Distal myopathies – New genetic entities expand diagnostic challenge

doi:10.1016/j.nmd.2011.10.003

Neuromuscular Disorders

Volume 22, Issue 1, January 2012, Pages 5-12

https://doi.org/10.1016/j.nmd.2011.10.003 Get rights and content

Abstract

Distal myopathies are a group of muscle diseases which share the clinical pattern of predominant weakness in the feet and/or hands. Rapid advance in the understanding of underlying gene defects have to date separated more than 20 distinct disorders and many are yet without genetic characterisation. No definite diagnosis can be made on other grounds than identification of the final molecular genetic defect. Besides usual investigations including EMG and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imaging, the number of underlying candidate genes for a certain disease can be significantly reduced, which is of help for the molecular genetic approach.

Introduction

Four different distal myopathies had been clinically described before the new era of molecular genetics: autosomal dominant Welander distal myopathy (WDM) [1], recessive Miyoshi myopathy (MM) [2], [3], recessive Distal myopathy with rimmed vacuoles (Nonaka, DMRV) [4], and dominant Tibial muscular dystrophy (Udd, TMD) [5]. Comprehensive descriptions of a few single families also represented different entities: early adult onset dominant distal myopathy (Milhorat and Wolff) [6], late onset dominant distal myopathy (Markesbery–Griggs) [7]. Molecular genetics has proved these all being caused by different genes (Table 1).

The advance in molecular genetics started in the 1990s with linkage in an Australian family with early-onset autosomal dominant distal myopathy (MPD1) [8]. Others soon followed: MM [9], DMRV [10], TMD [11], and WDM [12]. Subsequently the responsible genes and mutations in encoded proteins were identified: dysferlin for MM in 1998 [13], desmin in the Milhorat family 1998 [14], C-terminal mutations in M-line titin as the cause of TMD in 2002 [15], mutations in GNE for DMRV the same year [16], mutations in slow myosin MYH7 for Laing myopathy 2004 [17], and ZASP mutations responsible for Markesbery–Griggs myopathy 2007 [18].

New distal myopathies have expanded the list of separate diseases by molecular genetics to more than 20 different entities. The extensive developments prompt for an updated classification of the distal myopathies and for differential diagnostic algorithms to help the clinician identify the genetically determined forms (Fig. 2A, Fig. 2B). In addition, distal muscle weakness and atrophy is frequently the presenting symptom and sign in other disorders, characterized and classified on other ground by different terms, which need to be considered in the differential diagnostic approach (Table 2).

Section snippets

Welander distal myopathy

Weakness typically starts in index finger and wrist extensors usually in the fifth–sixth decade, followed by atrophy of thenar and intrinsic hand muscles. Finger and wrist flexors and weakness in toe and ankle extensors may develop after several years, although some patients have onset of weakness in the lower leg muscles. Some sensory involvement because patients may complain of cold fingers have been suggested but neuropathy has not been confirmed [19]. The progression is slow and patients

Management

The final genetic diagnosis is necessary to avoid wrong treatments due to erroneous diagnosis (Fig. 2A, Fig. 2B). In desminopathy associated cardiomyopathy and respiratory muscle involvement needs correct monitoring. In the case of VCP mutated distal myopathy Paget disease cannot be excluded even if it was not present in the primary distal myopathy family, and late dementia is a lethal complication. In the milder late onset forms orthoses are commonly used for stabilization of wrists, fingers,

References (60)

I. Nonaka et al.
Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation
J Neurol Sci
(1981)
H. Haravuori et al.
Assignment of the tibial muscular dystrophy (TMD) locus on chromosome 2q31
Am J Hum Genet
(1998)
P. Hackman et al.
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin
Am J Hum Genet
(2002)
C. Meredith et al.
Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1)
Am J Hum Genet
(2004)
K. Borg et al.
Welander distal myopathy: an overview
Neuromuscul Disord
(1998)
G. Ahlberg et al.
Distribution of muscle degeneration in Welander distal myopathy: a magnetic resonance imaging and muscle biopsy study
Neuromuscul Disord
(1994)
P. Hackman et al.
Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD)
Neuromusc Disord
(2008)
I. Penisson-Besnier et al.
Autosomal dominant late adult onset distal leg myopathy
Neuromuscul Disord
(1998)
I. Penisson-Besnier et al.
Myotilinopathy in a family with late onset myopathy
Neuromuscul Disord
(2006)
K. Claeys et al.
Electron microscopy in myofibrillar myopathies reveals clues to the mutated gene
Neuromusc Disord
(2008)

