An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean.

Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.

Pain perception genes, asthma, and oral health: A reverse genetics study.

Pain is an experience of a subjective nature, interpreted in a personal way and according to an extensive palette of factors unique to each individual. Orofacial pain can be acute or chronic and it is usually the main reason for the patient to seek dental care. Pain perception varies widely among individuals. This variability is considered a mosaic of factors, which include biopsychosocial factors and genetic factors. Understanding these differences can be extremely beneficial for pain management in a personalized and more efficient way. We performed association studies to investigate phenotypes associated with genetic markers in pain-related genes in two groups of patients who received more or less anesthesia during dental treatment. The study group was comprised of 1289 individuals participating in the Dental Registry and DNA Repository Project (DRDR) of the University of Pittsburgh, with 900 participants in the group that received the most anesthesia and 389 constituting the comparison group that received less anesthesia. We tested 58 phenotypes and genotypic data of seven SNPs in genes that are associated with pain perception, pain modulation and response to drugs used in pain treatment: COMT (rs4818 and rs6269), GCH1 (rs3783641), DRD2 (rs6276), OPRM1 (rs1799971), SCN9A (rs6746030) and SCN10A (rs6795970). The analysis revealed a protective effect of rs1799971 on asthma in the total sample. rs3783641 was associated with salivary secretion disorders in females who received more anesthesia. rs1799971 was also associated with periodontitis in Whites who received less anesthesia. rs4818 was associated with disease and other tongue conditions in the group composed of Blacks who received less anesthesia. In conclusion, our study implicated variants in pain-related genes in asthma and oral phenotypes.

The Cardiovascular Health Integrated Lifestyle Diet (CHILD) Lowers LDL-Cholesterol Levels in Brazilian Dyslipidemic Pediatric Patients.

OBJECTIVE: To analyze the impact of the CHILD-2 diet on the lipid profile of Brazilian children and adolescents with dyslipidemia. METHODS: This is a quasi-experimental study, where 149 participants (5-17 years) with mild-to-moderate hypercholesterolemia were divided into two groups (GI: low or normal weight; n = 58 and GII: overweight; n = 91). Both groups underwent the CHILD-2 diet, characterized by 25-30% total fat and less than 7% of low-saturated fat (SF) for 6 months. Changes from baseline in the lipid profile, including Total cholesterol (TC), LDL-C, triacylglycerols and glucose concentrations, dietary and anthropometric data were examined at 3 and 6 months. Longitudinal analyses were performed using linear mixed-effects models in SAS. RESULTS: Serum LDL-C concentrations reduced over time compared with baseline (Δ = -5.1 mg/dL; p < 0.01), with no difference between groups (p = 0.35). TC concentrations decreased by -2.0 mg/dL (p < 0.01); but no difference was observed between groups. We found no significant changes in body mass index/age Z scores after a dietary intervention compared with baseline in both groups (p = 0.94). CONCLUSION: Despite the modest reduction, our findings confirm that children with dyslipidemia can benefit from the CHILD-2 diet combined with a healthy lifestyle.

New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly.

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.

Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.

GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil.

Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.

GBA mutations p.N370S and p. L444P are associated with Parkinson's disease in patients from Northern Brazil / Mutações p.N370S e p. L444P no gene GBA estão associadas com doença de Parkinson em pacientes do norte do Brasil

ABSTRACT Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.

RESUMO Mutações no gene GBA têm sido reportadas em pacientes com doença de Parkinson (DP) em diferentes países, incluindo o Brasil. Com o objetivo de confirmar esse padrão em uma amostra de pacientes com DP provenientes do Norte brasileiro, foi conduzindo esse estudo caso-controle investigando a frequência das duas mutações mais comuns do gene GBA (c.1226A>G; p.N370S e c.1448T>C; p.L444P) em um grupo de 81 pacientes com DP e 81 controles, usando PCR-RFLP e confirmado pelo sequenciamento direto de produtos de PCR. No grupo experimental, três pacientes (3,7%) foram heterozigotos para a mutação c.1226A>G; p.N370S e três (3,7%), para a mutação c.1448T>C; p.L444P Nenhuma das duas mutações foi detectada no grupo controle (p =0,0284). Pacientes com a mutação c.1448T>C; p.L444P demonstraram uma tendência a apresentar os sintomas mais precocemente, porém um número amostrai maior é necessário para confirmar essa observação. Nossos resultados sugerem uma associação entre essas duas mutações no gene GBA e o desenvolvimento de DP na população de pacientes do norte Brasileiro.

Does the Polymorphism in the Length of the Polyalanine Tract of FOXE1 Gene Influence the Risk of Thyroid Dysgenesis Occurrence?

