Recessive Congenital Myopathy Research Articles

MEGF10 gene mutations causing a recessive congenital multiminicore myopathy (P9-9.010)

<h3>Objective:</h3> Congenital myopathies are classified into five main types: core myopathies, nemaline myopathies, centronuclear myopathies, congenital fiber-type disproportion, and myosin storage myopathies. The most common forms are core myopathies. Despite their phenotypic diversity, patients demonstrate common symptoms including hypotonia, muscle weakness, dysmorphic features, and respiratory problems. There are several mutations in <i>MEGF10</i> that have been reported to cause autosomal recessive congenital myopathy, areflexia, respiratory distress, muscle weakness, dysphagia with early or late-onset syndrome, minicore myopathy and limb girdle muscular dystrophy. Affected individuals frequently become ventilator dependent or die secondary to respiratory failure. <h3>Background:</h3> A 5-year-old girl from a consanguineous couple was referred to our service due to weakness and hypotonia. After birth, she developed respiratory failure. Severe motor delay was already evident in the first months of life: at 6 months she had no cervical control and at 12 months she could not sit without support. At age 3 she developed respiratory problems with apnea and hypercapnia, requiring ventilation with two levels of positive airway pressure. She was indicated for gastrostomy at age 4 after aspiration pneumonia. On her evaluation, she had axial and proximal muscle weakness, facial weakness, scoliosis, and nasal speech. Despite presenting hypotonia and gait difficulties, she was able to walk independently and had no cognitive changes. A muscle biopsy was performed which suggested multiminicore myopathy. Genetic investigation resulted in a homozygous mutation of the <i>MEGF10</i> gene. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> <i>MEGF10</i> mutations should be considered in the differential diagnosis of individuals with respiratory insufficiency and myopathy, particularly when accompanied by facial weakness, scoliosis or dysphagia. The phenotypic similarities with other congenital neuromuscular disorders may cause difficulties in reaching a definite diagnosis. Treatment with a multidisciplinary team is important and family counseling is essential since consanguineous unions play a role in recessive genetic mutations manifestations. <b>Disclosure:</b> Miss Faria has nothing to disclose. Dr. Barbosa has nothing to disclose. Mrs. Ribeiro Torres has nothing to disclose. Mr. E Souza Filho has received research support from Universidade Federal de Minas Gerais. Mrs. Thiersch has nothing to disclose. Mrs. Oliveira has nothing to disclose.

Identification of a novel mutation in the HACD1 gene in an Iranian family with autosomal recessive congenital myopathy, with fibre-type disproportion

Congenital fibre-type disproportion (CFTD) with myopathy, is a genetically heterogeneous disease in which there is relative hypotrophy of type-1-muscle-fibres compared to type-2-fibres on skeletal muscle biopsy. The classical characteristics of CFTD are infantile hypotonia and nonprogressive muscle weakness with a broad range of clinical manifestations. Pathogenic mutations in the HACD1 gene encoding 3-hydroxyacyl-CoA-dehydratase-1 have recently been reported to be associated with this disease. Whole-exome sequencing (WES) was conducted in a 12-year-old girl born to consanguineous parents from the Iranian-Azeri-Turkish population. She was diagnosed with congenital myopathy at the age of 4-month-old due to hypotonia and abnormal electromyography. DNAs were extracted from the blood samples of the proband and her parents, and subjected to PCR-Sanger-sequencing to confirm the WES result. WES data analysis identified a homozygous single nucleotide change (A>T) at position c.785-2 located in intron 6 of the HACD1 gene (NC_000010.11(NM_014241.4):c.785-2A>T). This novel mutation located at the splice-acceptor site is disturbing the splicing procedure. The absence of this mutation among our control group (100 normal healthy adults from the same ethnic group) and not being reported in any other population database confirms the pathogenicity of this mutation. Bioinformatics analysis also classified this variant as a pathogenic mutation. PCR-Sanger-sequencing data analysis confirmed the WES result in the proband and showed that the parents were carriers for the mutation. A substitution (NC_000010.11(NM_014241.4):c.785-2A>T) mutation resulted in the removal of the splicing acceptor site at the HACD1 gene. This pathogenic mutation is associated with CFTD disease.

