RESUMEN
Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives.
Asunto(s)
Enfermedades Raras , Ataxias Espinocerebelosas , Humanos , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/terapia , Ataxias Espinocerebelosas/diagnóstico , México/epidemiología , Femenino , Masculino , Enfermedades Raras/genética , Enfermedades Raras/terapia , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Adulto , Persona de Mediana Edad , Fenotipo , Expansión de Repetición de Trinucleótido , Haplotipos , Edad de InicioRESUMEN
Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.
Asunto(s)
Enfermedad de Huntington , Adulto , Femenino , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/diagnóstico , Colombia , Alelos , ADN , Linaje , Proteína Huntingtina/genética , Expansión de Repetición de TrinucleótidoRESUMEN
Spinocerebellar ataxias (SCAs) conform a heterogeneous group of neurodegenerative disorders with autosomal dominant inheritance. Five of the most frequent SCAs are caused by a CAG repeat expansion in the exons of specific genes. The SCAs incidence and the distribution of polymorphic CAG alleles vary among populations and ethnicities. Thus, characterization of the genetic architecture of ethnically diverse populations, which have undergone recent admixture and demographic events, could facilitate the identification of genetic risk factors. Owing to the great ethnic diversity of the Mexican population, this study aimed to analyze the allele frequencies of five SCA microsatellite loci (SCA1, SCA2, SCA3, SCA6, and SCA7) in eleven Mexican Native American (MNA) populations. Data from the literature were used to compare the allelic distribution of SCA loci with worldwide populations. The SCA loci allelic frequencies evidenced a certain genetic homogeneity in the MNA populations, except for Mayans, who exhibited distinctive genetic profiles. Neither pathological nor large normal alleles were found in MNA populations, except for the SCA2 pre-mutated allele in the Zapotec population. Collectively, our findings demonstrated the contribution of the MNA ancestry in shaping the genetic structure of contemporary Mexican Mestizo populations. Our results also suggest that Native American ancestry has no impact on the origin of SCAs in the Mexican population. Instead, the acquisition of pathological SCA alleles could be associated with European migration.
Asunto(s)
Indio Americano o Nativo de Alaska/genética , Ataxina-1/genética , Etnicidad/genética , Genética de Población , Repeticiones de Microsatélite , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido , Frecuencia de los Genes , Humanos , México/epidemiología , Ataxias Espinocerebelosas/epidemiologíaRESUMEN
Spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, is caused by an abnormal CAG repeat expansion in the ATXN7 gene coding region. The onset and severity of SCA7 are highly variable between patients, thus identification of sensitive biomarkers that accurately diagnose the disease and monitoring its progression are needed. With the aim of identified SCA7-specific metabolites with clinical relevance, we report for the first time, to the best of our knowledge, a metabolomics profiling of circulating acylcarnitines and amino acids in SCA7 patients. We identified 21 metabolites with altered levels in SCA7 patients and determined two different sets of metabolites with diagnostic power. The first signature of metabolites (Valine, Leucine, and Tyrosine) has the ability to discriminate between SCA7 patients and healthy controls, while the second one (Methionine, 3-hydroxytetradecanoyl-carnitine, and 3-hydroxyoctadecanoyl-carnitine) possess the capability to differentiate between early-onset and adult-onset patients, as shown by the multivariate model and ROC analyses. Furthermore, enrichment analyses of metabolic pathways suggest alterations in mitochondrial function, energy metabolism, and fatty acid beta-oxidation in SCA7 patients. In summary, circulating SCA7-specific metabolites identified in this study could serve as effective predictors of SCA7 progression in the clinics, as they are sampled in accessible biofluid and assessed by a relatively simple biochemical assay.
Asunto(s)
Aminoácidos/sangre , Carnitina/análogos & derivados , Ataxias Espinocerebelosas/sangre , Adulto , Biomarcadores/sangre , Carnitina/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Relative frequency of hereditary ataxias remains unknown in many regions of Latin America. We described the relative frequency in spinocerebellar ataxias (SCA) due to (CAG)n and to (ATTCT)n expansions, as well as Friedreich ataxia (FRDA), among cases series of ataxic individuals from Peru. Among ataxic index cases from 104 families (38 of them with and 66 without autosomal dominant pattern of inheritance), we identified 22 SCA10, 8 SCA2, 3 SCA6, 2 SCA3, 2 SCA7, 1 SCA1, and 9 FRDA cases (or families). SCA10 was by far the most frequent one. Findings in SCA10 and FRDA families were of note. Affected genitors were not detected in 7 out of 22 SCA10 nuclear families; then overall maximal penetrance of SCA10 was estimated as 85%; in multiplex families, penetrance was 94%. Two out of nine FRDA cases carried only one allele with a GAA expansion. SCA10 was the most frequent hereditary ataxia in Peru. Our data suggested that ATTCT expansions at ATXN10 might not be fully penetrant and/or instability between generations might frequently cross the limits between non-penetrant and penetrant lengths. A unique distribution of inherited ataxias in Peru requires specific screening panels, considering SCA10 as first line of local diagnosis guidelines.