Background. Recent data have suggested that polymorphisms in the length of the polyalanine tract (polyA) of FOXE1 gene may act as a susceptibility factor for thyroid dysgenesis. The main purpose of this study was to investigate the influence of polyA of FOXE1 gene on the risk of thyroid dysgenesis. Method. A case-control study was conducted in a sample of 90 Brazilian patients with thyroid dysgenesis and 131 controls without family history of thyroid disease. Genomic DNA was isolated from peripheral blood samples and the genotype of each individual was determined by automated sequencing. Results. More than 90% of genotypes found in the group of patients with thyroid dysgenesis and in controls subjects were represented by sizes 14 and 16 polymorphisms in the following combinations: 14/14, 14/16, and 16/16. Genotypes 14/16 and 16/16 were more frequent in the control group, while genotype 14/14 was more frequent in the group of patients with thyroid dysgenesis. There was no difference between agenesis group and control group. Genotype 14/14 when compared to genotypes 14/16 and 16/16A showed an association with thyroid dysgenesis. Conclusion. PolyA of FOXE1 gene alters the risk of thyroid dysgenesis, which may explain in part the etiology of this disease.

Effects of psyllium on LDL-cholesterol concentrations in Brazilian children and adolescents: a randomised, placebo-controlled, parallel clinical trial.

The present study investigated the LDL-cholesterol (LDL-C)-lowering effects of psyllium in Brazilian dyslipidaemic children and adolescents. A total of fifty-one individuals (6-19 years) with mild-to-moderate hypercholesterolaemia were evaluated by conducting a randomised, double-blind, placebo-controlled, parallel clinical trial. Over an 8-week trial period, the participants were randomly allocated to one of two groups (control: n 25 and psyllium: n 26) using a computer-generated random number sequence. Fasting blood samples, dietary records and anthropometric data were collected. Both groups were treated with the National Cholesterol Education Program Step 2 diet for 6 weeks before randomisation. After this run-in period, a daily supplement of 7·0 g psyllium was given to the intervention group, while an equivalent amount of cellulose was given to the control group. Statistically significant changes between the control and intervention groups over time were observed for total cholesterol (7·7%; - 0·39 mmol/l; P= 0·003) and LDL-C (10·7%; - 0·36 mmol/l; P= 0·01). None of the participants reported any aversion to the smell, taste, appearance or texture of psyllium. No serious adverse effects were reported during the study. In addition to causing a significant reduction in LDL-C concentrations, psyllium therapy was found to be both safe and acceptable for the treatment of hypercholesterolaemic children and adolescents.

Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network.

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.

Dislipidemia e fatores de risco (y factores de riesgo) cardiovascular na (en la) população pediátrica brasileira / Dyslipidemia and cardiovascular risk factors among the pediatric population in Brazil

Os fatores de risco (Los factores de riesgo) (FR) para doenças (enfermedades) cardiovasculares (DCV) não são mais uma (no son más una) exclusividade dos (de los) adultos, e estima-se que tais fatores já atinjam um (ya alcanzan un) quarto das crianças (de los niños) e adolescentes no mundo. O propósito deste estudo foi revisar as prevalências dos principais FR para DCV na (en la) população pediátrica brasileira. Pelo (Con el) método de revisão sistemática, realizou-se a busca de periódicos indexados nas bases Pubmed, Medline, Embase, Lilacs, Cochrane e Scielo publicados no período de 2001 a 2011, utilizando os seguintes (los siguientes) descritores em português e inglês: fatores de risco cardiovascular, hipertensão arterial, diabetes, dislipidemia, obesidade, tabagismo, atividade física, dieta e sedentarismo. Dos 190 resumos (De los 190 resúmenes) encontrados, 28 foram (fueron) selecionados para análise final. Os resultados confirmaram a ocorrência concomitante (aparición concomitante) de vários FR cardiovasculares já na faixa etária (ya en el grupo etario) pediátrica, porém não foi possível (todavía no ha sido posible) comparar sua distribuição entre as regiões brasileiras devido à falta (a causa de la falta) de padronização nos critérios (estandarización de los criterios) e pontos de corte de referência (valores decorte de referencia) e também pela carência (por la ausencia) de estudos realizados nas regiões Norte e Centro-Oeste. Diante destas (Frente a estas) limitações, recomenda-se que as (se recomienda que las) organizações de fomento no Brasil continuem apoiando projetos e (apoyando proyectos y) programas que visem mapear e padronizar os (con vistas a mapear y estandarizar los) critérios metodológicos e epidemiológicos para FR e para DCV, e que estes sejam adequados à (estos sean adecuados a la) população pediátrica, principalmente em regiões carentes de mais estudos...

Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes.

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.

Dentomaxillofacial manifestations of mucopolysaccharidosis VI: clinical and imaging findings from two cases, with an emphasis on the temporomandibular joint.

