RESUMEN
Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.
Asunto(s)
Síndrome de Andersen/epidemiología , Canalopatías/epidemiología , Parálisis Periódica Hipopotasémica/epidemiología , Mutación , Miotonía/epidemiología , Trastornos Miotónicos/epidemiología , Adulto , Anciano , Síndrome de Andersen/genética , Canales de Calcio/genética , Canales de Calcio Tipo L , Canalopatías/genética , Canales de Cloruro/genética , Femenino , Humanos , Parálisis Periódica Hipopotasémica/genética , Masculino , Persona de Mediana Edad , Miotonía/genética , Trastornos Miotónicos/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Países Bajos/epidemiología , Linaje , Canales de Potasio de Rectificación Interna/genética , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive muscle disease. No curative therapy is currently available, but in recent decades standards of care have improved. These improvements include the use of corticosteroids and mechanical ventilation. OBJECTIVE: To present a detailed population based report of the DMD disease course in The Netherlands (1980-2006) and evaluate the effect of changes in care by comparing it with an historical Dutch DMD cohort (1961-1974). METHODS: Information about DMD patients was gathered through the Dutch Dystrophinopathy Database using a standardized questionnaire and information from treating physicians. RESULTS: The study population involved 336 DMD patients (70% of the estimated prevalence), of whom 285 were still alive. Mean age at disease milestones was: diagnosis 4.3 years, wheelchair dependence 9.7 years, scoliosis surgery 14 years, cardiomyopathy (fractional shortening <27%) 15 years, mechanical ventilation 17 years and death 19 years. Within our cohort, corticosteroid use was associated with an increased age of wheelchair dependence from 9.8 to 11.6 years (p < 0.001). When comparing the recent cohort to the historical cohort, mean survival improved from 17 to 27 years (p < 0.001). CONCLUSION: The current study gives detailed information about the disease course of DMD patients, provides evidence for the positive effect of steroid treatment and mechanical ventilation and supports the use of patient registries as a valuable resource for evaluating improvements in care.
RESUMEN
Duchenne muscular dystrophy has a severe disease course, though variability exists. Case reports suggest a milder disease course of patients amenable to exon 44 skipping. In this study, we analyzed this and show that age at wheelchair dependence in patients with a dystrophin deletion requiring exon 44 skipping is postponed compared to patients with a deletion skippable by exon 45, 51 and 53 (10.8 versus 9.8 years; P 0.020). This may be explained by more frequent spontaneous exon 44 skipping in patients with a deletion flanking exon 44. This finding has important implications for the development of future Duchenne trials.
RESUMEN
OBJECTIVE: Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. METHODS: Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. RESULTS: Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. CONCLUSIONS: This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.
Asunto(s)
Exones/genética , Terapia Genética/métodos , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular de Duchenne/terapia , Adolescente , Adulto , Biopsia , Western Blotting , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/patología , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Bases de Datos Genéticas , Ecocardiografía , Escolaridad , Electrocardiografía , Femenino , Eliminación de Gen , Corazón/fisiopatología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/genética , Países Bajos/epidemiología , Análisis de Supervivencia , Silla de Ruedas , Adulto JovenRESUMEN
OBJECTIVE: Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45-47 deletion. METHODS: Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. RESULTS: 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%-78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45-47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45-47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients' age. CONCLUSIONS: Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45-47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.
