from 32 controls. The conditions studied were scans of genetically confirmed cases of Becker muscular dystrophy (BMD) [ n = 28], LGMD2C-F (Sarcoglycanopathies) [ n = 11], LGMD2I [ n = 4], LGMD1B [ n = 26], LGMD2A [ n = 24], Bethlem myopathy [ n = 14] and LGMD2L [ n = 11]. The control group [ n = 32] consisted of patients affected by muscular dystrophies manifesting with limb girdle weakness in which the aforementioned muscular dystrophies were excluded. The scans were compared with the characteristic patterns described in literature. The overall interobserver agreement was poor ( κ = 0,27), with markedly higher scores for Becker muscular dystrophy ( κ = 0,51) and Bethlem myopathy ( κ = 0,59). The sensitivity to detect selective patterns in relation to the genetic diagnosis was 40% if all limb girdle muscular dystrophies were taken together. The specificity was 58%, positive predictive value (PPV) 77% and 1-negative predictive value (1-NPV) 79%. Markedly better scores were observed for Becker muscular dystrophy (sensitivity 91%, PPV 66%, 1-NPV 3%) and Bethlem myopathy (sensitivity 90%, PPV 69%, 1-NPV 1%). Our findings suggest that muscle computed tomography might be an adjunct to the clinical diagnosis of Becker muscular dystrophy and Bethlem myopathy. However, pattern recognition was cumbersome in the other limb-girdle muscular dystrophies.

COL6-RM are a group of disorders with variable expressivity, from severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). The spectrum includes weakness, joint hyperlaxity, contractures, keratosis pilaris, keloid scarring, and respiratory insufficiency. Diagnosis is based on presentation, characteristic muscle imaging changes, and immunohistochemical findings in muscle and fibroblasts. Genetic confirmation is obtained through COL6A1–A3 sequencing. Mutations in COL6-RM can act via a dominant or recessive mechanism and may be inherited or de novo. Understanding the underlying genetic mechanism is essential for providing recurrence risk and genetic counseling. We report three families with novel mutations and pathogenic mechanisms predicted to cause variable severity of COL6-RM. A 40-yr-old male in Family 1 has typical findings of BM, while his 11-yr-old daughter has a UCMD phenotype. Fibroblasts showed reduced expression of Col6 in both. Genetic results were suggestive of somatic mosaicism in the father, whereas the child was a full carrier of a novel COL6A2 heterozygous c.900+1G>A mutation resulting in exon 7 skipping. In Family 2, two brothers presented with weakness, contractures, and keratosis pilaris. Their 43-yr-old father had only finger contractures but was found to have typical COL6 imaging findings on muscle ultrasound and MRI. Genetic testing revealed a variant in IVS9-22A>G in COL6A1 resulting in exon 10 skipping, segregating in all 3. Fibroblasts showed reduced expression of COL6. Family 3 showed three generations of AD inherited mutation c.6309+10C>G in COL6A3 creating a novel ‘leaking’ splice donor site. Phenotypic variability ranged from mild to severe contractures unrelated to muscle involvement. Advances in understanding of the genetics of Col6 myopathy will aid future clinical trials where modulation of the disease phenotype will serve as the target for intervention.

 Lampe, A.K., D.M. Dunn, A.C. von Niederhausern, C. Hamil, A. Aoyagi, S.H. Laval, S.K. Marie, M.L. Chu, K. Swoboda, F. Muntoni, C.G. Bonnemann, K.M. Flanigan, K.M. Bushby, and R.B. Weiss (2005) Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet, 42, 108-20.  Hicks, D., A.K. Lampe, R. Barresi, R. Charlton, C. Fiorillo, C.G. Bonnemann, J. Hudson, R. Sutton, H. Lochmuller, V. Straub, and K. Bushby (2008) A refined diagnostic algorithm for Bethlem myopathy. Neurology, 70, 1192-9. D. Hicks, E. Martoni, V. Straub, H. Lochmuller, S. H. Laval, K. Bushby. Newcastle Muscle Centre, Institute of Genetic Medicine, Newcastle University, UK.

