Pattern Of Selective Muscle Involvement Research Articles

NEW GENES, NEW TECHNIQUES IN NEUROMUSCULAR DISORDERS: O.10 Loss of function mutations in DNAJB4 cause a myopathy with early respiratory failure

Through next generation sequencing of patients with unexplained muscle disease, we identified four individuals from three unrelated families carrying homozygous variants in the DNAJB4 gene. Clinical presentation was similar with acute respiratory failure leading to life threatening hypercapnia and artificial ventilation. In addition, all patients presented some degree of spine rigidity. Disease onset was variable, between the 1st and 4th decade of life. MRI showed a similar selective pattern of muscle involvement. DNAJB4 is a heat shock protein belonging to the DNAJ/HSP40 family. DNAJ proteins are emerging as proteins critical for muscle protein homeostasis and another homologous protein, DNAJB6 – is causative for LGMD D1 (DNAJB6 related). LGMDD1 is characterized by proximal and/or distal muscle weakness, atrophy and protein aggregates, myofibrillar degeneration, and rimmed vacuoles on muscle biopsy. The DNAJB4 variants identified, a stop gain (c.856A>T; p.Lys286*) and two missense changes (c.74G>A; p.Arg25Gln and c.785T>C; p.Leu262Ser) are absent in the control population and are predicted to result in loss of protein, or protein function. Consistent with this, immunoblots from patient muscle tissue and fibroblasts confirmed the absence of DNAJB4 in the p.Lys286* and p.Leu262Ser patients. Functional studies confirm that the p.Lys286* and p.Leu262Ser variants are rapidly degraded in cells. In contrast the p.Arg25Gln is stable but behaves as a loss of function in cellular assays of DNAJB4 chaperone function. In muscle DNAJB4 localizes to the Z-disc and DNAJB4 knockout myotubes and mouse muscle accumulate desmin and other potential client proteins. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function mutations may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.

High prevalence of sporadic late-onset nemaline myopathy in a cohort of whole-exome sequencing negative myopathy patients

Sporadic late-onset nemaline myopathy (SLONM) is an enigmatic, supposedly very rare, putatively immune-mediated late-onset myopathy, typically presenting with subacutely progressive limb-girdle muscular weakness, yet slowly progressing cases have been described too. We systematically studied (para)clinical and histopathological findings in a cohort of 18 isolated yet suspected inherited myopathy patients, showing late-onset, slowly progressive limb-girdle muscle weakness, remaining unsolved after whole-exome sequencing. The presence of a monoclonal gammopathy of unknown significance (MGUS) and anti-HMGCR antibodies was determined. Biopsies were systematically re-evaluated and systematic immunohistochemical and electron microscopy studies were performed to particularly evaluate the presence of rods and/or inflammatory features. Ten patients showed rods as core feature on muscle biopsy on re-evaluation, four of these had an IgG κ MGUS in blood. As such, these ten patients represented suspected slowly progressing SLONM patients, with auxiliary data supporting this diagnosis: 1) additional muscle biopsy features pointing towards Z-disk and myofibrillar pathology; 2) a common selective pattern of muscle involvement on MRI; 3) inflammatory features on muscle biopsy. Findings in this proof-of-concept study highlight difficulties in reliably diagnosing slowly progressing SLONM and the probably underestimated prevalence of this entity in cohorts of whole exome sequencing negative myopathy patients, initially considered having an inherited myopathy.

MUSCLE IMAGING – MRI: P.162 The use of muscle MRI in the diagnosis of neuromuscular diseases

Inherited neuromuscular disorders (NMD) are a heterogeneous group of disorders characterized by progressive muscle weakness, different pattern of muscle involvement, age of onset. Thanks to next generation sequencing the numbers of genes responsible for NMD is growing. In recent years muscle MRI has contributed to the diagnosis of NMD by evaluating the selective pattern of muscle involvement. We retrospectively reviewed the muscle MRI of 533 individuals (age 5-93 years) performed at the John Walton muscular dystrophy research centre in Newcastle.

Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency

Glycogen storage disease XV is caused by variants in the glycogenin-1 gene, GYG1, and presents as a predominant skeletal myopathy or cardiomyopathy.We describe two patients with late-onset myopathy and biallelic GYG1 variants. In patient 1, the novel c.144–2A>G splice acceptor variant and the novel frameshift variant c.631delG (p.Val211Cysfs*30) were identified, and in patient 2, the previously described c.304G>C (p.Asp102His) and c.487delG (p.Asp163Thrfs*5) variants were found. Protein analysis showed total absence of glycogenin-1 expression in patient 1, whereas in patient 2 there was reduced expression of glycogenin-1, with the residual protein being non-functional. Both patients showed glycogen and polyglucosan storage in their muscle fibers, as revealed by PAS staining and electron microscopy. Age at onset of the myopathy phenotype was 53 years and 70 years respectively, with the selective pattern of muscle involvement on MRI corroborating the pattern of weakness.Cardiac evaluation of patient 1 and 2 did not show any specific abnormalities linked to the glycogenin-1 deficiency. In patient 2, who was shown to express the p.Asp102His mutated glycogenin-1, cardiac evaluation was still normal at age 77 years. This contrasts with the association of the p.Asp102His variant in homozygosity with a severe cardiomyopathy in several cases with an onset age between 30 and 50 years. This finding might indicate that the level of p.Asp102His mutated glycogenin-1 determines if a patient will develop a cardiomyopathy.

Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Background and objectiveDysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient...

Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.

Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.

Myopathology in times of modern imaging.

Over the last two decades, muscle (magnetic resonance) imaging has become an important complementary tool in the diagnosis and differential diagnosis of inherited neuromuscular disorders, particularly in conditions where the pattern of selective muscle involvement is often more predictive of the underlying genetic background than associated clinical and histopathological features. Following an overview of different imaging modalities, the present review will give a concise introduction to systematic image analysis and interpretation in genetic neuromuscular disorders. The pattern of selective muscle involvement will be presented in detail in conditions such as the congenital or myofibrillar myopathies where muscle imaging is particularly useful to inform the (differential) diagnosis, and in disorders such as Duchenne or fascioscapulohumeral muscular dystrophy where the diagnosis is usually made on clinical grounds but where detailed knowledge of disease progression on the muscle imaging level may inform better understanding of the natural history. Utilizing the group of the congenital myopathies as an example, selected case studies will illustrate how muscle MRI can be used to inform the diagnostic process in the clinico-pathological context. Future developments, in particular, concerning the increasing use of whole-body MRI protocols and novel quantitative fat assessments techniques potentially relevant as an outcome measure, will be briefly outlined.

Muscle magnetic resonance imaging in spinal muscular atrophy type 3: Selective and progressive involvement.

In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b). Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner. MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression. This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017.

O.1 Collagen XII as a new disease gene for Bethlem-like myopathy

Bethlem myopathy (BM) is a slowly progressive disorder characterized by contractures and a proximal myopathy, which can be caused by mutations in one of the collagen VI genes (COL6A1, COL6A2, and COL6A3), although genetic heterogeneity is predicted to be as high as 50%. Using whole exome sequencing (WES) we have identified mutations in a novel gene, COL12A1, a member of the FACIT collagens (fibril-associated collagens with interrupted triple helices) in five individuals from two families. In eighteen additional families we have excluded 12 other genes which were considered candidates for causative genes in non-collagen VI BM based on their function, including known binding partners of, and enzymes involved in correct post translational modification, assembly and secretion of collagen VI. Both families carry dominant mutations with a clinical phenotype indistinguishable from classical BM, apart from an intriguing improvement in disease course over time in one of the families and a different pattern of selective muscle involvement on MRI. Family 1 has a single-base substitution that leads to the replacement of one glycine residue in the triple helical domain, breaking the Gly-X-Y repeating pattern, which is known to destabilize the triple helix through a local disruption in hydrogen bonding. Family 2 has a missense mutation which creates a mutant protein with an unpaired cysteine residue. Deficiency at the protein level is confirmed in both families by the intracellular retention of collagen XII in patient dermal fibroblasts. Upregulation of genes associated with the endoplasmic reticulum-associated protein degradation (ERAD) pathway and swollen, dysmorphic rough-ER as determined by electron microscopy in three members of Family 2 lead to the hypothesis that the unfolded protein response (UPR) contributes to the disease pathomechanism in this family. We suggest that the spectrum of causative genes in BM be extended from the COL6A1-A3 genes to include COL12A1.

Selective pattern of muscle involvement seen in distal muscular dystrophy associated with anoctamin 5 mutations: A follow-up muscle MRI study

Anoctaminopathy is a new muscular dystrophy caused by mutations in the ANO5 gene. ANO5 mutations cause distal and proximal phenotypes. We report here a follow-up muscle MRI study on five patients affected by distal form of anoctaminopathy. T1 weighted scans showed subsequent involvement of gastrocnemius medialis and soleus, hip adductors, hamstrings, gastrocnemius lateralis and quadriceps muscles, and later on tensor fascia lata, gluteus minimus and biceps brachii muscles, respectively. The STIR weighted images showed in the early stages widely distributed hyperintense signals, myoedema, in the adductors, hamstrings, and quadriceps muscles, which at that time have normal T1 signals. All patients showed asymmetry of muscle involvement both clinically and on muscle imaging. The progression of muscle involvement was relatively slow. We conclude that the pattern of muscle involvement seen in patients with distal myopathy with anoctamin 5 mutations (MMD3) is typical and can thus be useful during the differential diagnosis process allowing for a more targeted molecular approach.

