Welander distal myopathy – an overview

Neuromuscular Disorders 8 (1998) 115–118

Welander distal myopathy – an overview ˚ hlberg a,b, Maria Anvret b, Lars Edstro¨m a Kristian Borg a,*, Gabrielle A a

b

Department of Neurology, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm Sweden

Received 17 November 1997; revised version received 15 January 1998; accepted 28 January 1998

Abstract Welander distal myopathy has an autosomal dominant inheritance and a late onset. The onset of symptoms is in the hands and gradually distal muscles of the lower extremities are involved. The most-affected muscles are the long extensors of the hands and feet. CK-values are normal or slightly elevated. There is never any cardiac involvement in Welander distal myopathy. Neurophysiological findings are of both myopathic and neuropathic character. Histopathological findings in muscle biopsies are mainly of myopathic type and include rimmed vacuoles which correspond to autophagic vacuoles on the ultrastructural level. Tubulo-filamentous inclusions with a diameter of 16–21 nm, i.e. of the same type as found in patients with Inclusion Body Myositis, are found in the sarcoplasm and in myofibre nuclei. A neurogenic component in Welander distal myopathy has been suggested, on the grounds of a sensory dysfunction, neuropathic findings on neurophysiology and muscle biopsy and a decrease of A-j nerve fibres on sural nerve biopsy. Genetic analysis has excluded linkage to other defined distal myopathies and hereditary Inclusion Body Myopathy loci.  1998 Elsevier Science B.V. Keywords: Distal myopathy (Welander); Muscle biopsy; Nuclear inclusions; Cytoplasmic inclusions; Rimmed vacuoles; Electron microscopy; Molecular genetics

1. Introduction

2. Symptoms and clinical findings

In 1951 Welander [1] described a distal myopathy in 249 cases from 72 pedigrees with an autosomal dominant mode of inheritance and late onset. The disorder is considered the most common distal myopathy but is found almost only in Sweden [2]. On clinical grounds the disorder is clearly separated from other distal myopathies, i.e. distal myopathies described by Markesberry et al. [3], Nonaka et al. [4], the Finnish tibial muscle dystrophy [5] and Miyoshi myopathy [6]. In all these disorders, including Welander distal myopathy (WDM), rimmed vacuoles are prominent findings in muscle biopsies. This constitutes one similarity between these disorders and Inclusion Body Myositis (IBM) [7,8], an acquired inflammatory myopathy, and hereditary inclusion body myopathy (HIBM) as described by Argov and Yarom [8,9].

Onset of symptoms before the age of 30 was considered exceedingly rare, and onset before the age of 40 considered uncommon by Welander [1]. The onset is slow and when young and middle-aged relatives of patients with WDM were examined, clinical signs were found [10]. There is a prerequisite for a significant patient delay because of the mild symptoms and slow progression rate of symptoms. The first symptom is most often weakness of the thumb and/or index finger with clumsiness in small precision movements which spreads to the other fingers and results in an inability to extend the fingers. Gradually, a weakness of the distal parts of the lower extremities develops. The most-affected muscle is the anterior tibial muscle, leading to the inability to raise the toes and difficulty in standing on the heels, which results in walking difficulties and steppage gait. On clinical examination, weakness and muscle atrophy is found in small muscles of the hands and feet and the long extensor muscles of the arms and lower legs. Tendon

* Corresponding author. Department of Neurology, Karolinska Hospital, S-171 76 Stockholm.

0960-8966/98/$19.00  1998 Elsevier Science B.V. All rights reserved PII S0960-8966 (98 )0 0008-X

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reflexes are weak or absent. An effect on the posterior distal muscles of the lower extremities has been detected by means of magnetic resonance imaging (MRI) and muscle biopsy [11] but weakness of this muscle group is seldom reported or found on examination. In the original report by Welander [1] affection of proximal limb muscles was observed in a few cases. Recently, a variation of clinical findings including onset of symptoms in the feet and weakness of proximal muscles of the lower extremities have been found in one family [12]. There is no cardiac involvement and CK-values are normal or slightly elevated in WDM patients. A sensory dysfunction, most pronounced for thermal stimuli in the distal parts of upper and lower extremities was described by Borg et al. [13] and was also found to precede other symptoms and signs of muscle effect in early cases of WDM [14].

3. Neurophysiological findings Nerve-conduction velocities are normal in most of the patients. Slight abnormalities may be found in severe cases. EMG changes are complex and include small polyphasic motor-unit potentials, reduced interference pattern, giant motor-unit potentials and spontaneous activity, including pseudomyotonia, fibrillations and complex potentials [7]. The neurophysiological findings are, thus, of both myopathic and neurogenic character. In early cases, however, pure myopathic EMG changes were found [10]. There were no signs of dysfunction of the peripheral autonomic nerves when autonomic cardiovascular responses were studied [14]. However, the WDM patients showed an altered peripheral vasomotor response following peripheral vasoconstriction, probably due to a more predominant activation of a- than b-adrenergic receptors. Quantitative determination of somatosensory thresholds have revealed increased thermal and vibratory thresholds in WDM patients [13].

