Rigid Spine Muscular Dystrophy Research Articles

A Case Report of Two Bahraini Siblings Presenting with Different Rare Neurogenetic Disorders: Congenital Insensitivity to Pain with Anhidrosis and Rigid Spine Muscular Dystrophy

AbstractCongenital insensitivity to pain and anhidrosis (CIPA) is a rare autosomal recessive disease and can pose a diagnostic challenge, as the initial presentation of the disease is varied and can be attributed to different causes. Muscular dystrophies are genetically and clinically heterogeneous. We describe a 2-year-old Bahraini boy who was evaluated in the neonatal period for pyrexia of unknown origin, and then noticed to have recurrent respiratory and gastrointestinal infections during infancy and abnormal behavior (self-mutilation). Whole-exome sequencing identified homozygous pathogenic variant in the NTRK1 gene. His 4 years old sister was followed by the pediatric neurology team for unexplained fluctuating muscle weakness since the age of 2 years. A genetic etiology was suspected in her case, in view of positive family history with similar presentation and the whole-exome sequencing revealed homozygous likely pathogenic variant in the SELENON gene, consistent with a genetic diagnosis of autosomal recessive disorders associated with SELENON gene.

Genetics and muscle pathology in the diagnosis of muscular dystrophies: An update.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders involving the skeletal muscles. They have a progressive clinical course and are characterized by muscle fiber degeneration. Congenital muscular dystrophies (CMD) include dystroglycanopathies, merosin-deficient CMD, collagen VI-deficient CMD, SELENON-related rigid spine muscular dystrophy, and LMNA-related CMD. Childhood and adult-onset muscular dystrophies include dystrophinopathies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Traditionally, muscle biopsy and histopathology along with special pathology techniques such as immunohistochemistry or immunoblotting were used for the diagnosis of muscular dystrophies. However, recent advances in molecular genetic testing, especially the next-generation sequencing technology, have revolutionized the diagnosis of muscular dystrophies. Identification of the underlying genetic basis helps in appropriate management and prognostication of the affected individual and genetic counseling of the family. In addition, identification of the exact disease-causing mutations is necessary for accurate prenatal genetic testing and carrier testing, to prevent recurrence in the family. Mutation identification is also essential for initiating mutation-specific therapies (which have been developed recently, especially for Duchenne muscular dystrophy) and for enrolment of patients into ongoing therapeutic clinical trials. The 'genetic testing first' approach has now become the norm in most centers. Nonetheless, muscle biopsy-based testing still has an important role to play, especially for cases where genetic testing is negative or inconclusive for the etiology.

1264 Innovation and Ingenuity to Improve Treatment Efficacy of Non-Invasive Positive Pressure Ventilation

Abstract Introduction Use of chronic non-invasive-positive-pressure ventilation (NIPPV) in individuals with neuromuscular disease allows for increased independence and mobility in this population. Optimal mask fit is imperative due to the chronic and extensive device use. Commonly cited side effects of improper mask fit include air leak, dermatitis, skin breakdown, nasal discomfort, and claustrophobia. Report of Case This is a case report of a 46-year-old female with rigid spine muscular dystrophy leading to chronic hypercarbic respiratory failure secondary to neuromuscular weakness and thoracic cage abnormalities. The patient is dependent on continuous use of NIPPV with a PLV 100 device (Philips Respironics; discontinued model). The patient prefers this model because of its unique ventilation delivery mode, which allows her to pause breaths to speak. The patient developed a significant air leak with her nasal mask and was unable to be fitted properly with commercially available nasal masks. In order to minimize her air leak her husband used an innovative approach using 3D printing technology. He created a 3D print of her facial and nose features and then used this to print a 3D mask. Additionally he 3D printed silicone nose clips, that reinforced the seal on the outside of her nose. The patient had a significant decrease in her air leak and subjectively reported improved comfort with use of the 3D printed mask. Conclusion This represents a case where application of ingenuity and innovative technology improved treatment efficacy and compliance with NIPPV. The combination of 3D custom fit mask (currently available from a limited number of vendors), with custom fit nasal clips may possibly be applied to a wider category of patients with similar complaints of nasal discomfort and frequent air leaks.

