Abstract Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient’s treatment. disorder study patient third cousins, cousins , cousins) lentis arthritis HCU (HCU) NM_000071.2CBSc.833T>C833T>C, NM0000712CBSc833TC833TC NMCBScTCTC NM_000071.2 c. 833T>C NM 000071 2 c 833T C T NM_000071.2(CBS):c.[833T>C];[833T>C] pyridoxineresponsive pyridoxine responsive performed identified NM_001256317.1TMPRSS3c.413C>A413C>A NM0012563171TMPRSS3c413CA413CA NMTMPRSScCACA NM_001256317.1 TMPRSS3 413C>A 001256317 1 413C A TMPRSS NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A] NM_005807.6PRG4c.3756dup3756dup, NM0058076PRG4c3756dup3756dup NMPRGcdupdup NM_005807.6 PRG4 3756dup 005807 6 PRG dup NM_005807.6(PRG4):c.[3756dup]:[3756dup] CamptodactylyArthropathyCoxa Camptodactyly Arthropathy Coxa VaraPericarditis Vara Pericarditis CACP, CACP (CACP) respectively patients s treatment (HCU 2CBSc C833T CBSc NM_000071.2CBSc.833T>C833T>C TC NM0000712 NM_000071. 833TC 00007 NM_000071.2(CBS):c.[833T>C];[833T>C 1TMPRSS3c A413C CA NM0012563171 NM_001256317. 413CA 00125631 NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A 6PRG4c 3756dup3756dup NM_005807.6PRG4c.3756dup3756dup NM0058076 NM_005807. 00580 NM_005807.6(PRG4):c.[3756dup]:[3756dup (CACP CT NM000071 NM_000071 0000 TMPRSSc AC NM001256317 NM_001256317 0012563 PRGc dupdup NM005807 NM_005807 0058 NM00007 NM_00007 000 NM00125631 NM_00125631 001256 NM00580 NM_00580 005 NM0000 NM_0000 00 NM0012563 NM_0012563 00125 NM0058 NM_0058 NM000 NM_000 0 NM001256 NM_001256 0012 NM005 NM_005 NM00 NM_00 NM00125 NM_00125 001 NM0 NM_0 NM0012 NM_0012 NM_ NM001 NM_001

Abstract Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In Brazil, the National Neonatal Screening Program tests for six diseases, with a new law issued in 2021 stating that it should incorporate more diseases, including SMA. In the present study, dried blood spot (DBS) samples collected by the Reference Services of Neonatal Screening of RS and SP, to perform the conventional test were also screened for SMA, using real-time PCR, with SALSA MC002 technique. A total of 40,000 samples were analyzed, enabling the identification of four positive cases of SMA, that were confirmed by MLPA. Considering our sampling, Brazil seems to have an incidence comparable to the described in other regions. This work demonstrated that the use of the MC002 technique in samples routinely collected for the conventional NBS program is suitable to screen for SMA in our conditions and can be included in the expansion of the neonatal screening programs. (SMA disorders 10000 10 000 10,00 births (NBS preearly pre early phases diseases 202 study DBS (DBS SP realtime real time PCR MC MC00 40000 40 40,00 analyzed MLPA sampling regions programs 1000 00 10,0 20 MC0 4000 4 40,0 100 0 10, 2 400 40,

Abstract 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.

RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

OBJETIVO: A doença de Parkinson é uma enfermidade neurodegenerativa com diversas manifestações motoras e não-motoras que podem provocar impacto na qualidade de vida. Este estudo teve como objetivo avaliar a qualidade de vida em pacientes com doença de Parkinson com idade superior a 60 anos por meio do questionário World Health Organization Quality of Life Assessment for Older Adults e possíveis fatores determinantes, tais como qualidade de sono, sintomas motores e depressivos. MÉTODO: Foi realizado estudo transversal avaliando a qualidade de vida pelo questionário World Health Organization Quality of Life Assessment for Older Adults em 57 pacientes com doença de Parkinson. RESULTADOS: World Health Organization Quality of Life Assessment for Older Adults total apresentou associação com a severidade da doença de Parkinson (r s= -0,43; p < 0,001). As facetas de habilidade sensorial e de participação social apresentaram maior pontuação nos indivíduos com estágio leve em comparação ao grupo com doença de Parkinson avançada. World Health Organization Quality of Life Assessment for Older Adults (faceta-I) apresentou associação com Índice de Qualidade de Sono de Pittsburg e Escala de Sono na Doença de Parkinson (r p= -0,46 e r p = 0,41; p < 0,001, respectivamente). A Escala Geriátrica de Depressão apresentou associação com World Health Organization Quality of Life Assessment for Older Adults (r p = -0,70; p < 0,001). CONCLUSÃO: A qualidade de vida em pacientes com doença de Parkinson pode ser avaliada pelo questionário World Health Organization Quality of Life Assessment for Older Adults e foi demonstrado que a severidade da doença de Parkinson e os sintomas depressivos podem comprometer negativamente a qualidade de vida.

OBJECTIVE: Parkinson's disease is a neurodegenerative disease with a number of motor and non-motor features that can affect quality of life. In this study, we aimed to assess quality of life, as well as to evaluate the potential determinants of quality of life, such as sleep quality, motor and depressive symptoms, in elderly patients with Parkinson's disease. METHOD: This was a cross-sectional study in which we applied the World Health Organization Quality of Life Assessment for Older Adults in 57 Parkinson's disease patients over 60 years of age. RESULTS: Total World Health Organization Quality of Life Assessment for Older Adults score was found to be associated with Parkinson's disease severity (rs = -0.43; p < 0.001). World Health Organization Quality of Life Assessment for Older Adults scores for sensory abilities (facet 1) and social participation (facet 4) were higher among the patients with mild Parkinson's disease than among those in the more advanced stages (rs = -0.43; p < 0.001). Facet 1 scores were found to be associated with Pittsburg Sleep Quality Index and Parkinson's Disease Sleep Scale score (rp = -0.46 and rp = 0.41; p < 0.001, respectively). The Geriatric Depression Scale score showed an association with the total score on the World Health Organization Quality of Life Assessment for Older Adults (rp = -0.70; p < 0.001) CONCLUSION: Quality of life in Parkinson's disease patients can be assessed by the World Health Organization Quality of Life Assessment for Older Adults. Greater Parkinson's disease severity can worsen patient quality of life, as can the presence of depressive symptoms.