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O Combarros

Publications and source records attributed to O Combarros.

At least 19 recordsLinked to original sources
PubMed2006

Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study.

OBJECTIVE: To describe a large pedigree with Charcot-Marie-Tooth disease type 1A (CMT1A) duplication in which severe pelvic and thigh musculature weakness occurred in two patients, detected by analysing the leg muscle atrophy pattern on magnetic resonance imaging (MRI). METHODS: The pedigree comprised 18 patients, aged between 15 and 85 (median 46) years, who were serially evaluated for up to three decades. All 18 patients and 13 non-affected at-risk people underwent electrophysiological examination. An MRI study of lower limb musculature was carried out in four patients. Three patients underwent sural-nerve biopsy. Genetic testing was carried out in 17 patients and in all 13 at-risk normal people. RESULTS: Fourteen patients were asymptomatic or slightly disabled. The two oldest patients, aged 84 and 80, showed a moderate phenotype. Two other patients, aged 70 and 53, showed late-onset and gradually progressive peroneal paresis extending up to the thigh and pelvic musculature, resulting in waddling gait. MRI scans of all three patients with a mild phenotype showed subtle and subclinical fatty infiltration of calf anterolateral muscle compartments, with thigh muscle involvement in one patient, and extensive atrophy of intrinsic foot muscles. In the youngest patient with proximal leg weakness, the MRI scan showed massive fatty atrophy of all the calf muscles, posteromedial thigh muscle compartments, and internal and external hip rotator muscles. Sural-nerve biopsy specimens showed hypertrophic neuropathy with no superimposed inflammation. Good correlation was seen between electrophysiological and genetic testing. CONCLUSIONS: Late in the clinical course, a small proportion of patients with CMT1A develop severe proximal leg weakness, and long-term follow-up is essential for its detection. MRI scans may show subclinical involvement of the thigh musculature.

Adolescent↗
PubMed2005

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE epsilon4 allele.

Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism.

Aged↗
PubMed2005

Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis.

INTRODUCTION: The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability. MATERIALS AND METHODS: We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated. RESULTS: Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population. CONCLUSIONS: This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.

Adolescent↗
PubMed2004

Expanded GAA repeats and clinical variation in Friedreich's ataxia.

INTRODUCTION: One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease. MATERIALS AND METHODS: We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. RESULTS: The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease. CONCLUSION: GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.

Adolescent↗
PubMed2002

Friedreich ataxia with minimal GAA expansion presenting as adult-onset spastic ataxia.

Around a quarter of Friedreich ataxia (FA) patients, despite being homozygous for GAA expansion within the FRDA gene, show atypical presentations. Our aim is to describe the case of three brothers with long-term follow-up suffering from late onset FA manifested with spastic ataxia. The three patients belong to a family with occipital dysplasia (OD) and Chiari I malformation previously reported by us. We have carried out serial examinations since 1977. Electrophysiological and neuroimaging studies, and molecular genetic analyses of hereditary ataxias are available in all three patients. Onset of symptoms occurred between 25 and 35 years. The clinical picture consisted of progressive spastic gait, truncal and limb ataxia, dysarthria, nystagmus, hyperreflexia with knee and ankle clonus and extensor plantar response, and mild hypopallesthesia. Ages at present vary between 50 and 59. One patient is wheelchair-bound but the other two are able to walk with support. Leaving OD aside, skeletal anomalies are not prominent. All three patients showed cardiomyopathy. MR imaging revealed atrophy of the cerebellum and spinal cord. Motor and sensory nerve conduction velocities were normal. Central conduction time of both motor and sensory pathways was delayed or unobtainable. All three patients were homozygous for the GAA expansion, the smaller expanded allele ranging between 131 and 156 repeats. Four heterozygotic carriers were detected among non-ataxic relatives including one with OD; furthermore, an asymptomatic OD patient showed normal genotype. We conclude that adult onset spastic ataxia is a distinctive FA phenotype associated with minimal GAA expansion. This phenotype represents a new cause of selective distal degeneration of central sensory axons. The present concurrence of OD and FA reflects coincidental cosegregation of two different inherited disorders.

Adult↗
PubMed2002

[Hereditary ataxias and paraplegias: a clinicogenetic review].

Hereditary ataxias encompass a series of syndromes basically characterised by progressive cerebellar ataxia of slow clinical course (occasionally, periodic ataxia or spastic paraparesis) and primary spinocerebellar degeneration. The prevalence ratio of these syndromes in Spain is 20 cases per 100,000 inhabitants. Initially the ataxias were classified on the basis of clinicopathological criteria. Starting from the seminal papers by Harding published 20 years ago, a clinicogenetic classification was introduced that has given way to the present molecular classification. There have been localised about forty loci. In dominant ataxias the most frequent molecular defect is a dynamic CAG expansion responsible for abnormal polyglutamine tract transcription. The identification of such molecular defect has made it possible detection of gene carriers in clinical practice, this involving both presymptomatic and prenatal diagnosis; moreover, such molecular discoveries have contributed to develop a new pathogenetic era. A homozygous and intronic GAA expansion is the molecular basis of Friedreich's ataxia. This finding has also made it possible a molecular diagnosis in clinical practice. Molecular studies have demonstrated that hereditary spastic paraplegia is another heterogeneous genetic disorder.

