RESUMEN
BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.
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Hipertermia Maligna/genética , Enfermedades Musculares/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Enfermedades Musculares/congénito , Mutación , Linaje , Fenotipo , Adulto JovenRESUMEN
This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.
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Pruebas Genéticas , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Diagnóstico Prenatal , Adulto , Femenino , Asesoramiento Genético , Haplotipos , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Riesgo , Expansión de Repetición de TrinucleótidoRESUMEN
Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.
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Algoritmos , Sistemas de Apoyo a Decisiones Clínicas , Degeneraciones Espinocerebelosas/diagnóstico , Adolescente , Niño , Diagnóstico Diferencial , Femenino , Humanos , MasculinoRESUMEN
The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.
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Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Brazo/anomalías , Radio (Anatomía)/anomalías , Trombocitopenia/genética , Trombocitopenia/fisiopatología , Niño , Aberraciones Cromosómicas , Cromosomas Humanos Par 22/genética , Anomalías del Sistema Digestivo , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , Pierna/anomalías , Masculino , Síndrome , Anomalías Urogenitales/genéticaRESUMEN
BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.
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Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética , Adulto , Edad de Inicio , Humanos , Persona de Mediana Edad , Mutación , Países Bajos/epidemiología , Prevalencia , Análisis de Regresión , Ataxias Espinocerebelosas/fisiopatología , Expansión de Repetición de TrinucleótidoRESUMEN
We report on a 22-year-old woman and her 21-year-old brother with mild mental retardation, long face, prominent forehead, retrognathia, and (relative) macrocephaly. At birth they were small for date, their length is now below the 10th centile. Chromosome analysis demonstrated a nearly pure trisomy 1q42 --> qter in both patients due to unbalanced segregation of a paternal reciprocal balanced translocation 46,XY,t(1;15) (q42;p11). This is the second report of a nearly pure trisomy 1q42 --> qter. When comparing the manifestations of our patients with those of other reported cases we conclude that the most characteristic clinical manifestations of this syndrome are macrocephaly, prominent forehead, micro/retrognathia, large fontanelle, intrauterine growth retardation, postnatal growth retardation, and mental retardation.
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Cráneo/anomalías , Trisomía , Adulto , Bandeo Cromosómico , Mapeo Cromosómico , Cromosomas Humanos Par 15 , Femenino , Humanos , Cariotipificación , Masculino , Núcleo Familiar , Síndrome , Translocación GenéticaRESUMEN
INTRODUCTION: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement. AIM: In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment. METHODS: During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores. RESULTS: In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05). CONCLUSION: In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.
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Antioxidantes/uso terapéutico , Ataxia de Friedreich/fisiopatología , Ubiquinona/análogos & derivados , Adolescente , Factores de Edad , Niño , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Ataxia de Friedreich/tratamiento farmacológico , Humanos , Estudios Longitudinales , Dinamómetro de Fuerza Muscular , Conducción Nerviosa/efectos de los fármacos , Resultado del Tratamiento , Ubiquinona/uso terapéuticoRESUMEN
Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.
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Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Unión Competitiva/fisiología , Biomarcadores , Cuerpo Estriado/patología , Análisis Mutacional de ADN , Progresión de la Enfermedad , Antagonistas de Dopamina/metabolismo , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , Proteína Huntingtina , Enfermedad de Huntington/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/genética , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatología , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Racloprida/metabolismo , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Mutation analysis was performed in four apparently unrelated Dutch families with pantothenate kinase-associated neurodegeneration, formerly known as Hallervorden-Spatz syndrome. A novel 3-bp deletion encompassing the nucleotides GAG at positions 1,142 to 1,144 of exon 5 of the PANK2 gene was found in all patients. One patient was compound heterozygous; she also carried a novel nonsense mutation (Ser68Stop). The other patients were homozygous for the 1142_1144delGAG mutation. The 1142_1144delGAG mutation was also found in a German patient of unknown descent. We used polymorphic microsatellite markers flanking the PANK2 gene (spanning a region of approximately 8 cM) for haplotype analyses in all these families. A conserved haplotype of 1.5 cM was found for the 1142_1144delGAG mutation carriers. All the Dutch families originated from the same geographical region within the Netherlands. The results indicate a founder effect and suggest that the 1142_1144delGAG mutation probably originated from one common ancestor. It was estimated that this mutation arose at the beginning of the ninth century, approximately 38 generations ago.
