RESUMEN
More than 140 different mutations have been reported in the Cu/Zn superoxide dismutase-1 (SOD1) gene in patients with amyotrophic lateral sclerosis (ALS), some occurring as founder mutations. Occasionally, specific mutations are associated with a particular phenotype. We evaluated a possible genotype-phenotype correlation and looked for a founder effect in nine patients from six unrelated families with ALS, all carrying the G41S mutation, originating from north-west Tuscany in central Italy. Mutational analysis of the SOD1 gene was carried out by direct sequencing. A haplotype study was carried out using eight polymorphic markers flanking the SOD1 gene. The clinical pattern of the nine familial ALS (FALS) patients was characterized by spinal onset with early upper and lower motor neuron involvement, appearance of bulbar signs within one year, and death a few months later. Mean age at onset was 49.3 years and mean duration of disease was 0.9 years. Genotyping revealed a common haplotype for the G41S allele. We provide the first evidence that the G41S mutation in Italy originates from a common founder. In addition, our findings strengthen the data reported previously and indicate that the G41S mutation is consistently associated with a uniform and dramatic, fast-progressing phenotype.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Mutación Puntual , Superóxido Dismutasa/genética , Adulto , Anciano , Progresión de la Enfermedad , Salud de la Familia , Femenino , Efecto Fundador , Haplotipos , Humanos , Italia , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Superóxido Dismutasa-1RESUMEN
Among the 140 Cu/Zn superoxide dismutase-1 (SOD1) gene mutations associated with ALS, only D90A, the most prevalent mutation in Europe, has been clearly shown to cause recessive and dominant ALS. Here we first describe two, apparently sporadic, Italian ALS patients heterozygous for the D90A mutation. One patient experienced early sensory involvement, confirmed by nerve biopsy. We review sensory symptoms in SOD1 ALS and discuss its possible origin in D90A heterozygous patients.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Heterocigoto , Mutación Puntual , Superóxido Dismutasa/genética , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/patología , Biopsia , Exones/genética , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Superóxido Dismutasa-1 , Nervio Sural/patologíaRESUMEN
Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait. In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified. The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Salud de la Familia , Mutación , Superóxido Dismutasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/epidemiología , Northern Blotting/métodos , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Exones , Femenino , Genotipo , Glicina/genética , Humanos , Intrones , Italia/epidemiología , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo Genético , ARN Mensajero/biosíntesis , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Serina/genética , Estadísticas no Paramétricas , Superóxido Dismutasa-1RESUMEN
Lower limb muscle chronic hyperactivity in hereditary spastic paraplegia (HSP) is the consequence of motor corticospinal tract involvement, which in turn has been hypothesized to be of mitochondrial origin. In order to assess skeletal muscle aerobic metabolism and sympathetic response during exercise in 10 HSP patients, we evaluated their blood lactate and catecholamine levels during an incremental workload bicycle exercise. Lactate, but not epinephrine or norepinephrine, levels were significantly higher in the HSP patients than in control subjects, in both resting conditions and during exercise. In the patients, the anaerobic lactate threshold was reached prematurely (at 50% of the predicted normal maximal power output) when compared to normal controls. This finding was not related to any specific muscle morphology or histochemical activity. Although other factors, including chronic spasticity and muscle deconditioning, have to be considered in the interpretation of our data, our results suggest the possible involvement of a mitochondrial mechanism, independently of sympathetic system overactivation, in exercising skeletal muscle of HSP patients.
Asunto(s)
Epinefrina/sangre , Lactatos/sangre , Norepinefrina/sangre , Esfuerzo Físico/fisiología , Paraplejía Espástica Hereditaria/fisiopatología , Adulto , Anciano , Umbral Anaerobio/fisiología , Biopsia , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Paraplejía Espástica Hereditaria/sangreRESUMEN
PURPOSE: To prospectively evaluate several diffusion-tensor magnetic resonance (MR) imaging indexes (mean diffusivity [MD], fractional anisotropy [FA], and eigenvalues) of corticospinal tract impairment in patients with progressive muscular atrophy (PMA) and patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: This study had institutional review board approval, and written informed consent was obtained from all subjects. Eight male patients with PMA (mean age, 63 years +/- 13 [standard deviation]), eighteen patients with ALS (14 men and four women; mean age, 64 years +/- 7), and twelve control subjects (four men and eight women; mean age, 65 years +/- 6) underwent diffusion-tensor MR imaging at which 25 spin-echo echo-planar imaging diffusion-weighted images (b = 1000 sec/mm2) were acquired along noncollinear directions. MD and FA were measured along the corticospinal tracts in each patient and subject. Changes in diffusion along and orthogonal to fiber bundles in patients were evaluated by using diffusion-tensor eigenvalues. Differences in diffusion-tensor imaging indexes between patients with PMA and those with ALS, as compared with these indexes in control subjects, were evaluated with Mann-Whitney testing. Correlations between diffusion-tensor imaging indexes and clinical variables were estimated with Pearson and Spearman rank correlation testing. RESULTS: As compared with MD (697.1 x 10(-6) mm2/sec +/- 28.1) and FA (0.585 +/- 0.032) in control subjects, MD was typically significantly increased (734.7 x 10(-6) mm2/sec +/- 41.2, P = .035) and FA significantly decreased (0.534 +/- 0.053, P = .037) along the corticospinal tracts in patients with ALS, while these parameters showed no significant change in patients with PMA (MD, 707.0 x 10(-6) mm2/sec +/- 44.2; FA, 0.559 +/- 0.028). Estimation of diffusion-tensor eigenvalues revealed normal diffusion along fiber tracts in all patients, while diffusion was increased orthogonal to fiber tracts only in patients with typical ALS. In patients with ALS, MD correlated with disease duration while FA correlated with disease severity. CONCLUSION: Diffusion-tensor MR imaging reveals corticospinal tract impairment in ALS but not in PMA.