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Fourteen asymptomatic normocephalic newborns with confirmed congenital Zika infection were investigated. All newborns presented Zika virus (ZIKV) positivity on reverse transcriptase polymerase chain reaction. Following ZIKV-specific NS5 gene fragment sequencing in one child, phylogenetic analysis revealed that this isolate belonged to the Asian genotype, and clustered closely with other sequences previously isolated in north-east and northern regions of Brazil.

Heterozygous variants in USP9X are associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome characterized by neurodevelopmental delay, intellectual disability (ID), and a wide variety of additional congenital anomalies. Here, we report a girl harboring a novel de novo loss-of-function variant in USP9X (c.4091delinsAG, p.Thr1364Lysfs*7), and literature review revealed novel prenatal features associated with MRXS99F, expanding the genotypic and phenotypic landscape of the syndrome. It is important to consider X-linked diseases in girls with ID and perform directed molecular investigation to provide correct diagnosis and prognosis.

Introduction Mucopolysaccharidosis (MPS) is a set of rare diseases caused by deficiency of lysosomal enzymes that lead to the accumulation of glycosaminoglycans (GAG) in tissues and organs, which, in turn, is responsible for the multisystemic clinical, chronic, and progressive symptoms. Objective To describe the profile of the otorhinolaryngological clinical examination and audiology tests of patients with MPS disease. Methods The present study is a case series. The evaluation was performed, initially, in 24 patients with MPS types I, II, IIIA, IV and VI. Results The most common hearing complaint was hearing loss, which was confirmed by audiology tests in almost 100% of the patients, most of whom presented conductive hearing loss. Conclusions It is important to evaluate the complaints, physical examination, and audiology tests in patients with MPS. The otorhinolaryngologistshould be part of the group of professionals that follows these patients to better monitor their hearing and provide early hearing rehabilitation.

Objective: Mucopolysaccharidosis is a rare genetic disease characterized by the intralysosomal deposition of glycosaminoglycans. Cardiovascular impairment is a common feature. Cardiac signs and symptoms are underestimated due to the disease involvement in other organs. Enzyme replacement therapy can be used in mucopolysaccharidosis I, II, IV, and VI. Thus, the knowledge about the use of new echocardiography tools is relevant to improve the care of this population. This study aimed to describe left ventricular function assessment by conventional echocardiography and left ventricular global longitudinal strain analysis and compare the alterations in patients receiving enzyme replacement therapy and who had different ages at the start of therapy. Method: Outpatient-based descriptive study. The patients were submitted to conventional echocardiography and left ventricular global longitudinal strain measurement. Results: Sixteen patients were evaluated; median age of 14.2 years (SD = 5.2 years). Left ventricular hypertrophy was found in nine patients (56.2%). All patients had preserved left ventricular systolic function (Simpson and Teichholz). Nine (56.2%) patients showed alterations in left ventricular global longitudinal strain. The study showed a positive association between left ventricular hypertrophy and alteration in the left ventricular global longitudinal strain, and late start of enzyme replacement therapy and alteration in the left ventricular global longitudinal strain. Conclusion: Echocardiographic alterations in patients with mucopolysaccharidosis were frequently observed, especially alterations in the left ventricular geometry and subclinical dysfunction. Patients who had a late enzyme replacement therapy start showed an association with worse left ventricular global longitudinal strain values, reinforcing the need for early diagnosis and treatment. The use of new echocardiographic tools may improve the follow-up of these patients. Resumo: Objetivo: A mucopolissacaridose é uma doença genética rara, caracterizada por depósito intralisossômico de glicosaminoglicanos. O comprometimento cardiovascular é frequente. Sinais e sintomas cardíacos são subestimados pelo envolvimento da doença em outros órgãos. A terapia de reposição enzimática pode ser usada em mucopolissacaridose I, II, IV e VI. Assim, o conhecimento da aplicação de novas ferramentas de ecocardiografia é relevante para melhorar a assistência dessa população. Este estudo visou descrever a função do ventrículo esquerdo pelo ecocardiograma convencional e pela análise do strain global longitudinal do ventrículo esquerdo e comparar as alterações em pacientes que fazem uso da terapia de reposição enzimática e que tiveram idades distintas de início da terapia. Método: Estudo descritivo de base ambulatorial. Os pacientes foram submetidos à ecocardiografia convencional e medida do strain global longitudinal do ventrículo esquerdo. Resultados: Foram avaliados 16 pacientes; mediana de 14,2 anos (desvio: 5,2 anos). Hipertrofia do ventrículo esquerdo foi encontrada em nove pacientes (56,2%). Todos os pacientes tiveram função sistólica do ventrículo esquerdo preservada (Simpson e Teichholz). Nove (56,2%) pacientes apresentaram alteração no strain global longitudinal do ventrículo esquerdo. O estudo mostrou associação positiva entre hipertrofia do ventrículo esquerdo e alteração no strain global longitudinal do ventrículo esquerdo e início tardio da terapia de reposição enzimática e alteração no strain global longitudinal do ventrículo esquerdo. Conclusão: Alterações ecocardiográficas em pacientes com mucopolissacaridose foram frequentes, especialmente alterações na geometria e disfunção subclínica do ventrículo esquerdo. Pacientes que iniciaram tardiamente a terapia de reposição enzimática apresentaram associação com piores valores de strain global longitudinal do ventrículo esquerdo, o que reforça a necessidade do diagnóstico e tratamento precoces. O uso de novas ferramentas de ecocardiografia pode melhorar o acompanhamento desses pacientes. Keywords: Mucopolysaccharidosis, Echocardiography, Cardiac function tests, Enzyme replacement therapy, Palavras-chave: Mucopolissacaridose, Ecocardiografia, Testes de função cardíaca, Terapia de reposição enzimática