J. Senderek et al.

Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3

Am J Hum Genet

(2009)

M. Walter et al.

Identification of a desmin gene mutation in scapuloperoneal syndrome type Kaeser

Neuromusc Disord

(2006)

R. Duff et al.

Mutations in the N-terminal actin-binding domain of filamin C (FLNC) cause a distinct distal myopathy

Am J Hum Genet

(2011)

V. Bolduc et al.

Recessive mutations in the putative calcium-activated chloride channel anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies

Am J Hum Genet

(2010)

K.J. Felice et al.

Autosomal dominant distal myopathy not linked to the known distal myopathy loci

Neuromuscul Disord

(1999)

H. Haravuori et al.

Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)

Neuromusc Disord

(2004)

W.H. Linssen et al.

Genetic heterogeneity in Miyoshi-type distal muscular dystrophy

Neuromuscul Disord

(1998)

B. Udd

165th ENMC International Workshop: distal myopathies III

Neuromusc Disord

(2009)

L. Welander

Myopathia distalis tarda hereditaria

Acta Med Scand

(1951)

K. Miyoshi et al.

Autosomal recessive distal muscular dystrophy: a new variety of distal muscular dystrophy predominantly seen in Japan

Nippon Rinsho (Tokyo)

(1977)

K. Miyoshi et al.

Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy

Brain

(1986)

B. Udd et al.

Tibial muscular dystrophy: late adult-onset distal myopathy in 66 Finnish patients

Arch Neurol

(1993)

A.T. Milhorat et al.

Studies in diseases of muscle XIII: progressive muscular dystrophy of atrophic distal type; report of a family; report of autopsy

Arch Neurol Psychiatry

(1943)

W.R. Markesbery et al.

Late onset hereditary distal myopathy

Neurology

(1974)

N.G. Laing et al.

Autosomal dominant distal myopathy: linkage to chromosome 14

Am J Hum Genet

(1995)

K. Bejaoui et al.

Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12–14

Neurology

(1995)

T. Asaka et al.

Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

Ann Neurol

(1997)

G. Ahlberg et al.

Genetic linkage of Welander distal myopathy to chromosome 2p13

Ann Neurol

(1999)

J. Liu et al.

Dysferlin, a novel skeletal muscle gene, is mutation in Miyoshi myopathy and limb girdle muscular dystrophy

Nat Genet

(1998)

G. Sjöberg et al.

A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation

Hum Mol Genet

(1999)

Cited by (91)