Asunto(s)
Distrofina/análisis , Distrofia Muscular de Duchenne/patología , Adulto , Factores de Edad , Anciano , Western Blotting , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Fuerza Muscular , Músculo Esquelético/química , Músculo Esquelético/patología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: To describe the long-term follow-up of a cohort of 22 patients with the Miyoshi phenotype of distal muscular dystrophy (MMD). METHODS: A long-term clinical follow-up study was conducted. Patients were genotyped for dysferlin (MMD1) or anoctamin 5 (MMD3) mutations. Patients also underwent cardiological evaluation. RESULTS: There were 10 patients with MMD1, eight patients with MMD3 and four patients with linkage to chromosome 10 (MMD2). All patients deteriorated over 5.7 (range: 4.2-6.6) years of follow-up. Weakness increased significantly (Pâ <â 0.035) in all but the neck extensor, serratus anterior, and wrist flexor and extensor muscles. The decrease of strength was most pronounced in the iliopsoas (15%), toe extensors (15%), anterior tibial and peroneal muscles (10%). Patients with MMD1 showed early onset of the disease (mean 22â years) with typically symmetrical distribution of weakness starting in the calf muscles. Patients with MMD1 had a worse clinical course compared with patients with MMD3. Ninety percent of the former had to make use of a wheelchair within 15â years after onset of the disease, whereas patients with MMD3, who have a significantly later onset (mean 35â years) of asymmetrical calf muscle weakness and atrophy, remained ambulant during the first 15â years of their disease. None of the patients with MMD2 became fully confined to the wheelchair. None of the 22 MMD phenotype patients had heart disease. CONCLUSIONS: Patients with MMD1 have a worse clinical course compared with patients with MMD3. There are no cardiological abnormalities in all MMD categories.
Asunto(s)
Miopatías Distales/diagnóstico , Miopatías Distales/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Fenotipo , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
To identify serum biomarkers that allow monitoring of disease progression and treatment effects in Duchenne muscular dystrophy (DMD) patients, levels of matrix metalloproteinase-9 (MMP-9), tissue inhibitors of metalloproteinase-1 (TIMP-1) and osteopontin (OPN) were determined in 63 DMD patients on corticosteroid therapy. These proteins were selected for their role in the pathogenesis of muscular dystrophy. Levels of MMP-9 and TIMP-1 were significantly higher in sera of DMD patients compared to healthy controls, whereas the OPN levels showed no significant difference. MMP-9 levels were also observed to be significantly higher in older, nonambulant patients, compared to ambulant patients. Longitudinal data from a smaller cohort of DMD patients followed up for over 4years showed that MMP-9, but not TIMP-1 increased significantly with age. Hence, MMP-9 is a potential DMD biomarker for disease progression. Future studies have to confirm whether serum MMP-9 levels can be used to monitor therapeutic response.
Asunto(s)
Progresión de la Enfermedad , Metaloproteinasa 9 de la Matriz/sangre , Distrofia Muscular de Duchenne/sangre , Distrofia Muscular de Duchenne/fisiopatología , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Animales , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/tratamiento farmacológico , Osteopontina/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease. After identification of the mutation in the index patient, family members can be reliably investigated. Carriers should be informed about their risk of having offspring with the disease and about their own risk for cardiomyopathy for which regular cardiac surveillance is recommended. In a small country like the Netherlands with well-organized genetic services, one would expect that most DMD families are adequately informed about the above mentioned risks for carriers. We have investigated whether women at risk had been tested at a molecular level. In the national Duchenne/Becker database 311 DMD and 99 Becker muscular dystrophy (BMD) patients had been registered up to 1 July 2009. These patients were asked to give information about the number of sisters and maternal aunts of the DMD/BMD patient and anything that was known about their genetic status and that of the mother. This information was compared with the information known at the genetic laboratory. Thirty-five of 104 adult sisters/maternal aunts of DMD patients with a 50% risk of being a carrier and 45 of 148 adult women with a 4.3% risk because of germ line mosaicism for DMD had not been tested by DNA analysis. Our study indicates that about one third of the potential carriers have not been tested. Given the possible far-reaching clinical consequences of being a carrier, further studies are needed to investigate the reasons why potential female carriers have not been tested.
