Contractile properties and magnetic resonance imaging-assessed fat replacement of muscles in myotonia congenita.

BACKGROUND AND PURPOSE: Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients. METHODS: Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole-body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross-sectional area (PT/CCSA). Muscle contractility was compared with clinical data. RESULTS: Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0-14.3% vs. 5.3-9.6%, PT/CCSA = 1.1-4.9 Nm/cm2 vs. 1.9-5.8 Nm/cm2 [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms. CONCLUSIONS: Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.

Clinico-pathological features and mutational spectrum of 16 nemaline myopathy patients from a Chinese neuromuscular center.

Nemaline myopathy (NM) is a congenital myopathy of great heterogeneity, characterized by the presence of rods in the cytoplasm of muscle fibers. The samples of 16 nemaline myopathy patients diagnosed by characteristically pathological features went through whole exon sequencing. Clinico-pathological and genetic features of the cases were systematically analyzed. According to the classification of nemaline myopathy by ENMC, 8 cases are typical congenital subtype, 6 cases are childhood/juvenile onset subtype and 2 case are adult onset subtype. In histological findings, characteristic purple-colored rods are discovered under modified gömöri trichrome staining (MGT). Electron microscopy revealed the presence of high electron-dense nemaline bodies around the submucosa and the nucleus nine patients (9/16 56.3%) were detected pathogenic causative mutations, among whom mutations in the NEB gene were the most frequent (6 patients, 66.7%). KBTBD13 gene mutation was discovered in two patients and ACTA1 gene mutation was discovered in 1 patient. Nemaline myopathy is a congenital myopathy with highly clinico-pathological and genetic heterogeneity. NEB gene mutation is the most common mutation, in which splicing change c.21522 +3A > G is hotspot mutation in Chinese NM patients.

Phenotypic Variability of MEGF10 Variants Causing Congenital Myopathy: Report of Two Unrelated Patients from a Highly Consanguineous Population.

Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in MEGF10 (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel MEGF10 deleterious variants. Interestingly, the presence of MEGF10 associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.

KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf.

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.

Diagnostic yield of muscle biopsy in infants: Retrospective analysis of clinical and histopathologic findings.

The aim was to define the clinical and histopathologic findings of infants who underwent muscle biopsy and identify the diagnostic yield of muscle biopsy in this cohort. Infants who underwent muscle biopsy from January 2010 to March 2017 at a tertiary hospital were included in the study (N = 87; 64 boys (73.6%), 23 girls (26.4%); age range 0 - 2 years; mean age 9.73 ± 7.04 months). Clinical and histopathologic data were obtained from medical records. Developmental delay (64.4%) and hypotonia (59.8%) were the most frequent clinical findings, and mitochondrial disease (61%) was the most frequent clinical diagnosis, followed by muscular dystrophy (15.9%) and congenital myopathy (11.5%). Creatine kinase level was normal in 65.9% and > 1,000 U/L in 17.1%. Specific pathologic findings were identified from 38 biopsies (43.7%). The most frequent pathologic findings were features compatible with mitochondrial/metabolic myopathy (14 patients, 16.1%) and muscular dystrophy (12 patients, 13.8%). Myopathic changes were present in 7 biopsy samples (8.0%) and neurogenic changes in 5 (5.7%). The clinical and pathologic diagnoses were compatible in 24 patients (63.2%). The diagnostic yield of muscle biopsy remains significant, especially in this age group. Mitochondrial disease is a major diagnostic challenge, and muscle biopsy helps to support the clinical diagnosis and guide further studies.

Association of Three Different Mutations in the CLCN1 Gene Modulating the Phenotype in a Consanguineous Family with Myotonia Congenita.