P.02 Mild nemaline myopathy 10 caused by a novel missense homozygous mutation in LMOD3: broadening the phenotype-genotype correlation

Nemaline myopathy (NM) is a heterogeneous group of conditions characterized by the presence of muscle weakness and the accumulation of nemaline bodies in the muscle biopsy. So far, mutations in 14 genes have been related to both recessive and dominant forms of NM. <i>LMOD3</i> encodes for the Leimodin-3 protein, which is expressed in the skeletal and cardiac muscle. The majority of described mutations in <i>LMOD3</i> are truncating mutations and cause a severe autosomal recessive congenital myopathy (NEM-10), characterized by early-onset hypotonia, generalized muscle weakness and respiratory insufficiency. Most of the patients also present polyhydramnios, reduced fetal movements, arthrogryposis or frequent contractures, and they usually die during early childhood. Here we describe a family with two affected adult sisters with a novel homozygous missense mutation in LMOD3 presenting a very mild phenotype, providing further evidence to the phenotype-genotype correlation of NEM-10. The proband, a 54-year-old woman was the first child of healthy consanguineous parents. She presented with mild hypotonia at birth and delayed motor milestones. She was never able to run, and presented frequent falls during infancy. Examination revealed high arched palate, bilateral facial weakness, and mild weakness involving neck flexors, iliopsoas and knee flexors. Her sister had the same phenotype. Serum CK were within normal levels. A muscle biopsy taken from the triceps brachii revealed mild variation in the fiber size, and very rare fibres containing nemaline bodies. Both affected sisters presented a novel homozygous missense c.1030C>T, p.Arg344Trp (NM_198271.4) mutation identified in the <i>LMOD3</i> gene through a NGS custom gene panel analyzing 139 neuromuscular-related genes. Our work broadens the mutational spectrum of <i>LMOD3</i> gene and contributes to better understand the clinical heterogeneity of nemaline myopathy.

STAC3 related congenital myopathy: A case series of seven Comorian patients

The Bailey-Bloch congenital myopathy, also known as Native American myopathy (NAM), is an autosomal recessive congenital myopathy first reported in the Lumbee tribe people settled in North Carolina (USA), and characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia. NAM is linked to STAC3 gene coding for a component of excitation-contraction coupling in skeletal muscles. A homozygous missense variant (c.851G > C; p.Trp284Ser) in STAC3 segregated with NAM in the Lumbee families. Non-Native American patients with STAC3 related congenital myopathy, and with other various variants of STAC3 have been reported. Here, we present seven patients from the Comoros Islands (located in the Mozambique Channel) diagnosed with STAC3 related congenital myopathy and having the recurrent variant identified in the Lumbee people. The series is the second largest series of patients having STAC3 related congenital myopathy with a shared ethnicity after le Lumbee series. Local history and geography may explain the overrepresentation of NAM in the Comorian Archipelago with a founder effect. Further researches would be necessary for the understanding of the onset of the NAM in Comorian population as search of the “classical” STAC3 variant in East African population, and haplotypes comparison between Comorian and Lumbee patients.

Short-Communication: Variable Expression of Clinical Symptoms and an Unexpected Finding of Vacuolar Myopathy Related to a Pathogenic Variant in the CACNA1S Gene in a Previous Case Report.

Several clinical phenotypes have been described related to the CACNA1S gene (calcium channel voltage-dependent L-type alpha-1S subunit), such as autosomal dominant hypokalemic periodic paralysis 1 and autosomal dominant malignant hyperthermia susceptibility and are associated with autosomal dominant and recessive congenital myopathy. Recently, an interesting case of a 58-year-old male patient was published describing an unusual clinical presentation of hypokalemic periodic paralysis where a late-onset limb-girdle myopathy had developed 41 years after paralysis occurred when the patient was 11 years old. Muscle biopsy results were consistent with myopathic changes and revealed the presence of vacuoles, without inflammatory reaction. Later, molecular analysis revealed a pathogenic variant c.3716G>A (p.Arg1239His) in exon 30 of the CACNA1S gene. This technical report provides an extension of the molecular findings and evaluates the clinical and histopathological relationship previously published regarding this case.

