Distinct phenotypic features and gender-specific disease manifestations in a Spanish family with desmin L370P mutation

Desminopathies represent a subtype of myofibrillar myopathy caused by mutations in the DES gene, which cause myofibril disruption and intracellular inclusions containing desmin and other protein components. Desminopathy mainly involves skeletal and cardiac muscle, separately or together. Both autosomal dominant and autosomal recessive inheritance have been reported. Here, we describe the second family identified to date with an L370P desmin mutation. The disease in this family shows autosomal dominant inheritance with a particular phenotype, where males suffer from sudden death of cardiac origin while females exhibit a more benign myopathy of distal onset and slower progression. Because the only family previously identified with this mutation was limited to one studied patient, the present kindred represents the largest clinical investigation of the phenotype associated with the L370P mutation.     

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.     

A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin

Abstract. Desminopathy is a familial or sporadic cardiac and skeletal muscular dystrophy associated with mutations in desmin. We have previously characterized a de novo desmin R406W mutation in a patient of European origin with early onset muscle weakness in the lower extremities and atrioventricular conduction block requiring a permanent pacemaker. The disease relentlessly progressed resulting in severe incapacity within 5 years after onset. We have now identified three other patients with early onset rapidly progressive cardiac and skeletal myopathy caused by this same desmin R406W mutation. The mutation was present in each studied patient, but not in their parents or other unaffected family members, indicating that the mutation in all four cases was generated de novo. The patients mutationcarrying chromosomes showed no similarity, suggesting that the R406W mutation has occurred independently. These observations strongly confirm that the de novo R406W desmin mutation is the genetic basis for early-onset cardiac and skeletal myopathy in patients with sporadic disease and indicate that desmin position 406 is a hot spot for spontaneous mutations. The high pathogenic potential of this mutation can be explained by its location in the highly conserved YRKLLEGEE motif at the C-terminal end of the 2B helix that has a critical role in the process of desmin filament assembly.     

A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene

D. Hong, Z. Wang, W. Zhang, J. Xi, J. Lu, X. Luan and Y. Yuan (2011) Neuropathology and Applied Neurobiology 37, 257–270
A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene Aims: Desminopathy is a hereditary cardiac and skeletal myopathy caused by mutations in the desmin gene. This study summarizes the clinical, myopathological and genetic features of a series of Chinese patients with desminopathy. Methods: Thirty‐nine cases from five families with autosomal dominant inheritance and two sporadic cases were investigated. The majority of patients presented with mild myopathy and prominent cardiomyopathy. Fifteen of 16 deceased cases died of cardiac causes. Of the 25 patients alive, 24 patients developed cardiac abnormalities with disease progression. Muscle specimens from nine patients were investigated in various morphological examinations. Gene sequencing and cell transfections were performed to determine whether the mutant desmin formed intermediate filaments. Results: Muscle biopsies revealed 5 cases with dystrophy‐like patterns and amorphous material deposits; four other cases showed myopathy‐like patterns with cytoplasmic bodies or nemaline bodies. Desmin and multiple proteins aggregated in the affected fibres. Six novel mutations and one previously reported mutation in the desmin gene were identified in the patients. All the mutant desmin genes except E457V produced multiple desmin‐positive clumps or abnormal solid large aggregates in transfected cells. Conclusions: This study enlarges the spectrum of desmin mutations and geographic distribution of desminopathy. Although many novel mutations were identified in Chinese patients, the main clinical and myopathological findings were similar to those in Caucasian patients. Cardiac conduction abnormalities were prominent and usually appeared later than skeletal myopathy. The myopathology exhibited some heterogeneity among our patients, but the pathological changes were not indicative of the mutation location in the desmin gene.     

Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies

Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.     

