Autosomal Dominant Distal Myopathy Research Articles

P.156 Novel repeat expansions in PLIN4 in two Spanish families suffering from autosomal dominant distal myopathy with unique pathological features

P.156 Novel repeat expansions in PLIN4 in two Spanish families suffering from autosomal dominant distal myopathy with unique pathological features

Gower laing: Early adult onset distal myopathy type III (MPD I): a case report

A rare case of sporadic Gower Laing: Early adultonset distal myopathy type III (MDP I) presenting to a medical ward in northern Sri Lanka is presented here. A 39-year-old female present with difficulty in walking from age 10 and was investigated leading to the above diagnosis. This is a rare autosomal dominant distal myopathy and there have been no similar cases reported from the Northern Province of Sri Lanka, as well as in Sri Lanka.

Dominant Distal Myopathy 3 (MPD3) Caused by a Deletion in the HNRNPA1 Gene.

Background and ObjectivesTo determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3).MethodsContinued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect.ResultsSmall hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele. Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions.DiscussionA small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.

O.20Mutations in ACTN2 gene cause a novel form of adult-onset distal myopathy

We studied three families from the same village in northern Spain and one family from Sweden with an autosomal dominant distal myopathy with rimmed vacuolar pathology. Affected members shared a very similar clinical phenotype, a characteristic pattern of muscle involvement by MRI and common histologic features. In particular, all the patients showed an adult-onset, asymmetric muscle weakness, with atrophy of tibialis anterior and initial involvement of ankle dorsiflexion later progressing to proximal limb muscles. We identified an ACTN2 c.1459T>C (p.C487R) variant co-segregating with the disease in families 1–3. An ACTN2 c.392T>C (p.L131P) variant was identified in the affected members of family 4. In all the families enrolled, the private ACTN2 variants are fully penetrant and co-segregate with the disease. ACTN2 encodes for alpha actinin2, a protein highly expressed in the Z-disk of cardiac and skeletal sarcomeres, where it plays several structural and functional roles through a complex network of interactions with other sarcomeric proteins. Our findings demonstrate that ACTN2 mutations cause a new type of dominant late-onset and slowly progressive distal myopathy. Dominant ACTN2 mutations were previously associated with hypertrophic and dilated cardiomyopathies. At the same time as our studies, two ACTN2 mutations have been described as the cause of a congenital core myopathy patients. Additional studies are needed to improve our understanding of the genotype-phenotype correlation and to clarify the molecular mechanisms of the actinopathies.

Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations.

To clinically and pathologically characterize a cohort of patients presenting with a novel form of distal myopathy and to identify the genetic cause of this new muscular dystrophy. We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles. In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant. ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy. ANN NEUROL 2019;85:899-906.

Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons. Mutations in the gene encoding the nuclear matrix protein Matrin 3 have been found in familial cases of ALS, as well as autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We previously found that spinal cord and muscle, organs involved in either ALS or distal myopathy, have relatively lower levels of Matrin 3 compared to the brain and other peripheral organs in the murine system. This suggests that these organs may be vulnerable to any changes in Matrin 3. In order to determine the role of Matrin 3 in these diseases, we created a transgenic mouse model for human wild-type Matrin 3 using the mouse prion promoter (MoPrP) on a FVB background.We identified three founder transgenic lines that produced offspring in which mice developed either hindlimb paresis or paralysis with hindlimb and forelimb muscle atrophy. Muscles of affected mice showed a striking increase in nuclear Matrin 3, as well as the presence of rounded fibers, vacuoles, nuclear chains, and subsarcolemmal nuclei. Immunoblot analysis of the gastrocnemius muscle from phenotypic mice showed increased levels of Matrin 3 products migrating at approximately 120 (doublet), 90, 70, and 55 kDa. While there was no significant change in the levels of Matrin 3 in the spinal cord in the phenotypic mice, the ventral horn contained individual cells with cytoplasmic redistribution of Matrin 3, as well as gliosis. The phenotypes of these mice indicate that dysregulation of Matrin 3 levels is deleterious to neuromuscular function.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0393-5) contains supplementary material, which is available to authorized users.

