Collagen VI involvement in Ullrich syndrome: A clinical, genetic, and immunohistochemical study

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.

[1]  J. Aicardi,et al.  Ullrich's congenital atonic sclerotic muscular dystrophy , 1989, Journal of Neurology.

[2]  K. Arimura,et al.  Frameshift mutation in the collagen VI gene causes Ullrich's disease , 2001, Annals of neurology.

[3]  E. Bertini,et al.  Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Arai,et al.  Cathepsin D polymorphism not associated with Alzheimer's disease in Japanese , 2001, Annals of neurology.

[5]  M. Speer,et al.  CA Repeat Polymorphism of theCOL6A3 Gene on Chromosome 2 q37 , 1998, Human Heredity.

[6]  T. Voit,et al.  Congenital muscular dystrophies: 1997 update , 1998, Brain and Development.

[7]  B. Saitta,et al.  Identification of a polymorphic CA repeat in the COL6A2 gene on human chromosome 21q22.3. , 1996, Human heredity.

[8]  J. Harpey,et al.  [Congenital muscular dystrophy with merosin deficiency: clinical, histopathological, immunocytochemical and genetic analysis]. , 1996, Revue neurologique.

[9]  L. Santoro,et al.  A new case of Ullrich's disease. , 1989, Clinical neuropathology.

[10]  G. Serratrice,et al.  [A forgotten muscular dystrophy: Ullrich's disease]. , 1983, Revue neurologique.

[11]  I. Nonaka,et al.  A clinical and histological study of Ullrich's disease (congenital atonic-sclerotic muscular dystrophy). , 1981, Neuropediatrics.

[12]  Kenji Nihei,et al.  A case of Ullrich's disease Kongenitale, atonisch-sklerotische muskeldystrophie , 1979, Brain and Development.