Progressive skeletal myopathy,a phenotypic variant of desmin myopathy associated with desmin mutations

Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.     

An adult onset metachromatic leukodystrophy with dominant inheritance and normal arylsulphatase A levels

A family with a variant of adult onset metachromatic leukodystrophy is presented. Clinical details from three affected members are given. The neurophysiological and neuroradiological data on the two brothers who have been recently studied are included. One of these died and the post-mortem findings are discussed along with those from a cousin who died some years ago. Arylsulphatase A levels were normal in both brothers yet the histological findings in the one who died are of a metachromatic leukodystrophy and thin-layer chromatography confirms an excess of sulphatides in the white matter of his brain. Disabling hypotension was a striking feature in both brothers but adrenal function was shown to be intact and autonomic neuropathy seemed the likely cause. Study of the family suggests a dominant mode of inheritance.     

Syncoilin accumulation in two patients with desmin-related myopathy

We have recently shown that syncoilin interacts with desmin in skeletal muscle and has a role in attaching and organising desmin filaments to the Z-lines. We have analysed patients with desmin accumulation and have found that syncoilin is both upregulated at the sarcolemma and aggregates with desmin indicating the presence of two distinct protein populations. Additional dystrophin-associated protein complex components also accumulate. The striking finding was that alpha-dystrobrevin-1 and neuronal nitric oxide synthase (nNOS) are almost completely lost from the membrane of these patients indicating that the myopathy may result from both the abnormal accumulation of proteins and an increase in ischaemic injury due to the loss of nNOS. We speculate that the loss of alpha-dystrobrevin from the membrane, and subsequent loss of nNOS, is due to the alpha-dystrobrevin-syncoilin-desmin interaction.     

Congenital myopathy associated with abnormal accumulation of desmin and dystrophin.

We studied a 5-yr-old boy clinically presenting congenital myopathy. Muscle biopsy showed sarcoplasmic accumulation of desmin filaments leading to diagnosis of desmin storage myopathy. An immunohistochemical study of other cytoskeletal proteins (actin, alpha-actinin, vimentin and dystrophin) was performed. Desmin positive areas reacted strongly with anti-mid-rod and C-terminus dystrophin antibodies. Probed with the same antibodies by Western blot, desmin and dystrophin showed normal molecular size but densitometric analysis demonstrated a parallel increase of both proteins. Our results indicate that intrasarcoplasmic desmin storage is associated with an abnormal accumulation of dystrophin. Since no other cytoskeletal proteins are accumulated this finding seems to be specific and suggests a possible structural and functional association between these two proteins in striated muscle.     

X-linked muscular dystrophy

X-linked muscular dystrophy has been separated into two types that are generally considered to be distinct entities. We have investigated three families with X-linked muscular dystrophy who demonstrate remarkable intrafamilial variability. In one family 2 brothers with a benign type had a maternal uncle who was affected with the Duchenne type. In another family, 4 members had the benign type but a fifth was much more severely affected than in the classic Duchenne dystrophy; therefore the presence of an "aggressive form" is proposed. A third family also had both benign and severe types. A search of the literature revealed families in which the severe and benign types coexisted. The genetic determinants of this heterogeneity are not yet known. Clinical similarities between benign and severe types of X-linked muscular dystrophy and the presence of families with both types suggest that the two are intimately related.     

Evidence of familial nature of male homosexuality

We recruited 51 predominantly homosexual and 50 predominantly heterosexual men as index subjects for a family study of sexual orientation. The sexual orientation of siblings (115 sisters and 123 brothers) was ascertained in two ways: via interview with the index subjects and via interview of and/or mailed questionnaire to the siblings themselves. Index subjects' knowledge of the sexual orientation of their siblings was, for the most part, quite accurate. Moreover, heterosexual index men had about as many homosexual brothers as would be predicted given national prevalence figures for homosexuality, but homosexual index men had about four times as many homosexual brothers, although in both cases most brothers were heterosexual. There was no significant difference between the index groups in number of homosexual sisters. We conclude that there is a significant familial component to male homosexuality.     

Recurrent cerebral infarctions in two brothers with antiphospholipid antibodies that block coagulation reactions

Inhibitors blocking coagulation reactions, often called lupus anticoagulants, are readily identifiable but rarely considered as risk factors for cerebral infarction. These inhibitors are inconsistently found in a number of diseases (often autoimmune) and after treatment with ceretain drugs and appear to be closely associated with, or identical to, antibodies to certain phospholipids. We have observed two brothers with these inhibitors who both experienced recurrent cerebral infarctions. Such familial occurrence has rarely been reported. In addition, some other family members were found to have depressed factor XII levels. Using the technique of double immunodiffusion, we found that the serum from these brothers formed precipitin lines against certain phospholipid substrates, lending further support to the antiphospholipid nature of this inhibitor.     

