Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy.

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

Homozygous deletion of an EGR2 enhancer in congenital amyelinating neuropathy.

The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.

New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease.

In this report, we describe a new mutation located in the coiled 1B domain of desmin and associated with a predominant cardiac involvement and a high degree of cardiac sudden death in a large Indian pedigree with 12 affected members. The index cases was 38-year-old man who presented with progressive difficulty in gripping footwear of 5 years duration with the onset in the left lower limb followed by right lower limb in 6 months. 3 years from onset, he developed lower limb proximal and truncal muscle weakness. There was mild atrophy of the shoulder girdle muscles with grade 3 weakness, moderate wasting of thigh and anterior leg muscles with proximal muscle weakness and foot drop. At 40 years, he had a pacemaker implanted. The 9 exons and intronic boundaries of the desmin gene were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was identified.

[The Schwartz-Jampel syndrome]. / Le syndrome de Schwartz-Jampel.

The Schwartz-Jampel syndrome (SJS, OMIM #255800) is an ultra-rare genetic disease characterized by myotonic manifestations combined with bone and cartilage abnormalities. Following an autosomal recessive mode of inheritance, its prevalence is more significant in highly-inbred areas. The unraveling of the HSPG2 gene encoding a protein of the basal lamina enabled a better nosological delineation of the syndrome. The diagnosis is usually strongly suspected at the clinical level and then confirmed by molecular biology. To date, the treatment remains essentially symptomatic.

Title: Le syndrome de Schwartz-Jampel. Abstract: Le syndrome de Schwartz-Jampel (SJS, OMIM #255800) est une affection génétique ultra-rare définie par des manifestations myotoniques et des anomalies ostéo-articulaires. Transmis selon un mode autosomique récessif, sa prévalence est plus élevée dans les zones de forte endogamie. La découverte du gène HSPG2 codant une protéine de la lame basale a permis de mieux en délimiter les contours nosologiques. Le diagnostic est généralement très fortement suspecté cliniquement puis confirmé en biologie moléculaire. Le traitement reste à ce jour essentiellement symptomatique.

What is the Next Step after an Electrodiagnostic Study in Children with Polyneuropathies? Rationale for Laboratory and Other Diagnostic Tests.

The etiology of polyneuropathies varies in the pediatric population, where hereditary or metabolic disorders are far more common than in adults. However, treatable polyneuropathies, also prevalent in these settings, are those to prioritize. Moreover, diagnosing subacute and chronic symptoms in children can be challenging compared to adults. Therefore, selecting the best and most relevant laboratory investigations and paraclinical studies is critical. This taskcan be relatively challenging in countries with limited resources or insurance coverage. This study describe the various types of polyneuropathies found in children and their characteristics and suggest an algorithm for using the best laboratory tests in the context of the Iranian healthcare system.

Impact of restricted access to, and low awareness of, mexiletine on people with myotonia: a real-world European survey.

Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research survey conducted January-June 2018 to evaluate consequences of limited access to/awareness of mexiletine in people with myotonia. Part A: qualitative structured interviews (clinicians; advocates for adult patients); Part B: quantitative online questionnaire completed by people with self-reported history of myotonia. Part A: Interviews (clinicians, n=12; patient advocates, n=5; 12 countries) indicated poor mexiletine awareness among general neurologists. Patients chose between living with myotonia (other treatments were generally unsatisfactory) or importing mexiletine. Part B: Questionnaire respondents, myotonic dystrophy (DM)1, n=213; DM2, n=128; non-dystrophic myotonia (NDM), n=41; other n=8; (11 countries). Of the respondents, 76/390 (20%) people with awareness of/access to mexiletine described profound improvements in myotonia and health-related quality of life following treatment. Respondents with NDM had greatest mexiletine experience (n=28/41). Mexiletine was associated with fewer falls, less muscle stiffness, increased mobility. Treatment interruptions worsened myotonia and were associated with fatigue, pain, dysphagia, breathing difficulty, impaired digestion, poor sleep. However, 36/54 (67%) of currently treated people expressed anxiety about mexiletine's availability: this finding was expected (MyoPath was undertaken before mexiletine's approval in NDM). MyoPath provides the largest European exploration of patients' views regarding impact of mexiletine on myotonia. Anticipated effects of mexiletine differ between people with different myotonic disorders: myotonia is the main symptom in NDM but one of many potential symptoms affecting those with DM. Nevertheless, findings indicate substantial harm caused to people with myotonia when mexiletine awareness/access is limited.

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.

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.

BACKGROUND: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. OBJECTIVE: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. METHODS: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. RESULTS: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4% of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3% of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17% of patients). These disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5% of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. CONCLUSIONS: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

[The SMA France national registry: already encouraging results]. / Le registre national SMA France : des résultats déjà encourageants.