Background Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with scarce epidemiological data and few publications about natural history and clinical spectrum. Methods We conducted a case series report which included retrospective data from all MPS VII patients diagnosed through the “MPS Brazil Network” who were known to be alive in 2020 in Brazil (N = 13). Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. Results The majority of the patients were from the Northeast region of Brazil. Among the signs and symptoms that raised the clinical suspicion of MPS, coarse face was the most frequent; 58% of the patients had a history of non-immune hydrops fetalis. All the subjects presented short neck and trunk. The majority presented typical phenotypical signs of MPS disorders. They all presented neurodevelopmental delay and cognitive impairment. About half of this cohort had knees deformities. Dysostosis multiplex was identified in almost all patients and cardiomyopathy was less frequent than observed in other types of MPSs. The mean age at diagnosis was 5 years, ranging from 1 to 14 years. Almost all patients (12/13) were homozygous for the c.526C>T (p.Leu176Phe) mutation. A novel variant of the GUSB gene was found, the c.875T>C (p.Leu292Pro), in a compound heterozygous with the c.526C>T (p.Leu176Phe) variant. Conclusions This case series is the biggest data collection of MPS VII patients alive in Latin America. The overall clinical picture of the MPS VII patients is very similar to other MPS disorders, including a spectrum of severity and delayed diagnosis.

Neuronal ceroid lipofuscinoses (NCLs), also referred as “Batten disease”, are a group of thirteen rare genetic conditions, which are part of the lysosomal storage disorders. CLN type 2 (CLN2) is caused by the deficient activity of the tripeptidyl peptidase I (TPP1) enzyme, encoded by the TPP1 gene, most frequently leading to the classic late infantile phenotype. Nearly 140 CLN2-causing mutations have been described. In this case report, we describe the identification of a new disease-causing mutation and highlight the importance of appropriate laboratory investigation based on clinical suspicion. The collection of dried blood spots (DBS) on filter paper, which is a convenient sample, can be used to measure the TPP1 enzyme activity and detect CLN2-related mutations. Since the biochemical and genetic diagnoses are possible and as the disease progression is fast and the therapeutic window is short, the investigation of CLN2 should be always considered when this diagnostic hypothesis is raised in order to enable the patients to benefit from the specific pharmacological treatment.

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.

