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Biomedical subjects

Alessandro Filla

Publications and source records attributed to Alessandro Filla.

At least 19 recordsLinked to original sources
PubMed2006

Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity.

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.

Adolescent↗
PubMed2006

Neurophysiological evidence of corticospinal tract abnormality in patients with Parkin mutations.

Mutations in the parkin gene (PARK2) are the most frequent cause of autosomal recessive early-onset Parkinson disease. We performed a transcranial magnetic stimulation study in four patients with parkin mutations. Two patients had a prolonged central motor conduction time at both upper and lower limb, one only at the arm and one only at the leg. The MEP threshold was increased in one patient for the arm and in two for the leg. The MEP amplitude was reduced in one and central silent period shortened in two. The findings demonstrate corticospinal dysfunction in these patients and suggest that the extent of central nervous system involvement in parkin disease may be wider that hitherto supposed.

Adolescent↗
PubMed2006

Suppression of myoclonus in SCA2 by piracetam.

We report on a 30-year-old patient with advanced cerebellar degeneration due to SCA2. He presented with severe myoclonus, which was resistant to conventional therapy and dramatically improved after administration of 12-18 gm/die piracetam. Piracetam may be considered in the treatment of refractory myoclonus in spinocerebellar degenerations.

Adult↗
PubMed2006

Characterization of nigrostriatal dysfunction in spinocerebellar ataxia 17.

Extrapyramidal signs are a main feature of spinocerebellar ataxia 17 (SCA17). However, the extent of dopaminergic dysfunction and its correlation with parkinsonian signs are not fully understood. In order to define this, we investigated five subjects from three different families with a pathological CAG/CAA expansion in the TATA-binding protein gene (SCA17), ranging from asymptomatic carrier to patient with advanced disease, by FP-CIT SPECT. Nigrostriatal dysfunction was present in patients manifesting a fully developed phenotype but not in preclinical and early stages. Dopamine transporter reduction was symmetrical and uniform in caudate and putamen and it correlated with the clinical severity of ataxia.

Corpus Striatum↗
PubMed2006

PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism.

We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good response to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson's disease and 3 further relatives were reported affected, according to an autosomal dominant transmission.

Age of Onset↗
PubMed2005

Autosomal recessive progressive myoclonus epilepsy with ataxia and mental retardation.

We describe two couples of sibs from a southern Italian family affected by epilepsy, myoclonus, mental retardation and slight ataxia. Onset was between 4 and 12 years and the course slowly progressive. The clinical picture suggested the diagnosis of Unverricht-Lundborg disease. Molecular study excluded linkage to EPM1. Other possible causes of progressive myoclonus epilepsy were also excluded.

Adult↗
PubMed2005

The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy.

Mutations in the SPG3A gene cause a form of pure, early-onset autosomal dominant hereditary spastic paraplegia linked to chromosome 14q. The encoded protein, atlastin, is a putative member of the dynamin superfamily of large GTPases involved in cellular trafficking patterns. We report a new atlastin mutation causing spastic paraplegia in association with axonal neuropathy in an Italian family.

Adolescent↗
PubMed2005

Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Adenosine Triphosphatases↗
PubMed2005

Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early-onset, spastic ataxia and peripheral neuropathy. It was originally described in an inbred population of Quebec and later in some other countries. We report a new missense SACS mutation (7848C>T) in a Spanish family whose phenotype is similar to that of the previously described ARSACS patients. 7848C>T is the first SACS mutation reported in Spain confirming worldwide distribution of the disease.

Adult↗
PubMed2005

Growth hormone response to arginine test distinguishes multiple system atrophy from Parkinson's disease and idiopathic late-onset cerebellar ataxia.

OBJECTIVE: Multiple system atrophy (MSA) is difficult to distinguish from idiopathic Parkinson's disease (PD) and idiopathic late-onset cerebellar ataxia (ILOCA). This study aimed to evaluate GH response to three different GH stimulation tests in order to establish a reliable test to differentiate these degenerative disorders. DESIGN: Twelve patients with MSA, 10 with PD, eight with ILOCA and 30 healthy controls entered the study. They were submitted to clonidine, arginine, and GH-releasing-hormone (GHRH) + arginine tests in a random manner on three different nonconsecutive days. The peak serum GH response was used as a primary variable for analysis of stimulation tests. By ROC analysis, the optimum cut-off level was considered as the cut-off with the maximal sum of sensitivity and specificity. RESULTS: After clonidine administration, GH peak was significantly lower in patients with MSA than in those with ILOCA (P < 0.05) and in the controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the clonidine test distinguished patients with MSA from those with PD with a sensitivity and specificity of 78%. Moreover, this test distinguished patients with MSA from those with ILOCA with a sensitivity of 100% and a specificity of 75% at a cut-off level of 5 mU/l, and with a sensitivity of 75% and a specificity of 100% at the cut-off level of 7.6 mU/l. After arginine administration, the GH peak was significantly lower in patients with MSA than in those with ILOCA (P = 0.001) and in controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the arginine test distinguished patients with MSA from those with PD with a sensitivity and a specificity of 100%. At a GH peak cut-off value of 3.6 mU/l the arginine test distinguished patients with MSA from those with ILOCA with a sensitivity and specificity of 100%. After GHRH + arginine administration, a significant GH increase was found in all groups of patients and controls. CONCLUSIONS: The GH response to arginine administration is impaired in MSA. Therefore, the arginine test showed the highest diagnostic accuracy to distinguish MSA from both PD and ILOCA, and could be used in the clinical practice of these neurodegenerative diseases.

