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1.
Pract Neurol ; 24(3): 235-237, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38272664

RESUMEN

Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment.


Asunto(s)
Neurolinfomatosis , Humanos , Neurolinfomatosis/diagnóstico por imagen , Neurolinfomatosis/patología , Femenino , Biopsia/métodos , Persona de Mediana Edad , Linfoma de Células T/patología , Linfoma de Células T/diagnóstico por imagen , Linfoma de Células T/diagnóstico , Tomografía de Emisión de Positrones
2.
Brain ; 145(2): 607-620, 2022 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-34529042

RESUMEN

High-throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in data interpretation and its useful translation into clinical and genetic counselling for families. Even when a plausible gene is identified with confidence, interpretation of the clinical significance and inheritance pattern of variants can be challenging. We report our approach to evaluating variants in the skeletal muscle chloride channel ClC-1 identified in 223 probands with myotonia congenita as an example of these challenges. Sequencing of CLCN1, the gene that encodes CLC-1, is central to the diagnosis of myotonia congenita. However, interpreting the pathogenicity and inheritance pattern of novel variants is notoriously difficult as both dominant and recessive mutations are reported throughout the channel sequence, ClC-1 structure-function is poorly understood and significant intra- and interfamilial variability in phenotype is reported. Heterologous expression systems to study functional consequences of CIC-1 variants are widely reported to aid the assessment of pathogenicity and inheritance pattern. However, heterogeneity of reported analyses does not allow for the systematic correlation of available functional and genetic data. We report the systematic evaluation of 95 CIC-1 variants in 223 probands, the largest reported patient cohort, in which we apply standardized functional analyses and correlate this with clinical assessment and inheritance pattern. Such correlation is important to determine whether functional data improves the accuracy of variant interpretation and likely mode of inheritance. Our data provide an evidence-based approach that functional characterization of ClC-1 variants improves clinical interpretation of their pathogenicity and inheritance pattern, and serve as reference for 34 previously unreported and 28 previously uncharacterized CLCN1 variants. In addition, we identify novel pathogenic mechanisms and find that variants that alter voltage dependence of activation cluster in the first half of the transmembrane domains and variants that yield no currents cluster in the second half of the transmembrane domain. None of the variants in the intracellular domains were associated with dominant functional features or dominant inheritance pattern of myotonia congenita. Our data help provide an initial estimate of the anticipated inheritance pattern based on the location of a novel variant and shows that systematic functional characterization can significantly refine the assessment of risk of an associated inheritance pattern and consequently the clinical and genetic counselling.


Asunto(s)
Miotonía Congénita , Miotonía , Canales de Cloruro/genética , Humanos , Mutación/genética , Miotonía/genética , Miotonía Congénita/genética , Fenotipo
3.
Brain ; 145(6): 2108-2120, 2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-34919635

RESUMEN

Andersen-Tawil syndrome is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterized by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multisystem phenotype is not well described. In-depth, multisystem phenotyping is required to inform diagnosis and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognized, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fat accumulation on MRI and tubular aggregates on muscle biopsy, emphasizing the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing was not reliable in predicting neuromuscular symptoms. A normal long exercise test was seen in five patients, of whom four had episodic weakness. Sixty-seven per cent of patients treated with acetazolamide reported a good neuromuscular response. Thirteen per cent of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but Holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal Holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature; however, 8% of patients did not have dysmorphic features and one-third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that Andersen-Tawil syndrome is not benign. We report marked neuromuscular morbidity and cardiac risk with multisystem involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of Andersen-Tawil syndrome patients have no (or few) dysmorphic features or negative long exercise test. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.