4. Muscle and nerve histopathology and ultrastructure Welander [1] described the histopathological changes in affected muscles as being typical of a primary myopathy and similar to other muscular dystrophies. However, abnormalities of neurogenic character are frequently found [2,10,11,15–19]. Light microscopic abnormalities consist of increased variation of muscle fibre diameters, centrallylocated nuclei, split fibres, group atrophy and scattered atrophic fibres of both type I and type II. The atrophic muscle fibres are mainly angulated, but rounded atrophic fibres are also found. Rimmed vacuoles are found in atrophic as well as in normal-sized muscle fibres (Fig. 1). They are abundant in muscle biopsies from patients with moderate and severe symptoms but were not found in muscle biopsies

from early cases [10]. In some cases, dystrophic features with fibrosis, fatty infiltrates and rounded atrophic muscle fibres are seen [12]. Inflammatory infiltrates are never seen in muscle biopsies from patients with WDM. Normal staining for dystrophin, spectrin and desmin in normal-sized muscle fibres has indicated a normal cytoskeletal structure [19]. However, an increased immunoreactivity was found for desmin, spectrin and Leu-19 (myoblast and satellite-cell related antigen) antibodies in atrophic muscle fibres. This staining pattern has earlier been seen in other neurogenic conditions [20] including patients with prior poliomyelitis [21], which suggests that these atrophic fibres are denervated. On electron microscopic examination, the rimmed vacuoles correspond to vacuoles containing membranous bodies with the appearance of dense bodies and myelin figures intermingled with collections of glycogen and amorphous material (Fig. 2), [7,17–19,22]. Tubulo-filamentous inclusions with a diameter of 16–21 nm are found in association with the vacuoles (Fig. 3). These filaments have the same size and shape as the ones described in IBM [7,8, 19,22–24]. More rarely, filamentous inclusions are found within myofibre nuclei [19,22]. Other ultrastructural abnormalities reported are fingerprint bodies, identical to those reported by Engel et al. [25] and Tome´ and Fardeau [26], and dense collections of Z-disc material or streaming, double Z-discs, honeycomb structures and abnormal mitochondria [7,17–19,22]. Sural nerve biopsy revealed a moderate loss of myelinated nerve fibres in two of five studied WDM cases [18]. The mean nerve fibre density was decreased and the mean nerve fibre area and circular diameter were increased, due to selective loss of small diameter (A-j) nerve fibres [18].

5. Molecular genetics The genetic location of the WDM trait is not yet known, nor is there any knowledge of an aberrant protein. In a genemapping project, that is now in the final analysing stage, several well-described families with WDM in subsequent generations have been investigated. Four families containing 71 subjects, 37 affected, were included in the study. All subjects had an autosomal dominant inheritance for the disease, showing weakness and wasting of the long extensor muscles of the fingers and the hands. To account for the late age of onset of the disease, asymptomatic individuals that were under the age of 30 years were not included in the study. Genomic DNA was extracted from peripheral blood white blood cells according to standard procedures. Individuals were genotyped using highly polymorphic microsatellites, amplified with polymerase chain reaction (PCR), separated by polyacrylamide gel electrophoresis and autoradiographed as described [27]. The Cooperative Human Linkage Center (CHLC) human screening set of microsa-

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Fig. 1. Cryostat cross-section of anterior tibial muscle stained with hematoxylin-eosin. A rimmed vacuole is seen in a slightly atrophic muscle fibre. Magnification is 600×. From [11] with permission.

tellite markers dispersed with an average spacing of 10 cM has been typed. Linkage analysis was performed as twopoint analysis with the MLINK program of the Linkage package, version 5.03 [28]. WDM was analysed as an autosomal dominant trait with complete penetrance, a gene frequency of 0.0001 and no new mutation rate. The chromosomal positions of the loci were estimated from the Ge´ne´thon linkage map [29]. Regarding specific regions of interest where other hereditary distal myopathies have been localised; the autosomal dominant late-onset distal myopathy described by Laing et al. [30] to chromosome 14q, and the autosomal recessive myopathy with rimmed vacuoles described originally by Nonaka et al. [4] and HIBM described by Argov and

Fig. 2. Electron microscope photograph of anterior tibial muscle showing an autophagic vacuole containing myelin bodies surrounded by normal myofilaments. Magnification is 7000×.

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Fig. 3. Electron microscope photograph of soleus muscle. An autophagic vacuole is shown surrounded by tubulo-filamentous inclusions and in the upper right corner normal myofilaments are seen. Magnification is 30 000×. From [19] with permission.

Yarom [9] to chromosome 9 [31,32]; these regions have clearly been excluded from linkage to WDM [33,34]. The Finnish tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late onset and a phenotype in several ways resembling WDM [5], furthermore the two disorders have geographical proximity. TMD has recently been mapped to chromosome 2q32 [35]. Regarding WDM, markers on chromosome 2q with linkage to TMD, are all entirely negative [34].

6. Discussion Welander distal myopathy is, on clinical, neurophysiological and morphological grounds, clearly separated from the other forms of distal myopathy and other muscle disorders characterised by rimmed vacuoles in muscle biopsies [2–6]. Rimmed vacuoles are found frequently and constitute a predominant change in muscle fibres from WDM patients. However, rimmed vacuoles and filamentous inclusions of the type described in IBM and HIBM are found in other conditions and are probably, as suggested by Dieler and Schro¨der [36], non-specific phenomena seen in degenerating muscle. Thus, they probably do not play a central role for the pathophysiology of WDM. Data from clinical, neurophysiological and muscle and nerve biopsy studies indicate a neurogenic component in WDM [10,11,13–19]. The sensory dysfunction has been shown to precede other effects of the disorder [10] and is therefore of value when diagnosing early cases. In a recent study, variability of the WDM phenotype was observed [12]. This indicates that WDM might be a heterogeneous disorder or that the clinical expression might be variable. The latter seems the more plausible explanation but this question will be finally answered by further genetic studies. Further genetic studies will also reveal the gene locus and gene product and shed further light on the pathophysiological events in Welander distal myopathy.

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Acknowledgements Supported by grants from the Swedish Medical Research Council (proj. 3875) and the Karolinska Institute.

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