RESUMEN
BACKGROUND AND PURPOSE: SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway. METHODS: Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described. RESULTS: The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant. CONCLUSION: SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway.
Asunto(s)
Metaloendopeptidasas/genética , Paraplejía/genética , Paraplejía Espástica Hereditaria/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adolescente , Adulto , Niño , Humanos , Mutación , Noruega , Paraplejía/patología , Paraplejía/fisiopatología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Paraplejía Espástica Hereditaria/patología , Paraplejía Espástica Hereditaria/fisiopatología , Adulto JovenRESUMEN
UNLABELLED: Current available therapies control Myasthenia gravis (MG) reasonably well, but Health Related Quality of life (HRQOL) remains lower than expected. The aim was provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders and assess the impact of potential predictors for quality of life such as a) clinical characteristics b) antibodies c) thymoma and d) treatment in a population-based cohort. METHODS: We designed a population-based cross-sectional study including 858 patients, 373 from Norway and 485 from the Netherlands. The Short Form Health Survey 36 (SF-36) and a cross-cultural validated questionnaire were used. Data were in addition compared to the general population, other chronic diseases and previous studies. RESULTS: Mean physical composite score was 59.4 and mental composite score 69.0 with no differences between the countries. The mean HRQOL score was lower in patients with bulbar and generalized symptoms (p < 0.001) compared to sex and age adjusted healthy controls, but not in patients with ocular symptoms or patients in remission. Multivariate analysis revealed that female gender, generalized symptoms and use of secondary immunosuppressive drugs at the time of testing were risk factors for reduced HRQOL. CONCLUSIONS: Remission and absence of generalized symptoms were favorable factors for HRQOL in MG patients. Historically, the HRQOL levels have not changed since 2001 and no new clinical predictors could be detected in this exhaustive population-based study. Further studies should explore the impact of non clinical factors like ethnic variations, socio-economic and hormonal factors on HRQOL.
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Indicadores de Salud , Miastenia Gravis/psicología , Calidad de Vida/psicología , Encuestas y Cuestionarios/normas , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/epidemiología , Miastenia Gravis/terapia , Países Bajos/epidemiología , Noruega/epidemiología , Psicometría , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: The influence of environmental factors in myasthenia gravis (MG) is unknown. The aim of this cross-sectional population-based study was to investigate if smoking and socio-economic status (SES) were associated with MG in the Norwegian population. METHODS: Subjects were 491 MG patients identified in Norway at the time of the study (point prevalence 12.7/100 000). A questionnaire covering smoking habits and markers of SES (education and occupation) was mailed to all patients. Population data were obtained from Statistics Norway. RESULTS: A total of 375 (76.6%) patients completed the questionnaire (236 women, mean age 59 ± 18 years), of which 193 reported to be early onset MG (EOMG, onset ≤40 years, 155 women). Compared with the general population, current smoking was more prevalent amongst MG patients [risk ratio (RR) 1.5; 95% confidence interval (CI) 1.1-1.9], most of whom had EOMG. Female MG patients had higher education compared with the general population (RR 4.5; 95% CI 3.2-6.2). Male MG patients were similar to the general population regarding both education and occupation, except for a subset of late onset MG who had shorter education (RR 1.9; 95% CI 1.1-3.2) and had worked in crafts and related trades. About half of working age MG patients received disability pension, a finding significantly related to low educational level and a more severe disease course (P < 0.001). CONCLUSION: This is the first report indicating that smoking and SES may affect MG. Further studies investigating their role as potential risk factors are warranted.
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Miastenia Gravis/epidemiología , Fumar/efectos adversos , Fumar/epidemiología , Clase Social , Adolescente , Adulto , Edad de Inicio , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/etiología , Noruega/epidemiología , Prevalencia , Adulto JovenRESUMEN
OBJECTIVES: Despite a similar prevalence of autosomal dominant cerebellar ataxia (ADCA) in Norway compared to other European countries, less than 10% of the families are explained by the CAG trinucleotide expansions. We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype. METHODS: We screened a large dominant cerebellar ataxia cohort for mutations in the PRKCG gene. Patients were evaluated according to a standard clinical protocol for ataxia patients. RESULTS: A novel mutation was found in two families, a C to A transversion altering Histidine to a Glutamine at codon 139, located in a highly concerved region in the gene. It completely co-segregated with the affected family members and was not seen in 576 control chromosomes. Genetic analysis revealed common alleles at three microsatellite markers between these two families suggesting a shared ancestral chromosome. Affected subjects displayed a mild, slowly progressive cerebellar syndrome that included gait and limb ataxia and saccadic pursuit and head tremor in one. Age at onset ranged from 10 to 45 years. CONCLUSIONS: These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%.
