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1.
Hum Mutat ; 43(4): 487-498, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35077597

RESUMEN

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.


Asunto(s)
Artrogriposis , Artrogriposis/diagnóstico , Artrogriposis/genética , Cara , Humanos , Músculo Esquelético , Mutación , Fenotipo
2.
Neuropathol Appl Neurobiol ; 48(2): e12771, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34648194

RESUMEN

AIMS: TRAPPC11, a subunit of the transport protein particle (TRAPP) complex, is important for complex integrity and anterograde membrane transport from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. Several individuals with TRAPPC11 mutations have been reported with muscle weakness and other features including brain, liver, skeletal and eye involvement. A detailed analysis of brain and muscle pathology will further our understanding of the presentation and aetiology of TRAPPC11 disease. METHODS: We describe five cases of early-onset TRAPPC11-related muscular dystrophy with a systematic review of muscle pathology in all five individuals, post-mortem brain pathology findings in one and membrane trafficking assays in another. RESULTS: All affected individuals presented in infancy with muscle weakness, motor delay and elevated serum creatine kinase (CK). Additional features included cataracts, liver disease, intellectual disability, cardiomyopathy, movement disorder and structural brain abnormalities. Muscle pathology in all five revealed dystrophic changes, universal hypoglycosylation of alpha-dystroglycan and variably reduced dystrophin-associated complex proteins. Membrane trafficking assays showed defective Golgi trafficking in one individual. Neuropathological examination of one individual revealed cerebellar atrophy, granule cell hypoplasia, Purkinje cell (PC) loss, degeneration and dendrite dystrophy, reduced alpha-dystroglycan (IIH6) expression in PC and dentate neurones and absence of neuronal migration defects. CONCLUSIONS: This report suggests that recessive mutations in TRAPPC11 are linked to muscular dystrophies with hypoglycosylation of alpha-dystroglycan. The structural cerebellar involvement that we document for the first time resembles the neuropathology reported in N-linked congenital disorders of glycosylation (CDG) such as PMM2-CDG, suggesting defects in multiple glycosylation pathways in this condition.


Asunto(s)
Encéfalo/metabolismo , Distroglicanos/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/genética , Proteínas de Transporte Vesicular/genética , Preescolar , Femenino , Glicosilación , Humanos , Lactante , Hígado/metabolismo , Masculino , Distrofias Musculares/metabolismo , Mutación , Proteínas de Transporte Vesicular/metabolismo
3.
Pract Neurol ; 2022 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-35534197

RESUMEN

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

4.
Acta Neuropathol ; 141(3): 431-453, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33449170

RESUMEN

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.


Asunto(s)
Conectina/genética , Miotonía Congénita/diagnóstico , Miotonía Congénita/genética , Miotonía Congénita/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación Missense , Adulto Joven
5.
Neuropediatrics ; 52(5): 390-393, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33352606

RESUMEN

Pur-α protein (PURA) syndrome manifests in early childhood with core features such as neurodevelopmental and speech delay, feeding difficulties, epilepsy, and hypotonia at birth. We identified three cases with PURA syndrome in a cohort of patients with unexplained muscular weakness, presenting with a predominantly neuromuscular and ataxic phenotype. We further characterize the clinical presentation of PURA syndrome including myopathic facies and muscular weakness as the main clinical symptoms in combination with elevated serum creatine kinase levels. Furthermore, we report two novel variants located in the conservative domains PUR-I and PUR-II. For the first time, we present the muscle biopsies of PURA syndrome patients, showing myopathic changes, fiber size variability, and fast fiber atrophy as the key features. PURA syndrome should be taken into consideration as a differential diagnosis in pediatric patients with unexplained muscle weakness.