Asunto(s)
Ataxina-10/genética , Penetrancia , Degeneraciones Espinocerebelosas/genética , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Perú , Adulto JovenRESUMEN
Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.
Asunto(s)
Aptitud Genética , Selección Genética , Ataxias Espinocerebelosas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Ataxina-2/genética , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Hermanos , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/fisiopatología , Expansión de Repetición de Trinucleótido , Adulto JovenRESUMEN
STUDY OBJECTIVE: The androgen receptor (AR) harbors a variable repeat number of glutamine residues codified by (CAG)n, which seems to inversely affect AR transcriptional activity. We assessed whether (CAG)n affects the sequence of the androgen-sensitive pubertal events and body composition in prepubertal girls. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (approximately 50% girls) from a university clinic in Santiago, Chile. Cases were girls with high dehydroepiandrosterone sulfate (DHEAS; >42 µg/dL; HD) at age 7.0 (±0.4) years (n = 58). On follow-up, 32 of them had thelarche (TB2) before the age of pubarche (PH2) and 26 had PH2 before the age of TB2. As controls, 107 age-matched girls with normal DHEAS (≤42 µg/dL; ND) were selected. MAIN OUTCOME MEASURES: Methylation-weighted mean (CAG)n (mw[CAG]n) was calculated through X-chromosome methylation-sensitive enzyme restriction and polymerase chain reaction followed by automated capillary electrophoresis in peripheral blood DNA. RESULTS: Girls with HD and PH2 before the age of TB2 showed a trend to higher frequency (7/26, 26.9%) of mw(CAG)n <20 compared with ND girls (12/107; 11.2%; P = .087). Accordingly, a direct correlation between age of PH2 and mw(CAG)n was observed in HD (r = 0.352; P = .007) and in ND girls (r = 0.207; P = .033). Moreover, HD girls with mw(CAG)n less than 20 had lower waist circumference and waist/height ratio than HD girls with mw(CAG)n from 20 to less than 25 (P = .027 and P = .012, respectively) at age of DHEAS determination. CONCLUSION: Our results suggest that a greater transcriptional activity of the AR, given by short number of CAG repeats, might favor the onset of pubarche and reduce central adiposity in prepubertal girls with HD.
Asunto(s)
Sulfato de Deshidroepiandrosterona/sangre , Obesidad/sangre , Receptores Androgénicos/sangre , Adiposidad , Composición Corporal , Estudios de Casos y Controles , Niño , Chile , Estudios de Cohortes , Femenino , Humanos , Polimorfismo Genético , Receptores Androgénicos/genéticaRESUMEN
This study aims to establish the current state of the IT-15 (HTT) gene in different Ecuadorian ethnic groups and patients by determining CAG triplet repeats, compared with the ethnicity of individuals. A total of 412 individuals were studied using nested polymerase chain reaction and Sanger sequencing: 75 individuals were indigenous (Kichwas), 211 mestizos, and 65 Afro-Ecuadorians. We included 31 patients who were clinically diagnosed with Huntington's disease (HD) and relatives of the affected patients (n = 30). Moreover, we correlated the presence of HD in Ecuadorian patients with 46 genetic ancestry-informative insertion-deletion polymorphic markers. We found that 77.20% had <28 CAG repetitions, 18.80% had mutable alleles, 2.27% had incomplete penetrance, and 1.70% reflected >39 repetitions. The average of CAG repetitions was 24 ± 3 for indigenous people; 28 ± 2 for mestizos; and 24 ± 3.2 repetitions for the Afro-Ecuadorians. The ancestral component showed that the main ancestry corresponded to Native Americans (0.873) and European ascendants (0.145), Africans were less represented in the evaluated population (0.018). There was a significant difference between the number of CAG repeats in mestizos and indigenous people (P < .01), suggesting that the Ecuadorian mestizo population has a risk factor for the gene mutation.