We describe a Danish family of five generations showing a slowly progressive autosomal dominant limb-girdle myopathy with onset in early childhood. Three patients from two generations were examined and showed weakness predominantly of the proximal muscles of upper and lower extremities. Early contractures of wrist, tight heel cords, metacarpophalangeal and interphalangeal joints were present. Walking ability was partly preserved. Serum creatine kinase activity was normal or slightly elevated. EMG and biopsy showed mildly myopathic changes. Magnetic resonance images of the thigh showed severe atrophy of all compartments but with musculus semimembranosus, sartorius, and gracilis relatively preserved. This myopathy has a clinical picture similar to the Bethlem myopathy.

mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD. In patient 1 SNP based genomic array analysis revealed a 69 kb genomic deletion at 21q22.3 encompassing at least 18 exons of the COL6A2 gene on one allele. Exonic sequencing of the non-deleted allele found an intronic nucleotide change (G > A) at position c.1970-9. cDNA sequencing of COL6A2 revealed a 7 base pair insertion resulting from the use of a novel splice acceptor site in intron 25 created by the mutation, resulting in a frameshift and a premature stop codon (G656AfsX17). Patient 1’s asymptomatic mother is heterozygous for (G > A) at c.1970-9 of COL6A2; his asymptomatic father is heterozygous for the 69 kb deletion. Patient 2 has two genomic deletions at 21q22.3: a deletion of 1.61Mb encompassing the entire COL6A1 and COL6A2 genes plus surrounding genes on one allele and a smaller deletion of 47 kb encompassing the entire COL6A2 gene on the other allele. Patient 2’s asymptomatic mother is heterozygous for the 1.61Mb deletion; his asymptomatic father is heterozygous for the 47 kb deletion. In addition, we incidentally identified an asymptomatic father and his son who are heterozygous for a 1.09Mb deletion of both the COL6A1 and COL6A2 loci but do not carry a mutation on the other allele and, therefore, do not manifest signs of the disease. Large genomic deletions add to the complexity of genetic evaluations in the collagen VI related myopathies. Clinically unaffected parents carrying large genomic deletions of COL6A1 and COL6A2 provide conclusive evidence that haploinsufficiency for COL6A1 and COL6A2 does not result in clinical neuromuscular disease and, in particular, is not a disease mechanism for Bethlem myopathy.

Background Bethlem myopathy is considered a relatively mild neuromuscular disorder without significant cardiac and respiratory involvement. Objective To investigate cardiac and respiratory involvement in Bethlem myopathy. Design Cross-sectional study. Setting University hospitals. Patients Fifty patients with Bethlem myopathy from 26 families. Interventions Cardiac examinations, including electrocardiography and echocardiography (n = 37) and pulmonary investigations (n = 43). Holter monitoring was performed in 16 patients. Main Outcome Measures Cardiac and respiratory abnormalities. Results Several cardiac abnormalities were found that were considered unrelated to the muscular disorder. Seven (16%) of 43 patients had a forced vital capacity less than 70% of the predicted value. One of 2 patients with a forced vital capacity less than 50% was also receiving respiratory support. All patients with compromised respiratory function were still ambulatory, and we found no significant correlation between the severity of arm weakness and the severity of respiratory muscle involvement. Conclusions There is no evidence of cardiac involvement in Bethlem myopathy. Respiratory failure is part of the clinical spectrum and can occur in ambulatory patients.

The natural course of Bethlem myopathy in five previously published kindreds and two novel pedigrees was investigated, with attention to the mode of onset in 23 children and the progression of weakness in 36 adult patients followed at the Academic Medical Center, Amsterdam, The Netherlands.

We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.

Bone formation is precisely regulated by cell-cell communication in osteoblasts. We have previously demonstrated that genetic deletion of Col6a1 or Col12a1 impairs osteoblast connections and/or communication in mice, resulting in bone mass reduction and bone fragility. Mutations of the genes encoding collagen VI cause Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM), which have overlapping phenotypes involving connective tissue and muscle. Recent studies have identified COL12A1 gene mutations in patients with UCMD- and BM-like disorders harboring no COL6 mutations, indicating the shared functions of these collagens in connective tissue homeostasis. The purpose of this investigation has been to test the hypothesis that collagens VI and XII have coordinate regulatory role(s) during bone formation. We analyzed the localization of collagens VI and XII relative to primary osteoblasts during osteogenesis. Immunofluorescence analysis demonstrated that collagens VI and XII colocalized in matrix bridges between adjacent cells during periods when osteoblasts were establishing cell-cell connections. Quantification of cells harboring collagen bridges demonstrated that matrix bridges were composed of collagens VI and XII but not collagen I. Interestingly, matrix bridge formation was impaired in osteoblasts deficient in either Col6a1 or Col12a1, suggesting that both collagens were indispensable for matrix bridge formation. These data demonstrate, for the first time, a functional relationship between collagens VI and XII during osteogenesis and indicate that a complex containing collagens VI and XII is essential for the formation of a communicating cellular network during bone formation.