Asunto(s)
Síndrome de Andersen , Síndrome de Andersen/diagnóstico , Síndrome de Andersen/genética , Síndrome de Andersen/terapia , Electrocardiografía , Pruebas Genéticas , Humanos , Morbilidad , Mutación/genética , Fenotipo
4.
Muscle Nerve ; 65(5): 581-585, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34817893

RESUMEN

AIMS: The aim of this study was to evaluate the sensitivity of the long exercise test (LET) in the diagnosis of periodic paralysis (PP) and assess correlations with clinical phenotypes and genotypes. METHODS: From an unselected cohort of 335 patients who had an LET we analyzed 67 patients with genetic confirmation of PP and/or a positive LET. RESULTS: 32/45 patients with genetically confirmed PP had a significant decrement after exercise (sensitivity of 71%). Performing the short exercise test before the LET in the same hand confounded results in four patients. Sensitivity was highest in patients with frequent (daily or weekly) attacks (8/8, 100%), intermediate with up to monthly attacks (15/21, 71%) and lowest in those with rare attacks (9/16, 56%) (p = .035, Mann-Whitney U-test). Patients with a positive LET without confirmed PP mutation comprised those with typical PP phenotype and a group with atypical features. DISCUSSION: In our cohort, the LET is strongly correlated with the frequency of paralytic attacks suggesting a role as a functional marker. A negative test in the context of frequent attacks makes a diagnosis of PP unlikely but it does not rule out the condition in less severely affected patients.


Asunto(s)
Parálisis Periódica Hipopotasémica , Distrofias Musculares , Parálisis Periódicas Familiares , Ejercicio Físico , Prueba de Esfuerzo/métodos , Humanos , Parálisis Periódica Hipopotasémica/diagnóstico , Parálisis Periódicas Familiares/diagnóstico , Parálisis , Fenotipo
5.
Pract Neurol ; 21(3): 196-204, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33563766

RESUMEN

Skeletal muscle channelopathies are a group of rare episodic genetic disorders comprising the periodic paralyses and the non-dystrophic myotonias. They may cause significant morbidity, limit vocational opportunities, be socially embarrassing, and sometimes are associated with sudden cardiac death. The diagnosis is often hampered by symptoms that patients may find difficult to describe, a normal examination in the absence of symptoms, and the need to interpret numerous tests that may be normal or abnormal. However, the symptoms respond very well to holistic management and pharmacological treatment, with great benefit to quality of life. Here, we review when to suspect a muscle channelopathy, how to investigate a possible case and the options for therapy once a diagnosis is made.


Asunto(s)
Canalopatías , Trastornos Miotónicos , Parálisis Periódicas Familiares , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Humanos , Músculo Esquelético , Calidad de Vida
6.
Brain ; 136(Pt 7): 2189-200, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23771340

RESUMEN

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.


Asunto(s)
Canales de Cloruro/genética , Fuerza Muscular/fisiología , Debilidad Muscular/etiología , Mutación/genética , Miotonía/clasificación , Miotonía/diagnóstico , Miotonía/genética , Adulto , Estudios de Cohortes , Electrodiagnóstico , Ejercicio Físico/fisiología , Femenino , Humanos , Cooperación Internacional , Masculino , Mexiletine/uso terapéutico , Persona de Mediana Edad , Fuerza Muscular/genética , Debilidad Muscular/genética , Miotonía/psicología , Canal de Sodio Activado por Voltaje NAV1.4/genética , Examen Neurológico , Calidad de Vida , Proteínas de Unión al ARN/genética , Estudios Retrospectivos , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico
7.
Neuromuscul Disord ; 35: 33-38, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38232533

RESUMEN

The aim of this study was to establish whether bumetanide can abort an acute attack of weakness in patients with HypoPP. This was a randomised, double-blind, cross-over, placebo-controlled phase II clinical trial. Focal attack of weakness was induced by isometric exercise of ADM followed by rest (McManis protocol). Participants had two study visits and received either placebo or 2 mg bumetanide at attack onset (defined as 40 % decrement in the abductor digiti minimi CMAP amplitude from peak). CMAP measurements assessed attack severity and duration. Nine participants completed both visits. CMAP percentage of peak amplitudes in the bumetanide (40.6 %) versus placebo (34.9 %) group at 1hr following treatment did not differ significantly (estimated effect difference 5.9 % (95 % CI: (-5.7 %; 17.5 %), p = 0.27, primary outcome). CMAP amplitudes assessed by the area under the curve for early (0-2hr post-treatment) and late (2-4 h post-treatment) efficacy were not statistically different between bumetanide and placebo (early effect estimate 0.043, p = 0.3; late effect estimate 0.085, p = 0.1). Two participants recovered from the attack following bumetanide intake; none recovered following placebo. Bumetanide was well tolerated but not efficacious to rescue a focal attack in an immobilised hand in the majority of patients, although data supports further studies of this agent.