Ataxia↗
PubMed2001

Case-control study and meta-analysis of low density lipoprotein receptor-related protein gene exon 3 polymorphism in Alzheimer's disease.

The low density lipoprotein receptor-related protein (LRP) may influence both the clearance and the production of beta-amyloid peptide and thus plays a role in Alzheimer's disease (AD) pathogenesis. Previous studies, although inconsistent, have suggested that the LRP exon 3 CC genotype contributes to the risk of AD. A case-control study utilizing a clinically well-defined group of 305 sporadic AD patients and 304 control subjects was performed to test this association in an ethnically homogeneous population from Spain. In the current study, the LRP CC genotype was not over-represented in AD patients compared to non-demented controls. A meta-analysis of previous studies revealed a weak correlation of LRP CC genotype with AD (odds ratio of 1.35, P=0.01).

Aged↗
PubMed2001

The --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer's disease.

Homozygosity for the A allele of the -491 A/T apolipoprotein E (APOE) promoter polymorphism has recently been reported to be associated with sporadic Alzheimer's disease (AD). Two hundred and fifty one patients with AD and an equal number of controls derived from the same region in a Spanish population, were genotyped for -491 A/T and epsilon2/epsilon3/epsilon4 APOE polymorphisms. We did not detect an elevated -491 AA genotype frequency when comparing AD cases to controls. In contrast, persons homozygous for the T allele were at a significantly reduced risk of AD (odds ratio of 0.10, P=0.006). Multiple logistic regression analysis indicated that the -491 TT polymorphism added information on the risk of AD which was independent of that of the APOE epsilon4 allele.

Adult↗
PubMed2001

Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion.

Clinical, electrophysiologic and molecular studies were performed on at-risk members of 14 families with hereditary neuropathy with liability to pressure palsies (HNPP), in order to detect asymptomatic carriers of the 17p11.2 deletion. Sporadic cases due to de novo deletion accounted for 21% of the investigated HNPP families. Approximately one half of deletion carriers were asymptomatic and did not display significant signs on clinical examination. The electrophysiologic hallmark in both symptomatic and asymptomatic deletion carriers was the presence of a nonuniform sensorimotor demyelinating polyneuropathy with conduction abnormalities preferentially located at common entrapment sites and distal nerve segments. A perfect correlation was found between the molecular and electrophysiologic analyses. A reliable screening method to detect clinically unaffected carriers of the deletion in families with HNPP was the evaluation of motor conduction in at least two nerves across usual entrapment sites, especially the ulnar nerve at the elbow, and evaluation of sensory conduction in the sural nerve. In sporadic cases due to a de novo deletion, electrophysiologic studies were suggestive but not sufficient for the diagnosis, and molecular analysis represented the most sensitive diagnostic tool.

Adult↗
PubMed2000

Polymorphism at codon 129 of the prion protein gene is not associated with sporadic AD.

An association between cognitive performance in elderly people and variability in the codon 129 of the prion protein gene (PRNP) has been recently described. The authors analyzed this polymorphism in 278 sporadic AD patients and 268 cognitively normal control subjects. Analyses stratifying by APOE genotype, age, and gender failed to reveal any association between homozygosity for the 129 PRNP methionine or valine alleles and AD.

Age of Onset↗
PubMed2000

Posterior column ataxia and retinitis pigmentosa: a distinct clinical and genetic disorder.

Autosomal recessive posterior column ataxia and retinitis pigmentosa (PCARP) is a movement disorder that was genetically mapped to a disease locus (AXPC1) on chromosome 1q32-q31 in an inbred population of Dutch-German ancestry in the continental United States. We performed genetic linkage analysis and haplotype reconstruction on a different family from Spain with an identical phenotype to determine if the neurologic signs of an early-onset ataxia, retinitis pigmentosa, and a sensory neuropathy also mapped to the AXPC1 locus. The disease phenotype was linked in the candidate interval with a maximum lod score of 3.56 at a recombination fraction of 0.0 for locus D1S414. Haplotypes were discordant and suggested that the disease mutation arose independently from at least two populations. These results refine the classification of early-onset ataxia, abrogate a founder effect for this recessive disorder, and provide evidence that PCARP is a distinct, homogeneous, clinical, and genetic disorder.

Child↗