A novel mutation in SEPN1 causing rigid spine muscular dystrophy 1: a Case report

BackgroundMuscular dystrophies are a clinically and genetically heterogeneous group of disorders characterized by variable degrees of progressive muscle degeneration and weakness. There is a wide variability in the age of onset, symptoms and rate of progression in subtypes of these disorders. Herein, we present the results of our study conducted to identify the pathogenic genetic variation involved in our patient affected by rigid spine muscular dystrophy.Case presentationA 14-year-old boy, product of a first-cousin marriage, was enrolled in our study with failure to thrive, fatigue, muscular dystrophy, generalized muscular atrophy, kyphoscoliosis, and flexion contracture of the knees and elbows. Whole-exome sequencing (WES) was carried out on the DNA of the patient to investigate all coding regions and uncovered a novel, homozygous missense mutation in SEPN1 gene (c. 1379 C > T, p.Ser460Phe). This mutation has not been reported before in different public variant databases and also our database (BayanGene), so it is classified as a variation of unknown significance (VUS). Subsequently, it was confirmed that the novel variation was homozygous in our patient and heterozygous in his parents. Different bioinformatics tools showed the damaging effects of the variant on protein. Multiple sequence alignment using BLASTP on ExPASy and WebLogo, revealed the conservation of the mutated residue.ConclusionWe reported a novel homozygous mutation in SEPN1 gene that expands our understanding of rigid spine muscular dystrophy. Although bioinformatics analyses of results were in favor of the pathogenicity of the mutation, functional studies are needed to establish the pathogenicity of the variant.

A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies.

BackgroundFifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies.ResultsOur panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield.ConclusionsOur neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0089-8) contains supplementary material, which is available to authorized users.

G.P.207: Clinical and genetic spectrum in a large cohort of patients with a genetic diagnosis of congenital muscular dystrophies: Analysis of the UK diagnostic service 2001–2013

Congenital muscular dystrophies (CMD) are a highly heterogeneous group of conditions clinically characterized by muscle weakness from birth, or shortly after, and variable involvement of eyes, heart and central nervous system. Some of these disorders are fatal in the first year of life, whereas others have a milder course and are compatible with survival into adulthood. The Dubowitz Neuromuscular Centre (DNC) is the National Specialist Commissioning Team (NSCT) referral centre for CMD in the UK. A few years ago we reported the relative frequency of CMD subtypes referred for clinical assessment to the DNC, with collagen VI related disorders being the most common diagnosis. This study reports the relative frequency and clinical and genetic spectrum of CMD in the entire cohort of UK patients in whom the genetic analysis for the CMD genes was requested between 2001 and 2013, including recently identified dystroglycanopathy genes. A total of 700 DNA samples were referred during this time interval and genetic diagnosis was reached in 366 of them. Detailed clinical information was available for 340 patients; 234 fulfilled a clinical diagnosis of CMD while the others had milder forms, such as LGMD. The most common type of genetically confirmed CMD was laminin α2 related dystrophy (MDC1A) accounting for about 44 % of cases, followed by dystroglycanopathies (26 %), Ullrich CMD (16 %) and Rigid Spine muscular dystrophy associated with SEPN1 gene mutations (14 %). Fifteen patients carried pathogenic mutations in the newly discovered ISPD, GMPPB and B3GALNT2 genes responsible for glycosylation defects in alpha-dystroglycan and here we also describe the associated phenotypes. Our results indicate MDC1A as the most common subtype of CMD in the UK and further expand the clinical and genetic spectrum of CMDs.

One gene, one or many diseases?

The proliferation of clinically distinct muscular dystrophies due to mutations in the same gene (phenotypic heterogeneity) is a challenge for the neurologist who is not a neuromuscular specialist. Lamin A/C gene mutations can be associated with diverse and clearly different phenotypes ranging from neuromuscular syndromes such as Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy to unrelated diseases such as progeria and mandibuloacral dysplasia.1 Other examples of phenotypic heterogeneity represent more subtle variations within the clinical spectrum, such as mutations of SEPN1 , where rigid spine muscular dystrophy shares many clinical features with multicore myopathy.2 Other diseases represent the extremes of a spectrum of severity caused by mutations in a single gene or genes, such as Duchenne and Becker muscular dystrophy, as well as Ullrich congenital muscular dystrophy and Bethlem myopathy. Now that many patients can be characterized at the genetic level, more precise genotype-phenotype associations …

Association of homozygous LMNA mutation R471C with new phenotype: Mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy

We report on a 7-year-old girl with a phenotype combining mandibuloacral dysplasia (MAD), progeria, and rigid spine muscular dystrophy. Mild proximal weakness, contractures, and rigidity of the spine were the primary findings. Although present since birth, dysmorphic manifestations typical for MAD and progeroid features became more prominent with time, and the full clinical phenotype was recognizable at early school age. Her phenotype was caused by a homozygous mutation in LMNA (c.1411C > T, which predicts p.R471C) inherited from the heterozygous, consanguineous, unaffected parents. This mutation has only been reported in compound heterozygous state and was associated with a milder phenotype. Some LMNA mutations are known to cause MAD and overlapping phenotypes (MAD spectrum) in an autosomal recessive pattern. The p.R471C homozygous LMNA mutation causes a severe phenotype of the MAD spectrum. This case extends the clinical spectrum of MAD and further expands the phenotypic range of lamin A/C associated diseases.

