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  • Updated 09.01.2023
  • Released 12.19.1994
  • Expires For CME 09.01.2026

Distal myopathies



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 authors provide an updated classification of distal myopathies and discuss the genetically identified forms along with new genetic mutations that have been associated with distal myopathy.

Key points

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

• Distal myopathies are a group of rare heterogenous disorders that represent 10% of all muscular dystrophies.

• Muscle imaging is an adjunct diagnostic tool for targeting optimal sites for muscle biopsy and possibly 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 (26). 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 (85). 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, four 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 (55); (2) autosomal recessive Miyoshi myopathy with early adult onset in the calf muscles (59); (3) autosomal-recessive distal myopathy with rimmed vacuoles, described by Nonaka and colleagues, with early adult onset in the anterior lower leg muscles (65); and (4) late-onset autosomal-dominant tibial muscular dystrophy (Udd myopathy) with lower-leg anterior compartment involvement (93).

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) (46), and the others soon followed: Miyoshi myopathy (04), distal myopathy with rimmed vacuoles (36), tibial muscular dystrophy (33), and Welander distal myopathy (02). The responsible gene encoding dysferlin was identified for Miyoshi myopathy in 1998 (52), mutations in M-line titin were identified as the cause of tibial muscular dystrophy in 2002 (29), and mutations in GNE were found in distal myopathy with rimmed vacuoles in the same year (63).

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 (27). 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 (101)
(b) Tibial muscular dystrophy (Udd myopathy) (93)
(c) Distal myotilinopathy (71)
(d) ZASPopathy (Markesbery-Griggs) (27)
(e) Matrin3 distal myopathy (VCPDM, MPD2) (83)
(f) Valosin-containing protein-mutated distal myopathy (68)
(g) Alpha-B crystallin-mutated distal myopathy (77)
(h) Sequestosome1 (SQSTM1) distal myopathy (09)

(2) Adult-onset autosomal dominant forms

(a) Desminopathy (85)
(b) Distal ABD-filaminopathy (16)
(c) Distal filaminopathy with onset in hands (28)
(d) Finnish-MPD3 (53)
(e) Italian 19p13-linked distal myopathy (84)
(f) U.S.-Polish family (20)
(g) Oculopharyngeal distal myopathy, OPDM (17)
(h) DNAJB6 distal myopathy (79)
(i) HSPB8 distal myopathy (25)
(j) ACTN2 distal myopathy (10)
(k) TPM3 mutated distal myopathy (11)
(l) CASQ1 mutated distal myopathy (104)

(3) Early-onset autosomal dominant forms

(a) Myosinopathy MYH7 (MPD1) (46)
(b) KHLH9 mutated distal myopathy (12)
(c) POLG1 mutated distal myopathy (74)
(d) BICD2 mutated distal myopathy (95)
(e) RYR1 distal myopathy variant (48)
(f) Collagen XII mutated distal myopathy but can present in 4th decade (61)
(g) TPM3 mutated distal myopathy (37)

(4) Early-onset autosomal recessive forms

(a) Distal nebulin myopathy (99)
(b) Distal nemaline myopathy (49)
(c) ADSSL1 distal myopathy (69)

(5) Early adult-onset autosomal recessive forms

(a) Dysferlinopathy (59)
(b) Distal anoctaminopathy (ANO5) (07)
(c) Distal myopathy with rimmed vacuoles (65)
(d) Oculopharyngeal distal myopathy, OPDM (17)

(6) Adult-onset autosomal recessive form

(a) Miyoshi-like non-DYSF/ANO5 (50)
(b) Telethonin-related distal myopathy (06)

(7) X-linked distal myopathy

(a) Small muscle protein X (SMPX)-linked distal myopathy (42)

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