Sanofi Genzyme Sanofi Genzyme, Cambridge, MA, USA Background: Enzyme replacement therapy (ERT) with laronidase (recombinant human alpha-L-iduronidase, Aldurazyme (R)) is indicated for non-neurological signs and symptoms of mucopolysaccharidosis type I (MPS I). The approved laronidase dose regimen is weekly infusions of 0.58mg/kg, however, patients and caregivers may have difficulty complying with the weekly regimen. We examined clinical outcomes, tolerability, compliance, and satisfaction in a series of patients who switched to every other week infusions. Methods: This multinational, retrospective, chart review case series analyzed data from 20 patients who had undergone ERT with laronidase 0.58mg/kg weekly for more than one year, and who then switched to 1.2mg/kg every other week. Results: The majority of patients had attenuated MPS I phenotypes (9 with Hurler-Scheie and 8 with Scheie syndromes) and 3 patients had severe MPS I (Hurler syndrome). Most patients presented with organomegaly (17/ 20), umbilical and/or inguinal hernia (16/20), cardiac abnormalities (17/20), musculoskeletal abnormalities (19/20), and neurological and/or developmental deficits (15/20). Following laronidase treatment, signs stabilized or improved. No deterioration or reversal of clinical outcome was noted in any patient who switched from the weekly dose of 0.58mg.kg to 1.2mg/kg every other week. There were no safety issues during the duration of every other week dosing. Patient compliance and satisfaction with the dosing regimen were greater with every other week dosing than weekly dosing. Conclusions: An alternative dose regimen of 1.2mg/kg laronidase every other week was well tolerated and clinically similar to the standard dose for patients who were stabilized with weekly 0.58 mg/kg for one year or more. When an individualized approach to laronidase therapy is necessary, every other week dosing may be an alternative for patients with difficulty receiving weekly infusions. Fiocruz MS, Inst Nacl Saude Mulher Crianca & Adolescente Fern, BR-21045900 Rio De Janeiro, Brazil Univ Fed Bahia, Dept Pediat, Serv Genet Med, Salvador, BA, Brazil Hosp Clin Alegre, Med Genet Serv, Porto Alegre, RS, Brazil Comenius Univ, Childrens Hosp, Dept Pediat 2, Bratislava, Slovakia Westmead Hosp, Dept Med Genet, Sydney, NSW, Australia Univ Sydney, Sydney, NSW 2006, Australia Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil Web of Science

This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels

Joubert syndrome (JS) is an autosomal recessive inherited disorder characterized by hypotonia, cerebellar vermis hypoplasia, ocular abnormalities (e.g, pigmentary retinopathy, oculomotor apraxia and nystagmus), renal cysts and hepatic fibrosis. Respiratory abnormalities, as apnea and hyperpnea, may be present, as well as mental retardation. At least seven JS loci have been determined and five genes identified. Herein, we report five children, belonging to independent families, with JS: they shared the same typical MRI abnormality, known as molar tooth sign, but had an otherwise quite variable phenotype, regarding mostly their cognitive performance, visual abilities and extra-neurological compromise.

Herein, we report a new locus, named SPG34, for a pure form of X-linked hereditary spastic paraplegia (HSP) in a large Brazilian family followed by our group since 1976 [1]. In 2002, a study of seven patients suggested linkage to Xq22.2 [2]. We now were able to perform a more comprehensive clinical and molecular evaluation, including five patients not previously ascertained, and reassigned the putative locus to Xq25. After Institutional Review Board approval, we genotyped 12 affected individuals (aged 24 to 79 years), one unaffected 60-year-old man, and 11 women (aged 40 to 81), seven of which were obligate carriers (Fig. 1). Neurological examination was performed in 11 of the 12 affected men and in all obligate women carriers. Age of onset varied from 12 to 25 years but was sometimes difficult to be determined. The clinical phenotype was stereotyped, and shuffling gait was the first recognized clinical sign. The disease was invariably progressive, and after two decades of onset, patients usually need support to walk; after three to four decades, they are usually wheelchair-bound. In upper limbs, strength was never affected, even late in life, but tendon reflexes were brisk. Lower limbs spasticity was progressive and debilitating. Babinski sign, ankle clonus, and brisk reflexes were frequently present. Lower limb vibratory sensibility was commonly reduced after the sixth decade of life; spontaneous lower limb pain was also a common complaint. No urinary or bowel sphincter dysfunction were ever reported. The SPG34 locus encompasses a 14 cM region at Xq24– q25, in which 69 genes and bona fide transcripts have been assigned. Using a candidate gene approach to try to identify the causative sequence abnormality of SPG34, we fully sequenced AIFM1, which encodes a mitochondrial flavoprotein essential for apoptotic nuclear disassembly [3], but no mutation was detected. Therefore, the molecular basis for SPG34 remains unknown and we will sequence additional candidate genes that are highly expressed in the central nervous system. The calculated logarithm of the odds score of 4.13 at marker DXS8057 was much higher than in the previous study [2], and additional markers definitely excluded Xq22.2. No other X-linked HSP have been so far assigned to this region, which defines the fourth locus for X-linked HSP. Differently from the other two well-characterized X-linked HSP, SPG1 and SPG2 [4, 5], SPG34 is not associated to mental retardation. Evidences for the SPG16 [6] locus, located in a large region at Xq11.2–q23 overlapping SPG2 locus, are weaker and based only in two small families. In short, we identified in a large multigenerational family with pure spastic paraplegia a new locus (named SPG34) at Xq25 for an X-linked pure form of HSP, with onset in the Neurogenetics (2008) 9:225–226 DOI 10.1007/s10048-008-0130-8