Improving Diagnostic Precision: Phenotype-Driven Analysis Uncovers a Maternal Mosaicism in an Individual with RYR1-Congenital Myopathy.

Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.

Full-Length SMN Transcript in Extracellular Vesicles as Biomarker in Individuals with Spinal Muscular Atrophy Type 2 Treated with Nusinersen.

BACKGROUND: Three therapeutic strategies have radically changed the therapeutic scenario for spinal muscular atrophy (SMA). However, therapeutic response differs between individuals. There is a need to identify biomarkers to further assess therapeutic response and to better understand which variables determine the extent of response. METHODS: We conducted a study using an optimized digital droplet PCR-based method for the ultra-sensitive detection of SMN transcript in serum EVs from SMA 2 individuals treated with nusinersen over 14 months. In parallel, we investigated levels of serum and CSF neurofilament heavy chain (pNF-H) in the same cohort. RESULTS: Expression of flSMN transcript in EVs of SMA 2 individuals prior to nusinersen was lower than in controls (0.40 vs 2.79 copies/ul; p < 0.05) and increased after 14 months of nusinersen (0.40 vs 1.11 copies/ul; p < 0.05). The increase in flSMN with nusinersen was significantly higher in younger individuals (p < 0.05). Serum pNF-h was higher in non-treated individuals with SMA 2 than in controls (230.72 vs 22.88 pg/ml; p < 0.05) and decreased with nusinersen (45.72 pg/ml at 6 months, 39.02 pg/ml at 14 months). CSF pNF-h in SMA 2 individuals also decreased with nusinersen (248.04 pg/ml prior to treatment, 197.10 pg/dl at 2 months, 104.43 pg/dl at 6 months, 131.03 pg/dl at 14 months). CONCLUSIONS: We identified an increase of flSMN transcript in serum EVs of SMA 2 individuals treated with nusinersen that was more pronounced in the younger individuals. Our results indicate that flSMN transcript expression in serum EVs is a possible biomarker in SMA to predict or monitor the response to treatment.

LMNA-related muscular dystrophy: Identification of variants in alternative genes and personalized clinical translation.

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences. Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes. Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, ß, δ and γ-sarcoglycans, and α and ß-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

Common pathophysiology for ANXA11 disorders caused by aspartate 40 variants.

OBJECTIVE: Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a cause of multisystem proteinopathy and adult-onset muscular dystrophy. These conditions are adult-onset diseases and result from the substitution of Aspartate 40 (Asp40) for an apolar residue in the intrinsically disordered domain (IDD) of ANXA11. Some ALS-related variants are known to affect ANXA11 IDD; however, the mechanism by which the myopathy occurs is unknown. METHODS: Genetic analysis was performed using WES-trio. For the study of variant pathogenicity, we used recombinant proteins, muscle biopsy, and fibroblasts. RESULTS: Here we describe an individual with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy who carries a new ANXA11 variant at position Asp40 (p.Asp40Ile; c.118_119delGAinsAT). p.Asp40Ile is predicted to enhance the aggregation propensity of ANXA11 to a greater extent than other changes affecting this residue. In vitro studies using recombinant ANXA11p.Asp40Ile showed abnormal phase separation and confirmed this variant is more aggregation-prone than the ALS-associated variant ANXA11p.Asp40Gly . The study of the patient's fibroblasts revealed defects in stress granules dynamics and clearance, and muscle histopathology showed a myopathic pattern with ANXA11 protein aggregates. Super-resolution imaging showed aggregates expressed as pearl strips or large complex structures in the sarcoplasm, and as layered subsarcolemmal chains probably reflecting ANXA11 multifunctionality. INTERPRETATION: We demonstrate common pathophysiology for disorders associated with ANXA11 Asp40 allelic variants. Clinical phenotypes may result from different deleterious impacts of variants upon ANXA11 stability against aggregation, and differential muscle or motor neuron dysfunction expressed as a temporal and tissue-specific continuum.

Pathological Features in Paediatric Patients with TK2 Deficiency.

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype.

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases.

Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients' fibroblasts except for CHKB Q198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1 W67L/W67L, DRP1 K75E/+, OPA1 F570L/+, and FXN R165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1 W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2 R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1 W67L/W67L and MFN2 R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria-lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1 K75E/+, GDAP1 W67L/W67L, OPA1 F570L/+, MFN2 R104W/+, and CHKB Q198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype.

BACKGROUND: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. METHODS: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1. RESULTS: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria. CONCLUSIONS: Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN.

Pediatric SMA patients with complex spinal anatomy: Implementation and evaluation of a decision-tree algorithm for administration of nusinersen.

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50° and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.

Association of Initial Maximal Motor Ability With Long-term Functional Outcome in Patients With COL6-Related Dystrophies.

OBJECTIVE: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness. METHODS: This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD. RESULTS: We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation. CONCLUSION: This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.

The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort.

BACKGROUND: Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts, and the relationship between phenotypes and genotypes is only partially understood. METHODS: This is a retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological, and molecular characterization of 104 patients with CM is reported. RESULTS: The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild-grade endomysial fibrosis (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with "specific" histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65 of 104 patients (62%), with RYR1 (24/104) and TTN (8/104) being the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in one of three patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%. CONCLUSIONS: This study provides an updated picture of the clinical, histopathological, and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy specimens are associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.

Early and long-term effect of the treatment with pyridostigmine in patients with GMPPB-related congenital myasthenic syndrome.