Asunto(s)
Parálisis Periódica Hipopotasémica , Humanos , Bumetanida/farmacología , Bumetanida/uso terapéutico , Músculo Esquelético , Mano , Extremidad Superior , Método Doble Ciego
8.
Ann Neurol ; 69(2): 328-40, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21387378

RESUMEN

OBJECTIVE: To improve the accuracy of genotype prediction and guide genetic testing in patients with muscle channelopathies we applied and refined specialized electrophysiological exercise test parameters. METHODS: We studied 56 genetically confirmed patients and 65 controls using needle electromyography, the long exercise test, and short exercise tests at room temperature, after cooling, and rewarming. RESULTS: Concordant amplitude-and-area decrements were more reliable than amplitude-only measurements when interpreting patterns of change during the short exercise tests. Concordant amplitude-and-area pattern I and pattern II decrements of >20% were 100% specific for paramyotonia congenita and myotonia congenita, respectively. When decrements at room temperature and after cooling were <20%, a repeat short exercise test after rewarming was useful in patients with myotonia congenita. Area measurements and rewarming distinguished true temperature sensitivity from amplitude reduction due to cold-induced slowing of muscle fiber conduction. In patients with negative short exercise tests, symptomatic eye closure myotonia predicted sodium channel myotonia over myotonia congenita. Distinctive "tornado-shaped" neuromyotonia-like discharges may be seen in patients with paramyotonia congenita. In the long exercise test, area decrements from pre-exercise baseline were more sensitive than amplitude decrements-from-maximum-compound muscle action potential (CMAP) in patients with Andersen-Tawil syndrome. Possible ethnic differences in the normative data of the long exercise test argue for the use of appropriate ethnically-matched controls. INTERPRETATION: Concordant CMAP amplitude-and-area decrements of >20% allow more reliable interpretation of the short exercise tests and aid accurate DNA-based diagnosis. In patients with negative exercise tests, specific clinical features are helpful in differentiating sodium from chloride channel myotonia. A modified algorithm is suggested.


Asunto(s)
Canalopatías/diagnóstico , Prueba de Esfuerzo , Debilidad Muscular/diagnóstico , Músculo Esquelético/patología , Trastornos Miotónicos/diagnóstico , Adolescente , Adulto , Anciano , Canalopatías/genética , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Trastornos Miotónicos/genética
9.
J Neuromuscul Dis ; 8(1): 151-154, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33074188

RESUMEN

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.


Asunto(s)
Síndrome de Andersen/complicaciones , Bloqueo Atrioventricular/etiología , Síndrome de Andersen/diagnóstico , Síndrome de Andersen/fisiopatología , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/fisiopatología , Diagnóstico Tardío , Humanos
10.
Curr Treat Options Neurol ; 22(10): 34, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32848354

RESUMEN

PURPOSE OF REVIEW: This article aims to review the current and upcoming treatment options of primary muscle channelopathies including the non-dystrophic myotonias and periodic paralyses. RECENT FINDINGS: The efficacy of mexiletine in the treatment of myotonia is now supported by two randomised placebo-controlled trials, one of which utilised a novel aggregated n-of-1 design. This has resulted in licencing of the drug via orphan drug status. There is also good evidence that mexiletine is well tolerated and safe in this patient group without the need for intensive monitoring. A range of alternative antimyotonic treatment options include lamotrigine, carbamazepine and ranolazine exist with variable evidence base. In vitro studies have shown insight into reasons for treatment failure of some medications with certain genotypes opening the era of mutation-specific therapy such as use of flecainide. In the periodic paralyses, the ability of MRI to distinguish between reversible oedema and irreversible fatty replacement makes it an increasingly useful tool to guide and assess pharmacological treatment. Unfortunately, the striking efficacy of bumetanide in hypokalaemic periodic paralysis animal models was not replicated in a recent pilot study in humans. SUMMARY: The treatment of skeletal muscle channelopathies combines dietary and lifestyle advice together with pharmacological interventions. The rarity of these conditions remains a barrier for clinical studies but the example of the aggregated n-of-1 trial of mexiletine shows that innovative trial design can overcome these hurdles. Further research is required to test efficacy of drugs shown to have promising characteristics in preclinical experiments such as safinamide, riluzule and magnesium for myotonia or bumetanide for hypokalaemic periodic paralysis.