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Eliminación de Gen , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Neurodegeneración Asociada a Pantotenato Quinasa/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Secuencia de Bases , Niño , Preescolar , Femenino , Efecto Fundador , Homocigoto , Humanos , Masculino , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Países Bajos , Linaje , Polimorfismo GenéticoRESUMEN
In 1958 chorionic villus samples, investigated by culture method, we found 137 (7%) abnormalities. The abnormal results were classified in certain abnormal (generalised abnormal at high probability) and uncertain abnormal (potentially confined to the placenta) results. Certain abnormal were 73 cases (3.7%). Uncertain abnormal were 64 cases (3.3%), in which confirmation studies were done in 47 cases. In 12 cases of these 47, the abnormality was confirmed and in 35 cases (1.8%) the abnormality was confined to the placenta. Among the latter cases, poor pregnancy outcome [16% intrauterine death (IUD), 6% intrauterine growth retardation (IUGR)] was increased. Total maternal cell contamination was not seen. The positive predictive value of all confirmed abnormal cases was 66%. The positive predictive value was 100% for indications 'ultrasound abnormalities' and 'carrier' and between 50 and 60% for all other indications. Predictive value among uncertain abnormal cases was low (26%). However, the positive predictive value depends of the type of abnormality. Therefore we conclude that the culture method for chorionic villi is a good test for indications 'ultrasound abnormalities' and 'carrier' and reliable for all other indications. Whether or not follow-up investigations should be offered to the parents depends of the type of abnormality. We conclude that the culture method is reliable for prenatal diagnosis and can be used as the sole investigative method.
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Muestra de la Vellosidad Coriónica/métodos , Aberraciones Cromosómicas/diagnóstico , Trastornos de los Cromosomas , Reacciones Falso Positivas , Femenino , Humanos , Embarazo , Resultado del EmbarazoRESUMEN
In the Northern Netherlands, we examined the live birth prevalence of Down syndrome (DS) and the impact of maternal serum screening (MSS) and prenatal cytogenetic diagnosis (PCD) during the period 1987-96. In this period the live birth prevalence, based on the maternal age distribution and the age specific risk of delivering a child with DS was expected to increase from 1.26 in 1987 to 1.62 in 1996. The introduction of MSS in 1991 made PCD available to women of all ages. Nevertheless, the utilization of PCD remained very stable. In 1991, 4.7% of pregnant women underwent a diagnostic test. In 1996 this percentage was 6.4%. As a result of MSS and PCD, the live birth prevalence of DS was 19% lower than expected (p<0.01). Despite utilization of PCD based on opting-in and a discouraging government policy regarding the offer of MSS, the percentage of DS cases detected by PCD increased from of 17% during the period 1987-90 to 27% in the period 1991-96 when MSS was available. The percentages have been corrected for spontaneous pregnancy loss. From a medical and financial point of view, MSS was the most cost-effective indication for PCD. However, the potential of reducing the birth prevalence of DS is limited by the low utilization of MSS and PCD by pregnant women.
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Síndrome de Down/epidemiología , Tamizaje Masivo , Diagnóstico Prenatal , Adulto , Factores de Edad , Análisis Costo-Beneficio , Síndrome de Down/sangre , Femenino , Humanos , Recién Nacido , Tamizaje Masivo/economía , Tamizaje Masivo/estadística & datos numéricos , Edad Materna , Países Bajos/epidemiología , Embarazo , Diagnóstico Prenatal/economía , Diagnóstico Prenatal/estadística & datos numéricos , Prevalencia , Factores de RiesgoRESUMEN
The autosomal dominant cerebellar ataxias (ADCA) are clinically and genetically heterogeneous. To date, several loci (SCAI-V) have been identified for ADCA type I. We have studied two large families from the northern part of The Netherlands with ADCA type I with a broad intra-familial variation of symptoms. In both families significant linkage is shown of the disease to the markers of the SCA3 locus on chromosome 14. Through recombinations, the candidate region for SCA3 could be refined to a 13-cM range between D14S256 and D14S81. No recombinations were detected with the markers D14S291 and D14S280, which suggests that the SCA3 gene lies close to these loci. This finding will benefit the individuals at risk in these two families who are seeking predictive testing or prenatal diagnosis.