Asunto(s)
Epilepsia , Discapacidad Intelectual , Enfermedades Neuromusculares , Niño , Preescolar , Proteínas de Unión al ADN/genética , Epilepsia/genética , Humanos , Discapacidad Intelectual/genética , Enfermedades Neuromusculares/complicaciones , Enfermedades Neuromusculares/diagnóstico , Factores de Transcripción/genética
6.
Hum Mol Genet ; 27(24): 4263-4272, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-30215711

RESUMEN

Congenital myopathies are typically characterised by early onset hypotonia, weakness and hallmark features on biopsy. Despite the rapid pace of gene discovery, ∼50% of patients with a congenital myopathy remain without a genetic diagnosis following screening of known disease genes. We performed exome sequencing on two consanguineous probands diagnosed with a congenital myopathy and muscle biopsy showing selective atrophy/hypotrophy or absence of type II myofibres. We identified variants in the gene (MYL1) encoding the skeletal muscle fast-twitch specific myosin essential light chain (ELC) in both probands. A homozygous essential splice acceptor variant (c.479-2A > G, predicted to result in skipping of exon 5 was identified in Proband 1, and a homozygous missense substitution (c.488T>G, p.(Met163Arg)) was identified in Proband 2. Protein modelling of the p.(Met163Arg) substitution predicted it might impede intermolecular interactions that facilitate binding to the IQ domain of myosin heavy chain, thus likely impacting on the structure and functioning of the myosin motor. MYL1 was markedly reduced in skeletal muscle from both probands, suggesting that the missense substitution likely results in an unstable protein. Knock down of myl1 in zebrafish resulted in abnormal morphology, disrupted muscle structure and impaired touch-evoked escape responses, thus confirming that skeletal muscle fast-twitch specific myosin ELC is critical for myofibre development and function. Our data implicate MYL1 as a crucial protein for adequate skeletal muscle function and that MYL1 deficiency is associated with severe congenital myopathy.


Asunto(s)
Músculo Esquelético/fisiopatología , Cadenas Ligeras de Miosina/genética , Miotonía Congénita/genética , Alelos , Animales , Consanguinidad , Modelos Animales de Enfermedad , Exoma/genética , Homocigoto , Humanos , Masculino , Músculo Esquelético/metabolismo , Mutación , Cadenas Pesadas de Miosina/genética , Miotonía Congénita/fisiopatología , Linaje , Pez Cebra/genética
7.
Am J Hum Genet ; 100(3): 523-536, 2017 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-28190456

RESUMEN

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.


Asunto(s)
Catarata/genética , Disfunción Cognitiva/genética , Distrofia Muscular de Cinturas/genética , Anomalías Musculoesqueléticas/genética , Monoéster Fosfórico Hidrolasas/genética , Adolescente , Adulto , Alelos , Animales , Encéfalo/patología , Niño , Preescolar , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Mutación , Linaje , Adulto Joven , Pez Cebra/embriología , Pez Cebra/genética
8.
Genet Med ; 22(1): 199-209, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31462754

RESUMEN

PURPOSE: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease. METHODS: Multinational series of new genetically confirmed cases from six pediatric centers. RESULTS: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. CONCLUSIONS: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.


Asunto(s)
Proteínas de Ciclo Celular/genética , Seudoobstrucción Intestinal/genética , Distrofia Muscular Oculofaríngea/genética , Mutación Missense , Ribonucleótido Reductasas/genética , Proteínas de Ciclo Celular/química , Femenino , Humanos , Lactante , Recién Nacido , Seudoobstrucción Intestinal/mortalidad , Masculino , Modelos Moleculares , Distrofia Muscular Oculofaríngea/mortalidad , Oftalmoplejía/congénito , Pronóstico , Conformación Proteica , Ribonucleótido Reductasas/química , Análisis de Supervivencia
9.
J Inherit Metab Dis ; 43(5): 1002-1013, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32187699

RESUMEN

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.


Asunto(s)
Glucanos/metabolismo , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Niño , Preescolar , Femenino , Humanos , Inflamación/patología , Masculino , Músculo Esquelético/patología , Enfermedades Musculares/patología , Reinfección/patología
10.
Br J Neurosurg ; 34(1): 112-114, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29355032

RESUMEN

We describe the unique case of a patient being diagnosed with a thoracic extradural chordoid meningioma following her presentation with mild lower limb pyramidal weakness and a T8 sensory level. This is the first report of an extradural chordoid meningioma being identified in the thoracic spine. The tumour was successfully resected through a posterior thoracic laminectomy approach. Post-operatively, her neurological deficit resolved and to date she has not experienced a radiological recurrence. In this report, we review the literature and discuss this unusual tumour's characteristics and prognostic significance.