Myotonia congenita is a genetic disease caused by mutations in the CLCN1 gene, which encodes for the major chloride skeletal channel ClC-1, involved in the normal repolarization of muscle action potentials and consequent relaxation of the muscle after contraction. Two allelic forms are recognized, depending on the phenotype and the inheritance pattern: the autosomal dominant Thomsen disease with milder symptoms and the autosomal recessive Becker disorder with a severe phenotype. Before the recent advances of molecular testing, the diagnosis and genetic counseling of families was a challenge due to the large number of mutations in the CLCN1 gene, found both in homozygous or in heterozygous state. Here, we studied a consanguineous family in which three members presented a variable phenotype of myotonia, associated to a combination of three different mutations in the CLCN1 gene. A pathogenic splicing site mutation which causes the skipping of exon 17 was present in homozygosis in one very severely affected son. This mutation was present in compound heterozygosis in the consanguineous parents, but interestingly it was associated to a different second variant in the other allele: c.1453 A > G in the mother and c.1842 G > C in the father. Both displayed variable, but less severe phenotypes than their homozygous son. These results highlight the importance of analyzing the combination of different variants in the same gene in particular in families with patients displaying different phenotypes. This approach may improve the diagnosis, prognosis, and genetic counseling of the involved families.

Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Recessive myotonia congenita caused by a homozygous splice site variant in CLCN1 gene: a case report.

BACKGROUND: Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state. CASE PRESENTATION: We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities. CONCLUSIONS: Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.

Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy.

Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as 3 weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in type I (slow) myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a congenital myopathy with dystrophic features. In this study, we performed whole genome sequencing of OCPMD sheep and identified a single base deletion at the splice donor site (+ 1) of intron 13 in the type I myofibre-specific TNNT1 gene (KT218690 c.614 + 1delG). All affected sheep were homozygous for this variant. Examination of TNNT1 splicing by RT-PCR showed intron retention and premature termination, which disrupts the highly conserved 14 amino acid C-terminus. The variant did not reduce TNNT1 protein levels or affect its localization but impaired its ability to modulate muscle contraction in response to Ca2+ levels. Identification of the causative variant in TNNT1 finally clarifies that the OCPMD sheep is in fact a large animal model of TNNT1 congenital myopathy. This model could now be used for testing molecular or gene therapies.

Extension of the phenotypic spectrum of GLE1-related disorders to a mild congenital form resembling congenital myopathy.

BACKGROUND: GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture syndrome 1 (LCCS1, OMIM#253310) and congenital arthrogryposis with anterior horn cell disease (CAAHD, OMIM#611890). The clinical spectrum of GLE1-related disorders has been expanding these past years, including with adult-onset amyotrophic lateral sclerosis (ALS) GLE1-related forms, especially through the new molecular diagnosis strategies associated with the emergence of next-generation sequencing (NGS) technologies. However, despite this phenotypic variability, reported congenital or ALS adult-onset forms remain severe, leading to premature death. METHODS: Through multidisciplinary interactions between our Neuropediatric and Medical Genetics departments, we were able to diagnose two siblings presenting with congenital disorder, using an NGS approach accordingly to the novel French national recommendations. RESULTS: Two siblings with very similar clinical features, meaning neuromuscular disorder of neonatal onset with progressive improvement, were examined in our Neuropediatrics department. The clinical presentation evoked initially congenital myopathy with autosomal recessive inheritance. However, additional symptoms such as mild dysmorphic features including high anterior hairline, downslanted palpebral fissures, anteverted nares, smooth philtrum with thin upper-lip, narrow mouth and microretrognathia or delayed expressive language and postnatal growth retardation were suggestive of a more complex clinical presentation and molecular diagnosis. Our NGS approach revealed an unexpected molecular diagnosis for these two siblings, meaning the presence of the homozygous c.1808G>T GLE1 variant. CONCLUSIONS: We here report the mildest phenotype ever described, in two siblings carrying the homozygous c.1808G>T GLE1 variant, further widening the clinical spectrum of GLE1-related diseases. Moreover, by reflecting current medical practice, this case report confirms the importance of establishing regular multidisciplinary meetings, essential for discussing such difficult clinical presentations to finally enable molecular diagnosis, especially when NGS technologies are used.

A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset.

BACKGROUND: αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance. METHODS: The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques. RESULTS: CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization. CONCLUSIONS: The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.

Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations.

Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.

Congenital Myotonic Dystrophy and Brugada Syndrome: A Report of Two Cases.

