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2.
Neurosci. lett ; Neurosci. lett;20(563): 140-143, 20/03/2014.
Article in English | LILACS, RESAPE, LIPECS | ID: biblio-1570947

ABSTRACT

Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family.


Las mutaciones del gen de presenilina 1 (PSEN1) se encuentran en el 30-70% de los casos de enfermedad de Alzheimer de inicio temprano (EAIP) familiar (inicio <60 años). La prevalencia de estas mutaciones es muy variable, incluidas las diferencias étnicas en todo el mundo. No se han descrito parientes peruanos con EA familiar (EAF). Se realizó una evaluación clínica estandarizada y una evaluación cognitiva en una familia peruana con EAIP grave. El curso clínico se caracterizó por un inicio muy temprano (antes de los 35 años), deterioro cognitivo progresivo con pérdida temprana de memoria, desorientación espacial y disfunción ejecutiva. Secuenciamos todos los exones de PSEN1 en el probando e identificamos un cambio de ADN c.475C>G que resultó en una mutación sin sentido p.L153V en el dominio transmembrana 2 del gen. Esta mutación también está presente en los tres hermanos afectados adicionales, pero no en un miembro de la familia no afectado, lo que es consistente con la segregación de esta mutación con la enfermedad. Este es el primer informe de una familia peruana afectada con EAIP asociada con una mutación PSEN1. Esta misma mutación se ha informado previamente en familias inglesas y francesas, pero una nueva variante muy cercana a la mutación y el análisis de marcadores informativos de ascendencia sugieren que la mutación podría ser de origen amerindio o africano en esta familia peruana.


Subject(s)
Presenilin-1
4.
N Engl J Med ; 361(17): 1651-61, 2009 Oct 22.
Article in English | MEDLINE | ID: mdl-19846850

ABSTRACT

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.


Subject(s)
Glucosylceramidase/genetics , Mutation , Parkinson Disease/genetics , Aged , Case-Control Studies , Genotype , Humans , Jews/genetics , Logistic Models , Middle Aged , Multivariate Analysis , Odds Ratio
5.
Eur J Neurol ; 13(4): 391-4, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16643318

ABSTRACT

Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2; PARK8) have been implicated in autosomal dominant, late-onset parkinsonism. The LRRK2 6055G > A (G2019S) mutation is the most common reported to date, and has been observed in a number of different European populations. So far, only the LRRK2 4321C > G (R1441G) mutation has been identified in the Spanish population. Herein we have assessed the frequency of G2019S in a referral-based series of 225 patients with Parkinson's disease (PD) from the region of Asturias, Northern Spain. The mutant allele was identified in five (2.7%) of the sporadic late-onset patients and was not present in control subjects. All carriers displayed genetic profiles consistent with the same haplotype, as previously reported for Lrrk2 G2019S-positive subjects. None of these patients presented with a family history of parkinsonism at the time of diagnosis. Thus, approximately 5% of sporadic patients with PD from the North of Spain have either Lrrk2 G2019S or R1441G substitutions.


Subject(s)
Genetic Predisposition to Disease , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Aged , DNA Mutational Analysis , Female , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Mutation , Polymorphism, Single Nucleotide , Spain
6.
Neurology ; 65(5): 738-40, 2005 Sep 13.
Article in English | MEDLINE | ID: mdl-16157908

ABSTRACT

To determine the frequency of LRRK2 mutations in idiopathic Parkinson disease (PD), the authors studied 786 PD probands, 32 affected siblings, 1,044 unaffected siblings, and 278 unrelated controls. The authors designed allelic discrimination assays for nine LRRK2 mutations and identified these in six probands with PD, one affected sibling, one unaffected sibling, and one unrelated control. Thus LRRK2 mutations only rarely cause idiopathic PD.


Subject(s)
Mutation/genetics , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Aged , DNA Mutational Analysis/methods , Family Health , Female , Founder Effect , Gene Frequency/genetics , Genetic Testing/methods , Genotype , Heterozygote , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Parkinson Disease/metabolism , Siblings
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