RESUMEN
BACKGROUND AND PURPOSE: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO. METHODS: This was a parametric survival modelling study. RESULTS: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. CONCLUSIONS: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins.
Asunto(s)
Edad de Inicio , Enfermedad de Machado-Joseph/fisiopatología , Adulto , Algoritmos , Pueblo Asiatico , Brasil , Portador Sano , Estudios de Cohortes , Femenino , Humanos , Enfermedad de Machado-Joseph/genética , Masculino , Persona de Mediana Edad , Población , Portugal , Valor Predictivo de las Pruebas , Taiwán , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 10 is a neurodegenerative disorder that is due to an expanded ATTCT repeat tract in the ATXN10 gene. Our aim was to describe clinical characteristics and intragenic haplotypes of patients with spinocerebellar ataxia type 10 from Brazil and Peru. METHODS: Expanded alleles were detected by repeat-primed polymerase chain reaction. Disease progression was measured by the Scale for the Assessment and Rating of Ataxia, and the Neurological Examination Score for Spinocerebellar Ataxias when possible. Haplotypes were constructed based on polymorphic markers within and outside the gene. RESULTS: Thirteen new families were diagnosed (three from Peru). Patients from three Brazilian families diagnosed previously were also reassessed. In total, 25 individuals (16 families) were evaluated. Mean (± SD) age at onset and disease duration were 34.8 ± 10.2 and 12 ± 8 years, respectively. Common findings were ataxia, dysarthria/dysphagia, nystagmus, pyramidal signs, ophthalmoparesis and seizures. No associations were found between clinical findings and geographical origins. Twelve patients living in remote regions were examined only once. In the remaining individuals, the Scale for the Assessment and Rating of Ataxia score, and Neurological Examination Score for Spinocerebellar Ataxias worsened by 0.444 (95% CI, -0.088 to 0.800) and 0.287 (95% CI, -0.061 to 0.635) points/year, respectively. A common haplotype, 19CGGC14, was found in 11/13 of Brazilian and in 1/3 of Peruvian families. CONCLUSIONS: The progression rate was slower than in other spinocerebellar ataxias. A consistently recurrent intragenic haplotype was found, suggesting a common ancestry for most, if not all, patients.
Asunto(s)
Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Adolescente , Adulto , Edad de Inicio , Alelos , Ataxina-10/genética , Brasil/epidemiología , Niño , ADN/genética , Progresión de la Enfermedad , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Perú/epidemiología , Convulsiones/epidemiología , Convulsiones/etiología , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). METHODS: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. RESULTS: Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). CONCLUSIONS: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.
Asunto(s)
Depresión/fisiopatología , Fatiga/fisiopatología , Dolor/fisiopatología , Paraplejía Espástica Hereditaria/fisiopatología , Adenosina Trifosfatasas/genética , Adulto , Depresión/etiología , Fatiga/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Dolor/etiología , Paraplejía Espástica Hereditaria/complicaciones , EspastinaRESUMEN
Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.
Asunto(s)
Ataxina-3/genética , Inestabilidad Genómica , Patrón de Herencia , Enfermedad de Machado-Joseph/genética , Proteínas Represoras/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Alelos , Enfermedades Asintomáticas , Segregación Cromosómica , Femenino , Frecuencia de los Genes , Heterocigoto , Humanos , Enfermedad de Machado-Joseph/patología , Masculino , Meiosis , Linaje , Índice de Severidad de la Enfermedad , Factores Sexuales , HermanosRESUMEN
We aimed to present a systematic review on Huntington's disease (HD) in Latin America (LA). PubMed and LILACS were searched up to March 2015, reporting confirmed HD cases in LA. Case series, cross-sectional, case-control, and prospective studies were included. From 534 communications, 47 were eligible. Population-based studies were not found; minimal prevalence of 0.5-4/100,000 was estimated for Venezuela and Mexico. Geographical isolates were well characterized in Venezuela and in Peru. CAG repeats at HTT gene varied between 7-33 and 37-112 in normal and expanded alleles, respectively. Intermediate alleles were found in 4-10% of controls. Ages at onset and the expanded CAG repeats correlated with r from - 0.55 to -0.91. While haplotype patterns of Venezuelan and Brazilian chromosomes were similar to those observed in Europeans, haplotypes from Peruvian HD patients did not match the same pattern. The limited number of papers found suggests that HD is poorly diagnosed in LA. Minimal prevalence seemed to be halfway between those of Caucasians and Asians. Range of CAG repeats was similar to those of Europeans. Haplotype studies indicate that majority of HD patients might be of Caucasian descent; an Asian origin for some Peruvian patients was proposed.