Intracranial arteriovenous malformations in two brothers with myotonic dystrophy.

We describe two brothers with myotonic muscular dystrophy and intracranial arteriovenous malformations who developed acute vascular neurological syndromes. The simultaneous occurrence of these two disorders in brothers could either be due to chance association, or due to a common causative mechanism, possibly a membrane abnormality.     

Familial desmin myopathies and cytoplasmic body myopathies

Clinicopathological, immunohistochemical and biochemical studies were performed on seven patients from five families showing an abnormal accumulation of desmin in the muscle fibers. Late onset myopathy was observed in all the cases studied. The clinical features were heterogeneous and usually nonspecific. However, some patients presented with dysphonia, dysphagia or cardiomyopathy. These features are highly suggestive of desmin myopathy. Using electron microscopy, desmin myopathy is characterized by an accumulation of granulofilamentous material. Depending on the distribution of the material, however, three different patterns of desmin accumulation can be observed: (1) large circumscribed inclusions, (2) intermyofibrillar areas of diffusely distributed material, and (3) deposits around large spheroid bodies. The second pattern is characterized by a rubbed-out appearance using oxidative enzyme reactions. For all the patients studied here, the immunohistochemical data showed that the desmin accumulation fitted these three patterns of distribution. For six patients, immunoblot analysis confirmed the desmin accumulation patterns and showed that an increase in the expression of the 53-kDa protein had occurred. The third pattern of desmin accumulation confirms the pathological heterogeneity of cytoplasmic and spheroid bodies. Desmin does not accumulate in all cytoplasmic and spheroid body myopathies, as observed in two other familial cases presented here. Received: 19 February 1996 / Revised, accepted: 30 May 1996     

Choreo-acanthocytosis

This is the first report from India of a family of 4 sisters and 3 brothers in whom the proband showed a complete form of the choreo-acanthocytosis syndrome, whereas the 2 brothers who had died earlier of this disease had no examination of their blood. The apparently healthy members of this family also showed acanthocytosis, suggesting that this is a multisystem disorder affecting cell membranes.     

Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine

PRRT2 is the gene recently associated with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, and choreoathetosis infantile convulsions. We report four family members with PRRT2 mutations who had heterogeneous paroxysmal disorders. The index patient had transient infantile paroxysmal torticollis, then benign infantile epilepsy that responded to carbamazepine. The index patient's father had PKD and migraine with aphasia, and his two brothers had hemiplegic migraine with onset in childhood. All four family members had the same PRRT2 c.649dupC mutation. We conclude that heterogeneous paroxysmal disorders are associated with PRRT2 mutations and include paroxysmal torticollis and hemiplegic migraine. We propose that PRRT2 is a new gene for hemiplegic migraine.     

Alternating hemiplegia of childhood: a syndrome inherited with an autosomal dominant trait

Alternating hemiplegia of childhood is a rare disorder characterized by recurrent attacks of hemiplegia affecting either side of the body, oculomotor and autonomic disturbances, movement disorders, and progressive cognitive impairment. We report on one family with autosomal dominant alternating hemiplegia. The disorder was first recognized in a 9-year-old child, the third son of the family, who presented with learning disability, tonic-clonic seizures, dystonic attacks, and episodes of alternating hemiplegia starting at the age of 2 1/2 years. His mother and three brothers had similar symptoms. The maternal uncle, who has learning disability, had experienced multiple dystonic attacks. Tests performed on the family, including computerized tomography, magnetic resonance imaging, and magnetic resonance angiography of the brain as well as metabolic evaluation, were normal. Cytogenetic analysis was normal and mitochondrial DNA analysis revealed no deletions or mutations in the four affected family members and the grandmother. An autosomal dominant mode of inheritance is suggested by the fact that both sexes are affected in two generations.     

Scheie syndrome presenting as myopathy.

We investigated two brothers with Scheie syndrome whose only complaint was exercise intolerance. In the quadriceps muscle biopsy of both patients, between the normal muscle fibres an increased number of markedly swollen periodic acid-Schiff-positive fibroblasts were seen. Ultrastructurally, these cells showed an accumulation of enlarged lysosomes, partly filled with electro-dense material. We hypothesize that the accumulation of pathological fibroblasts may interfere with intramuscular force transmission resulting in exercise intolerance.     

Desmin-related myopathy: report of a rare case

The Protein Surplus Myopathies (PSM) are characterized by accumulation of protein aggregates, identifiable ultrastructurally, resulting due to mutations of the encoding genes. Desmin-related myopathies (DRM) are a form of PSM characterized by mutations of the desmin gene resulting in the formation of protein aggregates comprising mutant protein desmin and disturbance of the regular desmin intermediate network in the muscle fibers. We describe a rare case of DRM in a 23-year-old man who presented with complaints of difficulty in climbing stairs and running since the age of 5 years. EMG studies revealed a myopathic pattern. Muscle biopsy showed the features of muscular dystrophy with bluish rimmed vacuoles and sarcoplasmic inclusions, which were immunoreactive to desmin. Ultrastructural examination showed sarcoplasmic bodies and granulofilamentous inclusions. Although rare, the possibility of DRM/desminopathy should be considered in the presence of bluish rimmed vacuoles on light microscopy and characteristic ultrastructural inclusions. To the best of our knowledge this is the first case of DRM/desminopathy reported from India.     