Myoimaging in the NGS era: the discovery of a novel mutation in MYH7 in a family with distal myopathy and core-like features – a case report

BackgroundMyosin heavy chain 7 related myopathies are rare disorders characterized by a wide phenotypic spectrum and heterogeneous pathological features. In the present study, we performed clinical, morphological, genetic and imaging investigations in three relatives affected by autosomal dominant distal myopathy. Whilst earlier traditional Sanger investigations had pointed to the wrong gene as disease causative, next-generation sequencing allowed us to obtain the definitive molecular genetic diagnosis in the family.Case presentationThe proposita, being found to harbor a novel heterozygous mutation in the RYR1 gene (p.Glu294Lys), was initially diagnosed with core myopathy. Subsequently, consideration of muscle magnetic resonance imaging (MRI) features and extension of family study led this diagnosis to be questioned. Use of next-generation sequencing analysis identified a novel mutation in the MYH7gene (p.Ser1435Pro) that segregated in the affected family members.ConclusionsThis study identified a novel mutation in MYH7 in a family where the conclusive molecular diagnosis was reached through a complicated path. This case report might raise awareness, among clinicians, of the need to interpret NGS data in combination with muscle MRI patterns so as to facilitate the pinpointing of the main molecular etiology in inherited muscle disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0288-0) contains supplementary material, which is available to authorized users.

Mutation analysis of MATR3 in Australian familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that arises from the progressive degeneration of the motor neurons. Recently, mutations in the matrin 3 (MATR3) gene were described in both ALS and autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We sought to determine the prevalence of MATR3 mutations in Australian familial ALS (n = 106) using whole exome sequencing. No mutations were identified, indicating that MATR3 mutations are not a common cause of ALS in Australian familial cases with predominately European ancestry.

Laing distal myopathy pathologically resembling inclusion body myositis.

Mutations in MYH7 cause autosomal dominant Laing distal myopathy. We present a family with a previously reported deletion (c.5186_5188delAGA, p.K1729del). Muscle pathology in one family member was characterized by an inflammatory myopathy with rimmed vacuoles, increased MHC Class I expression, and perivascular and endomysial muscle inflammation comprising CD3+, CD4+, CD8+, and CD68+ inflammatory cells. Interestingly, this biopsy specimen contained TDP-43, p62, and SMI-31-positive protein aggregates typical of inclusion body myositis. These findings should alert physicians to the possibility that patients with MYH7 mutations may have muscle biopsies showing pathologic findings similar to inclusion body myositis.

ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle.

ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.

Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy

Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.

Welander distal myopathy is caused by a mutation in the RNA‐binding protein TIA1

A study was undertaken to identify the molecular cause of Welander distal myopathy (WDM), a classic autosomal dominant distal myopathy. The genetic linkage was confirmed and defined by microsatellite and single nucleotide polymorphism haplotyping. The whole linked genomic region was sequenced with targeted high-throughput and Sanger sequencing, and coding transcripts were sequenced on the cDNA level. WDM muscle biopsies were studied by Western blotting and immunofluorescence microscopy. Splicing of TIA1 and its target genes in muscle and myoblast cultures was analyzed by reverse transcriptase polymerase chain reaction. Mutant TIA1 was characterized by cell biological studies on HeLa cells, including quantification of stress granules by high content analysis and fluorescence recovery after photobleaching (FRAP) experiments. The linked haplotype at 2p13 was narrowed down to <806 kb. Sequencing by multiple methods revealed only 1 segregating coding mutation, c.1362 G>A (p.E384K) in the RNA-binding protein TIA1, a key component of stress granules. Immunofluorescence microscopy of WDM biopsies showed a focal increase of TIA1 in atrophic and vacuolated fibers. In HeLa cells, mutant TIA1 constructs caused a mild increase in stress granule abundance compared to wild type, and showed slower average fluorescence recovery in FRAP. WDM is caused by mutated TIA1 through a dominant pathomechanism probably involving altered stress granule dynamics.

Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies

The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.

G.P.34 Gene expression profiling in tibial muscular dystrophy reveals new involved molecular pathways

Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. To identify these components we used gene expression profiling from muscle biopsies samples of TMD patients, healthy controls and from phenotypically overlapping Welander distal myopathy (WDM) patients. The profiling results were confirmed through RT-PCR and protein level analysis and we identified an activation of the unfolded protein response (UPR). UPR was then confirmed through elevation of marker genes HSPA5 (BIP) and XBP1 and the presence of ER-stress specific XBP1 splicing events. However, UPR activation appears to be insufficient, leading to build-up of ubiquitinated proteins which in turn cause activation of the autophagic system. Massive accumulation of LC3b positive autophagosomes within the rimmed vacuolated regions of degenerated muscle fibers suggests that this apparently compensatory mechanism is not capable of restoring equilibrium since these fibers degenerate further and disappear in the end stage of the pathology cascade.

D.P.8 Expanding the clinical and genetic phenotype of TPM2-related myopathies

The beta-tropomyosin gene (TPM2) encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin–myosin interactions, and TPM2 mutations have been associated with nemaline myopathy, cap myopathy and distal arthrogryposis. In this study, we expand the allelic spectrum of TPM2-related myopathies through the identification of a novel TPM2 mutation in a family with core-rod myopathy and in a family with trismus-pseudocamptodactyly. In addition, we describe the first animal models of TPM2 related myopathies, and use these models to compare and contrast pathogenic mechanisms related to distinct TPM2 mutations. The first new phenotype is core-rod myopathy, with the TPM2 mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy. The second phenotype is trismus-pseudocamptodactyly syndrome (previously associated exclusively with MYH8 mutations), with mutation identified by candidate gene analysis based on the observation of nemaline rods on muscle biopsy. In both cases, the mutation identified is a novel three base pair in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the 7th amino acid position. Conceptual modeling of this mutation predicts that it disrupts the N-terminal homodimeric alpha helix of TPM2, a change that likely alters protein–protein binding between TPM2 and other molecules. We are now utilizing the zebrafish model system to generate a transgenic model of both this TPM2 mutation as well as a recurrent TPM2 mutation (E139del) associated with cap myopathy. These models are used to determine the underlying pathomechanisms associated with different TPM2 mutations via direct comparisons as well as through comparison with existing nemaline myopathy and core myopathy zebrafish models. In all, we describe a novel TPM2 mutation, two clinical-histopathologic phenotypes not previously associated with TPM2, and the first animal models of TPM2 related myopathies.

G.O.1 Welander distal myopathy is caused by a mutated RNA binding protein

Abstract Welander distal myopathy (WDM) is a late onset, autosomal dominant distal myopathy prevalent in Finland and Sweden. First symptoms of finger extensor weakness occur after age 40, with progression to all hand muscles and ankle dorsiflexion. Rare homozygotes show also proximal muscular weakness, earlier onset and faster progression. WDM is linked to chromosome 2p13 with a maximal linked region of interest of

Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype.