Asunto(s)
Meningioma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Neoplasias de la Médula Espinal/cirugía , Dolor de Espalda/etiología , Femenino , Humanos , Laminectomía/métodos , Imagen por Resonancia Magnética , Meningioma/diagnóstico por imagen , Meningioma/patología , Persona de Mediana Edad , Debilidad Muscular/etiología , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/patología , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/patología , Vértebras Torácicas/cirugía , Resultado del Tratamiento
11.
Brain ; 141(12): 3308-3318, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30423015

RESUMEN

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.


Asunto(s)
Parálisis Periódica Hipopotasémica/genética , Parálisis Periódica Hipopotasémica/fisiopatología , ATPasa Intercambiadora de Sodio-Potasio/genética , Animales , Niño , Humanos , Parálisis Periódica Hipopotasémica/patología , Masculino , Potenciales de la Membrana , Músculo Esquelético/patología , Mutación Missense , Potasio/fisiología , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Xenopus laevis
12.
Hum Mutat ; 39(12): 1980-1994, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30168660

RESUMEN

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.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sustitución de Aminoácidos , Hipertermia Maligna/genética , Miotonía Congénita/genética , Proteínas Adaptadoras Transductoras de Señales/química , Adolescente , Calcio/metabolismo , Niño , Preescolar , Acoplamiento Excitación-Contracción , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio , Masculino , Hipertermia Maligna/etiología , Hipertermia Maligna/metabolismo , Miotonía Congénita/complicaciones , Miotonía Congénita/metabolismo , Linaje , Fenotipo , Unión Proteica , Transporte de Proteínas , Retículo Sarcoplasmático/metabolismo , Índice de Severidad de la Enfermedad , Secuenciación del Exoma , Adulto Joven
13.
J Neurol Neurosurg Psychiatry ; 89(7): 762-768, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29437916

RESUMEN

BACKGROUND: Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes. METHODS: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy. RESULTS: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (ß-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of ß-DG. CONCLUSIONS: Our data demonstrate that a change in ß-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.


Asunto(s)
Distroglicanos/metabolismo , Guanosina Difosfato Manosa/genética , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Mutación/genética , Nucleotidiltransferasas/genética , Adolescente , Anciano , Biomarcadores/metabolismo , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrofias Musculares/patología
14.
Hum Mutat ; 38(8): 970-977, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28544275

RESUMEN

We report here the first families carrying recessive variants in the MSTO1 gene: compound heterozygous mutations were identified in two sisters and in an unrelated singleton case, who presented a multisystem complex phenotype mainly characterized by myopathy and cerebellar ataxia. Human MSTO1 is a poorly studied protein, suggested to have mitochondrial localization and to regulate morphology and distribution of mitochondria. As for other mutations affecting genes involved in mitochondrial dynamics, no biochemical defects typical of mitochondrial disorders were reported. Studies in patients' fibroblasts revealed that MSTO1 protein levels were strongly reduced, the mitochondrial network was fragmented, and the fusion events among mitochondria were decreased, confirming the deleterious effect of the identified variants and the role of MSTO1 in modulating mitochondrial dynamics. We also found that MSTO1 is mainly a cytosolic protein. These findings indicate recessive mutations in MSTO1 as a new cause for inherited neuromuscular disorders with multisystem features.


Asunto(s)
Ataxia/genética , Proteínas de Ciclo Celular/genética , Proteínas del Citoesqueleto/genética , Dinámicas Mitocondriales/fisiología , Enfermedades Musculares/genética , Mutación/genética , Ataxia/etiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Dinámicas Mitocondriales/genética , Enfermedades Musculares/etiología
15.
Acta Neuropathol ; 133(4): 517-533, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28012042

RESUMEN

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.


Asunto(s)
Canales de Calcio/genética , Canales de Calcio/metabolismo , Miotonía Congénita/genética , Miotonía Congénita/metabolismo , Adolescente , Adulto , Calcio/metabolismo , Canales de Calcio Tipo L , Células Cultivadas , Niño , Estudios de Cohortes , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Musculares/metabolismo , Células Musculares/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Miotonía Congénita/diagnóstico por imagen , Miotonía Congénita/patología , Fenotipo , Homología de Secuencia de Aminoácido , Adulto Joven
16.
Brain ; 139(Pt 3): 674-91, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26700687

RESUMEN

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.