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Ataxia Cerebelosa/genética , Mutación Missense/genética , Proteína Quinasa C/genética , Degeneraciones Espinocerebelosas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega , Ataxias Espinocerebelosas , Adulto JovenRESUMEN
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
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Enfermedades del Sistema Nervioso Central/complicaciones , GTP Fosfohidrolasas/genética , Atrofia Óptica Autosómica Dominante/complicaciones , Adolescente , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Niño , Estudios de Cohortes , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/metabolismo , Atrofia Óptica Autosómica Dominante/patología , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: To date, the investigation of the epidemiological profile of myasthenia gravis (MG) is sparse, and the influence of environmental and lifestyle factors on the occurrence of the disease remains thus unknown. The main aim of this study, which is part of a European collaborative project (EuroMyasthenia), was to develop a self-administered questionnaire to investigate these potential predisposing factors for MG. No instrument for investigating these particular factors has previously been designed for MG patients. MATERIAL AND METHODS: The questionnaire was developed in 3 stages: (1) devising a draft questionnaire based on questions derived from previously validated questionnaires and self-designed questions on MG characteristics; (2) testing the questionnaire on Norwegian MG patients (n = 57), and (3) assessing the content and criterion validity, and test-retest reliability, of the final questionnaire. RESULTS: The questionnaire was easy to use and showed good feasibility for MG patients. Psychometric evaluation established the validity and reliability of the self-designed questions on MG characteristics. CONCLUSION: This is the first validated instrument developed to identify self-assessed environmental factors and potential predisposing factors for MG, and suitable for use in large-scale epidemiological studies.
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Miastenia Gravis/epidemiología , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Costo de Enfermedad , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Psicometría , Calidad de Vida , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.
Asunto(s)
Ataxia/diagnóstico , Ataxia/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Ataxia/metabolismo , Humanos , Paraplejía/diagnóstico , Paraplejía/genética , Paraplejía/metabolismo , Paraplejía Espástica Hereditaria/metabolismoRESUMEN
GM(2)-gangliosidosis is a rare and heterogeneous inherited metabolic disorder caused by autosomal recessive mutations in genes encoding the lysosomal enzyme ß-hexosaminidase, resulting in the accumulation of ganglioside GM(2) in various tissues, particularly the central nervous system. It is characterized by progressive neurological deterioration that mainly affects motor and spinocerebellar function. Several forms of GM(2)-gangliosidosis exist, including the Sandhoff variant. Currently there is no treatment for these conditions, except for palliative care. Miglustat (Zavesca) is a reversible inhibitor of glucosylceramide synthase, which catalyses the first committed step in the synthesis of glucose-based glycolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood-brain barrier, and preclinical data suggest that it may benefit neuronopathic lysosomal storage diseases. Here we present a case report of a Norwegian patient with Sandhoff disease treated with miglustat at our centre in Norway. The patient initially presented with ataxia and dysarthria at 2-3 years of age, which progressed slowly during childhood. At age 14, he experienced episodes of depression and apathy, leading to weight loss. He was diagnosed with Sandhoff disease at age 16. Following 2.5 years of treatment with miglustat, his body weight was stabilized and disease progression appeared to have slowed, as evidenced by the lack of progressive brain atrophy. His depressive symptoms were managed using electroconvulsive treatment (ECT), which improved general functioning. These findings suggest that miglustat may provide beneficial effects in patients with juvenile Sandhoff disease, and that ECT may alleviate depressive symptoms.
Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Sandhoff/diagnóstico , 1-Desoxinojirimicina/uso terapéutico , Adolescente , Cerebelo/patología , Preescolar , Depresión/terapia , Progresión de la Enfermedad , Terapia Electroconvulsiva , Inhibidores Enzimáticos/uso terapéutico , Glucosiltransferasas/antagonistas & inhibidores , Humanos , Masculino , Mutación , Enfermedad de Sandhoff/genética , Enfermedad de Sandhoff/patología , Cadena beta de beta-Hexosaminidasa/genéticaRESUMEN
The hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. Axonal loss in the long corticospinal tracts has been shown. Supraspinal symptoms and findings in the most common dominant HSP type, SPG4, support the theory that the disease also causes cerebral neuronal damage in specific parts of the brain. To investigate whether SPG4-HSP is associated with neuronal biochemical changes detectable on MR spectroscopy (MRS), single-voxel proton MRS of the brain was performed in eight subjects from four families with genetically confirmed SPG4-type HSP and eight healthy age-matched controls. Volumes of interest (VOI) were located in the frontal white matter and motor cortex. N-acetyl-aspartate-to-creatine ratio (NAA/Cr), N-acetyl-aspartate-to-choline (NAA/Cho), cholin to creatin (Cho/Cr) and myo-inositol-to-creatine (Ins/Cr) ratios were calculated for both locations. Neuropsychological tests were performed to support the neuroradiological findings. The Cho/Cr ratio in motor cortex (MC) of SPG4-HSP subjects was significantly lower than in controls. This reduction of the Cho/Cr ratio in SPG4 subjects was significantly associated with age-related verbal learning- and memory (CVLT) reduction. Our findings support involvement of motor cortex in SPG4-HSP. Proton MRS could be a useful tool for detecting metabolite abnormalities in areas of brain that appear normal on MRI. Cho/Cr ratio may be a marker of neurodegenerative process in SPG4-HSP.