GMPPB mutations cause congenital myasthenic syndromes (CMS) overlapping with muscular dystrophy. Treatment with pyridostigmine has been reported to be effective in those patients. Nevertheless, results of functional motor assessments to determine its precise impact on the short and long term were not available. We describe the response to treatment with pyridostigmine in three siblings with GMPPB-related CMS using functional motor scales performed regularly over a period of 40 months. The beneficial effect of the treatment was outstanding within the first hours, with all the scales showing a dramatic increase in only two days. This remarkable improvement remained steady during 12 months but a moderate decrease was subsequently detected in two of the three patients. Despite this decline in the scores of the scales at the end of follow up, the functional motor status of the patients was still significantly better than it was before starting treatment. The introduction of pyridostigmine at an early age of the disease in one of the patients, before the onset of scoliosis, may have had a protective effect on it.

Epilepsy in LAMA2-related muscular dystrophy: An electro-clinico-radiological characterization.

OBJECTIVE: To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype. METHODS: Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed. RESULTS: Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8 years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle. SIGNIFICANCE: The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence.

[Advances in the treatment of Duchenne muscular dystrophy]. / Avances en el tratamiento de la distrofia de Duchenne.

Duchenne muscular dystrophy is a genetically determined disease, linked to the X chromosome, c haracterized clinically by producing progressive muscle weakness, with an incidence of 1 per 3500-6000 males born. It is caused by the mutation of the DMD gene, which encodes dystrophin, a sub-sarcolemmal protein essential for structural muscle stability. The genetic defects in the DMD gene are divided into: deletions (65%) duplications (5.10%) and point mutations (10-15%). At present there is no curative treatment, the only drug that has been shown to modify the natural history of the disease (independently of the genetic mutation) are corticosteroids, currently indicated in early stages of the disease. In relation to clinical trials, in the last ten years, has experienced great advances in the field of therapeutic options, divided into two major therapeutic targets: 1) the area of gene therapies and 2) trying to reverse or block the pathophysiological processes of the disease, such as inflammation, fibrosis, muscle regeneration, etc. It is likely that an effective treatment for Duchenne muscular dystrophy requires combinations of therapies that address both the primary defect and its secondary pathophysiological consequences.

La distrofia muscular de Duchenne es una enfermedad genéticamente determinada, ligada al cromosoma X y caracterizada clínicamente por producir debilidad muscular progresiva, con una incidencia de 1 por cada 3500-6000 varones nacidos. Es causada por la mutaciones en el gen DMD, el cual codifica la distrofina, una proteína sub-sarcolémica esencial para la estabilidad estructural del músculo. Los defectos genéticos en el gen DMD, se dividen en: deleciones (65%) duplicaciones (5-10%) y mutaciones puntuales (10-15%). Actualmente no se dispone de tratamiento curativo, el único fármaco que ha demostrado modificar la historia natural de la enfermedad (independientemente de la mutación genética) son los corticoides, los cuales están indicados en estadios tempranos de la enfermedad. En relación a los ensayos clínicos, en los últimos diez años se han experimentado grandes avances en el campo de las opciones terapéuticas, divididos en dos grandes dianas terapéuticas: 1) el área de las terapias génicas y 2) tratar de revertir o bloquear los procesos fisiopatológicos de la enfermedad, tales como inflamación, fibrosis, regeneración muscular, etc. Es probable que un tratamiento eficaz para la distrofia muscular de Duchenne requiera combinaciones que se apliquen tanto al defecto primario como las consecuencias fisiopatológicas secundarias.

[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.

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.

Avances en el tratamiento de la distrofia de Duchenne / Advances in the treatment of Duchenne muscular dystrophy

La distrofia muscular de Duchenne es una enfermedad genéticamente determinada, ligada al cromosoma X y caracterizada clínicamente por producir debilidad muscular progresiva, con una incidencia de 1 por cada 3500-6000 varones nacidos. Es causada por la mutaciones en el gen DMD, el cual codifica la distrofina, una proteína sub-sarcolémica esencial para la estabilidad estructural del músculo. Los defectos genéticos en el gen DMD, se dividen en: deleciones (65%) duplicaciones (5-10%) y mutaciones puntuales (10-15%). Actualmente no se dispone de tratamiento curativo, el único fármaco que ha demostrado modificar la historia natural de la enfermedad (independientemente de la mutación genética) son los corticoides, los cuales están indicados en estadios tempranos de la enfermedad. En relación a los ensayos clínicos, en los últimos diez años se han experimentado grandes avances en el campo de las opciones terapéuticas, divididos en dos grandes dianas terapéuticas: 1) el área de las terapias génicas y 2) tratar de revertir o bloquear los procesos fisiopatológicos de la enfermedad, tales como inflamación, fibrosis, regeneración muscular, etc. Es probable que un tratamiento eficaz para la distrofia muscular de Duchenne requiera combinaciones que se apliquen tanto al defecto primario como las consecuencias fisiopatológicas secundarias.

Duchenne muscular dystrophy is a genetically determined disease, linked to the X chromosome, c haracterized clinically by producing progressive muscle weakness, with an incidence of 1 per 3500-6000 males born. It is caused by the mutation of the DMD gene, which encodes dystrophin, a sub-sarcolemmal protein essential for structural muscle stability. The genetic defects in the DMD gene are divided into: deletions (65%) duplications (5.10%) and point mutations (10-15%). At present there is no curative treatment, the only drug that has been shown to modify the natural history of the disease (independently of the genetic mutation) are corticosteroids, currently indicated in early stages of the disease. In relation to clinical trials, in the last ten years, has experienced great advances in the field of therapeutic options, divided into two major therapeutic targets: 1) the area of gene therapies and 2) trying to reverse or block the pathophysiological processes of the disease, such as inflammation, fibrosis, muscle regeneration, etc. It is likely that an effective treatment for Duchenne muscular dystrophy requires combinations of therapies that address both the primary defect and its secondary pathophysiological consequences.

CHRNG-related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings.

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG-related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.