Asunto(s)
Hipocinesia/diagnóstico , Hipocinesia/genética , Mutación/genética , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Células HEK293 , Humanos , Recién Nacido , Masculino , Linaje , Índice de Severidad de la Enfermedad , Xenopus laevis
17.
J Neurol Neurosurg Psychiatry ; 87(5): 512-9, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-25935893

RESUMEN

BACKGROUND: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. METHODS: In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. RESULTS: Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. CONCLUSION: We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.


Asunto(s)
Axones/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Trastornos Parkinsonianos/patología , Receptores del Factor Estimulante de Colonias/genética , Vasculitis del Sistema Nervioso Central/patología , Adulto , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/complicaciones , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Leucoencefalopatías/complicaciones , Masculino , Persona de Mediana Edad , Mutación , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/genética , Fenotipo , Vasculitis del Sistema Nervioso Central/complicaciones , Vasculitis del Sistema Nervioso Central/genética
18.
Brain ; 138(Pt 2): 293-310, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25497877

RESUMEN

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.


Asunto(s)
Proteínas Asociadas a Microtúbulos/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Mutación/genética , Linaje , Fenotipo , Unión Proteica , Columna Vertebral/patología , Adulto Joven
19.
Clin Infect Dis ; 60(6): 919-23, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25572898

RESUMEN

Metagenomic next-generation sequencing (NGS) was used to diagnose an unusual and fatal case of progressive encephalitis in an immunocompromised adult presenting at disease onset as bilateral hearing loss. The sequencing and confirmatory studies revealed neuroinvasive infection of the brain by an astrovirus belonging to a recently discovered VA/HMO clade.


Asunto(s)
Infecciones por Astroviridae/diagnóstico , Encefalitis Viral/diagnóstico , Mamastrovirus/genética , Mamastrovirus/aislamiento & purificación , Adulto , Encéfalo/patología , Proteínas de la Cápside/genética , Encefalitis Viral/complicaciones , Resultado Fatal , Pérdida Auditiva Bilateral/etiología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leucemia Linfoide/complicaciones , Filogenia
20.
Crit Care Med ; 43(8): 1603-11, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25882765

RESUMEN

OBJECTIVES: A rapid and early loss of skeletal muscle mass underlies the physical disability common amongst survivors of critical illness. However, skeletal muscle function depends not only on its quantity but its quality, which may be adversely affected. We set out to characterise the changes in macroscopic muscle echogenicity and fascial characteristics that occur early in critical illness, and to relate these to microscopic histologically defined myofibre necrosis and fascial pathology. DESIGN AND SETTING: Prospective two center observational study. PATIENTS: Thirty subjects comprising a subgroup of patients recruited to the Musculoskeletal Ultrasound in Critical Illness: Longitudinal Evaluation (MUSCLE) study. MEASUREMENTS AND MAIN RESULTS: Comparisons were made between sequential Vastus Lateralis histological specimens and ultrasound assessment of Rectus Femoris echogenicity. Change in muscle echogenicity was greater in patients who developed muscle necrosis (n = 15) than in those who did not (8.2% [95% CI, -5.3 to 21.7] vs -15.0% [95% CI, -28.9 to -1.09]; p = 0.016). The area under receiver operator curve for ultrasound echogenicity's prediction of myofiber necrosis was 0.74 (95% CI, 0.565 to 0.919; p = 0.024) increasing to 0.85 (95% CI, 0.703 to -0.995; p = 0.003) with the removal of those with potential iatrogenic muscle damage. Fasciitis was observed in 18 of 30 biopsies (60%). CONCLUSIONS: Myofiber necrosis and fascial inflammation can be detected noninvasively using ultrasound in the critically ill. Fasciitis precedes and frequently accompanies muscle necrosis. These findings may have functional implications for survivors of critical illness.


Asunto(s)
Enfermedad Crítica , Fascitis/diagnóstico por imagen , Fascitis/patología , Fibras Musculares Esqueléticas/patología , Atrofia Muscular/diagnóstico por imagen , Atrofia Muscular/patología , Enfermedad Aguda , Adulto , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/patología , Ultrasonografía
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