Titin mutation segregates with hereditary myopathy with early respiratory failure

In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.

Selectivity of muscle sparing in Emery–Dreifuss muscular dystrophy

The clinical features of Emery-Dreifuss muscular dystrophy (EDMD) are quite distinctive: early contractures of the Achilles tendons, elbows and post-cervical muscles, slowly progressive muscle weakness with an essentially humero-peroneal distribution at the beginning, and cardiac conduction defects. The X-linked (EDMD1) and autosomal dominant (EDMD2) forms of the disease are clinically similar and are caused by defects of the nuclear membrane proteins emerin and lamins A/C, respectively. The selective pattern of muscle involvement in EDMD2 has been confirmed with muscle CT and MRI [1,2].

Central core disease

Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations.

The differential gene expression profiles of proximal and distal muscle groups are altered in pre-pathological dysferlin-deficient mice

The selective pattern of muscle involvement is a key feature of muscular dystrophies. Dysferlinopathy is a good model for studying this process since it shows variable muscle involvement that can be highly selective even in individual patients. The transcriptomes of proximal and distal muscles from wildtype C57BL/10 and dysferlin deficient C57BL/10.SJL- Dysf mice at a prepathological stage were assessed using the Affymetrix oligonucleotide-microarray system. We detected significant variation in gene expression between proximal and distal muscle in wildtype mice. Dysferlin defiency, even in the absence of pathological changes, altered this proximal distal difference but with little specific overlap with previous microarray analyses of dysferlinopathy. In conclusion, proximal and distal muscle groups show distinct patterns of gene expression and respond differently to dysferlin deficiency. This has implications for the selection of muscles for future microarray analyses, and also offers new routes for investigating the selectivity of muscle involvement in muscular dystrophies.

Magnetic resonance imaging of muscle in nemaline myopathy

We report muscle MRI findings of 10 patients from 8 families with nemaline myopathy. Patients with involvement of the nebulin ( NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there was complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus. In moderate cases, there was predominant involvement of rectus femoris, vastus lateralis and hamstring muscles and diffuse involvement of anterior compartment and soleus. Patients with nemaline myopathy secondary to mutations in the skeletal muscle α-actin ( ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii. Selective muscle involvement in both genetic categories was distinct from what has been reported in other congenital myopathies. We conclude that muscle MRI may be applied to distinguish nemaline myopathy from other conditions with similar clinical and histopathological features, to supplement clinical assessment in individual patients and to help direct genetic testing.

111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9–11 November 2002, Naarden, The Netherlands

111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9–11 November 2002, Naarden, The Netherlands

Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1)

We report clinical and imaging findings in six cases from five families affected by the form of congenital muscular dystrophy with rigid spine linked to the locus rigid spine muscular dystrophy 1 on chromosome 1p35-36. All cases showed rigidity of the spine, predominant neck and trunk weakness and frequent and severe thoracic scoliosis. Respiratory impairment was always observed in the first decade. Muscle imaging showed a marked involvement of adductors, sartorius and biceps femoris while rectus femoris and gracilis were relatively spared. This pattern of selective muscle involvement was consistent in all six cases and could be easily observed on either computerised tomography or magnetic resonance imaging. The results of this study suggest that muscle imaging, in combination with clinical assessment can help to identify the rigid spine muscular dystrophy 1 form of congenital muscular dystrophy and can help to target the appropriate genetic investigations.

Ultrasonography, CT, and MRI of muscles in congenital nemaline myopathy

Twelve patients with congenital nemaline myopathy were examined by ultrasonography and computed tomography (CT) and 4 of them by low-field magnetic resonance imaging (MRI) to investigate the distribution and nature of muscle involvement and to evaluate the yield of these techniques. A pattern of selective muscle involvement was consistently found. Ultrasonography revealed abnormally high muscle echogenicity. In contrast to the controls with simple disuse and/or neurogenic atrophy, CT revealed low muscle density in our patients. MRI confirmed that this pattern reflects patchy, fatty degeneration, a new finding in congenital nemaline myopathy. Ultrasonography appears useful for screening, provided that the dorsiflexors of the feet are examined. CT and MRI can be used to demonstrate abnormalities in mild cases, to select the biopsy site, and for follow-up. MRI, because it provides good soft tissue contrast, is useful for determining fatty infiltration.