Elisa Alonso

Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10

Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1,2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13–qter (refs 1,2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r2=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.

Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by expansion of an unstable ATTCT repeat. SCA10 has been described as a pure cerebellar syndrome accompanied by seizures and has been recognized only in families of Mexican origin. We describe clinical and molecular findings of 18 patients in four Mexican families with SCA10. Affected individuals had an average age at onset of 26.7 years (range 14–44 years) and ATTCT repeats ranging from 920 to 4,140 repeats. We could not detect significant anticipation or correlation between repeat size and age at onset, probably due to the small sample size. In addition to pure cerebellar ataxia and seizures, patients often showed soft pyramidal signs, ocular dyskinesia, cognitive impairment, and/or behavioral disturbances. Brain magnetic resonance imaging showed predominant cerebellar atrophy, and nerve conduction studies indicated polyneuropathy in 66% of patients. One family showed hepatic, cardiac, and hematological abnormalities in affected members. These findings suggest that a wide range of tissues may be affected in SCA10, including those outside of the cerebellum and cerebral cortex.

Hyperhomocysteinemia, Low Folate and Vitamin B12 Concentrations, and Methylene Tetrahydrofolate Reductase Mutation in Cerebral Venous Thrombosis

Background and Purpose— Elevated plasma levels of homocysteine are associated with an increased risk of deep-vein thrombosis. Through a case–control study, we examined the potential association among homocysteine, folate and vitamin B12 levels, and the common C677→T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene in patients with cerebral venous thrombosis (CVT). Methods— Forty-five patients with CVT and 90 control subjects were studied. Plasma levels of homocysteine (fasting and after methionine load), folate, and vitamin B12 were measured. Genotyping of the MTHFR gene was also performed. The estimated risk of CVT associated with hyperhomocysteinemia, low vitamin levels, and MTHFR mutation were expressed as odds ratio (OR) and its 95% CI (crude and after adjusting by other independent variables). Results— The adjusted OR for CVT associated with high (>90th percentile) fasting levels of homocysteine was 4.6 (1.6 to 12.8). The association between low plasma folate values (<10th percentile) and presence of CVT was 3.5 (1.2 to 10.0) after adjustment for confounding factors. There was a higher frequency of MTHFR mutation in patients with CVT (22% versus 10%), but it was not statistically significant (P = 0.098). Patients with MTHFR mutation and low folate levels presented the highest homocysteine levels. Conclusions— High plasma concentrations of homocysteine and low plasma folate levels were associated with an increased risk of CVT in this population in which low socioeconomic conditions and deficient nutritional status may contribute to its relatively high incidence.

Huntington’s disease-like 2 can present as chorea-acanthocytosis

Three patients from a previously described family with autosomal dominant chorea-acanthocytosis were found to have the CTG trinucleotide repeat expansion mutation of the junctophilin-3 gene associated with Huntington’s disease–like 2 (HDL2). One of six previously identified patients with HDL2 had acanthocytosis on peripheral blood smear, suggesting that HDL2 should be considered in the differential of chorea-acanthocytosis.

Mild Hyperhomocysteinemia and Low Folate Concentrations as Risk Factors for Cervical Arterial Dissection

Background and Purpose: Elevated homocysteine (Hcy) plasma levels are associated with an increased risk of spontaneous cervical artery dissection (sCAD). We examined the potential association between Hcy, folate, vitamin B12 levels and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms in patients with cerebral infarct caused by sCAD. Patients and Methods: 39 patients who survived a cerebral infarct caused by sCAD [20 (51%) women; 24 (61.5%) vertebral and 15 (38.5%) internal carotid arteries], and 76 healthy control subjects were included. Hcy plasma levels (fasting and after methionine load), folate and vitamin B12 levels were measured. We also performed polymorphisms of MTHFR. Hcy, vitamin B12, folates and polymorphisms of MTHFR were assessed and any associations were analyzed using multivariate statistics. Results: Mean plasma fasting Hcy level was 9.81 µmol/l for cases and 6.38 for controls (p = 0.001). The occurrence of sCAD was associated with elevated fasting Hcy levels (>95th percentile over the control group) with an adjusted odds ratio of 7.9 (95% CI 1.66–35). The association between low plasma folate values (<5th percentile) and the presence of CAD was 7.9 (95% CI 1.6–31) after adjusting for confounding variables. The distribution of the MTHFR genotype showed a higher TT mutant frequency among CAD patients (p = 0.034). Conclusions: High plasma concentrations of Hcy and low plasma levels of folate were associated with an increased risk of sCAD in the sample studied. We conclude that deficiencies in nutritional status may contribute to the relatively high incidence of CAD in Mexico.

Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population

Dominant ataxias show wide geographic variation. We analyzed 108 dominant families and 123 sporadic ataxia patients from Mexico for mutations causing SCA1–3, 6–8, 10, 12, 17 and DRPLA. Only 18.5% of dominant families remained undiagnosed; SCA2 accounted for half (45.4%), followed by SCA10 (13.9%), SCA3 (12%), SCA7 (7.4%), and SCA17 (2.8%). None had SCA1, 6, 8, 12 or DRPLA. Among sporadic cases, 6 had SCA2 (4.9%), and 2 had SCA17 (1.6%). In the SCA2 patients we identified 6 individuals with the rare (CAG)33 allele, 2 of whom showed early onset ataxia. The distribution of dominant ataxia mutations in Mexicans is distinct from other populations.

Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease.

Backgroundvon Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children.MethodsWe tested 17 families (n = 109 individuals) for VHL mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the VHL gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations.ResultsMutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01).ConclusionsThe high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.

Prevalence of Acute Intermittent Porphyria in a Mexican Psychiatric Population

BACKGROUND Acute intermittent porphyria is a hereditary error of porphyrin metabolism in which the main metabolic defect is caused by a decrease in porphobilinogen deaminase activity. Previous work has demonstrated a higher prevalence of acute intermittent porphyria in the psychiatric patient population than in the general population. The goal of this study was evaluate 300 psychiatric patients and 150 control subjects to detect acute intermittent porphyria by measurement of porphobilinogen (PBG) deaminase activity in blood. METHODS Screening for porphobilinogen deaminase activity was carried out by fluorometric measurement of porphyrins synthesized during 1 h in blood and the measurement of delta-aminolevulinic acid and porphobilinogen in urine. RESULTS We found two psychiatric patients, one male and one female, with decreased porphobilinogen deaminase activity. When the families of these patients were studied, one brother was found to have an abnormality. Among controls, a woman was found to have the abnormality and her father was found to have typical features of the disease. CONCLUSIONS These results indicate a prevalence of porphyria in Mexican psychiatric patients similar to controls, and that measurement of PBG deaminase activity is a good tool for defining acute intermittent porphyria carriers.

CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas

AIM In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. MATERIALS & METHODS In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. RESULTS The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. CONCLUSION The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations.

Cognitive impairment and mortality in older healthy Mexican subjects: a population-based 10-year follow-up study

Abstract Objectives: To estimate the incidence of cognitive impairment (CI) among cognitively healthy, Mexican subjects, and to evaluate the impact of demographic and vascular factors on the conversion to CI and mortality. Methods: 734 eligible subjects (aged 55 to >90 years) from a population-based sample were examined. The cognitive function of participants was assessed using the Mini-Mental State Examination (MMSE) every 2 years. The subjects were followed for an average of 3.2 years. The CI was defined using two sets of criteria: (i) moderate CI, as a drop to 25–21 on the MMSE at 2-year follow-up or a decrease of at least four points and (ii) severe CI, defined as a drop of 21 or less in MMES at follow-up. The incidence density and period prevalence were determined as epidemiological measures as well as the cumulative incidence as a risk measure. Kaplan—Meier survival curves were used to analyse the main points of interest: CI, dementia and mortality. Results: The period prevalence of moderate CI was 20%, and 10% for severe CI. During 1959 person-years of follow-up, severe CI developed in 33 of the 361 participants. While during 2096 person-years of follow-up; 80 of 361 participants developed moderate CI. The rate of progression to severe CI in moderate CI subjects gradually increases with follow-up. Both, moderate and severe CI were associated with low educational level, higher age and higher mortality. Conclusions: Elderly people with moderate CI have an increased risk of severe CI. Moderate and severe CI are both predictive of higher mortality in Mexican subjects.