The age of single-gene neurological disorders is not dead

This edition of Brain sees the first of a series of articles describing new genes responsible for inherited neurological disease, thus expanding the clinical neurogenetics portfolio. Sebahattin Cirak from the Institute of Child Health in London led a transcontinental consortium of clinical and basic science researchers who map the locus for a gene responsible for an autosomal dominant distal myopathy (Cirak et al. , 2010). Their work casts new light on the disease mechanisms of these poorly understood disorders; but at the same time, they broaden concepts on the potential mechanisms involved. Distal myopathies provide a classical example of the way that molecular genetics has revolutionized classifications in clinical neurology (Table 1). First described in the early part of the last century (Gowers, 1902), they were the focus of that old neurological chestnut ‘is the distal weakness due to muscle or nerve dysfunction?’ and were latterly subdivided into discrete entities based on astute clinical examination (reviewed in Barohn et al. , 1998). Early gene mapping studies identified several loci, highlighted the likely aetiological heterogeneity and led to the further delineation of different clinical groups (Udd, 2009). A major subgroup was associated with pathological myofibrils (myfibrillar myopathies) (Udd, 2009), overlapping with inherited limb girdle syndromes. Positional cloning and candidate gene analysis led to the rounding-up of some obvious culprits [ MYO7 , the myosin heavy chain 7 gene (Meredith et al. , 2004) and fast IIa myosin as recently published in Brain (Tajsharghi et al. , 2010)] and provided a satisfying explanation for the muscle group specificity of some distal myopathies [including the ophthalmoplegia in inclusion body myopathy-3, due to mutations in the myosin heavy chain IIa gene (Martinsson et al. , 2000)], but the real power of these ‘reverse genetic studies’ was in revealing new proteins required for intact muscle …

Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy

Distal myopathies are a heterogeneous group of disorders characterized by progressive weakness and muscular atrophy, beginning in distal limb muscles and affecting proximal limb muscles at a later stage. We studied a large German kindred with 10 affected members. Weakness and atrophy of the anterior tibial muscles started between the ages of 8 and 16 years, followed by atrophy of intrinsic hand muscles. Progression was slow, and patients retained the ability to walk until the seventh decade. Serum creatinine kinase levels were increased in the range of 150–1400 U/l. Muscle biopsies showed myopathic changes, whereas immunohistochemistry showed normal expression of marker proteins for muscular dystrophies. Patients had reduced sensation with stocking-glove distribution in the distal limbs in later life. Nerve conduction studies revealed no evidence of neuropathy. Genome-wide linkage analysis in this family revealed a new locus for distal myopathy at 9p21.2-p22.3 (multipoint logarithm of the odds ratio = 4.21). By positional cloning we found a heterozygous mutation L95F in the Kelch-like homologue 9 gene, encoding a bric-a-brac Kelch protein. Molecular modelling indicated that the mutation may interfere with the interaction of the bric-a-brac domain with Cullin 3. Coimmunoprecipitation experiments confirmed that the mutation reduces association with Cullin 3 in the Kelch-like homologue 9-Cullin 3–E3 ubiquitin ligase complex, which is involved in ubiquitin-dependent protein degradation. We identified a unique form of early onset autosomal dominant distal myopathy which is associated with a Kelch-like homologue 9 mutation and interferes with normal skeletal muscle through a novel pathogenetic mechanism.

The first Italian family with tibial muscular dystrophy caused by a novel titin mutation

Tibial muscular dystrophy (TMD) or Udd myopathy is an autosomal dominant distal myopathy with late onset, at first described in the Finnish population. We report here the first Italian cases of TTN mutated titinopathy. The proband, a 60 year-old female, had the first muscular signs at the age of 59 years, with difficulty in walking and right foot drop. Muscle imaging showed selective fatty degenerative change in the anterior compartment of leg muscles. Her 67 year-old brother, started to show muscle weakness, pain at lower limbs and hypertrophy of calf muscles at the age of 66 years. Their mother began to show foot drop and impaired walking from the age of 60 years. Other relatives are reported to be affected in a similar way. Because the phenotype appeared compatible with TMD, we analyzed the TTN gene in the DNA of the proband and we identified a heterozygous mutation 293326A>C. This mutation is also present in the brother and in the other affected individuals of the same family. The mutation predicts a His33378Pro change located next to the previously known Belgian TMD mutation. The mutation was not found in 100 Italian control DNA samples. Then, since the introduction of a proline in the last domain of titin was previously known to cause TMD in French families, we can conclude that this missense mutation is the obvious pathogenetic mutation in the affected patients. No other disease causing mutations in the TTN gene have so far been reported in the Italian population.