Manuela Caracciolo

Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.

APOE and risk of cognitive impairment in multiple sclerosis

Objectives‐ The APOE gene polymorphism and the −491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimers disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. Material and methods‐ Eighty‐nine relapsing‐remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and −491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. Results‐ The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the −491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. Conclusion‐ The AA homozygous state of the −491 AIT polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease

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 Parkinsons 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 B1 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.

Anti-GM1 ganglioside antibodies in Parkinson's disease

Objectives– To determine whether anti‐GM1 antibodies are increased in Parkinsons disease (PD). Methods– Serum immunoglobulin M (IgM) and IgG anti‐GM1 antibodies were detected by enzyme‐linked immunosorbent assay (ELISA) in 147 patients with PD and in 186 age‐matched normal control subjects. Sera were assayed at initial dilution of 1:800 for IgM and 1:200 for IgG and were considered positive at absorbance values exceeding the value of 0.05 for IgM and 0.1 for IgG. Results– Forty patients with PD (27.2%) had sera positive for IgM anti‐GM1 antibodies, whereas only five normal controls (2.7%) resulted positive (P < 0.0001). Most of patients (75%) with positive sera had a tremor‐dominant form of PD. Only two patients with PD (1.4%) and none of normal controls had sera positive for IgG anti‐GM1 antibodies. Conclusion– A consistent portion of parkinsonians, mainly with a tremor‐dominant form of PD, may have increased circulating IgM anti‐GM1 antibodies.

A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.

Body weight, levodopa pharmacokinetics and dyskinesia in Parkinson's disease.

Abstract. We conducted a pharmacokinetic study in 164 patients with sporadic Parkinsons disease (PD) to address the relationship between body weight and levodopa pharmacokinetics. Patients underwent an oral acute levodopa test with 250 mg levodopa and pharmacokinetic variables were further assessed. Plasmatic levodopa area under the curve (AUC-l) and body weight were significantly and inversely correlated. Women were significantly lighter and more dyskinetic than men, and had greater AUC-l values. Our data suggest that during long-term treatment, lighter PD patients, especially women, may receive a greater cumulative dosage of levodopa per kilogram of body weight. This could explain gender differences for the development of levodopa-induced peak-dose dyskinesias observed during the course of the disease.

The long-duration response to L-dopa in the treatment of early PD.

Objective: To investigate the long-duration response (LDR) to l-dopa resulting from different regimens of l-dopa. Background: In clinical practice, l-dopa is usually administered without considering the LDR due to the drug. Moreover, it has not been established whether in early PD a multiple daily intake of small doses of l-dopa may induce a sustained LDR. Methods: Twenty-four patients with early PD underwent a double-blind, crossover trial, comparing three different 15-day treatment periods with l-dopa: treatment A (250 mg every 24 hours); treatment B (250 mg every 8 hours); and treatment C (125 mg every 8 hours). After completion, 20 patients underwent a subsequent open-label randomized trial with prolonged treatments (250 mg every 24 hours or 125 mg every 8 hours) up to 3 months. LDR was measured at the end of each treatment. Results: All patients achieved a sustained LDR after treatments A and B, whereas only 17% of patients reached a sustained LDR after treatment C. Overall, the LDRs resulting from treatments A and B had similar magnitude and were larger than the LDR deriving from treatment C. After 3 months of prolonged treatments, only three of 10 patients treated with 125 mg every 8 hours increased their LDR, whereas all 10 patients treated with 250 mg every 24 hours had a maximal and stable LDR. Conclusions: Sustained LDR to l-dopa is dependent on the amount of the single doses of the drug. A regimen scheduling small, divided doses during the day, as done in clinical practice, is a questionable therapy for the achievement of a sustained LDR.

Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson’s disease

The effects of serotonin (5-HT) in the CNS are mediated through receptor subtypes distinguished by seven major families. The 5-HT6 receptor gene maps to the human chromosome region 1p35-p36 and a polymorphism (C267T) of the 5-HT6 gene has been associated with the risk of developing schizophrenia.1 Unlike most 5-HT receptors, the 5-HT6 receptor is highly expressed in the striatum,2 suggesting a possible involvement of this receptor in the extrapyramidal function. In this study, we investigated whether the allelic variant C267T of the 5-HT6 gene could contribute to the risk for developing PD. Patients diagnosed with sporadic PD (n = 243) and control subjects (n = 234) were included in our study. Patients with PD were consecutively selected starting in March 1999 until December 2000 from the outpatients attending the Institute of Neurology of the University of Catanzaro, Italy. PD was defined by the presence of at least two of four cardinal signs (bradykinesia, rigidity, rest tremor, and postural instability). Only cases with idiopathic PD responsive to levodopa were included. No patient had …

A phenotypic variation of dominant optic atrophy and deafness (ADOAD) due to a novel OPA1 mutation.

