Caracterização clínica com ênfase em aspectos neuropsiquiátricos, cardiológicos e qualidade de vida de uma coorte de pacientes do Sul do Brasil com diagnóstico tardio de homocistinúria clássica

Introdução: A Homocistinúria Clássica ou Deficiência de Cistationina βsintase é uma doença genética, autossômica recessiva, multissistêmica de curso lento e progressivo que ocorre pela alteração no metabolismo dos aminoácidos sulfurados, com aumento dos níveis de homocisteína, metionina, S adenosil homocisteína e redução de cistationina e cisteína. A Homocistinúria Clássica pode ser classificada em três formas: responsiva à piridoxina (vitamina B6), nãoresponsiva à piridoxina e com resposta intermediária à piridoxina. Sem o diagnóstico e tratamento precoces, os pacientes apresentam um quadro clínico caracterizado por anormalidades oftalmológicas, ósseas, vasculares e no sistema nervoso central. Todos os pacientes devem receber tratamento com suplementação de ácido fólico e vitamina B12 se houver deficiência. O tratamento recomendado para pacientes responsivos é o uso de piridoxina 10 mg/Kg/dia evitando doses acima de 500 mg/dia por risco de neuropatia periférica. O uso do tratamento dietético e betaína deve ser considerado para os pacientes que não atingiram níveis ideais de homocisteína total apenas com a suplementação de piridoxina. Objetivos: avaliar a qualidade de vida, detectar prevalência de deficiência intelectual, descrever quadro psiquiátrico e caracterizar alterações em Sistema Nervoso Central através de volumetria cerebral em pacientes com Homocistinúria Clássica acompanhados no ambulatório de Genética do Hospital de Clínicas de Porto Alegre. Métodos: o estudo foi realizado em três etapas. Os pacientes incluídos são acompanhados em um ambulatório especializado no Hospital de Clínicas de Porto Alegre. A amostra foi por conveniência e os pacientes tinham que ter diagnóstico confirmado de Homocistinúria Clássica. Na primeira etapa, realizou-se um estudo retrospectivo avaliando qualidade de vida através da aplicação do questionário WHOQOL-BREF em 11 pacientes. Além disso, foi avaliado o QI através do questionário WASI de 8 pacientes. Na segunda etapa, para avaliar quadro psiquiátrico, foi realizado um estudo transversal, prospectivo através da aplicação das escalas Brief Psychiatric Rating Scale (BPRS), Escala de Ansiedade de Beck, Hamilton e Escala de Depressão de Beck (BD) em 8 pacientes. Após, um estudo transversal de volumetria cerebral foi realizado nestes 8 pacientes. Na terceira etapa, foi realizada uma análise retrospectiva de 14 pacientes para avaliar alterações cardiológicas através da análise de eletrocardiogramas e ecocardiogramas. Resultados: na primeira etapa foi verificado que os pacientes em tratamento para Homocistinúria Clássica apresentaram escores mais elevados no domínio psicológico quando comparados aos pacientes não tratados. A segunda etapa mostrou que o volume total do tálamo controlado pelo volume craniano e idade teve correlações negativas com a Escala de Depressão de Beck, Escala de Hamilton, BPRS e com dois subitens do BPRS, preocupações somáticas e maneirismos. Pacientes com Homocistinúria Clássica, quando comparados a indivíduos saudáveis, pareados por idade e sexo, apresentaram mais locais de hipointensidade de substância branca. Na terceira etapa foi verificada uma alta prevalência de valvulopatias. Conclusão: Nossos dados sugerem que o tratamento de pacientes com Homocistinúria Clássica associa-se a uma melhora na qualidade de vida no aspecto psicológico, que as alterações no QI são prevalentes e que os pacientes apresentam quadro compatível com depressão, ansiedade e esquizofrenia. Há uma tendência no envolvimento do tálamo como uma das estruturas relacionadas às condições psiquiátricas nos pacientes com Homocistinúria Clássica e valvulopatias são frequentemente encontradas em pacientes com Homocistinúria Clássica não responsivos à piridoxina. Apenas um paciente responsivo à piridoxina apresentou ectasia de raiz da aorta.Introduction: Classic Homocystinuria or Cystathionine β-synthase Deficiency, is a genetic autosomal recessive and multisystemic disease. It is characterized by a slow and progressive course and impaired metabolism of sulfur amino acids, leading to increased levels of homocysteine, methionine, S adenosyl homocysteine and reduced cystathionine and cysteine. Classical Homocystinuria can be classified into three forms: responsive to pyridoxine (vitamin B6), unresponsive to pyridoxine and intermediate response to pyridoxine. Ophthalmological, bone, vascular and central nervous system