Eugênia Ribeiro Valadares

A clinical study of 77 patients with mucopolysaccharidosis type II

Aim: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II).

Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI

This paper presents data collected by a Brazilian center in a multinational multicenter observational study of patients with mucopolysaccharidosis type VI (MPS VI), aiming at determining the epidemiological, clinical, and biochemical profile of these patients. Twenty‐eight south‐American patients with MPS VI were evaluated through medical interview, physical exam, echocardiogram, electrocardiogram, ophthalmologic evaluation, quantification of glycosaminoglycans (GAGs) in urine, and measurement of the activity of N‐acetylgalactosamine‐4‐sulfatase (ARSB) in leukocytes. 92.9% of patients were Brazilian. Mean age at diagnosis and at evaluation was 48.4 months and 97.1 months, respectively. 88% of patients had onset of symptomatology before the age of 36 months. Consanguinity was reported by 27% of the families. Mean weight and height at birth were 3.481 kg and 51.3 cm, respectively. The most frequently reported clinical manifestations were short stature, corneal clouding, coarse facial features, joint contractures, and claw hands. All patients presented with echocardiogram changes as well as corneal clouding. Mean ARSB activity in leukocytes was 5.4 nmoles/h/mg protein (reference values: 72–174), and urinary excretion of GAGs was on average 7.9 times higher than normal. The number of clinical manifestations did not show a significant correlation with the levels of urinary GAGs nor with the ARSB activity. Also, no significant correlation was found between the levels of urinary GAGs and the ARSB activity. It was concluded that MPS VI has high morbidity and that, when compared with data published in the literature, patients in our study were diagnosed later and presented with a higher frequency of cardiological findings.

Guidelines for the Management of Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is the prototype of the MPS disorders, a subgroup of lysosomal storage diseases. The incidence of MPS I in Brazil is unknown, but a retrospective population study in Australia conducted between 1980 and 1996 yielded an overall prevalence of 1 in 22 500 for all MPS types. 1 In British Columbia, cases ascertained between 1952 and 1986 determined that the frequency of MPS type I Hurler, the most severe form of the disease, was approximately 1 in 144 000 newborns, 2 a result similar to that found in The Netherlands. 3 A recent analysis of data collected by the Society for Mucopolysaccharides in the United Kingdom in patients with MPS I found a prevalence of 1.07 per 100 000 births. 4 MPS I is characterized by a deficiency in a-L-iduronidase enzyme activity, leading to buildup and urinary excretion of high levels of glycosaminoglycans (GAGs), specifically dermatan and heparan sulfates. The disease is genetically determined and shows autosomal recessive inheritance. 5,6 MPS

A dose-optimization trial of laronidase (Aldurazyme®) in patients with mucopolysaccharidosis I

Recombinant human alpha-l-iduronidase (Aldurazyme), laronidase) is approved as an enzyme replacement therapy to treat the lysosomal storage disorder, mucopolysaccharidosis type I (MPS I) at a dose of 0.58 mg/kg by once-weekly intravenous infusion. To assess whether alternate dosing regimens might provide a better reduction in lysosomal storage, a 26-week, randomized, open-label, multinational dose-optimization trial was conducted. The pharmacodynamic effect and safety of the approved laronidase dose was compared to three alternative regimens (1.2mg/kg every 2 weeks; 1.2mg/kg every week; 1.8 mg/kg every 2 weeks) among 33 MPS I patients. The four treatment regimens showed no significant differences in the reduction of urinary glycosaminoglycan excretion or liver volume. Laronidase had an acceptable safety profile in all dose regimen groups. Infusion-associated reactions were the most common drug-related adverse events across dose regimens (by patient incidence), and included pyrexia (21%), vomiting (15%), rash (15%), and urticaria (12%). Patients in the approved dose group had the lowest incidence of drug-related adverse events (38% vs. 63-75%) and infusion-associated reactions (25% vs. 25-63%). There was one death: a patient with acute bronchitis died of respiratory failure 6h after completing the first laronidase infusion. The approved 0.58 mg/kg/week laronidase dose regimen provided near-maximal reductions in glycosaminoglycan storage and the best benefit-to-risk ratio. The 1.2mg/kg every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions, but the long-term effects of this regimen are unknown.

