Abstract: Contradictory evidence has been reported on the role of the polymorphic mixed dinucleotide repeat (NACP-REP1) of the alpha-synuclein gene as a risk factor for sporadic Parkinson's disease (PD). In the present study we genotyped the NACP-REP1 polymorphism in 189 PD patients from southern Italy and 182 healthy control subjects. We failed to demonstrate an association of any NACP-REP1 allele with PD.
Abstract: We investigated the segregation of the dinucleotide GT repeat polymorphism in the intron between exons 9 and 10 of the tau gene in 300 patients with Parkinson's disease (PD) and in 197 normal controls. The A3 allele was more frequent in cases than in controls (30% versus 16%, p<0.001), and individuals carrying at least one A3 allele in their genotype had an increased risk of developing PD (odds ratio 2.78, 95% confidence interval 1.81-4.29). No significant differences were found between patients by considering the age at onset and the presence of family history or dementia. Our findings suggest a possible involvement of the tau gene in the pathogenesis of PD.
Abstract: Alpha-2 macroglobulin (A2M) is a component of Lewy bodies, a hallmark of Parkinson's disease (PD). In 159 PD patients and 190 normal controls, we studied two A2M polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism method: a five-nucleotide deletion at the 5' splice site of exon 18; and a valine to isoleucine exchange in amino acid position 1000 near the thiolester active site. No significant differences in allelic and genotypic distribution were found between cases and controls or between early and late-onset PD patients. The present data suggest that these polymorphisms do not represent a risk factor for PD and do not modulate the age at onset of PD.
Abstract: We investigated the parkin gene in 118 patients with typical Parkinson's disease (PD), i.e. in patients who had an onset of PD after the age of 45 years. The study group included 95 subjects with sporadic PD and 23 subjects from 18 families with autosomal recessive PD. No pathogenetic mutations in the parkin gene were detected either in familial or in sporadic patients. Our findings indicate that the parkin gene is not involved in the pathogenesis of classic late-onset PD.
Abstract: Mutations in the parkin gene have been reported in patients with early onset PD. The authors investigated the parkin gene in 118 patients who had an onset of PD after age 45 years: 95 subjects were sporadic patients and 23 subjects were from 18 families with a probable autosomal recessive inheritance. No pathogenetic mutations in the parkin gene were detected either in familial or in sporadic patients. Moreover, no differences were found between patients and 100 age-matched normal controls in the allele and genotype frequencies of four exonic parkin polymorphisms.
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by mutations in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) gene, mapping on chromosome 20q13.2. A second ADNFLE locus was mapped on chromosome 15q24.
Abstract: We report on 2 brothers (aged 19 and 12 years) with Marinesco-Sjögren syndrome who also had very low serum vitamin E concentrations with an absence of postprandial chylomicrons. The molecular study ruled out ataxia with isolated vitamin E deficiency, abetalipoproteinemia, and hypobetalipoproteinemia. The electron microscopy of the intestinal mucosa was consistent with a chylomicron retention disease. We speculate that both chylomicron retention disease and Marinesco-Sjögren syndrome are related to defects in a gene crucial for the assembly or secretion of the chylomicron particles, leading to very low serum levels of vitamin E.
Abstract: The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.
Abstract: To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD.
Abstract: We report on the clinical, neuropsychological, neurophysiological, computerized eye movement, magnetic resonance imaging (MRI) and molecular findings from 17 individuals affected with spinocerebellar ataxia type 2 (SCA2) belonging to three families. The average age at onset of the symptoms was 35.6, 11.9 (mean, SD) years. The mean age at onset of the symptoms in the parents was 44.8, 8.2 years, and in the offspring it was 28.7, 7.2 years. In 12 parent-child pairs, the mean anticipation was -15.75, 9.1 years (range -8.1 to -23.3 years, t = -4.9, P = < 0.002). The mutated SCA2 alleles ranged from 38 to 42 CAG repeats, while the normal alleles ranged from 22 to 24 repeats, with 97% of the alleles having 22 repeats. Small differences in the number of CAG repeats influenced the age at onset and rate of progression of the disease considerably. Indeed, patients presenting with their first symptom at an age of 35 years or later with a slower course of the disease harboured between 38 and 39 repeats. In contrast, patients carrying > or = 40 CAG repeats manifested the disease prior to 30 years of age and had a faster disease progression toward incapacity. The presenting symptom was always gait ataxia. Slow saccades occured from the beginning of the disease despite normal delay, accuracy and smooth pursuit eye movements. The neuropsychological study showed early and selective impairment of conceptual reasoning ability, as detected by the Wisconsin Card Sorting Test (WCST). It is noteworthy that a significant mutual relationship was observed between performance on the WCST and saccade velocity. All of these findings favour the hypothesis that the disease process of SCA2 in regions other than the cerebellum and brain stem affects severely and early those cortical structures involved in the control of both visually guided saccades and WCST performance.
Abstract: Patients with autosomal recessive spinal muscular atrophy (SMA) usually carry a homozygous deletion of exons 7 and 8 of the telomeric survival motor neuron (SMN(T)) gene, although an isolated deletion of SMN(T) exon 8 has never been found. We now report on 2 patients with the typical features of SMA types II and III, who carried a homozygous deletion of SMN(T) exon 8 but retained SMN(T) exon 7. Importantly, to exclude a sequence conversion event of telomeric exon 8, we amplified a fragment that spanned exons 7 and 8 of the SMN gene. The resulting 1,010-base pair (bp) fragments were subjected to nested polymerase chain reaction (PCR) of exon 7. The subsequent restriction analysis failed to show any products of telomeric exon 7, as the site for primer 541C1120 was lost in both alleles. These findings indicate a homozygous deletion of SMN(T) exon 8. Direct sequencing of the cloned 1,010-bp fragment further confirmed that these 2 SMA patients did not possess telomeric exon 8. The more severely affected child also showed a deletion of the neuronal apoptosis inhibitory protein (NAIP) gene. The present findings provide evidence that an isolated deletion of SMN(T) exon 8 is associated with the milder subtypes of SMA. Our data also demonstrate that the additional deletion of the NAIP gene exacerbates the severity of the disease.
Abstract: A Calabrian family (Southern Italy) with Sp alpha(I/74) hereditary elliptocytosis (HE) in the heterozygous state was studied. Sp alpha(I/74) HE is associated with asymptomatic elliptocytosis, a defect in spectrin dimer self association and an increase of the alpha(I/74) kD fragment from the alpha chain after partial tryptic digestion of spectrin. To identify the underlying molecular defect, we analysed exons V, W, X, Y, Z of the beta gene and exon 2 of the alpha gene by single-strand conformational polymorphism (SSCP) of the amplification products. Direct DNA sequencing of the mutant exon showed a C-->G substitution at position 6284 of the beta gene. The corresponding substitution at the protein level was Arg-->Pro in the 2064 position of the beta-spectrin chain.
Abstract: The alpha I/65 variant of spectrin has been described in black people, in North Africans and recently in two southern Italian families. This variant is associated in the heterozygous state with mild Hereditary Elliptocytosis (HE) and the molecular basis of the defect is invariably the duplication of TTG at codon 154 of the alpha spectrin gene. The present study reports the identification of five Calabrian families with SP alpha I/65 HE and their distribution in the population.