Myofibrillar (desmin-related) myopathy: clinico-pathological spectrum in 3 cases and review of the literature

Myofibrillar or desmin-related myopathies encompass neuromuscular disorders with abnormal deposits of desmin and myofibrillar alterations. We report 3 unrelated patients presenting with proximal and distal myopathy, and, as a unique congenital syndrome, diffusely distributed myopathy, osteoporosis and myopia. Muscle biopsies shared cytoplasmic inclusions, rimmed vacuoles, and ragged-red-like fibers. Sarcoplasmic inclusions, either plaque-like or amorphous, strongly immunoreacted on dystrophin and variably for desmin, alphaB crystallin and ubiquitin. Cyclin-dependent kinases CDK1, CDK2 and CDK5 were overexpressed in affected fibers. Ultrastructurally, focal myofibrillar disruption was accompanied by tubulo-filamentous inclusions in one case and abundant glycogen and enlarged mitochondria displaying respiratory chain dysfunction at biochemistry in another case. Molecular analysis of the alphaB crystallin gene coding sequence and exons 4, 5 and 6 of the desmin gene did not reveal any mutation. The morphologic denominator of hyaline structures and areas of myofibrillar destruction occurs in heterogeneous conditions and may overlap with features of inclusion body myopathy and mitochondrial myopathy.     

A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates

OBJECTIVE: To determine the cause and pathogenic mechanisms of a 21-year-old patient's cardioskeletal myopathy. The patient's muscle atrophy and weakness began in distal parts of limbs; cardiac and facial muscles were later involved. BACKGROUND: Desmin myopathy is a skeletal myopathy often associated with cardiomyopathy, caused by mutations in the desmin gene and characterized by desmin accumulation in affected muscle fibers, a leading marker of myofibrillar myopathies. Two kinds of deletions and seven missense mutations in the desmin gene have been identified. METHODS: Clinical examination, electron microscopy of muscle tissue, two-dimensional gel electrophoresis, DNA sequencing, restriction enzyme analysis, and gene transfection were performed. RESULTS: Electron microscopy showed disruption of sarcomeres at Z discs and electron-dense aggregates in biopsied skeletal and heart muscle. Two-dimensional gel electrophoresis of the patient's skeletal muscle proteins showed massive accumulation of desmin. The authors identified a novel desmin mutation, L385P in one allele in the carboxyl end of the rod domain 2B in the patient's leukocytes and skeletal muscle; neither parent had the mutation. Serologic study and DNA markers confirmed the de novo mutation. A peptide harboring desmin rod domains 2A and 2B with L385P tagged with green fluorescent protein induced cytoplasmic aggregates, nuclear DNA condensation, and cell death. CONCLUSIONS: A novel de novo mutation, L385P, causes desmin myopathy. An expression study indicated the toxic effect of the L385P mutation.     

Myelinopathia centralis diffusa (vanishing white matter disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development

Muscle proteins were extracted in various sodium dodecyl sulfate buffers from 6 patients with myofibrillar myopathy (MFM) and previously identified with mutations in the desmin gene (desmin myopathy; DesM), 6 with MFM without mutations, and 14 disease controls to search for alterations in biochemistry and solubility of mutated desmin filaments. In the 1% posthigh-speed pellet fraction, desmin was detected with immunoblots only in DesM and not the other MFM. We conclude that mutant desmin forms insoluble aggregates that are specific for the DesM and can be detected with Western blots.     

Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy

Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy.     

Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene

Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.     

Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G > A (p.E1856K) with high interfamilial cardiac variability and putative anticipation

Myosin-heavy-chain 7 (MYH7)-myopathy manifests clinically with a distal, scapuloperoneal, limb-girdle (proximal), or axial distribution and may involve the respiratory muscles. Cardiac involvement is frequent, ranging from relaxation impairment to severe dilative cardiomyopathy. Progression and earlier onset of cardiac disease in successive generations with MYH7-myopathy is unreported. In a five-generation family MYH7-myopathy due to the novel c.5566G > A (p.E1856 K) mutation manifested with late-onset, distal > proximal myopathy and variable degree of cardiac involvement. The index patient developed distal myopathy since age 49 y and anginal chest pain. Her mother had distal myopathy and impaired myocardial relaxation. The daughter of the index patient had discrete myopathy but left ventricular hypertrabeculation/noncompaction and ventricular arrhythmias requiring an implantable cardioverter defibrillator. The granddaughter of the index patient had infantile dilated cardiomyopathy without overt myopathy. Cardiac involvement may be present in MYH7-myopathy and may be progressive between the generations, ranging from relaxation abnormality to noncompaction, ventricular arrhythmias, and dilated cardiomyopathy.     

Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain

Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.     

A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient

Laing early-onset distal myopathy is a rare autosomal dominant myopathy and caused by mutations in the MYH7 gene, encoding the slow beta myosin heavy chain. We report the first molecularly verified Laing distal myopathy in a French family caused by a novel p.Glu1508del mutation in the MYH7 gene. Interestingly, we identified the identical mutation in an unrelated Norwegian family and, as a de novo mutation, in one sporadic Finnish patient. Described in detail are the clinical and electrophysiological characteristics of 5 patients from the French family. The phenotype in the Finnish patient and the Norwegian patients is largely similar. This mutation causes a benign myopathy within the range of previously reported Laing myopathy phenotype variations. Onset of weakness in the tibialis anterior (TA) muscles occurred in early childhood in all patients. Finger extensor and neck flexor weakness together with Achilles tendon retractions were other frequent findings. The independent recurrence of the identical mutation without any founder background may reflect a mutational susceptibility of this residue, in accordance with some other MYH7 mutations previously reported. De novo mutations seem to be frequent in Laing distal myopathy. This is of clinical importance since a dominant family history is missing, which may confuse differential diagnostic efforts.     

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q

Twenty-one members of a Swedish family suffering from myopathy and cardiomyopathy underwent neurological and cardiological investigations. Medical charts of 2 affected deceased patients were reviewed. Twelve patients had myopathy. The distribution of weakness was axial in mildly affected, axial and predominantly distal in moderately affected, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy revealed granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic right ventribular cardiomyopathy. Nonsustained ventribular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of them had a pacemaker implanted because of atrioventricular block and sick sinus syndrome. Inheritance is autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. Linkage analysis of candidate chromosomal regions showed a maximum 2-point LOD score of 2.76 for marker locus D10S1752 on chromosome 10q. A multipoint peak LOD score of 3.06 between markers D10S605 and D10S215 suggests linkage to chromosome 10q22.3, and this region may harbor a genetic defect for myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopahty.     

An autosomal dominant early adult-onset distal muscular dystrophy

In this study we describe an autosomal dominant distal muscular dystrophy in a small Austrian family. The myopathy started in early adulthood with a slowly progressive weakness of the muscles of the anterior tibial compartment, followed by the long finger extensors and sternocleidomastoids in some family members. Other muscles were spared. Histopathology showed fiber size variation and autophagic vacuoles. This disease pattern is similar to Laing distal myopathy, which has been described previously in only one other family.     

Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment

Mutations in desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates. We characterized two new desminopathy families with unusual features of adult-onset, slowly progressive, diffuse skeletal myopathy and respiratory insufficiency. Progressive reduction of respiratory muscle strength became clinically detectable between the 3rd and the 8th years of illness and led to recurrent chest infections and death in one of the patients. Novel mutations, A357P and L370P, predicted to introduce proline residue into a highly conserved alpha-helical region of desmin, were identified. Proline is known to disrupt the alpha-helix. In addition, the A357P mutation distorts a unique stutter sequence that is considered to be critically important for proper filament assembly. Functional assessment in two cell-lines, one of which does and the other of which does not constitutively produce type III intermediate filaments, demonstrated the inability of mutant desmin carrying either the A357P or the L370P mutation to polymerize and form an intracellular filamentous network. The results of this study indicate that respiratory insufficiency is an intrinsic feature of disease associated with specific desmin mutations; in some patients, respiratory weakness may present as a dominant clinical manifestation and a major cause of disability and death.     

Characterization of a novel S13F desmin mutation associated with desmin myopathy and heart block in a Chinese family

Desmin myopathy was identified in a Chinese man with complete heart block and mild proximal and distal limb weakness. A novel heterozygous missense S13F mutation of the desmin gene was found to be associated with the myopathy. Family members carrying the mutation showed a similar or milder phenotype. The mutation is located at a protein kinase-C phosphorylation site within a highly conserved nonapeptide sequence in the head domain of the desmin protein. Expression of the mutant desmin cDNA in cell lines induced large desmin accumulations associated with preservation of a filamentous network.     