What is new in genetics and osteogenesis imperfecta classification

OBJECTIVE Literature review of new genes related to osteogenesis imperfecta (OI) and update of its classification. SOURCES Literature review in the PubMed and OMIM databases, followed by selection of relevant references. SUMMARY OF THE FINDINGS In 1979, Sillence et al. developed a classification of OI subtypes based on clinical features and disease severity: OI type I, mild, common, with blue sclera; OI type II, perinatal lethal form; OI type III, severe and progressively deforming, with normal sclera; and OI type IV, moderate severity with normal sclera. Approximately 90% of individuals with OI are heterozygous for mutations in the COL1A1 and COL1A2 genes, with dominant pattern of inheritance or sporadic mutations. After 2006, mutations were identified in the CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, and TMEM38B genes, associated with recessive OI and mutation in the IFITM5 gene associated with dominant OI. Mutations in PLS3 were recently identified in families with osteoporosis and fractures, with X-linked inheritance pattern. In addition to the genetic complexity of the molecular basis of OI, extensive phenotypic variability resulting from individual loci has also been documented. CONCLUSIONS Considering the discovery of new genes and limited genotype-phenotype correlation, the use of next-generation sequencing tools has become useful in molecular studies of OI cases. The recommendation of the Nosology Group of the International Society of Skeletal Dysplasias is to maintain the classification of Sillence as the prototypical form, universally accepted to classify the degree of severity in OI, while maintaining it free from direct molecular reference.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80s treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90s, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.As mucopolissacaridoses (MPS) sao doencas geneticas raras causadas pela deficiencia de enzimas lisossomicas especificas que afetam o catabolismo de glicosaminoglicanos (GAG). O acumulo de GAG em varios orgaos e tecidos nos pacientes afetados pelas MPS resulta em uma serie de sinais e sintomas, integrantes de um quadro clinico multissistemico que compromete ossos e articulacoes, vias respiratorias, sistema cardiovascular e muitos outros orgaos e tecidos, incluindo, em alguns casos, as funcoes cognitivas. Ja foram identificados 11 defeitos enzimaticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauracao da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevencao e o cuidado das complicacoes, aspecto ainda bastante importante no manejo desses pacientes. Na decada de 80 foi proposto o tratamento das MPS com transplante de medula ossea/transplante de celulas tronco hematopoieticas (TMO/TCTH) e na decada de 90 comecou o desenvolvimento da Terapia de Reposicao Enzimatica (TRE), que se tornou uma realidade aprovada para uso clinico nas MPS I, II e VI na primeira decada do seculo 21. Os autores deste trabalho tem a conviccao de que um melhor futuro para os pacientes afetados pelas MPS depende da identificacao, compreensao e manejo adequado das manifestacoes multissistemicas dessas doencas, incluindo medidas de suporte (que devem fazer parte da assistencia multidisciplinar regular destes pacientes) e terapias especificas. Embora a inibicao da sintese de GAG e o resgate da atividade enzimatica com moleculas pequenas tambem possam vir a ter um papel no manejo das MPS, o grande avanco disponivel no momento e a TRE intravenosa. A TRE permitiu modificar radicalmente o panorama do tratamento das mucopolissacaridoses I, II e VI na ultima decada, sendo que ainda pode estender seus beneficios em breve para a MPS IV A (cuja TRE ja esta em desenvolvimento clinico), com perspectivas para o tratamento da MPS III A e do deficit cognitivo na MPS II atraves de administracao da enzima diretamente no sistema nervoso central (SNC). Um grande numero de centros brasileiros, incluindo servicos de todas as regioes do pais, ja tem experiencia com TRE para MPS I, II e VI. Essa experiencia foi adquirida nao so com o tratamento de pacientes como tambem com a participacao de alguns grupos em ensaios clinicos envolvendo TRE para essas condicoes. Somados os tres tipos de MPS, mais de 250 pacientes ja foram tratados com TRE em nosso pais. A experiencia dos profissionais brasileiros, somada aos dados disponiveis na literatura internacional, permitiu elaborar este documento, produzido com o objetivo de reunir e harmonizar as informacoes disponiveis sobre o tratamento destas doencas graves e progressivas, mas que, felizmente, sao hoje trataveis, uma realidade que traz novas perspectivas para os pacientes brasileiros afetados por essas condicoes.

Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene.

UNLABELLED Mucolipidosis II and III (MLII and MLIII) alpha/beta are rare autosomal recessive lysosomal storage diseases (LSDs) caused by pathogenic variations in the GNPTAB gene. GNPTAB gene codes for the α and β subunits of phosphotransferase, the enzyme responsible for synthesis of the mannose-6-phosphate (M6P) marker that directs lysosomal enzymes to the lysosome. OBJECTIVES The objective of this study is to identify sequence variations of the GNPTAB gene in Brazilian patients with MLII and MLIII alpha/beta. METHOD Sequencing of the GNPTAB gene was performed in samples of gDNA extracted from the peripheral blood of patients with MLII/III diagnosed at a national reference center for LSDs. RESULTS Twelve unrelated patients, from several regions of Brazil, were included in this study. Only one was born of consanguineous parents. All patients were found to carry at least one nonpathogenic variation. Nine causal sequence variations were found: c.242G>T (p.W81L); c.1123C>T (p.R375X); c.1196C>T (p.S399F); c.1208T>C (p.I403T); c.1514G>A (p.C505Y); c.1759C>T (p.R587X); c.2808A>G (p.Y937_M972del, novel mutation); c. 2269_2273delGAAAC (p.E757KfsX2, novel mutation); and c.3503_3504delTC (p.L1168QfsX5). Both pathogenic variations were identified in 8 of 12 patients; in four patients, only one pathogenic variation was identified. Mutation c.3503_3504delTC, located in exon 19, was the most frequent pathogenic variation found (n=11/24 alleles). The deleterious effect of the c.2808A>C mutation on splicing was confirmed by cDNA analysis. DISCUSSION/CONCLUSIONS Our findings confirm that the GNPTAB gene presents broad allelic heterogeneity and suggests that, in Brazilian ML II and III patients, screening for mutations should begin at exon 19 of the GNPTAB gene. Further analyses will be conducted on patients in whom both pathogenic mutations have not been found in this study.

Neurofibromatoses: part 1 ? diagnosis and differential diagnosis

Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management.

Tratamento da doença de Gaucher: um consenso brasileiro

A doenca de Gaucher (DG) e um erro inato do metabolismo do grupo das doencas lisossomicas de deposito, sendo a mais frequente do referido grupo. E de heranca autossomica recessiva, portanto com risco de 25% a cada gestacao de casal heterozigoto. A doenca e resultante da deficiencia da beta-glicosidase acida ou beta-glicocerebrosidase, que leva ao acumulo de glicolipidios nos macrofagos principalmente em baco, figado, medula ossea e pulmao. As manifestacoes clinicas ou fenotipicas da DG vao depender do grau de deficiencia da enzima, existindo tres tipos: Tipo I, forma nao neuropatica, afeta criancas e adultos com hepatoesplenomegalia, anemia, trombocitopenia, leucopenia e lesoes osseas; Tipo II, forma neuropatica aguda, afeta criancas com 4-5 meses com quadro neurologico grave, hepatoesplenomegalia e comprometimento pulmonar e o Tipo III, forma neuropatica cronica, afeta criancas e adolescentes com quadro neurologico menos grave que o Tipo II e ainda pode comprometer figado, baco e ossos. Um grupo de catorze medicos com experiencia no tratamento da DG com reposicao enzimatica realizaram extensa revisao da literatura, confrontaram com os dados evolutivos dos pacientes brasileiros e chegaram a um consenso quanto aos criterios para iniciar o tratamento, a dose da enzima e frequencia das infusoes, do acompanhamento ambulatorial, laboratorial e radiologico. O Grupo Brasileiro de Estudos em Doenca de Gaucher e outras Doencas de Deposito Lisossomico (GBDDL) tem o objetivo de estabelecer diretrizes para o diagnostico, tratamento e acompanhamento de pacientes com doenca de Gaucher no Brasil. Esta iniciativa pioneira visa uniformizar a conduta no pais com relacao ao tratamento de DG com reposicao enzimatica, tratamento de alto custo porem de grande eficacia.

Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia†

Spondylo‐megaepiphyseal‐metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox‐containing gene, NKX3‐2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3‐2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round “balloon‐like” epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck‐like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.