11.
Neuromuscul Disord ; 18(11): 869-72, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18815035

RESUMEN

Myotonia congenita is caused by mutations in the voltage-gated chloride channel ClC-1. It is more severe in men than women and often worsens during pregnancy, but the basis for these gender differences is not known. We show here that both testosterone and progesterone rapidly and reversibly inhibit wild-type ClC-1 channels expressed in Xenopus oocytes by causing a prominent rightward shift in the voltage dependence of their open probability. In contrast, 17beta-estradiol at similar concentrations causes only a small shift. Progesterone and testosterone also profoundly inhibit ClC-1 channels containing the mutation F297S associated with dominantly inherited myotonia congenita. The effects of sex hormones are likely to be non-genomic because of their speed of onset and reversibility. These results suggest a possible mechanism to explain how the severity of myotonia congenita can be modulated by sex hormones.


Asunto(s)
Canales de Cloruro/fisiología , Miotonía Congénita/fisiopatología , Progesterona/farmacología , Testosterona/farmacología , Animales , Células Cultivadas , Canales de Cloruro/genética , Electrodos , Electrofisiología/instrumentación , Electrofisiología/métodos , Femenino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Mutagénesis Sitio-Dirigida , Mutación , Miotonía Congénita/genética , Oocitos/citología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp/instrumentación , Técnicas de Placa-Clamp/métodos , Factores Sexuales , Xenopus
12.
Handb Clin Neurol ; 148: 505-520, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29478596

RESUMEN

The periodic paralyses are a group of skeletal muscle channelopathies characterizeed by intermittent attacks of muscle weakness often associated with altered serum potassium levels. The underlying genetic defects include mutations in genes encoding the skeletal muscle calcium channel Cav1.1, sodium channel Nav1.4, and potassium channels Kir2.1, Kir3.4, and possibly Kir2.6. Our increasing knowledge of how mutant channels affect muscle excitability has resulted in better understanding of many clinical phenomena which have been known for decades and sheds light on some of the factors that trigger attacks. Insights into the pathophysiology are also leading to new therapeutic approaches.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Canales Iónicos/genética , Mutación/genética , Parálisis Periódicas Familiares/genética , Humanos , Parálisis Periódicas Familiares/fisiopatología
13.
Clin Neurophysiol ; 129(2): 473-486, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29254860

RESUMEN

OBJECTIVES: To report Somatosensory Evoked Potentials (SEPs) and Central Motor Conduction Times (CMCT) in children with dystonia and to test the hypothesis that these parameters predict outcome from Deep Brain Stimulation (DBS). METHODS: 180 children with dystonia underwent assessment for Globus pallidus internus (GPi) DBS, mean age 10 years (range 2.5-19). CMCT to each limb was calculated using Transcranial Magnetic Stimulation. Median and posterior tibial nerve SEPs were recorded over contralateral and midline centro-parietal scalp. Structural abnormalities were assessed with cranial MRI. One-year outcome from DBS was assessed as percentage improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m). RESULTS: Abnormal CMCTs and SEPs were found in 19% and 47% of children respectively and were observed more frequently in secondary than primary dystonia. Of children proceeding to DBS, better outcome was seen in those with normal (n = 78/89) versus abnormal CMCT (n = 11/89) (p = 0.002) and those with normal (n = 35/51) versus abnormal SEPs (n = 16/51) (p = 0.001). These relationships were independent of dystonia aetiology and cranial MRI findings. CONCLUSIONS: CMCTs and SEPs provide objective evidence of motor and sensory pathway dysfunction in children with dystonia and relate to DBS outcome. SIGNIFICANCE: CMCTs and SEPs can contribute to patient selection and counselling of families about potential benefit from neuromodulation for dystonia.