Sirs: Autosomal Dominant Optic Atrophy (ADOA or Kier’s disease, OMIM #165500) is one of the most frequent forms of inherited optic atrophy [1], often presenting in the first decade of life with progressive impairment of visual acuity, variably combined with dyschromatopsia and optic nerve pallor [2]. More than 90 mutations spanning throughout the Optic Atrophy 1 (OPA1) gene were disease-associated with most cases of ADOA (http://lbbma.univ-angers.fr/ eOPA1/) [3]; the gene encodes a dynamin-related GTPase involved in mitochondrial biogenesis [4]. Genotype-phenotype comparisons have been inconclusive except for ADOA complicated with a rare sensorineural deafness (ADOAD); some authors reported that only the R445H mutation could be linked to ADOAD, as hearing loss has never been associated to other OPA1 mutations [5, 6]. Here we present a family with an unusual phenotype of ADOAD and peripheral polineuropathy associated with a novel OPA1 mutation. The proband (IV.13) (pedigree reported in Fig. 1) was a 38-year-old man from Southern Italy, who complained of bilateral and progressive reduction of visual acuity since the age of 7 years. In the second decade of his life, he experienced progressive deafness followed by development of an ataxic gait. At the time of the evaluation, he was legally blind (bilateral visual acuity less than 0.3) and almost deaf (loss of hearing more than 90 dB); on neurological examination he presented bilateral ophthalmoplegia, mild ataxia, distal weakness and severe reduction of proprioception. The auditory brainstem responses (ABRs) were suggestive of bilateral neurosensorial deafness; the electrodiagnostic study of his legs showed decreased amplitude of sensory potentials and motor responses which were consistent with a peripheral axonal neuropathy. Brain and spinal cord MRI were normal. Complete clinical, ophthalmological and audiological examinations were performed on the living family members (Fig. 1a). They were negative except for the proband’s daughter (V.14), a 6year-old child who was showing modest but progressive difficulties in visual acuity and hearing abilities during the last year. The ophthalmologic examination revealed mild bilateral optic pallor and the ABRs were bilaterally impaired (hearing loss < 40 dB); brain MRI and peripheral nerves electrophysiology were normal. After informed consent, genomic DNA was obtained from the proband and his relatives (the proband’s father, his daughter and wife, the 7 siblings and their spouses). The entire coding region and the intron-exon junctions of OPA1 were sequenced by ABIPRISM 3130xl Genetic Analyzer (Applied Biosystems – Foster City, CA), as described elsewhere [7]. A novel missense 1316 G > T mutation was found in exon 14 of the proband and his daughter (Fig. 1b–c). This base change causes the amino acid substitution of a highly conserved Glycine to Valine at codon 439 (G439V) in the GTPase domain of OPA1 gene. No other family members harbored the same DNA mutation. For confirmation, 100 gender, age and ethnicity matched chromosomes controls were analyzed with the same procedure; no one carried the novel OPA1 mutation. OPA1 is believed to play a key role in mitochondrial morphology and function, by promoting its fusion (with the interaction of Mitofusin-1,2) and regulating mitochondrial apoptosis. Frezza et al. [8] demonstrated that oligomerization of OPA1 regulates mitochondrial apoptosis by maintaining the tightness of cristae junctions. Experimental data suggested that the pathogenesis of ADOA may result from haploinsufficiency, with most of the OPA1 mutations causing loss of function of the mutant allele [7, 9]. Recently, the authors reported that OPA1 mutations spanning the GTP-binding pocket disorganize the mitochondrial pathway by abolishing GTPase activity or affecting the self-assembly of OPA1 proteins. These mechanisms could impair the energy supply in the highly energy-demanding compartments, LETTER TO THE EDITORS

Apolipoprotein E polymorphisms and Parkinson's disease.

The apolipoprotein E (APOE) gene polymorphism has been studied in Parkinsons disease (PD) with conflicting results. Recently, a newly described functional polymorphism in the regulatory region of the APOE gene, (-491 A/T), has been associated with late-onset Alzheimers disease. We studied the association between these two polymorphisms of the APOE gene with PD in a sample of 126 PD patients and in 119 controls from the same geographic background. Allelic and genotypic frequencies were not different between PD cases and population controls for either the APOE or -491 A/T polymorphism. The age at onset of the disease was not different according to the specific genotypes of the two polymorphisms of the APOE gene.