Ullrich congenital muscular dystrophy and bethlem myopathy: clinical and genetic heterogeneity

Abstract

-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 observ e d . 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 diff e rent: 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 stud y, perf o rmed 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 inheri t a n c e . Conclusion: Bethlem myopathy should be considered in the diff e rential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.KEY WORDS: Ullrich congenital muscular dystrophy, congenital muscular dystrophy, joint hyperlaxity, collagen VI, Bethlem myopathy. D i s t rofia muscular congênita com hiperextensibilidade articular distal (Ullrich) e miopatia de Bethlem: heterogeneidade clínica e genética RESUMO -A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) a ssocia-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso pro g ressivo, ocasionalmente mostrando menor gravidade. Objetivo: Av a l i a r o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente d o colágeno VI na biópsia muscular. Resultados: E n t re 60 pacientes com DMC, dois mostravam imunomarc ação 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. C o n c l u s ã o : 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.PA L AV R A S -C H AVE: distrofia muscular congênita; hiperextensibilidade art i c u l a r, colágeno VI, fenótipo Ullrich, miopatia de Bethlem.

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…In 2003, the first heterozygous in-frame deletions acting in a dominantly-negative way was found in the Col6A1 gene 75 in one Brazilian patient with severe Ullrich phenotype 131 ; soon, more patients with a dominantly acting mutation in the Col6A1 were reported [132][133][134] , and finally this same type of mutation has also been found in Ullrich patients with mutations in Col6A2 and Col6A3 genes 132 . heterozygously occurring N-terminal triple helical inframe deletions allow mutant monomers to form dimers but secreted tetramers are abnormal with a consequent dominant negative effect on microfibrillar assembly 132 .…”

“…The concept of a spectrum of collagen VI-related disorders with marked clinical and genetic heterogeneity has emerged from the recent advances on the molecular mechanism of both diseases 69 . The complex genotype/phenotype correlations that have been broadly analysed in these two conditions clearly indicate that in both collagen VI-related disorders the main pathomechanism is due to the disruption of collagen VI anchorage to the basal lamina of the muscular fibers 74,75,[120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138] .…”

Position of Glycine Substitutions in the Triple Helix ofCOL6A1,COL6A2, andCOL6A3is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies

“…Genotype/phenotype associations in the collagen VI myopathies have been difficult to assess due to the considerable clinical and genetic heterogeneity, including presentations of UCMD, BM, and INT phenotypes in patients with similar mutations [Baker et al., ; ; Brinas et al., ; Lampe et al., ; Reed et al., ]. Missense mutations involving the conserved glycine residue in the repeated Gly‐X‐Y motif in the TH domain are a common pathogenic mutation in both collagen VI myopathies and in disorders of other collagens.…”

“…Size of the globular N-and C-terminal domains and the length of the TH domain are proportional to size estimations proposed by Beecher et al (2011Beecher et al ( ). 2007Brinas et al, 2010;Reed et al, 2005]. Missense mutations involving the conserved glycine residue in the repeated Gly-X-Y motif in the TH domain are a common pathogenic mutation in both collagen VI myopathies and in disorders of other collagens.…”

Juvenile polymyositis or paediatric muscular dystrophy: a detailed re‐analysis of 13 cases

“…However, prominent inflammatory infiltrates are also common in facioscapulohumeral dystrophy (FSHD) and dysferlinopathies. 5,[11][12][13] Histological specimens from patients with MD may be morphologically indistinguishable from those of polymyositis. 8 Pathological studies of JPM are limited and there are no studies describing immunopathological features, such as expression of the major histocompatibility class I and II antigens (MHC-I, MHC-II) or CD4+ ⁄ CD8+ lymphocyte expression pattern in JPM.…”