Asunto(s)
Familia , Pruebas Genéticas , Heterocigoto , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Adolescente , Niño , Preescolar , Distrofina/genética , Femenino , Humanos , Mosaicismo , Distrofia Muscular de Duchenne/mortalidad , Mutación , Riesgo , Adulto JovenRESUMEN
Theoretically, 13% of patients with Duchenne muscular dystrophy may benefit from antisense-mediated skipping of exon 51 to restore the reading frame, which results in the production of a shortened dystrophin protein. We give a detailed description with longitudinal follow up of three patients with Becker muscular dystrophy with in-frame deletions in the DMD gene encompassing exon 51. Their internally deleted, but essentially functional, dystrophins are identical to those that are expected as end products in DMD patients treated with the exon 51 skipping therapy. The mild phenotype encourages further development of exon 51 skipping therapy.
Asunto(s)
Distrofina/genética , Exones/genética , Predisposición Genética a la Enfermedad/genética , Terapia Genética/métodos , Distrofia Muscular de Duchenne/genética , Mutación/genética , Adolescente , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Distrofina/química , Distrofina/metabolismo , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatología , Oligorribonucleótidos Antisentido/farmacología , Oligorribonucleótidos Antisentido/uso terapéutico , Sistemas de Lectura Abierta/genética , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype-phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194-202, 2005). We describe the first distinctive clinical genotype-phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype-phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.
Asunto(s)
Canalopatías/genética , Párpados/fisiopatología , Mutación , Miotonía/genética , Canales de Sodio/genética , Adulto , Anciano , Secuencia de Bases , Análisis Mutacional de ADN , Párpados/anatomía & histología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miotonía/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.4 , Linaje , Adulto JovenRESUMEN
The presence of multiple affected offspring from apparently non-carrier parents is caused by germ line mosaicism. Although germ line mosaicism has been reported for many diseases, figures for recurrence risks are known for only a few of them. In X-linked Duchenne and Becker muscular dystrophies (DMD/BMD), the recurrence risk for non-carrier females due to germ line mosaicism has been estimated to be between 14% and 20% (95% confidence interval 3-30) if the risk haplotype is transmitted. In this study, we have analyzed 318 DMD/BMD cases in which the detected mutation was de novo with the aim of obtaining a better estimate of the 'true' number of germ line mosaics and a more precise recurrence risk. This knowledge is essential for genetic counseling. Our data indicate a recurrence risk of 8.6% (4.8-12.2) if the risk haplotype is transmitted, but there is a remarkable difference between proximal (15.6%) (4.1-27.0) and distal (6.4%) (2.1-10.6) deletions. Overall, most mutations originated in the female. Deletions occur more often on the X chromosome of the maternal grandmother, whereas point mutations occur on the X chromosome of the maternal grandfather. In unhaplotyped de novo DMD/BMD families, the risk of recurrence of the mutation is 4.3%.
Asunto(s)
Mutación de Línea Germinal/genética , Mosaicismo , Distrofia Muscular de Duchenne/genética , Femenino , Humanos , Masculino , Recurrencia , Factores de RiesgoRESUMEN
To determine self-reported health status in non-dystrophic myotonias (NDM) and its relationship to painful myotonia and fatigue. In a cross-sectional study, 32 NDM patients with chloride and 30 with sodium channelopathies, all off treatment, completed a standardised interview, the fatigue assessment scale (FAS), and the 36-item Short-Form Health Survey (SF-36). Beside formal assessment of pain, assessment of painful or painless myotonia was determined. The domain scores of the SF-36 were compared with Dutch community scores. Apart from the relationship among SF-36 scores and (1) painful myotonia and (2) fatigue, regression analyses in both NDM groups were conducted to determine the strongest determinants of the SF-36 domains general health perception, physical component (PCS) and mental component summary (MCS). All physically oriented SF-36 domains in both NDM groups (P Asunto(s)
Fatiga/complicaciones
, Estado de Salud
, Miotonía/complicaciones
, Miotonía/psicología
, Dolor/complicaciones
, Adulto