Asunto(s)
Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Edad de Inicio , Anciano , Pueblo Asiatico/genética , Niño , Preescolar , Haplotipos , Humanos , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/etnología , América Latina/etnología , Persona de Mediana Edad , Prevalencia , Población Blanca/genética , Adulto JovenRESUMEN
The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.
Asunto(s)
Corea/genética , Demencia/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedad de Huntington/genética , Ataxias Espinocerebelosas/genética , Adulto , Brasil , Corea/diagnóstico , Corea/epidemiología , Corea/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Demencia/diagnóstico , Demencia/epidemiología , Demencia/patología , Femenino , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/epidemiología , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/patología , Masculino , Persona de Mediana Edad , Fenotipo , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/patología , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter- and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = -0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = -0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies.
Asunto(s)
Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Evaluación de la Discapacidad , Índice de Severidad de la Enfermedad , Enfermedades de la Médula Espinal/diagnóstico , Variaciones Dependientes del Observador , Enfermedades de la Médula Espinal/etiologíaRESUMEN
Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter- and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = -0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = -0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies.
Asunto(s)
Evaluación de la Discapacidad , Índice de Severidad de la Enfermedad , Enfermedades de la Médula Espinal/diagnóstico , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Enfermedades de la Médula Espinal/etiología , Adulto JovenRESUMEN
UNLABELLED: Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without them. METHODS: MJD/SCA3 patients with parkinsonian features were identified and compared to relatives and to a MJD/SCA3 control group with no such features. The GBA gene was sequenced and, in a subset of patients and in normal volunteers, GBA enzyme activity was measured. RESULTS: We have identified nine index MJD/SCA3 patients with parkinsonian manifestations. Overall, GBA sequence variations were found in 3/9 MJD/SCA3 index cases with parkinsonian manifestations (33%) and in 0/40 MJD/SCA3 controls without parkinsonism (p=0.03, Fisher exact test). The GBA sequence variations found were p.K(-27)R, p.E326K, and p.T369M. The latter two sequence variations were also found in two symptomatic relatives with no parkinsonian manifestations. A MJD/SCA3 relative belonging to the first positive pedigree and carrier of the p.K(-27)R mutation also presented parkinsonian manifestations. GBA activity in MJD/SCA3 patients was similar to those found in the normal control group. CONCLUSION: Sequence variations at the GBA gene may play a role as a minor, modifying gene of MJD/SCA3 phenotype. This hypothetical role was not related to changes in GBA activity in peripheral leukocytes.
Asunto(s)
Variación Genética , Glucosilceramidasa/genética , Enfermedad de Machado-Joseph/enzimología , Enfermedad de Machado-Joseph/genética , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Adrenoleukodystrophy is a neurodegenerative X-linked recessive disorder. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids in plasma and tissues, especially in the cortex of adrenal glands and white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease). It is caused by a mutation in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1), which encodes the protein adrenoleukodystrophy that is involved in the transport of fatty acids into the peroxisome for degradation. Variable expression has been recognized in families of patients who have this disease. A Brazilian family from Minas Gerais State, Brazil, was studied. The proband is an adult living in Minas Gerais State, Brazil; he had adrenomyeloneuropathy, adrenocortical insufficiency and a stable cerebral form. DNA was extracted from a blood sample and was sequenced to identify the mutation. The patient's exons were cloned for confirmation. A new mutation was found in exon 5 of the ABCD1 gene (c.1430delA), as well as a single-nucleotide polymorphism in exon 6. The mutation causes a frame shift, resulting in a truncated protein with almost total absence of the ATP binding domain.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Exones , Eliminación de Secuencia , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Adulto , Secuencia de Bases , Brasil , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Occupational therapy (OT) is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3) patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF), was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn), age, age of onset, or neurological scores at baseline (Spearman test). Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Depresión/rehabilitación , Enfermedad de Machado-Joseph/rehabilitación , Terapia Ocupacional , Calidad de Vida/psicología , Depresión/psicología , Estudios de Seguimiento , Enfermedad de Machado-Joseph/psicología , Resultado del Tratamiento , Adulto JovenRESUMEN
Occupational therapy (OT) is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3) patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF), was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn), age, age of onset, or neurological scores at baseline (Spearman test). Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.