Asunto(s)
Etnicidad/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Adolescente , Adulto , Anciano , Demografía , Ecuador , Femenino , Humanos , Masculino , Persona de Mediana Edad , Expansión de Repetición de Trinucleótido/genética , Adulto JovenRESUMEN
BACKGROUND/OBJECTIVES: Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by the expansion of a cytosine-adenine-guanine triplet located in the coding region of the ATXN7 gene, which is characterized by cerebellar ataxia, pigmentary macular degeneration, and dysarthria. Although dysarthria is a common feature in various SCA, its clinical characterization has been barely approached. PATIENTS/METHODS: In this study, we report, to our knowledge for the first time, a detailed voice analysis in a large series of patients with SCA7, using different vocal parameters, including jitter, shimmer, and fundamental frequency. Patients were molecularly diagnosed using fluorescent-based polymerase chain reaction and capillary electrophoresis, and clinically characterized using the Scale for the Assessment and Rating of Ataxia and the Inventory of Non-Ataxia Symptoms. RESULTS: We found altered jitter, shimmer, and fundamental frequency measurements in patients with SCA7 compared with control subjects (P < 0.05). However, voice impairment was found unrelated with both age at disease onset and size of the cytosine-adenine-guanine triplet tract. Remarkably, jitter and shimmer measurements of patients were found to correlate with their Inventory of Non-Ataxia Symptoms, but not with their Scale for the Assessment and Rating of Ataxia scores, implying that voice impairment is the result of extra-cerebellar manifestations of the disease. CONCLUSIONS: We propose that deficiency of the extra-cerebellar component of SCA7 might lead to sudden changes in laryngeal muscle tone, producing instability in sustained vowel phonation. Clinical characterization of voice will help to discriminate SCA7 from other SCA and to guide vocal therapy treatments.
Asunto(s)
Ataxina-7/genética , Músculos Laríngeos/inervación , Mutación , Fonación , Acústica del Lenguaje , Ataxias Espinocerebelosas/complicaciones , Trastornos de la Voz/etiología , Calidad de la Voz , Acústica , Adulto , Anciano , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , México , Persona de Mediana Edad , Fenotipo , Medición de la Producción del Habla , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genética , Trastornos de la Voz/diagnóstico , Trastornos de la Voz/fisiopatologíaRESUMEN
We aimed to present a systematic review on Huntington's disease (HD) in Latin America (LA). PubMed and LILACS were searched up to March 2015, reporting confirmed HD cases in LA. Case series, cross-sectional, case-control, and prospective studies were included. From 534 communications, 47 were eligible. Population-based studies were not found; minimal prevalence of 0.5-4/100,000 was estimated for Venezuela and Mexico. Geographical isolates were well characterized in Venezuela and in Peru. CAG repeats at HTT gene varied between 7-33 and 37-112 in normal and expanded alleles, respectively. Intermediate alleles were found in 4-10% of controls. Ages at onset and the expanded CAG repeats correlated with r from - 0.55 to -0.91. While haplotype patterns of Venezuelan and Brazilian chromosomes were similar to those observed in Europeans, haplotypes from Peruvian HD patients did not match the same pattern. The limited number of papers found suggests that HD is poorly diagnosed in LA. Minimal prevalence seemed to be halfway between those of Caucasians and Asians. Range of CAG repeats was similar to those of Europeans. Haplotype studies indicate that majority of HD patients might be of Caucasian descent; an Asian origin for some Peruvian patients was proposed.
Asunto(s)
Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Edad de Inicio , Anciano , Pueblo Asiatico/genética , Niño , Preescolar , Haplotipos , Humanos , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/etnología , América Latina/etnología , Persona de Mediana Edad , Prevalencia , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD) is a hereditary neurodegenerative disorder resulting from the expansion of CAG repeats in the ATXN3 gene. It is the most common autosomal dominant ataxia in the world, but its frequency prevalence in Cuba remains uncertain. We undertook a national study in order to characterize the ATXN3 gene and to determine the prevalence of SCA3/MJD in Cuba. RESULTS: Twenty-two individuals belonging to 8 non-related families were identified as carriers of an expanded ATXN3 allele. The affected families come from the central and western region of the country. Ataxia of gait was the initial symptom in all of the cases. The normal alleles ranged between 14 and 33 CAG repeats while the expanded ones ranged from 63 to 77 repeats. The mean age at onset was 40 ± 9 years and significantly correlated with the number of CAG repeats in the expanded alleles. CONCLUSIONS: This disorder was identified as the second most common form of spinocerebellar ataxia (SCA) in Cuba based on molecular testing, and showing a different geographical distribution from that of SCA2. This research constitutes the first clinical and molecular characterization of Cuban SCA3 families, opening the way for the implementation of predictive diagnosis for at risk family members.