, Anciano
, Canales de Cloruro
, Estudios Transversales
, Femenino
, Humanos
, Entrevista Psicológica
, Masculino
, Persona de Mediana Edad
, Análisis Multivariante
, Análisis de Regresión
, Reproducibilidad de los Resultados
, Índice de Severidad de la Enfermedad
, Canales de Sodio
, Adulto Joven
RESUMEN
OBJECTIVE: To redefine phenotypical characteristics for both chloride (ClCh) and sodium channelopathies (NaCh) in non-dystrophic myotonic syndromes (NDM). METHODS: In a cross-sectional, nationwide study, standardised interviews and clinical bedside tests were performed in 62 genetically confirmed NDM patients, 32 ClCh and 30 NaCh. RESULTS: Standardised interviews revealed that ClCh reported a higher frequency of muscle weakness (75 vs 36.7%; p<0.01), the warm-up phenomenon (100 vs 46.7%; p<0.001), and difficulties in standing up quickly (90.6 vs 50.0%; p<0.001), running (90.6% vs 66.7; p<0.05) and climbing stairs (90.6 vs 63.3%; p = 0.01). Patients with NaCh reported an earlier onset (4.4 vs 9.6 years; p<0.001), and higher frequencies of paradoxical (50.0 vs 0%; p<0.001) and painful myotonia (56.7 vs 28.1%; p<0.05). Standardised clinical bedside tests showed a higher incidence and longer relaxation times of myotonia in the leg muscles for ClCh (100 vs 60%; mean duration of chair tests 12.5 vs 6.3 s; p<0.001), and in eyelid muscles for NaCh (96.7 vs 46.9%; mean relaxation time of 19.2 vs 4.3 s; p<0.001). Transient paresis was only observed in ClCh (62.5%) and paradoxical myotonia only in NaCh (30.0%). Multivariate logistic regression analyses allowed clinical guidelines to be proposed for genetic testing. CONCLUSION: This study redefined the phenotypical characteristics of NDM in both ClCh and NaCh. The clinical guidelines proposed may help clinicians working in outpatient clinics to perform a focused genetic analysis of either CLCN1 or SCN4A.
Asunto(s)
Canalopatías/genética , Canales de Cloruro/genética , Trastornos Miotónicos/genética , Fenotipo , Canales de Sodio/genética , Adulto , Anciano , Canalopatías/clasificación , Canalopatías/diagnóstico , Estudios Transversales , Análisis Mutacional de ADN , Electromiografía , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Trastornos Miotónicos/clasificación , Trastornos Miotónicos/diagnóstico , Canal de Sodio Activado por Voltaje NAV1.4 , Países Bajos , Examen Neurológico , Síndrome , Adulto JovenRESUMEN
We report on a 16-year-old Dutch patient in whom rippling muscle disease (RMD) was diagnosed years after his mother had been falsely diagnosed with acid maltase deficiency. The autosomal dominant mode of inheritance of the neuromuscular symptoms in this family had led to a re-evaluation of the diagnosis of acid maltase deficiency. Physical examination revealed the three key features leading to the clinical diagnosis of RMD: rippling, mounding, and percussion-induced rapid muscle contraction. Mutation analysis revealed a novel heterozygous missense mutation in the caveolin-3 gene (c.79C > G; p.Arg27Gly) in both the index patient and his mother. This case report stresses the importance of adhering to the mode of inheritance in the diagnosis of neuromuscular disorders. It also indicates that typical RMD phenomena are not easily acknowledged among paediatricians or neurologists. We therefore present an overview of these clinical characteristics of rippling muscle disease RMD.
Asunto(s)
Caveolina 3/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Mutación Missense , Adolescente , Adulto , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Masculino , Contracción Muscular/fisiología , Enfermedades Musculares/fisiopatologíaRESUMEN
A 71-year-old woman presented with recurrent episodes of headache accompanied by hemihypoesthesia, fever, aphasia, reduced consciousness and worsening of pre-existing ataxia. Brain imaging revealed atrophy of the cerebellum. The white cell count in the cerebrospinal fluid was slightly increased. The patient had a family history of migraine and cerebellar ataxia. DNA testing revealed a missense mutation in the CACNA1A gene, confirming the diagnosis of familial hemiplegic migraine. Familial hemiplegic migraine is a rare subtype of migraine with aura. It follows an autosomal dominant pattern of inheritance. Patients with familial hemiplegic migraine exhibit a wide spectrum of symptoms, which can hinder the diagnosis. If a patient presents with recurrent coma or encephalitis with or without cerebellar ataxia, familial hemiplegic migraine should be included in the differential diagnosis.