A novel homozygous LMNA mutation (R471C) is associated with a complex phenotype combining mandibuloacral dysplasia, rigid spine muscular dystrophy, and progeria

A novel homozygous LMNA mutation (R471C) is associated with a complex phenotype combining mandibuloacral dysplasia, rigid spine muscular dystrophy, and progeria

The phenotype of juvenile selenoprotein N-related myopathy (SEPN1-RM)

Background: The selenoprotein N-related myopathies (SEPN1-RM) comprise four autosomal-recessive disorders: rigid spine muscular dystrophy (RSMD1), a form of multiminicore disease (MmD), a desmin-related myopathy with Mallory body like inclusions and a form of congenital fibre-type disproportion (CFTD).

Ex vivo correction of selenoprotein N deficiency in rigid spine muscular dystrophy caused by a mutation in the selenocysteine codon

Premature termination of translation due to nonsense mutations is a frequent cause of inherited diseases. Therefore, many efforts were invested in the development of strategies or compounds to selectively suppress this default. Selenoproteins are interesting candidates considering the idiosyncrasy of the amino acid selenocysteine (Sec) insertion mechanism. Here, we focused our studies on SEPN1, a selenoprotein gene whose mutations entail genetic disorders resulting in different forms of muscular diseases. Selective correction of a nonsense mutation at the Sec codon (UGA to UAA) was undertaken with a corrector tRNASec that was engineered to harbor a compensatory mutation in the anticodon. We demonstrated that its expression restored synthesis of a full-length selenoprotein N both in HeLa cells and in skin fibroblasts from a patient carrying the mutated Sec codon. Readthrough of the UAA codon was effectively dependent on the Sec insertion machinery, therefore being highly selective for this gene and unlikely to generate off-target effects. In addition, we observed that expression of the corrector tRNASec stabilized the mutated SEPN1 transcript that was otherwise more subject to degradation. In conclusion, our data provide interesting evidence that premature termination of translation due to nonsense mutations is amenable to correction, in the context of the specialized selenoprotein synthesis mechanism.

The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy

The selenoprotein N1-related myopathies comprise rigid spine muscular dystrophy, the “classical” form of multiminicore disease, a desmin-related myopathy with Mallory body like inclusions and a form of congenital fiber-type disproportion. To define the phenotype and long-term clinical course in juvenile Selenoprotein N1-related myopathies 11 juvenile patients from eight families with SEPN1 mutations were assessed over a mean period of 7.2 years. Clinical findings, histomorphological studies, respiratory investigations and genetic data were analyzed: age of manifestation varied within the first 2 years of life with muscle hypotonia, lag of head control and delayed motor development. Further gross motor development was normal in 9/11 patients. All patients were ambulant for at least 1000 m at a mean age of 13.7 years. Eight patients exhibited a rigid spine diagnosed at a mean age of 10 years. All patients had respiratory impairment with a vital capacity ranging from 18% to 65%. Four patients were intermittently nocturnally ventilated at a mean age of 11 years. Body mass index was below 20 (kg m −2) in all patients. Muscle biopsies of eight individuals revealed multiminicores ( n=2), congenital fiber-type disproportion ( n=1), myopathic changes with single cores ( n=2) and unspecific myopathic features ( n=3). Mutations were distributed throughout the entire SEPN1 gene. Although the phenotype of juvenile selenoprotein N1-related myopathies is homogenous regarding the main symptoms we describe a variable degree of clinical severity. Major complications were early respiratory failure, impaired increase in weight and orthopedic problems. There seems to be no correlation between skeletal muscle weakness and respiratory failure.

C.O.6 Selenoprotein N, mutated in SEPN-related myopathy, protects human cells against oxidative stress

Mutations of the selenoprotein N gene (SEPN1) have been identified as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy regrouping four different nosological categories: rigid spine muscular dystrophy, the severe form of classical multiminicore disease, desmin-related myopathy with Mallory body-like inclusions and CFTD. Despite these recent advances, the pathophysiological mechanisms involved in SEPN-RM were not elucidated. SelN is the only selenoprotein implicated in a human genetic disorder but its function remained fully unknown.