We report the first Japanese patients, a mother and son, with early-onset, benign, autosomal-dominant, limb-girdle myopathy with contractures (Bethlem myopathy). The clinical features revealed predominantly proximal muscle weakness — especially in the limb-girdle muscles — joint contractures increasing with age, a benign course, and the absence of cardiac involvement. Muscle histology revealed nonspecific myopathic changes without dystrophic features. Electromyogram revealed a reduced interference pattern with a giant spike suggesting a neurogenic process.

We report a large French-Canadian kindred with 33 affected members in six generations showing early-onset autosomal dominant limb-girdle myopathy and contractures. This myopathy is unique because of its benign course, with many members only minimally impaired even in old age. Examination of affected members revealed mild to moderate proximal weakness and wasting. Contractures were observed at the elbows and ankles in all, while in some they were more widespread. Serum CK was either normal or slightly raised, and electrodiagnostic studies suggested a primary myopathy. Muscle biopsy revealed nonspecific features of a myopathy without fiber necrosis or regeneration. Cardiac involvement was absent clinically in all patients and at autopsy in two affected individuals. The similarities between four previously reported families and our own establishes this myopathy as a distinct clinicogenetic entity, for which we propose the name "Bethlem myopathy."

Clinical characteristics recognized in five cases with Ullrich's disease included muscle weakness and wasting, striking contracture of proximal (sclerotic) joints and hyperflexibility of distal (atonic) joints since an early infantile stage, and slowly progressive course. The biopsied muscles demonstrated myopathic changes including a remarkable variation in fiber size, notably proliferated endomysial connective tissue, increased myofibers with centralized nuclei and a few necrotic fibers with active phagocytosis. On histochemical examination, no specific intracytoplasmic structural abnormalities such as nemaline bodies, cores and myotubes were recognized. Although both type 1 and 2 fibers were distributed in checkerboard pattern in most muscle fascicles, type 1 fiber predominance or type 2 fiber deficiency was common in severely damaged muscles, suggesting the presence of some kind of neural influence exerting on the myopathic process as the disease progressed. Since it still remains uncertain whether this disorder belongs to the muscular dystrophies, or to other neuromuscular or mesodermal diseases, we would rather label it Ullrich's disease then Ullrich's muscular "dystrophy" until its pathogenesis becomes clear.

Three pedigrees are described in which 28 living siblings suffered from a benign myopathy. The first symptoms were observed around the fifth year of life. The proximal muscles were more involved than the distal muscles, the extensors more than the flexors. Due to a marked paresis of the extensor digitorum communis muscles 22 patients showed a flexion contracture of the interphalangeal joints of the last four fingers. In addition 20 patients showed a flexion contracture of the elbows and 12 patients had a plantar flexion contracture of the ankles. A high incidence of congenital torticollis was found. The histopathological features were non-specific and remarkably uniform and consisted of a marked variation in muslce fibre diameter and a very marked increase of fatty tissue. Light-microscopy and electronmicroscopy did not show any specific structural changes. There was normal distribution of type I and type II fibres, without type-grouping or preferential atrophy of one of the fibre types. Lobulated type I fibres were found in 6 out of 12 biopsies. Post-mortem study of one case did not show any convincing features of a neurogenic disorder. As no relationship could be found between the siblings of the 3 pedigrees as far back as the beginning of the eighteenth century, this myopathy seemed to be a new nosological entity.

Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty ; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed. A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) associa-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso progressivo, ocasionalmente mostrando menor gravidade. OBJETIVO: Avaliar o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente do colágeno VI na biópsia muscular. RESULTADOS: Entre 60 pacientes com DMC, dois mostravam imunomarcação negativa do colágeno VI. Mostravam-se clinicamente essencialmente diferentes: o primeiro, com 8 anos de idade e três de seguimento mostra leve dificuldade motora; o segundo, com 14 anos de idade e 8 de seguimento, não deambula e apresenta insuficiência respiratória. O estudo molecular, realizado na Thomas Jefferson University por Pan et al., revelou no primeiro, no gene COL6A1, mutação típica da miopatia de Bethlem, que tem curso benigno e herança autossômica dominante; e no segundo a primeira mutação de efeito dominante e do gene COL6A1, previamente associado apenas à miopatia de Bethlem. CONCLUSÃO: A miopatia de Bethlem deve constar no diagnóstico diferencial da DMC tipo Ullrich, mesmo na ausência das típicas contraturas dos dedos; pode existir sobreposição dos fenótipos Ullrich e Bethlem.

Background Clinicians are faced with unprecedented opportunities to identify the genetic aetiologies of hitherto molecularly uncharacterised conditions via the use of high-throughput sequencing. Access to genomic technology and resultant data is no longer limited to clinicians, geneticists and bioinformaticians, however; ongoing commercialisation gives patients themselves ever greater access to sequencing services. We report an increasingly common medical scenario by describing two neuromuscular patients—a mother and adult son— whose consumer access to whole-genome sequencing affected their diagnostic journey. Results Whole-genome sequencing initiated by the patients—to predict their risk of common diseases— revealed that they share several variants potentially relevant to neuromuscular diseases, which initially sidetracked diagnostic efforts. Since eventual clinical reassessment, including muscle imaging, pointed towards Bethlem myopathy, a collagen VI-related myopathy, we pursued Sanger sequencing of COL6A1, COL6A2 and COL6A3. This targeted approach revealed a heterozygous causative variant in COL6A3 (c.6365G>T (p.Gly2122Val)), shared by both individuals, that was not flagged by the interpretation of the whole-genome sequencing data. Conclusions This report highlights the essential interplay of clinical and genomic expertise in realising the potential of high-throughput sequencing. In an era when patients themselves may bring their own data to the table, definitively identifying clinically significant genomic variants will require close collaboration among clinicians, geneticists and bioinformaticians.

The classical phenotypes of collagen VI-associated myopathies are well described. Little is known, however, about the progression of patients at the mildest end of the clinical spectrum. In this report, we describe the clinical findings and the results of MRI, muscle biopsy, collagen VI expression in cultured skin fibroblasts and genetic tests of a series of patients with Bethlem myopathy. Our series highlights the existence of mild presentations of this disorder that progresses only slightly and can easily be overlooked. Analysis of the genetic studies suggests that missense mutations can be associated to a milder clinical presentation. Muscle MRI is extremely useful as it shows a pathognomonic pattern in most patients, especially those with some degree of muscle weakness.

The authors identified eight patients with Ullrich disease in whom collagen VI was present in the interstitium but was absent from the sarcolemma. By electron microscopy, collagen VI in the interstitium was never linked to the basal lamina. These findings suggest that in these patients it is not the total absence of collagen VI from the muscle but the failure of collagen VI to anchor the basal lamina to the interstitium that is the cause of Ullrich disease. Only one of the patients had a mutation in the collagen VI gene, suggesting that the primary abnormality in most of the patients involved some other molecules.

In this article, we review the molecular pathology of muscular dystrophies caused by defects of proteins located within or near cell membranes. These disorders include Bethlem myopathy, merosinopathy, dystrophinopathy, sarcoglycanopathies, integrinopathy, dysferlinopathy and caveolinopathy. We refer to these diseases collectively as sarcolemmopathy. Here, we describe the biological functions of these proteins in the context of muscular contractions and their roles in the infrastructure of muscle; defects of muscle infrastructures cause those diseases. As an example, in dystrophinopathy, cell membranes have mechanical defects due to the absence of dystrophin. Cracks of the cell membrane induced by muscle contraction may allow the influx and efflux of substances that trigger muscle cell degeneration. However, such cracks may be resealed on relaxation. In addition, dystrophinopathy causes secondary defects of various dystrophin-associated proteins suggesting that defects in cell signaling participate in the pathologic process. With regard to other sarcolemmopathies, we discuss pathological mechanisms based on available data.