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Adenosina Trifosfatasas/genética , Trastornos del Conocimiento/metabolismo , Espectroscopía de Resonancia Magnética , Paraplejía Espástica Hereditaria/metabolismo , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Colina/metabolismo , Trastornos del Conocimiento/genética , Creatina/metabolismo , Femenino , Humanos , Inositol/metabolismo , Masculino , Persona de Mediana Edad , Corteza Motora/metabolismo , Degeneración Nerviosa/diagnóstico , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Protones , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , EspastinaRESUMEN
OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.
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Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Biología Molecular/métodos , HumanosRESUMEN
BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity with additional neurological symptoms and signs in complicated forms. Among the many autosomal recessive forms, SPG11 appears to be one of the most frequent. OBJECTIVE: Our objective was to select potential SPG11 patients based on phenotypes in our material, identify eventual disease-causing variants with the collaboration of laboratories abroad, estimate the frequency and spectrum of SPG11-mutations and describe their associated phenotypes. MATERIAL AND METHODS: Two isolated cases and two affected members of one family with cognitive impairment and confirmed thin corpus callosum on magnetic resonance imaging were selected from our database for inclusion into a multicenter study. Results - Mutations were found in the two isolated cases but not in the proband of the family. CONCLUSION: We present the first SPG11-HSP in the Norwegian population. SPG11 should be suspected in patients with isolated or recessive HSP, thin corpus callosum and mental retardation.
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Genes Recesivos/genética , Proteínas/genética , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Adulto , Cuerpo Calloso/patología , Femenino , Humanos , Discapacidad Intelectual/etiología , Masculino , Persona de Mediana Edad , Noruega , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/psicologíaRESUMEN
INTRODUCTION: The relative frequencies of different ataxias vary among different ethnic and geographic groups. The aim of this study was to examine patients with cerebellar ataxia and find the occurrence of autosomal dominant and recessive cerebellar ataxias in the population of the southern and eastern parts of Norway and estimate its prevalence. MATERIALS AND METHODS: Probands were systematically tested for spinocerebellar ataxia 1, 2, 3, 6 and Friedreich's ataxia. A total of 94 patients with ataxia were assessed. RESULTS: We registered 60 patients from 39 unrelated families with hereditary ataxias. One family with SCA2 (two patients), one family with Friedreich's ataxia (two patients), two patients heterozygote for Friedreich's ataxia and one metabolic ataxia were identified. CONCLUSIONS: We have few Friedreich's ataxia and SCA 1,2,3 and 6 in our population. Prevalence in Oslo County was estimated at 2.2/100,000 for autosomal recessive and 3.0/100,000 for autosomal dominant ataxia, respectively.
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Ataxia Cerebelosa/epidemiología , Ataxia Cerebelosa/genética , Predisposición Genética a la Enfermedad/genética , Adolescente , Adulto , Distribución por Edad , Edad de Inicio , Anciano , Ataxia Cerebelosa/etnología , Niño , Preescolar , Trastornos de los Cromosomas/genética , Análisis Mutacional de ADN , Femenino , Ataxia de Friedreich/epidemiología , Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatología , Trastornos Neurológicos de la Marcha/epidemiología , Trastornos Neurológicos de la Marcha/etnología , Trastornos Neurológicos de la Marcha/genética , Genes Dominantes/genética , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/etnología , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Noruega/etnología , Prevalencia , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatologíaRESUMEN
To establish the phenotypic variation and frequency of SPAST mutations or deletions in Norwegian patients with hereditary spastic paraplegia (HSP), we examined 59 unrelated patients with HSP and screened for DNA point mutations and microdeletions in SPG4. Forty-one had a familial history, 35 had a clear dominant inheritance, six had other affected sibs and 18 were sporadic. We found 12 mutations in SPG4, seven of them novel, and four different heterozygous exon deletions, two of them novel. Mutations were found in 16 families showing autosomal dominant (AD) inheritance, and in one sporadic case. In two non-SPG4 families the S44L polymorphism/modifier was found in both affected and unaffected individuals. This is the first study of Norwegian patients with HSP since the 1970s, and the first report on SPG4 in Norway. Our results show that SPG4 mutations and deletions are a significant cause of HSP in our population and warrant SPG4 screening in AD families and selected sporadic cases.