Myotonic dystrophy: hypotheses and facts about the illness of the Ypsilante brothers

A study was undertaken in order to determine the state of health of the Ypsilante brothers, leaders of the Greek revolution. Available data, which are considered reliable, indicate that the Ypsilante brothers were affected by a chronic hereditary degenerative disease. A comparison of the symptoms of the illness of the Ypsilante brothers with those of myotonic dystrophy discloses many similarities between the two diseases. Also, myotonic dystrophy has been diagnosed in a female descendant of the family, examined in 1932 in London.     

Peripheral neuropathy with giant axons and cardiomyopathy associated with desmin type intermediate filaments in skeletal muscle.

A sporadic case (female, aged 14 years) is reported who was affected by myopathy, restrictive cardiomyopathy and sensory motor polyneuropathy. A muscle biopsy showed accumulation of osmiophilic granular and filamentous material on electron microscopy, which stained positively in immunofluorescence for desmin. Increased desmin phosphorylated isoforms have been demonstrated by one- and two-dimensional electrophoresis. Sural nerve biopsy showed a peripheral neuropathy with giant axons, filled with closely packed neurofilaments. Clinical and morphological aspects of this new disease entity are discussed with regards to the classical form of giant axonal neuropathy and to other conditions of peripheral neuropathy with giant axons.     

Adrenoleukodystrophy: clinical, pathological and biochemical findings in two brothers with the onset of cerebral disease in adult life

Adrenoleukodystrophy: clinical, pathological and biochemical findings in two brothers with the onset of cerebral disease in adult life
Two brothers are described in whom adrenoleukodystrophy (ALD) presented as progressive cerebral degeneration in early adult life. Diagnosis during the life of one brother was based on cerebral biopsy appearances. At autopsy there was a leucodystrophy and an additional myelopathy in both cases. Biochemical studies carried out on the propositi and other family members revealed characteristic abnormalities of ALD in the propositi and two, as yet clinically unaffected, adult brothers, and abnormalities characteristic of the heterozygous state in their mother. Neither of the clinically affected brothers showed clinical features of hypoadrenalism and these cases emphasize the importance of considering the diagnosis of ALD in adult males with leucodystrophy even in the absence of overt adrenal insufficiency.     

Desmin phosphorylation abnormalities in cytoplasmic body and desmin-related myopathies.

Cytoplasmic body myopathy (CBM) and desmin-related myopathy (DRM) are both characterized by an abnormal accumulation of desmin. To determine whether these abnormalities involve similar or different forms of desmin, we performed desmin two-dimensional electrophoresis: our results showed an increase in the two acidic isoforms in CBM muscles as compared with an increase in the number of acidic isovariants in DRM samples. A process of hyperphosphorylation involved in these acidic forms was confirmed by alkaline phosphatase application onto the muscle samples in both pathological conditions.     

Sialidosis type 1: cherry red spot-myoclonus syndrome with sialidase deficiency and altered electrophoretic mobilities of some enzymes known to be glycoproteins. 1. Clinical findings.

A family is described with three affected brothers, two of whom were examined, born to consanguineous parent, who in early adult life began to experience ataxia, intention myoclonus, and progressive visual failure. The brothers examined had cherry red spots at the maculae and cataracts. They were of normal intelligence. The intention myoclonus responded partially to treatment with clonazepam and pheneturide, but not to 5-hydroxytryptophan in combination with carbidopa or to sodium valproate. Studies in one patient showed the excretion of large quantities of sialylated oligosaccharides in the urine. Both patients showed deficient sialidase activity in their cultured fibroblasts. Further studies on cultured skin fibroblasts revealed increased electrophoretic mobility of six glycoprotein enzymes that was returned approximately to normal by treatment with sialidase. The clinical and biochemical findings indicate that these patients are further cases of the newly described condition sialidosis type 1.     

Absence of upregulated genes associated with protein accumulations in desmin myopathy

In desmin myopathy but not hereditary inclusion-body myopathy (hIBM), there is accumulation of myofibrillar proteins including desmin, myotilin, dystrophin, gelsolin, actin, and CDC kinase. To assess the cause of protein excess, we studied the genes coding the accumulated proteins in desmin myopathy, hIBM, and controls. No differences were found among them. In desmin myopathy, protein accumulation is not due to upregulation of genes triggered by mutant desmin, but rather to posttranslational disassembly of intermediate filaments.