C.P.2.11 Expression of selenoprotein N in mice during development and in muscle regeneration

Selenoprotein N-related myopathy is a rare congenital disorder characterized by axial muscle weakness, scoliosis, and respiratory failure, caused by mutations in the selenoprotein N (SelN) encoded by SEPN1. Four pathological entities have been associated with SEPN1 mutations: Rigid Spine Muscular Dystrophy, Multi-minicore Disease, Desmin-Related Myopathy with Mallory Body – like Inclusions, and Congenital Fibre Type Disproportion. SelN is a glycoprotein of unknown function, localized in the membrane of the endoplasmic reticulum, and it is characterized, as all the selenoproteins, by a specific selenocysteine residue.

T.O. 3 Rescue of selenoprotein N deficiency in rigid spine muscular dystrophy caused by a homozygous mutation in the selenocysteine codon of SEPN1

T.O. 3 Rescue of selenoprotein N deficiency in rigid spine muscular dystrophy caused by a homozygous mutation in the selenocysteine codon of SEPN1

Selenoprotein N Muscular Dystrophy

Early spinal rigidity is a nonspecific feature reported in diseases such as neuromuscular and central movement disorders. We present a male patient with rigid spine muscular dystrophy caused by newly identified compound heterozygote mutations of the selenoprotein N gene and discuss this disease as a possible differential diagnosis for early-onset reduced spine mobility. Rigid spine muscular dystrophy is a rare myopathy presenting in childhood with a typical combination of stable or slowly progressive mild to moderate muscle weakness, limitation in flexion of the spine, and progressive restrictive ventilatory disorder. The clinical features of our patient include early-onset rigidity of his spine, scoliosis, mild muscular weakness predominantly of neck and trunk flexors, and restrictive ventilatory disorder. Biopsy of the biceps muscle revealed nonspecific myopathic changes, and molecular analysis confirmed the diagnosis of rigid spine muscular dystrophy. Thus, neuromuscular diseases such as muscular dystrophy must be considered in all patients presenting with early spinal rigidity, and genetic determination is a possible way to determine the diagnosis.

A single homozygous point mutation in a 3′untranslated region motif of selenoprotein N mRNA causes SEPN1‐related myopathy

Mutations in the SEPN1 gene encoding the selenoprotein N (SelN) have been described in different congenital myopathies. Here, we report the first mutation in the selenocysteine insertion sequence (SECIS) of SelN messenger RNA, a hairpin structure located in the 3' untranslated region, in a patient presenting a classical although mild form of rigid spine muscular dystrophy. We detected a significant reduction in both mRNA and protein levels in the patient's skin fibroblasts. The SECIS element is crucial for the insertion of selenocysteine at the reprogrammed UGA codon by recruiting the SECIS-binding protein 2 (SBP2), and we demonstrated that this mutation abolishes SBP2 binding to SECIS in vitro, thereby preventing co-translational incorporation of selenocysteine and SelN synthesis. The identification of this mutation affecting a conserved base in the SECIS functional motif thereby reveals the structural basis for a novel pathological mechanism leading to SEPN1-related myopathy.

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).

Rigid spine muscular dystrophy due to SEPN1 mutation presenting as cor pulmonale

The nonspecific “rigid spine syndrome” (RSS) is characterized by restricted spine mobility, kyphoscoliosis, reduced vital capacity, and nonprogressive proximal weakness. A subgroup of patients is classified as having rigid spine muscular dystrophy (RSMD), a laminin-α2–positive congenital muscular dystrophy. RSMD linked to chromosome 1p35–361 is caused by mutation in the SEPN1 gene encoding selenoprotein N.2 We describe a patient with RSMD, homozygous for an SEPN1 mutation, who had life-threatening yet reversible right heart failure caused by severe involvement of the diaphragm with nocturnal hypoventilation and pulmonary hypertension. He improved with nocturnal ventilatory assistance. The clinical and genetic findings in his mother and seven siblings are also described. Born to nonconsanguineous healthy parents, the patient was the youngest of 10 children. Developmental motor milestones were normal. Slight difficulty running and climbing stairs, restricted neck movements, elbow contractures, and scoliosis were noted during childhood and adolescence. Family history was unremarkable. He presented at age 26 years with rapidly progressive respiratory and right heart failure with cough, orthopnea, interrupted …

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.