An unusual phenotype of recessive congenital myopathy: Expanding the spectrum of ORAI-1 associated disorders

The primary storehouse of the intracellular calcium ions, which play a crucial role in the excitation-contraction of skeletal muscles, is the sarcoplasmic reticulum. Calcium flux is mediated by the store-operated Ca2+ entry(SOCE) pathway interacting with stromal interacting molecule -1 (STIM-1),an SR calcium sensor, and ORAI-1,a plasma membrane calcium release-activated channel(CRAC). Loss of function mutation of ORAI-1 Cause severe combined immunodeficiency (SCID), non-progressive muscle hypotonia, and anhidrotic ectodermal dysplasia.

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy.

ObjectivePathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants.MethodsClinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy.ResultsA homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here.ConclusionsThis report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies

Next generation sequencing (NGS) has allowed the titin gene (TTN) to be identified as a major contributor to neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and the dominant or recessive pattern of inheritance are unclear. Titin is involved in the formation and stability of the sarcomeres. The effects of the different TTN variants can be harmless or pathogenic (recessive or dominant) but the interpretation is tricky because the current bioinformatics tools can not predict their functional impact effectively. Moreover, TTN variants are very frequent in the general population. The combination of deep phenotyping associated with RNA molecular analyses, western blot (WB) and functional studies is often essential for the interpretation of genetic variants in patients suspected of titinopathy. In line with the current guidelines and suggestions, we implemented for patients with skeletal myopathy and with potentially disease causing TTN variant(s) an integrated genotype-transcripts-protein-phenotype approach, associated with phenotype and variants segregation studies in relatives and confrontation with published data on titinopathies to evaluate pathogenic effects of TTN variants (even truncating ones) on titin transcripts, amount, size and functionality. We illustrate this integrated approach in four patients with recessive congenital myopathy.

CONGENITAL MYOPATHIES 1 – NEMALINE: P.25 Autosomal recessive congenital myopathy with splicing mutation (c.21522+3A>G) of NEB gene

Congenital myopathies are a heterogeneous group of hereditary primary muscle disorders that are present from birth, although their onset may be delayed until later in infancy or early childhood. The most common of these rare disorders are nemaline myopathy, central core disease, centronuclear (myotubular) myopathies, and congenital fiber type disproportion. Among them, nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes.

Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

BackgroundLimb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible.AimThis study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10.MethodsDNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing.ResultsWhole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10.ConclusionWe identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

P.235Clinico-pathological characterisation of CACNA1S related congenital myopathy in children

Mutations in the CACNA1S gene were recently identified as a new cause of congenital myopathy (CM). To date only a few cases have been described, with limited phenotypic data. We report the clinical, pathological and radiological phenotype in five children with genetically confirmed CACNA1S-CM. →Patients were referred to our national highly specialised service for CM at The Dubowitz Neuromuscular Centre, UK. We conducted retrospective case note analysis. Two patients had recessive inheritance and three autosomal dominant. →Four of five patients (age range 7-18 years) had severe neonatal presentation with foetal akinesia, weakness, hypotonia, contractures, feeding difficulties and respiratory compromise. The 5th patient presented with motor delay in infancy. All five patients had proximal predominant, bulbar and facial weakness but showed spontaneous improvement over time. Ophthalmoplegia was noted in three. Two patients remain non-ambulant. Two developed scoliosis. Two are on nocturnal non-invasive ventilation initiated at age of 5 months and 7 years. All apart from one required nasogastric/gastrostomy feeding up until 2-5 years of age, but all were able to feed orally from age 5 years. One patient had clear history of periodic weakness well responding to Acetazolamide. Two children reported fatigue and limited endurance but no abnormalities of neuromuscular transmission were detected. All muscle biopsies showed fibre size variation and marked slow fibre predominance. Additional findings included mild central nucleation, few central cores and focally accentuated pseudo-dystrophic changes. Three out of the five patients had abnormal lower limb muscle MRI but with no specific muscle pattern. →CACNA1S related myopathy is a recently described form of congenital myopathy and should be considered in cases of undiagnosed dominant and recessive congenital myopathies with phenotypical features presented above.

A ‘second truncation’ in TTN causes early onset recessive muscular dystrophy

Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies ±cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a ‘second truncation’ in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations.

Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems

Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated withHACD1 mutations should be investigated in humans with related phenotypes.

Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies – central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype–genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.

Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores

We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-012-0315-z) contains supplementary material, which is available to authorized users.