Asunto(s)
Canales de Calcio/genética , Migraña con Aura/diagnóstico , Migraña con Aura/genética , Anciano , Coma/diagnóstico , Coma/etiología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Humanos , RecurrenciaRESUMEN
Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.
Asunto(s)
Canales de Calcio/genética , Migraña con Aura/genética , Mutación , Adolescente , Anciano , Análisis Mutacional de ADN , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Linaje , FenotipoRESUMEN
Pheno- and genotype correlation is attempted in a Dutch cross-sectional study on limb- girdle muscular dystrophy. Sarcoglycans, caveolin-3, calpain-3, and dysferlin were analyzed on muscle tissue. Mutation analysis of the calpain-3, caveolin-3, and fukutin-related protein gene was executed in successive order for all samples. In 51% of all families a classifying diagnosis was made. Several new mutations in LGMD2A, B, and C patients have been found in this population.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/genética , Mutación/genética , Adolescente , Adulto , Calpaína/genética , Caveolina 3/genética , Mapeo Cromosómico , Estudios Transversales , Análisis Mutacional de ADN , Disferlina , Femenino , Pruebas Genéticas , Genotipo , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Países Bajos , Pentosiltransferasa , Fenotipo , Proteínas/genéticaRESUMEN
A 22-month-old girl had cramps and stiffness of her muscles. After medical history, physical examination and an EMG, a short differential diagnosis based on the symptoms of myotonia was made. Initially, the symptoms were incorrectly assumed to be due to Becker's myotonia, an autosomal recessive condition caused by a mutation in the chloride channel. Molecular analysis did not show a defect in the chloride channel, but instead a defect in the sodium channel of the muscle fibre. Since defects in the sodium channel are responsible for several myotonic diseases, further analysis was necessary. Based on knowledge of the structure and mechanism of the sodium channel and study of literature on cases involving the identical mutation, the diagnosis 'potassium-aggravated myotonia' (PAM) was made. Re-evaluation of the patient showed that her symptoms fitted the diagnosis 'myotonia permanens', the severest form of PAM. She was treated with mexiletine. In myotonia several features can give direction to the diagnosis, including sensitivity to temperature and exercise, and family history. However, it is often necessary to use molecular analysis to be able to diagnose the disease correctly, make a prognosis and predict the risk of recurrence as well as to formulate a treatment plan.
Asunto(s)
Calambre Muscular/genética , Miotonía/diagnóstico , Miotonía/genética , Canales de Sodio/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Electromiografía , Femenino , Humanos , Lactante , Músculo Esquelético/inervación , Potasio/efectos adversos , Canales de Sodio/metabolismoRESUMEN
The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrangements. We report here the detection and analysis of 118 duplications in the DMD gene of DMD/BMD patients. In an unselected patient series the duplication frequency was 7%. In patients already screened for deletions and point mutations, duplications were detected in 87% of cases. There were four complex, noncontiguous rearrangements, with two also involving a partial triplication. In one of the few cases where RNA was analyzed, a seemingly contiguous duplication turned out to be a duplication/deletion case generating a transcript with an unexpected single-exon deletion and an initially undetected duplication. These findings indicate that for clinical diagnosis, duplications should be treated with special care, and without further analysis the reading frame rule should not be applied. As with deletions, duplications occur nonrandomly but with a dramatically different distribution. Duplication frequency is highest near the 5' end of the gene, with a duplication of exon 2 being the single most common duplication identified. Analysis of the extent of 11 exon 2 duplications revealed two intron 2 recombination hotspots. Sequencing four of the breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining. There appear to be fundamental differences therefore in the origin of deletions and duplications in the DMD gene.