Muscle “islands”: An MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness
2022, Neuromuscular Disorders
Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n = 24) or clinically (n = 13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy. An initial exploratory phase reviewed 11 scans from genetically confirmed patients identifying a single potential discriminatory marker concerning the pattern of fat replacement within muscle, coined “islands”. This pattern comprised small areas of muscle tissue with normal signal intensity completely surrounded by areas with similar intensity to subcutaneous fat. In the subsequent validation phase, islands correctly classified scans from all 12 remaining genetically confirmed patients, and 12/13 clinically classified patients. In the genetically confirmed patients MRI classification of neurogenic/myopathic aetiology had 100% accuracy (24/24) compared with 65% accuracy (15/23) for EMG, and 79% accuracy (15/19) for muscle biopsy. Future studies are needed in other clinical contexts, however the presence of islands appears to highly suggestive of a neurogenic aetiology in patients presenting with early onset distal motor weakness.
Cutaneous T-cell lymphoma mimicking myopathy with lipoatrophy
2022, Neuromuscular Disorders
Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphoma. Classic MF usually follows a rather benign course over many years or decades, rarely ever leading to fatal extracutaneous organ involvement. Single cases of muscular involvement have been reported. Here we describe a 42-year-old male patient with hair loss and lipoatrophy since six months diagnosed as follicular MF and with a two months history of progressive distal leg weakness. Muscle biopsy and whole body muscle MRI showed an extensive muscular and subcutaneous fatty tissue infiltration. After therapy with topical steroids and acitretin/PUVA, systemic chemotherapy (CHOP) was initiated. The patient suffered from a rapid disease progression with fatal outcome 2.5 years after the first skin lesions, displaying progressive cachexia, muscular atrophy and weakness with scapuloperoneal distribution and cardiac dysfunction. So far, extensive muscular involvement by MF mimicking a distinct muscular phenotype has not been reported.
TTN missense variants in two siblings with asymmetric facial and limb weakness
2020, Journal of the Neurological Sciences
Distal Myopathies
2020, Neurologic Clinics
Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients
2020, Autoimmunity Reviews
Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported.
We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10–14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24–73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31–237 months). IM was suspected by CK elevation in all patients (ranging 800–3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.
Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre
2019, Neuromuscular Disorders
Diagnosis of inherited myopathies can be a challenging and lengthy process due to broad genetic and phenotypic heterogeneity. In this study we applied focused exome sequencing to investigate a cohort of 100 complex adult myopathy cases who remained undiagnosed despite extensive investigation. We evaluated the frequency of genetic diagnoses, clinical and pathological factors most likely to be associated with a positive diagnosis, clinical pitfalls and new phenotypic insights that could help to guide future clinical practice. We identified pathogenic/likely pathogenic variants in 32/100 cases. TTN-related myopathy was the most common diagnosis (4/32 cases) but the majority of positive diagnoses related to a single gene each. Childhood onset of symptoms was more likely to be associated with a positive diagnosis. Atypical and new clinico-pathological phenotypes with diagnostic pitfalls were identified. These include the new emerging group of neuromyopathy genes (HSPB1, BICD2) and atypical biopsy findings: COL6A-related myopathy with mitochondrial features, DOK7 presenting as myopathy with minicores and DES-related myopathy without myofibrillar pathology. Our data demonstrates the diagnostic efficacy of broad NGS screening when combined with detailed clinico-pathological phenotyping in a complex neuromuscular cohort. Atypical clinico-pathological features may delay the diagnostic process if smaller targeted gene panels are used.

View all citing articles on Scopus

View full text

ReviewDistal myopathies – New genetic entities expand diagnostic challenge

Abstract

Introduction

Section snippets

Welander distal myopathy

Management

J Neurol Sci

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Neuromuscul Disord

Neuromuscul Disord

Neuromusc Disord

Neuromuscul Disord

Neuromuscul Disord

Neuromusc Disord

Am J Hum Genet

Neuromusc Disord

Am J Hum Genet

Am J Hum Genet

Neuromuscul Disord

Neuromusc Disord

Neuromuscul Disord

Neuromusc Disord

Myopathia distalis tarda hereditaria

Acta Med Scand

Autosomal recessive distal muscular dystrophy: a new variety of distal muscular dystrophy predominantly seen in Japan

Nippon Rinsho (Tokyo)

Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy

Brain

Tibial muscular dystrophy: late adult-onset distal myopathy in 66 Finnish patients

Arch Neurol

Studies in diseases of muscle XIII: progressive muscular dystrophy of atrophic distal type; report of a family; report of autopsy

Arch Neurol Psychiatry

Late onset hereditary distal myopathy

Neurology

Autosomal dominant distal myopathy: linkage to chromosome 14

Am J Hum Genet

Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12–14

Neurology

Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

Ann Neurol

Genetic linkage of Welander distal myopathy to chromosome 2p13

Ann Neurol

Dysferlin, a novel skeletal muscle gene, is mutation in Miyoshi myopathy and limb girdle muscular dystrophy

Nat Genet

A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation

Hum Mol Genet

Review
Distal myopathies – New genetic entities expand diagnostic challenge