OBJECTIVES: Using a clinical survey, panoramic, cone-beam computed tomography (CBCT), and magnetic resonance (MR) imaging, this study was conducted to ascertain primary maxillofacial abnormalities in patients with mucopolysaccharidosis VI (MPS VI). STUDY DESIGN: Two patients previously diagnosed with MPS VI underwent clinical and imaging surveys (panoramic radiographs, CBCT, and MR imaging). RESULTS: Jaw involvement was present in all patients. The most prevalent findings were enlarged marrow spaces, osteopenia, dentigerous cyst-like follicles, effacement of the jaw structures, and osteosclerosis. This is the first study to describe temporomandibular joint (TMJ) involvement for MPS VI. CONCLUSIONS: CBCT and MR imaging were needed to observe features that were not clear in conventional radiographs. Both patients reported symptoms in the TMJ and demonstrated involvement during their examinations. A multicenter study is necessary to better document maxillofacial involvement in MPS VI.

Avaliação antropométrica de pacientes com suspeita de erros inatos do metabolismo / Anthropometric evaluation of patients with suspected innate errors of metabolism

Avaliar antropometricamente os pacientes com suspeita de erros inatos do metabolismo (EIM) e descrever a prevalência de distúrbios nutricionais (desnutrição, sobrepeso e obesidade). MÉTODOS: foram avaliados 55 pacientes de 0 a 10 anos, de acordo com os índices antropométricos (A/I, P/I E P/A e IMC/I), no laboratório de erros inatos do metabolismo (LEIM) da Universidade Federal do Pará, através de balança e antropômetro. Os dados foram coletados a partir da ficha de atendimento do LEIM. Para o diagnóstico nutricional foram utilizados os programas Anthro e Anthro Plus e o programa SPSS para a análise estatística. RESULTADOS: os pacientes atendidos pertenciam, na maioria, a faixa etária de sete meses a nove anos. Os principais sintomas foram atraso no desenvolvimento neuropsicomotor e infecções frequentes. Quanto ao estado nutricional, foi observado déficit de 23,7 por cento no indicador de peso para idade, déficit de 50,9 por cento no indicador de altura para idade, excesso de peso e obesidade de 15,4 por cento para peso para altura, e 25,1 por cento para índice de massa corporal para idade. CONCLUSÕES: os pacientes apresentaram estado nutricional inadequados, o qual na ausência de diagnóstico de EIM, os fatores envolvidos devem ser mais bem averiguados...

To provide an anthropometric evaluation of patients suspected of having innate errors of metabolism (IEMs) and report the prevalence of nutritional disorders (malnutrition, overweight and obesity). METHODS: fifty-five patients aged between 0 and 10 years were evaluated for anthropometric indices (H/A, W/A and W/H and BMI/A), in the innate errors of metabolism laboratory (LEIM) of the Federal University of Pará, using scales and an anthropometer. The data were collected using an LEIM form. Nutritional diagnosis was carried out using the Anthro and Anthro Plus programs and the SPSS statistics package. RESULTS: the patients attended were mostly aged between seven months and nine years. The main symptoms were delayed neuropsychomotor development and frequent infections. As for the nutritional status, a deficit of 23.7 percent was observed in weight for age, a deficit of 50.9 percent in height for age, and the prevalence of overweight and obesity was 15.4 percent according to weight for height, and 25,1 percent according to body mass index for age. CONCLUSIONS: the nutritional status of the patients was inadequate and, given the absence of a diagnosis of IEMs, the factors involved should be investigated more thoroughly...

Molecular characterization of phenylketonuria in South Brazil.

Phenylketonuria (PKU) is an autosomal recessive disorder due to phenylalanine hydroxylase (PAH) deficiency. The PAH gene, located at 12q22-q24.1, includes about 90kb and contains 13 exons. To date, more than 420 different alterations have been identified in the PAH gene. To determine the nature and frequency of PAH mutations in PKU patients from South Brazil, mutation analysis was performed on genomic DNA from 23 unrelated PKU patients. The 13 exons and flanking regions of the PAH gene were amplified by PCR and the amplicons were analyzed by single strand conformation polymorphism (SSCP). Amplicons that showed abnormal migration patterns were analyzed by restriction endonuclease digestion and/or sequencing. Twenty-two previously reported mutations were identified including R261X, R408W, IVS2nt5g-->c, R261Q, and V388M. Polymorphisms were observed in 48.8% of the PKU patients, the most frequent being IVS2nt19t-->c, V245V, and IVS12nt-35c-->t. In addition, two novel sequence variants were identified: 1378g-->t in the 3(')-untranslated region in exon 13 which may be disease-causing and an intron 12 polymorphism, IVS12nt-15t-->c. The mutation spectrum in the patients from Southern Brazil differed from that observed in patients from other Latin American countries and further defined the molecular heterogeneity of this disease.