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Objective: To discuss the importance of a thorough clinical examination and evaluation of symptoms in upper and lower motor neurone lesions., Design: Case report., Methods: Post-polio outpatient clinic, Danderyds University Hospital, Stockholm, Sweden. We describe here two patients with a past history of poliomyelitis, who were experiencing increasing muscular weakness. Clinical evaluation led to diagnoses of spinal cord injury and statin myopathy, respectively., Conclusion: In order to make a correct diagnosis it is essential to distinguish between lower and upper motor neurone lesions. In the case of a lower motor neurone disorder a neurophysiological examination is necessary for a correct diagnosis, and is a prerequisite for adequate treatment and rehabilitation.

In 2005 the commonality of sarcotubular myopathy (STM) and limb girdle muscular dystrophy type 2H (LGMD2H) was demonstrated, as both are caused by the p D487N missense mutation in TRIM32 originally found in the Manitoba Hutterite population. Recently, three novel homozygous TRIM32 mutations have been described in LGMD patients. Here we describe a three generation Swedish family clinically presenting with limb girdle muscular weakness and histological features of a microvacuolar myopathy. The two index patients were compound heterozygotes for a frameshift mutation in TRIM32 (c.1560delC ) and a 30 kb intragenic deletion, encompassing parts of intron 1 and the entire exon 2 of TRIM32. In these patients, no full-length or truncated TRIM32 could be detected. Interestingly, heterozygous family members carrying only one mutation showed mild clinical symptoms and vacuolar changes in muscle. In our family, the phenotype encompasses additionally a mild demyelinating polyneuropathic syndrome. Thus STM and LGMD2H are the result of loss of function mutations that can be either deletions or missense mutations.

Welander distal myopathy is a late onset disorder that is mainly seen in Sweden. It is linked to chromosome 2p13 and all Swedish patients show a common shared haplotype, indicating a founder mutation. Here we report the clinical manifestations, magnetic resonance imaging, pathophysiology and haplotype analysis of Welander patients in the Finnish population. The clinical examination of patients from 12 different families showed a distal myopathy with onset in the long extensor muscles of the hands and fingers, also seen in Swedish Welander patients. Muscle biopsies showed characteristic myopathic changes. Haplotype analysis with the five polymorphic markers that make up the common core haplotype, seen in the Swedish patients, revealed that this haplotype is also co-segregating in the Finnish patients and a common ancestry is therefore further supported for patients with Welander distal myopathy.

Welander distal myopathy (WDM) is an autosomal dominant myopathy with late-adult onset characterized by slow progression of distal muscle weakness. The disorder is considered a model disease for hereditary distal myopathies and is almost only seen in Sweden and some parts of Finland. A genomewide screening has been performed in initially two Swedish families with 400 highly polymorphic microsatellite markers. We report here that the disease is linked to chromosome 2p13. Seven additional nonrelated families have subsequently been mapped to the same area where a maximum two-point LOD score of 17.97 was obtained with the marker D2S2113 at 0.0 recombination fraction. The region has been restricted by recombinations and the finding of a common shared haplotype through all analyzed families. This restricts the gene locus region to 2.4 cM. These findings provide evidence for the involvement of a single locus for WDM. The WDM region overlaps with the linkage region for Miyoshi myopathy and limb-girdle muscular dystrophy 2B. The dysferlin gene responsible for these disorders is considered a primary candidate gene for WDM.

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-delta nerve fibres on sural nerve biopsy. Genetic analysis has excluded linkage to other defined distal myopathies and hereditary Inclusion Body Myopathy loci.

Welander distal myopathy (WDM) is an autosomal dominant disorder with late onset predominantly affecting distal extensor muscles of the hands and the feet. The disorder is considered as the most common of the distal myopathies but is almost only seen in Sweden and some parts of Finland. The finding of rimmed vacuoles in muscle biopsies from patients with moderate and severe symptoms constitutes one similarity with hereditary inclusion body myopathy (HIBM) sparing the quadriceps as described by Argov and Yarom [Argov Z, Yarom R. J Neurol Sci 1984;64:33-43]. The question has been raised whether some of the different forms of distal myopathy might be allelic. In previous reports the gene defects for HIBM and autosomal recessive hereditary distal myopathy with rimmed vacuoles (DMRV) have been mapped to chromosome 9pl-q1. The Finnish tibial muscular dystrophy (TMD) that displays similar histopathological findings has recently been linked to chromosome 2q. We have investigated the regions of interest with dispersed microsatellite markers in four well-described pedigrees, and this study now excludes the regions on chromosome 9pl-q1 and 2q from linkage to WDM both by haplotype analysis and linkage analysis with the MLINK program. WDM, showing morphological similarities with HIBM, is clearly separated from the disorders mapped to chromosomes 9 and 2 on clinical and genetical grounds.