Arginine↗
PubMed2004

Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation.

BACKGROUND: Spinocerebellar ataxia type 17 is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in the TATA box-binding protein gene. Ataxia is typically the first sign whereas behavioral symptoms occur later. OBJECTIVE: To characterize the unusual phenotypic expression of a large spinocerebellar ataxia type 17 kindred. DESIGN: Clinical, neuropathological, and molecular genetic characterization of a 4-generation family with 16 affected patients. RESULTS: Behavioral symptoms and frontal impairment dominated the early stages preceding ataxia, rigidity, and dystonic movements. Neuropathological examination showed cortical, subcortical, and cerebellar atrophy. Purkinje cell loss and gliosis, pseudohypertrophic degeneration of the inferior olive, marked neuronal loss and gliosis in the caudate nucleus, and in the medial thalamic nuclei were salient features together with neuronal intranuclear inclusions stained with anti-TATA box-binding protein and antipolyglutamine antibodies. The disease was caused by a stable 52 CAG repeat expansion of the TATA box-binding protein gene, although there was apparent variability in the age of onset. CONCLUSION: The characteristics of this family broaden the clinical picture of spinocerebellar ataxia type 17: initial presenile dementia with behavioral symptoms should be added to ataxia, rigidity, and dystonic movements, which are more commonly encountered.

Adult↗
PubMed2004

Reduced striatal [123 I]FP-CIT binding in SCA2 patients without parkinsonism.

Degeneration of substantia nigra has been described in spinocerebellar ataxia type 2 (SCA2). In this study, dopamine transporter (DAT) density with [123 I]FP-CIT SPECT was studied in six SCA2 patients with no parkinsonian signs, six Parkinson's disease (PD) patients, and six controls. Marked striatal DAT loss was found in both SCA2 and PD patients. However, a more severe reduction in the caudate and a higher putamen to caudate ratio distinguished SCA2 from PD patients, suggesting a more uniform nigrostriatal impairment in SCA2. Striatal DAT density of SCA2 patients correlated with the severity of cerebellar ataxia.

Adult↗
PubMed2004

Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.

We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.

Adult↗
PubMed2004

A pathogenetic classification of hereditary ataxias: is the time ripe?

Harding's classification takes credits for defining the homogeneous phenotypes that have been essential for the genetic linkage studies and it is still useful for didactic purposes. The advances in pathogenetic knowledge make it now possible to modify Harding's classification. Five main pathogenetic mechanisms may be distinguished: 1) mitochondrial; 2) metabolic; 3) defective DNA repair; 4) abnormal protein folding and degradation; 5) channelopathies. The present attempt to classify ataxia disorders according to their pathogenetic mechanism is a work in progress, since the pathogenesis of several disorders is still unknown. A pathogenetic classification may be useful in clinical practice and when new therapeutic strategies become available.

Ataxia↗
PubMed2003

DNA damage induced by polyglutamine-expanded proteins.

We have developed stable cell lines expressing green fluorescent protein fusion proteins containing polyglutamine repeats of various lengths under tetracycline control. The expression of the expanded (43Q) repeat protein resulted in aggregate formation in a time-dependent fashion. The accumulation of aggregates did not induce apoptosis, although the survival of these cells was critically dependent on the presence of serum and growth factors. However, the expression of 43Q expanded protein strongly activated the ataxia telangiectasia mutated kinase/ATM and Rad3-related kinase (ATM/ATR)-dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. This activation was dependent on 43 CAG protein expression, reversible and sensitive to caffeine and reducing agents. Similarly, we found phosphorylated ATM substrates in fibroblasts from Huntington's disease or SCA-2 patients. Oxidative stress induced accumulation of ATM/ATR phosphorylated protein in HD and SCA-2 patients, but not in normal controls. Furthermore, a significant phosphorylation of H2AX was shown by fibroblasts from patients. We conclude that polyglutamine induces ATM/ATR-dependent DNA damage response through accumulation of reactive oxygen species. ATM activation can be used to monitor the disease in vivo.

Amino Acid Sequence↗