RESUMEN
Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders. CAG (cytosine-adenine-guanine) trinucleotide repeat expansions in the causative genes have been identified as the cause of different SCA. In this study, we simultaneously genotyped SCA1, SCA2, SCA3, SCA6, and SCA7 applying a fluorescent multiplex polymerase chain reaction assay. We analyzed 10 families with SCA (64 patients) from five different communities of Veracruz, a Mexican southeastern state, and identified 55 patients for SCA7 and 9 for SCA2, but none for SCA1, SCA3, or SCA6. To our knowledge, this sample represents one of the largest series of SCA7 cases reported worldwide. Genotyping of 300 healthy individuals from Mexican population and compiled data from different ethnicities showed discordant results concerning the hypothesis that SCA disease alleles arise by expansion of large normal alleles.
Asunto(s)
Efecto Fundador , Proteínas del Tejido Nervioso/genética , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido/genética , Ataxina-7 , Fluorescencia , Frecuencia de los Genes , Genotipo , Humanos , México/epidemiología , Reacción en Cadena de la Polimerasa Multiplex , PrevalenciaRESUMEN
Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder characterized by degeneration of the cerebellum, brainstem, and retina that is caused by abnormal expansion of a CAG repeat located in the ATXN7 gene encoding sequence on chromosome 3p21.1. Although SCA7 is an uncommon autosomal dominant ataxia, we previously found increased prevalence of the disease in a Southeastern Mexican population. In this study, we described to our knowledge for the first time a marriage of consanguineous SCA7 mutation carriers and their offspring effect. We characterized a severely affected infantile-onset female patient whose parents and two siblings exhibited no symptoms of the disease at time of diagnosis. A comprehensive clinical analysis of the proband showed a progressive cerebellar syndrome, including gait ataxia, movement disorders, and saccadic movements, as well as hyperreflexia, visual deterioration, urinary and cardiovascular dysfunction, and impaired nerve conduction. The SCA7 mutation was detected in the proband patient. Subsequently, genetic examination using four ATXN7 gene-linked markers (three centromeric microsatellite markers [D3S1228, D3S1287, and D3S3635] and an intragenic Single Nucleotide Polymorphism [SNP-3145G/A]) revealed that the proband descends from a couple of consanguineous SCA7 mutation carriers. Genotyping analysis demonstrated that all offspring inherited only one mutant allele, and that the severe infantile-onset phenotype is caused by germinal expansion (from 37 to 72 CAG repeats) of the paternal mutant allele. Interestingly, the couple also referred a miscarriage. Finally, we found no CAA interruptions in the ATXN7 gene CAG repeats tract in this family, which might explain, at least in part, the triplet instability in the proband.
RESUMEN
Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease. Sixty-two patients with chorea belonging to 16 unrelated families carried a pathological CAG expansion in the HTT gene, ranging from 39 to 67 repeats. Eighty-three percent of them come from the eastern region of the country. A significant inverse correlation between age at onset and expanded CAG repeats was seen. Intermediate alleles in affected individuals and controls represented 4.8% and 3.97% respectively, which have been a putative source of de novo mutation. This study represents the largest molecular characterization of Huntington disease in the Cuban population. These results may have significant implications for an understanding of the disease, its diagnosis and prognosis in Cuban patients, giving health professionals the tools to implement confirmatory genetic testing, pre-symptomatic testing and clinical trials in this population.
Asunto(s)
Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Cuba/epidemiología , Femenino , Frecuencia de los Genes , Humanos , Proteína Huntingtina , Masculino , Persona de Mediana Edad , Fenotipo , Estadísticas no Paramétricas , Adulto JovenRESUMEN
The objective of this study was to determine the prevalence of hereditaryataxias in Cuba, with a specialfocus on the clinical and molecular features of SCA2. Clinical assessmentswere performed by neurologicalexaminations and application of the SARA scale. Molecular analyses ofgenes SCA13, SCA6, SCA17and DRPLA identified 753 patients with SCA and 7173 asymptomaticrelatives, belonging to 200 unrelatedfamilies. 86.79 percent of all SCA patients were affected with SCA2. In the Holguin province, the averagepopulation prevalence of SCA2 is 40.18×105 inhabitants, with theremarkable figure of 141.66×105 inthe Baguanos municipality. The high prevalence of the SCA2 mutation inHolguin reflects most likelya founder effect. The stabilization of the prevalence along time suggeststhe existence of premutatedchromosomes with pure CAG, acting as reservoir for further expansions. CAGrepeat length correlatedinversely with age at onset, accounting for 80 percent of the variability. Genetic anticipation was observed in the 80 percent of transmissions. Repeat instability was greater in paternaltransmissions whereas CAG expansionswithout anticipation was observed in 10.97 percent suggesting the effect of CAA interruptions in the CAGsegment, which decrease the toxicity of the abnormal ataxin-2, and/orother protective factors...(AU)