ZASP基因突变所致肌原纤维病一家系报道及文献复习

目的通过对ZASP基因突变所致肌原纤维病一家系报道及文献复习,了解该病的临床、病理及基因突变特点。方法分析1例远端肌病患者的临床、肌肉MRI及肌肉病理特点,并追踪其家系家族史。先证者外周血提取DNA,进行目标区序列捕获二代测序(含58个肌病相关基因),明确存在ZASP基因变异。对家系其他成员进行Sanger测序进一步明确及验证突变位点。结果先证者为中年女性,52岁起病,表现为进行性双下肢无力伴双腿变细。先证者家系2代15名中,除先证者外共6名存在肌肉受累,4名为先证者同代亲属,临床特点与先证者类似;2名为先证者下一代亲属,其中1名仅有闭目肌受累及肌酸激酶(CK)轻度升高(291 U·L-1),另1名仅有CK轻度升高(199 U·L-1)。先证者肌肉病理发现肌细胞内有异常嗜伊红物质沉积和镶边空泡形成,免疫组化染色可见肌纤维内desmin蛋白沉积。电镜下可见Z线附近致密颗粒沉积。目标区序列捕获二代测序及Sanger测序确定该家系致病基因为ZASP基因已报道错义突变p.A147T(c.G439A)。结论 ZASP基因突变所致的肌原纤维病家系为国内首次报道。     

Different early pathogenesis in myotilinopathy compared to primary desminopathy

Mutations in the human myotilin gene may cause limb-girdle muscular dystrophy 1A and myofibrillar myopathy. Here, we describe a German patient with the clinically distinct disease phenotype of late adult onset distal anterior leg myopathy caused by a heterozygous S55F myotilin mutation. In addition to a thorough morphological and clinical analysis, we performed for the first time a protein chemical analysis and transient transfections. Morphological analysis revealed an inclusion body myopathy with myotilin- and desmin-positive aggregates. The clinical and pathological phenotype considerably overlaps with late onset distal anterior leg myopathy of the Markesbery-Griggs type. Interestingly, all three analyzed myotilin missense mutations (S55F, S60F and S60C) do not lead to gross changes in the total amount of myotilin or to aberrant posttranslational modifications in diseased muscle, as observed in a number of muscular dystrophies. Transiently transfected wild-type and S55F mutant myotilin similarly colocalised with actin-containing stress fibers in BHK-21 cells. Like the wild-type protein, mutated myotilin did not disrupt the endogenous desmin cytoskeleton or lead to pathological protein aggregation in these cells. This lack of an obvious dominant negative effect sharply contrasts to transfections with, for instance, the disease-causing A357P desmin mutant. In conclusion our data indicate that the disorganization of the extrasarcomeric cytoskeleton and the presence of desmin-positive aggregates are in fact late secondary events in the pathogenesis of primary myotilinopathies, rather than directly related. These findings suggest that unrelated molecular pathways may result in seemingly similar disease phenotypes at late disease stages.     

Infantile autosomal dominant distal myopathy.

Introduction – Distal myopathies are currently regarded as a non-homogeneous group of disorders including different autosomal dominant, recessive and sporadic forms. Material and methods - The cases of a mother and her son and daughter are described and compared to previously reported cases from 4 families. Despite minor differences, the clinical picture is remarkably homogeneous, both within the same family and among different families. Conclusion - A distinct clinical form can be identified including: a) autosomal dominant inheritance; b) onset in infancy or childhood with peroneal muscles weakness; c) not disabling evolution in spite of possible late involvement of muscles others than tibio-peroneal; d) usually normal serum CK and other muscle enzymes; e) EMG evidence of primary myogenic damage; f) morphological findings of non-specific myopathy. Because of the benign evolution and the absence of true dystrophic changes in most biopsies we suggest the term infantile autosomal dominant distal myopathy should be preferred to infantile autosomal dominant distal muscular dystrophy.