First genomic rearrangement of the RYR1 gene associated with an atypical presentation of lethal neonatal hypotonia

Neonatal hypotonia is frequently observed with a highly variable clinical presentation. Congenital myopathies that are classically characterized by the presence of structural changes of the muscle fibres such as cores, rods and aggregates have been reported to be occasionally associated with this presentation. However, the identification of the causing defect can be a challenging task in severe neonatal forms of the disease since specific structural changes might not always be present in affected newborn’s muscles. The RYR1 gene encodes the skeletal muscle isoform of a calcium channel, the ryanodine receptor, and has been involved in both dominant and recessive congenital myopathies associated with structural changes and presenting with various degree of severity. Here we report the case of a child presenting at birth with a lethal form of neonatal hypotonia associated with an atypical congenital myopathy. Molecular investigations showed that the disease was caused by two novel RYR1 mutations. One of the mutations was a large-sized genomic deletion. This is the first genomic rearrangement identified into the RYR1 gene to our knowledge. This new class of mutation of the RYR1 gene will clearly have consequences for the molecular investigation of RYR1-related diseases.

A RYR1 mutation associated with recessive congenital myopathy and dominant malignant hyperthermia in Asian families

In this study we present 3 families with malignant hyperthermia (MH), all of Indian subcontinent descent. One individual from each of these families was fully sequenced for RYR1 and presented with the non-synonymous change c.11315G>A/p.R3772Q. When present in the homozygous state c.11315*A is associated with myopathic symptoms.

Novel congenital myopathy locus identified in Native American Indians at 12q13.13-14.1

Native American myopathy (NAM) is an autosomal recessive congenital myopathy first reported in the Lumbee Indian people. Features of NAM include congenital weakness, cleft palate, ptosis, short stature, and susceptibility to malignant hyperthermia provoked by anesthesia. We identified five individuals with NAM from the Lumbee population, and hypothesized that these affected individuals have disease alleles shared identical-by-descent inherited from common ancestry. To identify a NAM disease locus, homozygosity mapping methods were employed on a genomewide 10K single-nucleotide polymorphism (SNP) screen. To confirm regions of homozygosity identified in the SNP screen, microsatellite repeat markers were genotyped within those homozygous segments. The SNP data demonstrated five regions of shared homozygosity in individuals with NAM. The additional genotyping data narrowed the region to one common segment of homozygosity spanning D12S398 to rs3842936 mapping to 12q13.13-14.1. Notably, loss of heterozygosity estimates from the SNP data also detected this same 12q region in the affected individuals. This study reports the first gene mapping of Native American myopathy (NAM) using single-nucleotide polymorphism-based homozygosity mapping in only a few affected individuals from simplex families and identified a novel NAM locus. Identifying the genetic basis of NAM may suggest new genetic etiologies for other more common conditions such as congenital myopathy and malignant hyperthermia.

Functional effects of mutations identified in patients with Multiminicore disease

Multiminicore disease is a recessive congenital myopathy characterized by the presence of small cores or areas lacking oxidative enzymes, in skeletal muscle fibres. From a clinical point of view, the condition is widely heterogeneous and at least four phenotypes have been identified; genetic analysis has revealed that most patients with the classical form of multiminicore characterized by rigidity of the spine, early onset and respiratory impairment harbour recessive mutations in the SEPN1 gene, whereas the majority of patients belonging to the other categories, including patients with ophthalmoplegia or patients with a phenotype similar to central core disease, carry recessive mutations in the RYR1. In the present review we discuss the most recent findings on the functional effect of mutations in SEPN1 and RYR1 and discuss how they may adversely affect muscle function and lead to the clinical phenotype.

Early onset myopathy with a novel mutation in the Selenoprotein N gene ( SEPN1)

Mutations in SEPN1 have been associated with three autosomal recessive congenital myopathies, including rigid spine muscular dystrophy, multiminicore disease and desmin-related myopathy with Mallory body-like inclusions. These disorders constitute the SEPN1 related myopathies (SEPN-RM). On the basis of clinical and laboratory features compatible with SEPN-RM, we performed mutation analysis of SEPN1 in 11 unrelated patients and found one case with pathogenic mutations. He showed early onset axial muscle weakness and developed scoliosis with respiratory insufficiency. Muscle biopsy showed increased variability of fiber size and slight, focal increase of connective tissue. A few fibers showed mini-core changes. SEPN1 mutation analysis revealed that the patient was a compound heterozygote: a previously described insertion (713–714 insA), and a novel nonsense mutation (R439stop).