BACKGROUND Congenital myotonic dystrophy is a subtype of type 1 myotonic dystrophy presenting in the neonatal period. Cardiac involvement is commonly seen in patients with type 1 myotonic dystrophy beyond the neonatal period. Brugada syndrome is a conduction abnormality associated with a mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and has been described in adult patients with type 1 myotonic dystrophy. Two cases are presented of type 1 myotonic dystrophy in neonates, one who had family members with a confirmed diagnosis of Brugada syndrome. CASE REPORT Case 1: A female infant at 40 weeks gestational age, birth weight of 3,395 grams was born to a 40-year-old gravida 4, para 3 (G4P3) mother. The mother had previously been diagnosed with Brugada syndrome. Multiple family members were identified and diagnosed with type 1 myotonic dystrophy and Brugada syndrome. The infant is being monitored closely with a plan to perform genetic testing for Brugada syndrome if she develops cardiac conduction abnormalities. Case 2: A male infant at 37 weeks gestational age, with a birth weight of 2,900 grams, was born to a 24-year-old gravida 2, para 1 (G2P1) mother. He was admitted to the neonatal intensive care unit (NICU) secondary to poor respiratory effort and generalized hypotonia. Severe polyhydramnios was diagnosed during pregnancy. The mother had previously been diagnosed with type 1 myotonic dystrophy. CONCLUSIONS Infants with congenital myotonic dystrophy should be carefully monitored for both structural and conduction abnormalities of the heart, supported by genetic testing.

[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.

Transcriptomic Analysis Reveals Involvement of the Macrophage Migration Inhibitory Factor Gene Network in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of dystrophin determines membrane instability, causing cell damage and inflammatory response. Macrophage migration inhibitory factor (MIF) is a cytokine that exerts pleiotropic properties and is implicated in the pathogenesis of a variety of diseases. Recently, converging data from independent studies have pointed to a possible role of MIF in dystrophic muscle disorders, including DMD. In the present study, we have investigated the modulation of MIF and MIF-related genes in degenerative muscle disorders, by making use of publicly available whole-genome expression datasets. We show here a significant enrichment of MIF and related genes in muscle samples from DMD patients, as well as from patients suffering from Becker's disease and limb-girdle muscular dystrophy type 2B. On the other hand, transcriptomic analysis of in vitro differentiated myotubes from healthy controls and DMD patients revealed no significant alteration in the expression levels of MIF-related genes. Finally, by analyzing DMD samples as a time series, we show that the modulation of the genes belonging to the MIF network is an early event in the DMD muscle and does not change with the increasing age of the patients, Overall, our analysis suggests that MIF may play a role in vivo during muscle degeneration, likely promoting inflammation and local microenvironment reaction.

[Diagnosis and treatment of congenital myopaties]. / Diagnóstico y tratamiento de las miopatías congénitas.

Important advances have been made in the field of congenital myopathies in recent years, forcing clinicians to constantly review and update this group of diseases. The increasing identification of new genes and phenotypes associated with already known genes has been possible to a great extent thanks to the development accomplished in next generation sequencing techniques, which are increasingly accessible. Knowing better the phenotypic spectrum of these entities allows to establish a phenotype/genotype correlation in some subgroups. The best understanding of the pathophysiology and natural history of these diseases are fundamental to design new therapies. The first clinical trials in the field of gene therapy are already a reality and are showing positive results, creating a new expectation for patients, families and specialists, which will be reflected in the need to adapt the protocols of care, diagnosis and treatment of some of these entities. It is essential that pediatric neurologists, pediatricians, physiotherapists and other professionals involved in the care of these patients are informed and updated on the advances in this group of diseases.

Existen importantes avances en el campo de las miopatías congénitas en los últimos años que obligan a la revisión y actualización constante de este grupo de enfermedades. La identificación creciente de nuevos genes y fenotipos asociados a genes ya conocidos, fue posible en gran medida gracias al avance de las técnicas de secuenciación de nueva generación, cada vez más accesibles. El conocer mejor el espectro fenotípico de estas entidades, permite establecer una correlación fenotipo/genotipo en algunos subgrupos. La mejor compresión de la fisiopatología e historia natural de estas enfermedades, son fundamentales para el desarrollo de nuevas terapias. Los primeros ensayos clínicos en el campo de la terapia génica ya son una realidad y están mostrando resultados positivos, creando una nueva expectativa en paciente, familiares y especialistas, lo que se verá reflejado en la necesidad de adaptar los protocolos de atención, diagnóstico y tratamiento de algunas de estas entidades. Es fundamental que los neuropediatras, pediatras, fisioterapeutas y otros profesionales involucrados en el cuidado de estos pacientes, estén informados y actualizados de los avances en este grupo de enfermedades.