abnormalities can occur if no early diagnosis or treatment are provided. All patients should be treated with folic acid and vitamin B12 supplementation, if they are deficient. Recommended pyridoxine dose for responsive patients is 10 mg/kg/day, up to 500 mg/day, due to the risk of peripheral neuropathy caused by higher doses. Additionally, dietary treatment and betaine should be considered on those who did not reach ideal levels of total homocysteine with pyridoxine supplementation. There is little data about cardiac, neuropsychiatric problems and quality of life in Classic Homocystinuria patients and, to this date, there is no data about brain volume. Objectives: to assess quality of life, detect prevalence of intellectual disability, describe psychiatric conditions and characterize alterations in the Central Nervous System through cerebral volumetry in HCU patients followed at Genetics Service of Hospital de Clínicas de Porto Alegre. Method: the study was performed in three steps. Included patients are monitored at a specialized clinic at the Hospital de Clinicas de Porto Alegre. The sample was by convenience and the patients have a confirmed diagnosis of Classical Homocystinuria. First, a retrospective study assessed quality of life in 11 patients, through WHOQOL-BREF questionnaire. In addition to that, the IQ was assessed using the WASI questionnaire in eight patients. In the second step, psychiatric conditions were evaluated in eight patients through a cross-sectional, prospective study, using Brief Psychiatric Rating Scale (BPRS), Beck Anxiety Scale, Hamilton and Beck Depression Scale (BD). Afterwards, a cross-sectional study of cerebral volumetry was carried out in these eight patients. Finally, the third step was a retrospective analysis of 14 patients, in order to assess cardiac alterations via electrocardiogram and echocardiogram. Results: in the first stage, it was found that patients undergoing treatment had higher scores in the psychological domain when compared to untreated patients. The second step showed that total thalamus volume, adjusted by cranial volume and age, had negative correlations with the Beck Depression Scale, Hamilton Scale, BPRS and with two BPRS sub-items: somatic concerns and mannerisms. Patients with Classical Homocystinuria, when compared to healthy individuals, matched for age and sex, had more sites of white matter hypointensity. In the third step, a high prevalence of valvulopathies was verified. Conclusion: Our data suggest that the treatment of patients with Classic Homocystinuria is associated with an improvement in quality of life in the psychological aspect, that changes in IQ are prevalent and that patients present depression, anxiety and schizophrenia. There is a trend towards involvement of the thalamus as one of the structures related to psychiatric conditions in Classic Homocystinuria patients and valvulopathies are frequently found in unresponsive pyridoxine Classic Homocystinuria patients. Only one pyridoxine-responsive patient had aortic root ectasia

Clinical research challenges in rare genetic diseases in Brazil

Rare diseases are defined as conditions with a prevalence of no more than 6.5 per 10,000 people. Although each rare disease individually affects a small number of people, collectively, the 6,000 to 8,000 rare conditions (80% of them with genetic cause) affect around 8% of the world’s population. Research about the natural history and underlying pathophysiological mechanisms of rare diseases, as well as clinical trials with new drugs, are important and necessary to develop new strategies for the treatment of these conditions. This report describes the experience of a clinical research group working with rare diseases in a reference center for lysosomal diseases in Brazil (Medical Genetics Service, Hospital de Clínicas de Porto Alegre). The activities of this research group enabled its participation in several international multicenter clinical research protocols related to the natural history or therapy development for rare genetic diseases. This participation has allowed the development of personal skills and institutional facilities for clinical research. The clinical research developed in our center has raised the quality of the medical assistance provided to non-clinical research patients in addition to enabling early access to new therapies to many patients with orphan conditions

Elevated holo-transcobalamin in Gaucher disease type II : a case report

Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of β-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II