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Adenosina Trifosfatasas/genética , Mutación Puntual , Eliminación de Secuencia , Paraplejía Espástica Hereditaria/genética , Adenosina Trifosfatasas/fisiología , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Exones/genética , Femenino , Genes Dominantes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Noruega/epidemiología , Fenotipo , Polimorfismo de Nucleótido Simple , Alineación de Secuencia , Paraplejía Espástica Hereditaria/epidemiología , EspastinaRESUMEN
Thiamin, thiamin monophosphate, ascorbic acid, and folic acid were determined in serum and cerebrospinal fluid (CSF) in 31 outpatients who underwent a myelography because of back-pain. All subjects were otherwise healthy. The CSF concentration (mean +/- SD) was 8.6 +/- 3.9 nmol thiamin/L, 16.9 +/- 8.3 nmol thiamin monophosphate/L, 133 +/- 58.8 mumol ascorbic acid/L, and 44.9 +/- 13.2 nmol folic acid/L. The CSF-serum ratio was 2.1 +/- 0.8 for thiamin, 8.3 +/- 4.3 for thiamin monophosphate, 3.0 +/- 1.4 for ascorbic acid, and 3.3 +/- 0.8 for folic acid; the amount in CSF was significantly higher than in serum for each compound. These results support the existence of a saturated transport mechanism of water-soluble vitamins from serum into CSF for thiamin monophosphate, ascorbic acid, and folic acid. However, low CSF concentrations are correlated with low serum concentrations for the three vitamins. High serum concentrations should therefore be advocated to ensure high CSF concentrations.
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Ácido Ascórbico/sangre , Ácido Ascórbico/líquido cefalorraquídeo , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Tiamina/sangre , Tiamina/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
OBJECTIVES: Sepiapterin reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder. MATERIALS AND METHODS: We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the sepiapterin reductase gene (SPR) was sequenced. RESULTS: The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A>G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation. CONCLUSIONS: A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.
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Oxidorreductasas de Alcohol/genética , Trastornos Distónicos/genética , Predisposición Genética a la Enfermedad , Levodopa/genética , Mutación/genética , Adolescente , Niño , Femenino , Humanos , Linaje , Pterinas/metabolismoAsunto(s)
Tiamina/sangre , Tiamina/orina , Humanos , Métodos , Tiamina Monofosfato/sangre , Tiamina Monofosfato/orinaRESUMEN
BACKGROUND: Ataxia with vitamin E deficiency (AVED) is a rare cause of hereditary ataxia in north European countries with unknown prevalence. Few cases are reported from these countries. METHODS: Through a systematic population based study of hereditary ataxia in southeast Norway subjects were classified and investigated. AIMS: To report a subject with ataxia due to vitamin E deficiency in Norway. RESULTS: One patient with AVED was identified. The subject was a 45 years old woman with progressive ataxia from preschool age. When she was 12 years old Friedreich's ataxia was diagnosed after neurological examination. At the age of 45 re-evaluation and re-examination was performed and genetic analysis of the Frataxin gene was negative. At that time she had truncal and extremities ataxia, titubation of the head, pes cavus, inverted plantar response, loss of proprioceptive and vibration sense and a severe sensory neuropathy. Vitamin E in serum was undetectable and genetic analysis detected a compound heterozygous mutation, p.A120T and p.R134X, in the alpha-tocopherol transport protein gene on chromosome 8q13. DISCUSSION: Vitamin E should always be assessed in progressive ataxia of genetic or unexplained causes and especially with a Friedreich's ataxia-like phenotype since treatment is available. CONCLUSION: AVED is rare in Norway, but exists, and we here report the first genetically confirmed subject with ataxia due to vitamin E deficiency in Norway.
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Ataxia/genética , Deficiencia de Vitamina E/genética , Ataxia/diagnóstico , Ataxia/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Ataxia de Friedreich/genética , Genes Recesivos , Humanos , Persona de Mediana Edad , Vitamina E/uso terapéutico , Deficiencia de Vitamina E/tratamiento farmacológicoRESUMEN
The biochemical hallmark of adult Refsum disease (ARD) is an isolated deficiency in the breakdown of phytanic acid. This usually results from a PHYH gene defect, although some cases have been found to carry a PEX7 defect. We describe the phenotype of such a patient, indistinguishable from that of classic ARD. Hence, we propose the subdivision of ARD into type 1 and type 2, depending on which gene is defective.
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Fenotipo , Receptores Citoplasmáticos y Nucleares/genética , Enfermedad de Refsum/diagnóstico , Enfermedad de Refsum/genética , Anciano , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Mutación , Receptor de la Señal 2 de Direccionamiento al Peroxisoma , Enfermedad de Refsum/clasificaciónRESUMEN
BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.