Asunto(s)
Estimulación Encefálica Profunda , Distonía/terapia , Potenciales Evocados Somatosensoriales/fisiología , Globo Pálido/fisiopatología , Conducción Nerviosa/fisiología , Adolescente , Niño , Preescolar , Distonía/fisiopatología , Femenino , Humanos , Masculino , Corteza Motora/fisiopatología , Corteza Somatosensorial/fisiopatología , Estimulación Magnética Transcraneal , Resultado del Tratamiento , Adulto Joven
14.
Neurology ; 90(5): e412-e418, 2018 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-29298851

RESUMEN

OBJECTIVE: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations. METHODS: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. RESULTS: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases. CONCLUSIONS: RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.


Asunto(s)
Mutación/genética , Mialgia/genética , Parálisis Periódicas Familiares/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Mialgia/diagnóstico por imagen , Mialgia/fisiopatología , Parálisis Periódicas Familiares/diagnóstico por imagen , Parálisis Periódicas Familiares/fisiopatología , Fenotipo
15.
Brain ; 129(Pt 7): 1674-84, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16621917

RESUMEN

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.


Asunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedades Mitocondriales/genética , Mutación , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/genética , Femenino , Frecuencia de los Genes , Humanos , Lactante , Masculino , Persona de Mediana Edad , Encefalomiopatías Mitocondriales/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Fenotipo , Factores Sexuales
17.
Neuromuscul Disord ; 26(8): 504-10, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27312022

RESUMEN

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.


Asunto(s)
Caveolina 3/genética , Tolerancia al Ejercicio , Mialgia/genética , Rabdomiólisis/genética , Adolescente , Adulto , Anciano de 80 o más Años , Caveolina 3/metabolismo , Niño , Distroglicanos/metabolismo , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Músculo Esquelético/patología , Mutación , Mialgia/metabolismo , Mialgia/patología , Fenotipo , Rabdomiólisis/metabolismo , Rabdomiólisis/patología
18.
Expert Opin Med Diagn ; 7(6): 517-29, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24066928

RESUMEN

INTRODUCTION: Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection. AREAS COVERED: An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed. EXPERT OPINION: A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants.


Asunto(s)
Canalopatías/diagnóstico , Canalopatías/genética , Músculo Esquelético/fisiopatología , Canalopatías/clasificación , Prueba de Esfuerzo , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética
19.
Neurology ; 80(16): 1472-5, 2013 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-23516313

RESUMEN

OBJECTIVES: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders. METHODS: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011. RESULTS: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. CONCLUSION: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.


Asunto(s)
Canalopatías/epidemiología , Canalopatías/genética , Músculo Esquelético/fisiología , Enfermedades Musculares/epidemiología , Enfermedades Musculares/genética , Adulto , Canales de Cloruro/genética , Interpretación Estadística de Datos , Bases de Datos Genéticas , Inglaterra/epidemiología , Femenino , Humanos , Parálisis Periódica Hipopotasémica/epidemiología , Parálisis Periódica Hipopotasémica/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Mutación/fisiología , Miotonía/epidemiología , Miotonía/genética , Trastornos Miotónicos/epidemiología , Trastornos Miotónicos/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Parálisis Periódicas Familiares/epidemiología , Parálisis Periódicas Familiares/genética , Parálisis Periódica Hiperpotasémica/epidemiología , Parálisis Periódica Hiperpotasémica/genética , Canales de Potasio de Rectificación Interna/genética , Prevalencia , Canales de Sodio/genética , Canales de Sodio/fisiología , Reino Unido/epidemiología
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