The collagen VI-related myopathies comprise two major forms, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. Specific diagnosis requires molecular genetic testing showing mutation in one of the three genes involved. This review summarizes current treatments, in particular indication for physiotherapy, orthopedic treatment for correction of foot deformity, scoliosis, and flexion contractures of elbows, and treatment of respiratory failure. The turning point in basic research on collagen VI myopathies was the discovery of an unexpected mitochondrial dysfunction as a pathogenetic mechanism underlying the myopathic syndrome seen in Col6a1 null mice. Treatment of Col6a1(-/-) mice with cyclosporin A (CsA) rescued the mitochondrial dysfunction and decreased apoptosis. Similar mitochondrial defects were revealed in cultures of UCMD patients. The results of an open pilot trial with CsA in five patients with collagen VI-related myopathies are summarized and discussed. With the availability of new potential effective treatments, several challenges must be addressed in conducting trials in orphan diseases and in neuromuscular disorders in particular. Outcome measures are discussed in the context of the expected effect of the cure. Randomized clinical trials often are not feasible for rare diseases, and sometimes would be ethically inappropriate. The need to develop alternative outcome measures or biomarkers using platforms such as genomics and proteomics is stressed in this context.

Ullrich syndrome is a recessive congenital muscular dystrophy affecting connective tissue and muscle. The molecular basis is unknown. Reverse transcription–PCR amplification performed on RNA extracted from fibroblasts or muscle of three Ullrich patients followed by heteroduplex analysis displayed heteroduplexes in one of the three genes coding for collagen type VI (COL6). In patient A, we detected a homozygous insertion of a C leading to a premature termination codon in the triple-helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. In patient B, we found a deletion of 28 nucleotides because of an A → G substitution at nucleotide −2 of intron 17 causing the activation of a cryptic acceptor site inside exon 18. The second mutation was an exon skipping because of a G → A substitution at nucleotide −1 of intron 23. Both mutations are present in an affected brother. The first mutation is also present in the healthy mother, whereas the second mutation is carried by their healthy father. In patient C, we found only one mutation so far—the same deletion of 28 nucleotides found in patient B. In this case, it was a de novo mutation, as it is absent in her parents. mRNA and protein analysis of patient B showed very low amounts of COL6A2 mRNA and of COL6. A near total absence of COL6 was demonstrated by immunofluorescence in fibroblasts and muscle. Our results demonstrate that Ullrich syndrome is caused by recessive mutations leading to a severe reduction of COL6.

Background: Ullrich congenital muscular dystrophy (UCMD) is a form of merosin-positive congenital muscular dystrophy characterized by proximal contractures, distal laxity, rigidity of the spine, and respiratory complications. Recently, a deficiency of collagen VI on muscle and skin biopsy together with recessive mutations in the collagen 6A2 gene were reported in three families with UCMD. However, the clinical spectrum, frequency, and level of heterogeneity of this disorder are not known. Subjects and Methods: The authors studied 15 patients (aged 3 to 23.6 years) with a clinical diagnosis of UCMD. Linkage analysis to the three collagen VI genes was performed in all informative families (n = 7), whereas immunohistochemical analysis of collagen VI expression in muscle was performed in the remaining cases. Results: An immunocytochemical reduction of collagen VI was observed in six patients. Three of the six patients belonged to informative families, and haplotype analysis clearly suggested linkage to the COL6A1/2 locus in two cases and to the COL6A3 loci in the third case. In the remaining nine patients, primary collagen VI involvement was excluded based on either the linkage analysis (four families) or considered unlikely based on normal immunolabeling of collagen VI. Age and presentation at onset, the distribution and severity of weakness and contractures, and the frequency of nonambulant patients were similar in the patients with and without collagen VI involvement. Distal laxity, rigidity of the spine, scoliosis, failure to thrive, and early and severe respiratory impairment were found in all patients by the end of the first decade of life, irrespective of their maximum motor functional ability or their collagen status. Conclusions: These results suggest that collagen VI involvement is relatively common in UCMD (40%); however, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of this condition.