Welander distal myopathy is an autosomal dominant disorder with late onset that affects extensor muscles of the hands and the feet. The disorder is considered as the most prevalent of the distal myopathies and is almost only seen in Sweden and in some parts of Finland. On clinical, morphological and genetical grounds the disorder is clearly separated from other distal myopathies. We have performed linkage analysis with the MLINK program in a total of six families with microsatellite markers dispersed throughout the genome and report exclusion for the localisation of the gene of 64% of the human genome. These studies have clearly separated Welander distal myopathy from previously mapped forms of distal myopathy such as the Miyoshi myopathy by excluding linkage to chromosome 2. The region on 14q that has been suggested to house the gene of the distal myopathy described by Laing et al. (Am J Hum Genet 1995;56:422-7), has as well been excluded by several markers.

Seven patients with Welander distal myopathy were subjected to magnetic resonance imaging (MRI) of the lower extremity, and muscle biopsies of the tibialis anterior, soleus and vastus lateralis muscles. MRI revealed abnormalities in both the anterior and posterior compartments of the lower leg in three of the patients, and in only the posterior compartment in the rest of the patients. No MRI abnormalities were found in either the proximal muscles of the leg or in the peroneal or posterior tibial muscle groups. Affected muscles had T1- and T2-values indicating a replacement of muscle fibres with fat tissue. Muscle biopsies showed pathological changes varying from slight to severe in tibialis anterior and soleus muscles in all patients. No muscle fibre abnormalities were seen in the vastus lateralis muscle in any of the patients. In accordance with earlier reports from patients with Welander distal myopathy, there was muscle degeneration of tibialis anterior muscles corresponding to the weakness of dorsal extension of the feet, but also degeneration in the muscles of the posterior compartment. The patients did not, however, show any clinical signs of weakness related to posterior muscle groups. There is no evidence of involvement of proximal muscles of the leg clinically, with MRI or in muscle biopsies.

In seven patients with long-standing and six patients with early symptoms of Welander distal myopathy (WDM), monoclonal antibodies directed against such cytoskeletal proteins as dystrophin, spectrin and desmin and against Leu-19, a myoblast and satellite cell related antigen, were applied to muscle biopsies from the anterior tibial and soleus muscles. In addition, ultrastructural studies were carried out on biopsies from the soleus muscle. In muscle fibres from patients with early symptoms there was normal immunostaining for dystrophin, spectrin, desmin and Leu-19. In the patients with long-standing symptoms, there was also a normal expression of dystrophin, and a normal staining for spectrin and desmin was found in normal sized muscle fibres. Occasionally normal sized muscle fibres showed staining for Leu-19. Increased staining for spectrin and desmin and a strong Leu-19 staining was seen in normal sized muscle fibres with rimmed vacuoles and in atrophic fibres. Increased staining for spectrin, desmin and Leu-19 has been described in denervated muscle fibres and, thus, the present findings may support earlier findings of a neurogenic component in Welander distal myopathy. In the soleus muscle, ultrastructural muscle fibre abnormalities conformed to those in the anterior tibial muscle. Many rimmed vacuoles were observed which corresponded, at the ultrastructural level, to autophagic vacuoles. Intranuclear and cytoplasmic filamentous inclusions of the same shape and diameter as in inclusion body myositis were observed.

Ultrastructural examination of anterior tibial muscle from four patients with late-onset autosomal dominant distal myopathy of Welander-type revealed intrasarcoplasmic filamentous inclusions in association with rimmed vacuoles. In one of the patients, identical intranuclear filamentous inclusions were also found. These filamentous inclusions are similar to those described in inclusion body myositis (IBM). They have also been observed in hereditary neuromuscular disorders including autosomal recessive distal myopathy. Thus, the filamentous inclusions occur in different neuromuscular conditions with different etiologies. These findings further raise the question of the specificity of the filamentous inclusions in IBM.

Autonomically mediated cardiovascular responses were evaluated in 9 patients with Welander distal myopathy and compared to data from an age- and sex-matched control group. The myopathy patients had a normal respiratory sinus arrhythmia and a normal heart rate response to the Valsalva menoeuvre, indicating a normal vagal function. They had a normal initial heart rate response to the orthostatic position, indicating a normal function of the sympathetic nerves. The main difference between the groups was found in the orthostatic position. The myopathy patients reacted with a greater increase in systolic blood pressure and a smaller heart rate increase than the controls. This suggests an altered peripheral vasomotor function, possibly with a more predominant activation of alfa than beta adrenergic receptors leading to vasoconstriction. In addition, a low forearm blood flow at rest and a les pronounced blood flow increase during the isometric handgrip were found in the myopathy patients. This finding could also be explained by proneness to vasoconstriction. It is concluded that patients with Welander distal myopathy have no signs of dysfunction of the peripheral autonomic nerves.