Identification of two novel compound heterozygous CLCN1 mutations associated with autosomal recessive myotonia congenita.

Objectives: Myotonia congenita (MC) is a rare genetic muscular disorder caused by CLCN1 mutations, which codes for skeletal muscle chloride channel CLC1. MC is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness. This study aimed to identify the genetic etiology of a Chinese family affected with recessive MC. Methods: Whole exome sequencing was performed to identify the disease-associated variants. The candidate causal genes discovered by WES were then confirmed by Sanger sequencing and co-segregation analyses were also conducted. Results: Two novel compound heterozygous mutations in CLCN1 gene, p.D94Y (paternal allele) and p.Y206* (maternal allele), were successfully identified as the pathogenic mutations by whole-exome sequencing (WES). The mutations were confirmed with Sanger sequencing in the family members and cosegregated with the MC phenotype. The two mutations have not been reported in the HGMD, dbSNP, 1000 Genomes project, ClinVar database, ExAC, and gnomAD previously. Mutation p.D94Y is predicted to be deleterious by using in silico tools and p.Y206* is a nonsense mutation, causing protein synthesis termination. Conclusions: Molecular genetics analysis offers an accurate method for diagnosing MC. Our results expand the mutational spectrum of recessive MC.

Diagnóstico y tratamiento de las miopatías congénitas / Diagnosis and treatment of congenital myopaties

Existen importantes avances en el campo de las miopatías congénitas en los últimos años que obligan a la revisión y actualización constante de este grupo de enfermedades. La identificación creciente de nuevos genes y fenotipos asociados a genes ya conocidos, fue posible en gran medida gracias al avance de las técnicas de secuenciación de nueva generación, cada vez más accesibles. El conocer mejor el espectro fenotípico de estas entidades, permite establecer una correlación fenotipo/genotipo en algunos subgrupos. La mejor compresión de la fisiopatología e historia natural de estas enfermedades, son fundamentales para el desarrollo de nuevas terapias. Los primeros ensayos clínicos en el campo de la terapia génica ya son una realidad y están mostrando resultados positivos, creando una nueva expectativa en paciente, familiares y especialistas, lo que se verá reflejado en la necesidad de adaptar los protocolos de atención, diagnóstico y tratamiento de algunas de estas entidades. Es fundamental que los neuropediatras, pediatras, fisioterapeutas y otros profesionales involucrados en el cuidado de estos pacientes, estén informados y actualizados de los avances en este grupo de enfermedades.

Important advances have been made in the field of congenital myopathies in recent years, forcing clinicians to constantly review and update this group of diseases. The increasing identification of new genes and phenotypes associated with already known genes has been possible to a great extent thanks to the development accomplished in next generation sequencing techniques, which are increasingly accessible. Knowing better the phenotypic spectrum of these entities allows to establish a phenotype/genotype correlation in some subgroups. The best understanding of the pathophysiology and natural history of these diseases are fundamental to design new therapies. The first clinical trials in the field of gene therapy are already a reality and are showing positive results, creating a new expectation for patients, families and specialists, which will be reflected in the need to adapt the protocols of care, diagnosis and treatment of some of these entities. It is essential that pediatric neurologists, pediatricians, physiotherapists and other professionals involved in the care of these patients are informed and updated on the advances in this group of diseases.

Dihydropyridine Receptor Congenital Myopathy In A Consangineous Turkish Family.

Dihydropyridine receptor congenital myopathy is a recently described congenital myopathy caused by dominant or recessive mutations in the CACNA1S gene. To date, only 11 cases from 7 families were described in a single report. Here, we describe a consanguineous family with three affected children, presenting congenital hypotonia, contractures, ophthalmoplegia and respiratory insufficiency, with a novel homozygous mutation in the CACNA1S gene. They also showed cognitive delay, pes equinovarus deformity and neurogenic changes that have not been associated with this myopathy in the previous reports. This report expands the phenotypic spectrum of dihydropyridine receptor congenital myopathy and underscores the importance of whole exome sequencing in early onset neuromuscular disorders.