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Imagen de Difusión por Resonancia Magnética , Atrofia Muscular Espinal/diagnóstico , Tractos Piramidales/patología , Anciano , Anisotropía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: The physical quality index (QI) of radiological devices summarises in a single numerical value between 0 and 1 the results of constancy tests. The aim of this paper is to illustrate the results of the use of such an index on all public radiological devices in the Livorno province over one year. MATERIALS AND METHODS: The quality index was calculated for 82 radiological devices of a wide range of types by implementing its algorithm in a spreadsheet-based software for the automatic handling of quality control data. RESULTS AND DISCUSSION: The distribution of quality index values was computed together with the associated statistical quantities. This distribution is strongly asymmetrical, with a sharp peak near the highest QI values. The mean quality index values for the different types of device show some inhomogeneity: in particular, mammography and panoramic dental radiography devices show far lower quality than other devices. In addition, our analysis has identified the parameters that most frequently do not pass the quality tests for each type of device. Finally, we sought some correlation between quality and age of the device, but this was poorly significant. CONCLUSIONS: The quality index proved to be a useful tool providing an overview of the physical conditions of radiological devices. By selecting adequate QI threshold values for, it also helps to decide whether a given device should be upgraded or replaced. The identification of critical parameters for each type of device may be used to improve the definition of the QI by attributing greater weights to critical parameters, so as to better address the maintenance of radiological devices.
Asunto(s)
Algoritmos , Control de Calidad , Tecnología Radiológica/instrumentaciónRESUMEN
The Aspartate-90-Alanine (D90A) mutation on SOD-1 gene, the only known change causing recessive familial amyotrophic lateral sclerosis (FALS), is associated with a uniform phenotype characterized by slowly ascending paresis and long survival. Originally reported in Scandinavian cases, it has also been detected in patients from other countries. A common haplotype, probably of Scandinavian origin, has been demonstrated in D90A recessive pedigrees. In this study we screened the SOD-1 gene for the D90A mutation in 56 Italian patients from north-west Tuscany with sporadic ALS in order to evaluate the occurrence of this mutation and its genotype-phenotype correlation in Italy. We found the homozygous D90A mutation in one patient (1.8%), harboring the classical phenotype related to this mutation. No other mutations were detected in any of the five SOD-1 exons in our group. Our results confirm that recessive D90A mutation is present in Italy and it is associated with the phenotype already described A screening for that mutation, easily made by RFLP, should be made in sporadic ALS patients, especially where clinical investigation indicates its presence.
Asunto(s)
Alanina/genética , Esclerosis Amiotrófica Lateral/genética , Ácido Aspártico/genética , Mutación Puntual , Superóxido Dismutasa/genética , Adulto , Anciano , Sustitución de Aminoácidos , Cartilla de ADN , Femenino , Pruebas Genéticas/métodos , Humanos , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Superóxido Dismutasa-1RESUMEN
BACKGROUND: Although the pathogenic mechanisms of selective loss of motor neurons in amyotrophic lateral sclerosis (ALS) are unknown, there is increasing evidence for the hypothesis of an oxidative stress-related mitochondrial involvement as key determinant of motor neuron degeneration OBJECTIVE: The aim of our study has been to assess blood levels of peroxidation markers and to relate them to in-vivo oxidative metabolism in exercising muscle in patients affected by ALS. METHOD: For this purpose 10 patients (seven men and three women, mean age 58.5 +/- 8.2 SD), performed an incremental bicycling test for the assessment of lipoperoxides and lactate during exercise. RESULTS: At rest, the ALS patients had higher than normal levels of both lactate (2.82 +/- 0.76 mmol/L; normal range: 0.67-2.47 mmol/L) and lipoperoxides (361.7 +/- 40.2 AU; normal range: 250-320 AU), the latter corresponding to a level of moderate oxidative stress. A further increment during exercise was observed both at lactate threshold and maximal power output levels. Values of blood lipoperoxides were significantly higher (P < 0.05) than those in control patients affected by chronic motor denervating processes of different origins and related (P < 0.01) to lactate production on exercising. CONCLUSIONS: These findings indicate the occurrence of an abnormally increased size of blood free radical pool in resting conditions and during exercise in ALS patients. The relationship between the levels of reactive oxygen species and lactate production is indicative of a tight link between mitochondrial function and oxidative stress in ALS.