Asunto(s)
Depresión/rehabilitación , Enfermedad de Machado-Joseph/rehabilitación , Terapia Ocupacional , Calidad de Vida/psicología , Adulto , Depresión/psicología , Femenino , Estudios de Seguimiento , Humanos , Enfermedad de Machado-Joseph/psicología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Parkinson's disease (PD) has been related to mutations associated with spinocerebellar ataxias (SCA); the frequency of the diagnosis of these mutations is low in general late-onset PD cases. Our aim was to investigate a selected high-risk group of PD patients. METHODS: PD patients with autosomal dominant inheritance or atypical neurological manifestations were enrolled, underwent a full neurological examination and had the CAG tracts of their SCA1, 2, 3, 6 and 7 genes analyzed. RESULTS: Of the 23 studied families, two SCA3 and one SCA2 cases were identified. All had autosomal dominant inheritance. In the SCA2 pedigree, four affected sibs had a homogeneous PD phenotype. CAG repeats varied between 35 and 44 with CAA interruptions. Intrafamilial phenotypic heterogeneity was identified in the SCA3 pedigrees; parkinsonian and ataxic phenotypes coexisted in both kindreds. CAGn varied between 69 and 71 repeats. Age of onset was lower in the SCA3 patients than in the remaining 24 cases (38 versus 46.7+/-12 years of age, p=0.003). CONCLUSIONS: SCA2 and SCA3 mutations were detected in 13% of the present sample: the strategy of selecting a high-risk group increased the rate of making these diagnoses. The SCA2 cases confirmed an association between PD and interrupted expansions, as well as PD intrafamilial phenotypic homogeneity. Clinical heterogeneity of SCA3 pedigrees suggests that disease-modifying agents outside the MJD1 gene may play a role in determining PD symptoms in this disorder.
Asunto(s)
Expansión de las Repeticiones de ADN , Familia , Variación Genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Adulto , Edad de Inicio , Antiparkinsonianos/uso terapéutico , Ataxina-3 , Ataxinas , Femenino , Genes Dominantes , Humanos , Levodopa/uso terapéutico , Enfermedad de Machado-Joseph/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Linaje , Fenotipo , Proteínas Represoras/genética , Degeneraciones Espinocerebelosas/genéticaRESUMEN
Spinocerebellar ataxias (SCAs) are characterized by a heterogeneous set of clinical manifestations. Our aims were to assess the neurological features of SCA3, and to describe and test the feasibility, reliability, and validity of a comprehensive Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). The NESSCA was administered to molecularly diagnosed SCA3 patients at an outpatient neurogenetics clinic. The scale, based on the standardized neurological examination, consisted of 18 items that yielded a total score ranging from 0 to 40. The score's interrater reliability and internal consistency were investigated, and a principal components analysis and a correlation with external measures were performed. Ninety-nine individuals were evaluated. Interrater reliability ranged from 0.8 to 1 across individual items (P < 0.001); internal consistency, indicated by Cronbach's alpha, was 0.77. NESSCA scores were significantly correlated with measures of disease severity: disease stage (rho = 0.76, P < 0.001), duration (rho = 0.56, P < 0.001), and length of CAG repeat (rho = 0.30, P < 0.05). NESSCA was a reliable measure for the assessment of distinct neurological deficits in SCA3 patients. Global scores correlated with all external variables tested, showing NESSCA to be a comprehensive measure of disease severity that is both clinically useful and scientifically valid.
