Distal myopathies

Bjarne Udd MD PhD (Dr. Udd of the University of Helsinki and the University Hospital of Tampere has no relevant financial relationships to disclose.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released December 19, 1994; last updated September 24, 2014; expires September 24, 2017

This article includes discussion of distal myopathies, distal titinopathy, tibial muscular dystrophy, TMD, and Udd myopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The distal myopathies are an expanding group of muscle diseases with the uncharacteristic pattern of predominant weakness in the feet or hands. Rapid advances in our understanding of the underlying gene defects of these myopathies have, to date, separated more than 20 distinct disorders, and many are yet without characterization. In this article, the author provides an updated classification of the distal myopathies and discusses the genetically identified forms. In this recent update, the author has added discussion of the long-awaited gene causing Welander distal myopathy, as well as POLG1 mutations also causing significant distal myopathy.

Key points

 

• Distal myopathies are still frequently confused with Charcot-Marie-Tooth types of neurogenic disorders.

 

• Muscle imaging is an important diagnostic tool for targeting optimal sites for muscle biopsy and for suggesting diagnostic alternatives.

 

• Many genetic forms are late-onset, such that a positive inheritance may be missed.

 

• Many underlying gene defects occur as “de novo” mutations with negative family history.

Historical note and terminology

Distal myopathy as a clinical term is usually credited to Gowers, who in 1902 described distal weakness in a young man, most likely a case of juvenile onset recessive oculopharyngeal distal myopathy (Gowers 1902). However, the term had been used earlier by others, and the first family with a dominant distal myopathy may have been described by the Russian neurologist V Roth in his book on muscular atrophies in 1893. Subsequently, a number of cases were reported as having distal myopathy, but only the family described in 1943 by Milhorat and Wolff was ever confirmed to have a distal myopathy when a mutation in the desmin gene was later identified (Sjoberg et al 1999). The disease described by Welander in 1951 was long the prototype of distal myopathy. She described 249 patients from 72 Swedish pedigrees under the title of “myopathia distalis tarda hereditaria” (Welander distal myopathy) with onset in the hands. Between 1974 and 1993, 4 new entities were clinically defined: (1) late-onset distal myopathy of the lower leg with autosomal-dominant inheritance described by Markesbery and colleagues in 1974 (Markesbery et al 1974); (2) autosomal recessive Miyoshi myopathy with early adult onset in the calf muscles (Miyoshi et al 1977); (3) autosomal-recessive distal myopathy with rimmed vacuoles, described by Nonaka and colleagues, with early adult onset in the anterior lower leg muscles (Nonaka et al 1981); and (4) late-onset autosomal-dominant tibial muscular dystrophy (Udd myopathy) with lower-leg anterior compartment involvement (Udd et al 1993).

A new era for the distal myopathies began with the progress of molecular genetics in the 1990s. The first disorder linked to a chromosomal locus was that of an Australian family with dominant early-onset distal myopathy (MPD1) (Laing et al 1995), and the others soon followed: Miyoshi myopathy (Bejaoui et al 1995), distal myopathy with rimmed vacuoles (Ikeuchi et al 1997), tibial muscular dystrophy (Haravuori et al 1998), and Welander distal myopathy (Ahlberg et al 1999). The responsible gene encoding dysferlin was identified for Miyoshi myopathy in 1998 (Liu et al 1998), mutations in M-line titin were identified as the cause of tibial muscular dystrophy in 2002 (Hackman et al 2002), and mutations in GNE were found in distal myopathy with rimmed vacuoles in the same year (Nishino et al 2002).

Distal muscle weakness and atrophy is frequently the presenting symptom and sign in myopathies otherwise characterized by the histopathological findings of myofibrillar myopathy, including accumulations of desmin and other proteins. This is particularly true for gene defects in ZASP, myotilin, and desmin. In fact, ZASP proved to be the responsible gene in the classic late-onset distal myopathy family reported by Markesbery (Griggs et al 2007). During the last decade, a number of new entities of distal myopathy have been delineated by molecular genetic definition, making all previous classifications obsolete. However, from a clinical and diagnostic perspective, to narrow the field of gene candidates a broad separation in groups based on genetic transmission and age of onset is still meaningful:

 

(1) Late adult onset autosomal dominant forms

 

(a) Welander distal myopathy (Welander 1951)

(b) Tibial muscular dystrophy (Udd myopathy) (Udd et al 1993)

(c) Distal myotilinopathy (Penisson-Besnier et al 2006)

(d) ZASPopathy (Markesbery-Griggs) (Griggs et al 2007)

(e) Matrin3 distal myopathy (VCPDM, MPD2) (Senderek et al 2009)

(f) Valosin-containing, protein-mutated distal myopathy (Palmio et al 2011)

(g) Alpha-B crystallin-mutated distal myopathy (Reilich et al 2010)

(2) Adult-onset autosomal dominant forms

 

(a) Desminopathy (Sjoberg et al 1999)

(b) Distal ABD-filaminopathy (Duff et al 2011)

(c) Distal filaminopathy with onset in hands (Guergueltcheva et al 2011)

(d) Finnish-MPD3 (Mahjneh et al 2003)

(e) Italian 19p13-linked distal myopathy (Servidei et al 1999)

(f) U.S.-Polish family (Felice et al 1999)

 

(g) Oculopharyngeal distal myopathy, OPDM (Durmus et al 2011)

(3) Early-onset autosomal dominant forms

 

(a) Myosinopathy MYH7 (MPD1) (Laing et al 1995)

 

(b) KHLH9 mutated distal myopathy (Cirak et al 2010)

 

(c) POLG1 mutated distal myopathy (Pitceathly et al 2013)

(4) Early-onset autosomal recessive forms

 

(a) Distal nebulin myopathy (Wallgren-Pettersson et al 2007)

 

(b) Distal nemaline myopathy (Lehtokari et al 2011)

(5) Early adult onset autosomal recessive forms

 

(a) Dysferlinopathy (Miyoshi 1977)

(b) Distal anoctaminopathy (Bolduc et al 2010)

(c) Distal myopathy with rimmed vacuoles (Nonaka et al 1981)

 

(d) Oculopharyngeal distal myopathy, OPDM (Durmus et al 2011)

(6) Adult-onset autosomal recessive form

 

(a) Miyoshi-like non-DYSF/ANO5 (Linssen et al 1998)

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