Spinal muscular atrophy is a debilitating neuromuscular disease due to the deletion of the SMN1 gene (SMA). The emergence of innovative targeted therapies changed the natural history of this condition. The French registry of SMA (Registre SMA France) was launched in 2020 to obtain a better knowledge of the pathology. The goal of the register was also to meet the need for real-life data regarding the arrival of these innovative therapies in order to identify the best therapeutic strategies and to improve patient care. The registry collects retrospective and prospective data of all genetically confirmed SMA, treated or not treated, in reference centers belonging to the national neuromuscular network (FILNEMUS). The estimated enrollment is 1,000 patients (50% children). On October 1st, 666 patients have been enrolled (357 children and 309 adults) by 44 out of 51 open centers of the national network (FILNEMUS) with: 150 type 1 (22%); 278 type 2 (42%), 232 type 3 (35%) and 4 type 4 (1%) respectively.

TITLE: Le registre national SMA France : des résultats déjà encourageants. ABSTRACT: L'amyotrophie spinale proximale liée au gène SMN1 (SMA) est une maladie neuromusculaire invalidante dont l'histoire naturelle a été sensiblement modifiée ces dernières années du fait de l'apparition de thérapies innovantes. Le registre SMA France a été mis en place en 2020 afin de mieux connaître la pathologie et répondre au besoin de données en vie réelle induit par l'arrivée de ces nouveaux médicaments. Le but est aussi d'essayer d'identifier les meilleures stratégies thérapeutiques et d'améliorer in fine la prise en charge de ces patients. Ce registre a le statut d'entrepôt de données de santé et collecte des informations rétrospectives et prospectives de patients SMA de tous types, génétiquement confirmés, traités ou non par thérapies innovantes, et suivis dans les centres du réseau FILNEMUS. La population-cible est estimée à 1 000 patients, dont la moitié d'âge pédiatrique. Au 1er octobre 2021, 666 patients ont été inclus dans la base (357 enfants et 309 adultes) par 44 des 51 centres spécialisés du réseau neuromusculaire FILNEMUS ayant accepté de participer. Parmi ces patients, 150 étaient de type 1 (22 %), 278 (42 %) de type 2, 232 (35 %) de type 3, et 4 de type 4 (1 %).

[The Frozen Man and the Chinese Alphabet]. / L'Homme Gelé (渐冻人) et le déficit en cristalline αB.

The Confucian philosophy teaches us that the search for truth does not always follow a straight line. The clinical observation presented here illustrates this perfectly and is about a child afflicted by a rare neuromuscular disorder (in Chinese, the word 'myopathy' is translated to meaning 'frozen man') in whom was suspected a deficit in αB crystallin. The authors take the opportunity to put the spotlight on China, this great country which did not wait for Alain Peyrefitte to wake up or, more precisely, to rewake. In the light of past and recent missions in the former Middle Kingdom, an update is made on the medico-scientific but also societal issues of this country on the verge of becoming, perhaps, a giant in the field of neuromuscular diseases.

TITLE: L'Homme Gelé (渐冻人) et le déficit en cristalline αB. ABSTRACT: La philosophie confucéenne nous enseigne que la recherche de la vérité n'emprunte pas toujours un chemin rectiligne. L'observation clinique présentée ici l'illustre parfaitement. Il y est question d'un enfant souffrant d'une maladie neuromusculaire rare (en chinois, le mot myopathie se traduit par 渐冻人 soit « homme gelé ¼) chez qui fut suspecté un déficit en cristalline αB. Les auteurs profitent de l'occasion pour mettre le projecteur sur la Chine, ce grand pays qui n'a pas attendu Alain Peyrefitte pour s'éveiller ou, plus exactement, se réveiller. à la lumière de missions passées et récentes dans l'ex-Empire du Milieu, le point est fait sur les enjeux médico-scientifiques mais aussi sociétaux de ce pays en passe de devenir, peut-être, un géant dans le domaine des maladies neuromusculaires.

The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

[When all roads lead to Africa ]. / Quand tous les chemins mènent à l'Afrique .

Congenital myopathies represent a quite heterogeneous group of neuromuscular disorders both at the clinical and genetic level. High-throughput sequencing (NGS), targeted or not, combined with muscle pathology, greatly facilitate their accurate characterization and occasionally lead to unexpected discoveries like in the case reported here in a Kuwaiti family facing a long diagnostic odyssey.

TITLE: Quand tous les chemins mènent à l'Afrique…. ABSTRACT: Les myopathies congénitales constituent un ensemble hétérogène de maladies neuromusculaires aussi bien sur le plan clinique que génétique. Le séquençage à haut débit, ciblé ou non, couplé à l'analyse de la biopsie musculaire, facilite grandement leur caractérisation précise et conduisent parfois à des découvertes inattendues comme dans le cas rapporté ci-dessous d'une famille koweitienne en errance diagnostique depuis de nombreuses années.

Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome.

OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. CONCLUSIONS: GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.

Dysferlinopathies.

Dysferlinopathies encompass a large variety of neuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. So far, three main phenotypes have been reported: Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). A growing number of clinical variants have recently been described with a much wider range of symptoms and onset. Although rare, dysferlinopathies can account for up to 30% of progressive recessive muscular dystrophies in certain geographical areas, notably in the Middle East and the Indian subcontinent. Dysferlin is a large protein involved in membrane repair and vesicle trafficking and interacts probably with important immunological pathways. New insights in its pathophysiology may result in innovative therapies in the near future.