Asunto(s)
Enfermedad de Machado-Joseph/diagnóstico , Enfermedad de Machado-Joseph/fisiopatología , Examen Neurológico/métodos , Adolescente , Adulto , Anciano , Niño , Estudios de Evaluación como Asunto , Femenino , Humanos , Enfermedad de Machado-Joseph/clasificación , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Perfil de Impacto de EnfermedadRESUMEN
BACKGROUND: Machado-Joseph disease (MJD SCA3), a spinocerebellar ataxia related to expansion of a CAG tract, has already been related to anticipation and meiotic drift. However, fitness of MJD carriers has been little studied. OBJECTIVE: To analyze genetic fitness of MJD patients, comparing them to their unaffected relatives and to the general population (GP) of origin. SUBJECTS AND METHODS: 182 informants, belonging to 82 MJD families, agreed to participate in the study. Informants supplied data about 828 MJD patients. Number of children (NC), gender, age, school attainment, menarche and menopause were compared between general and emeritus (older than 45 years of age or deceased) groups. RESULTS: Mean NC of the GP and of MJD patients were respectively 1.90 and 2.93+/-2.3 (p = 0.0037). Comparisons within families also showed differences: the mean NC of unaffected and affected emeritus MJD women were, respectively, 2.68 and 3.89 (p = 0.0037). Affected MJD women had earlier mean ages at the delivery of their first child and menopause (p < 0.011 and 0.07, respectively). Among affected women those who did not have children had larger CAG tracts than those who had children (p < 0.05). CONCLUSION: MJD enhances the fitness of its carriers, and this phenomenon seems to have a biological basis.
Asunto(s)
Enfermedad de Machado-Joseph/genética , Grupos de Población , Edad de Inicio , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Enfermedad de Machado-Joseph/epidemiología , Enfermedad de Machado-Joseph/patología , PrevalenciaRESUMEN
Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the a-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease, the finding of the same mutation previously detected in another Fabry family from our region raises the possibility of some founder effect, or genetic drift. Finally, the present study highlights the importance of molecular analysis for carrier detection and genetic counseling.
Asunto(s)
Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Fabry/genética , Mutación/genética , alfa-Galactosidasa/genética , ADN Complementario/genética , Exones/genética , Enfermedad de Fabry/enzimología , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
Machado-Joseph disease (MJD), one of the most prevalent autosomal dominant cerebellar ataxias, is a neurodegenerative disease that starts during adulthood, with patients showing difficulties in gait, later becoming bedridden, and ultimately presenting premature death. There is, however, scarce data quantifying disease impact on patient survival. We investigated the overall survival of a large series of MJD patients and compared it with the survival of their asymptomatic relatives. A total of 412 affected and 413 unaffected individuals were ascertained from a consecutive sample of 82 families with a molecular diagnosis of MJD. Estimated mean survival time was 63.96 years [95% confidence interval (CI), 62.09-65.83] for the affected group and 78.61 years (95% CI, 74.75-82.47) for the unaffected group (p < 0.001). For a subset of 366 patients, mean age at onset was 36.37 years (95% CI, 35.21-37.53) and survival after disease onset was estimated as 21.18 years. Early onset and large CAG length predicted shorter overall survival times. This study presents quantitative data on the impact of MJD on overall survival, a phenomenon that is related to CAG length, age at onset, and year of birth.
Asunto(s)
Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/mortalidad , Adolescente , Adulto , Edad de Inicio , Anciano , Ataxina-3 , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Tasa de Supervivencia , Expansión de Repetición de TrinucleótidoRESUMEN
Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the alpha-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease, the finding of the same mutation previously detected in another Fabry family from our region raises the possibility of some founder effect, or genetic drift. Finally, the present study highlights the importance of molecular analysis for carrier detection and genetic counseling.
Asunto(s)
Enfermedad de Fabry/genética , Mutación/genética , alfa-Galactosidasa/genética , Adolescente , Adulto , ADN Complementario/genética , Exones/genética , Enfermedad de Fabry/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). METHODS: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. RESULTS: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. CONCLUSIONS: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.