Rachel Sayuri Honjo

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.

Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome

Silver–Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth retardation in association with a typical small triangular face and other variable features. Genetic and epigenetic disturbances are detected in about 50% of the patients. Most frequently, SRS is caused by altered gene expression on chromosome 11p15 due to hypomethylation of the telomeric imprinting center (ICR1) that is present in at least 40% of the patients. Maternally inherited duplications encompassing ICR1 and ICR2 domains at 11p15 were found in a few patients, and a microduplication restricted to ICR2 was described in a single SRS child. We report on a microduplication of the ICR2 domain encompassing the KCNQ1, KCNQ1OT1, and CDKN1C genes in a three‐generation family: there were four instances of paternal transmissions of the microduplication from a single male uniformly resulting in normal offspring, and five maternal transmissions, via two clinically normal sisters, with all the children exhibiting SRS. This report provides confirmatory evidence that a microduplication restricted to the ICR2 domain results in SRS when maternally transmitted.

A Known SOST Gene Mutation Causes Sclerosteosis in a Familial and an Isolated Case from Brazilian Origin

Sclerosteosis is a severe, rare, autosomal recessive bone condition that is characterized by a progressive craniotubular hyperostosis. The main features are a significant sclerosis of the long bones, ribs, pelvis, and skull, leading to facial distortion and entrapment of cranial nerves. Clinical features include a tall stature, nail dysplasia, cutaneous syndactyly of some fingers, and raised intracranial pressure. The sclerosteosis gene has been mapped to chromosome 17q12-21 and is currently known as the SOST gene encoding the sclerostin protein. Here, we report on one familial and one isolated case of Brazilian origin with the clinical and molecular diagnosis of sclerosteosis. The radiological and clinical features are described, and the diagnosis of sclerosteosis was confirmed in both cases by mutation analysis of the SOST gene showing a homozygous nonsense mutation (Trp124X) in the two patients. We reported this mutation previously in other sclerosteosis patients from a consanguineous Brazilian family. Interestingly, all three families were from the same state in Brazil, but they denied familial relationship. These patients confirm the clinical picture as found in other cases with a loss of function mutation in the SOST gene.

Mutations, Clinical Findings and Survival Estimates in South American Patients with X-Linked Adrenoleukodystrophy

In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. Methods X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. Results We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1–12.7) and 24.7 (19.8–29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. Conclusions This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

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.

Copy number variation in Williams-Beuren syndrome: suitable diagnostic strategy for developing countries

BackgroundWilliams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis (SVAS), mental retardation, and overfriendliness comprise typical symptoms of WBS. Although fluorescence in situ hybridization (FISH) is considered the gold standard technique, the microsatellite DNA markers and multiplex ligation-dependent probe amplification (MLPA) could be used for to confirm the diagnosis of WBS.ResultsWe have evaluated a total cohort of 88 patients with a suspicion clinical diagnosis of WBS using a collection of five markers (D7S1870, D7S489, D7S613, D7S2476, and D7S489_A) and a commercial MLPA kit (P029). The microdeletion was present in 64 (72.7%) patients and absent in 24 (27.3%) patients. The parental origin of deletion was maternal in 36 of 64 patients (56.3%) paternal in 28 of 64 patients (43.7%). The deletion size was 1.55 Mb in 57 of 64 patients (89.1%) and 1.84 Mb in 7 of 64 patients (10.9%). The results were concordant using both techniques, except for four patients whose microsatellite markers were uninformative. There were no clinical differences in relation to either the size or parental origin of the deletion.ConclusionMLPA was considered a faster and more economical method in a single assay, whereas the microsatellite markers could determine both the size and parental origin of the deletion in WBS. The microsatellite marker and MLPA techniques are effective in deletion detection in WBS, and both methods provide a useful diagnostic strategy mainly for developing countries.

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

INTRODUCTION: Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis, mental retardation, overfriendliness, and ocular and renal abnormalities comprise typical symptoms in WBS. Although fluorescence in situ hybridization is widely used for diagnostic confirmation, microsatellite DNA markers are considered highly informative and easily manageable. OBJECTIVES: This study aimed to test the microsatellite markers for the diagnosis of Williams-Beuren syndrome, to determine the size and parental origin of microdeletion, compare the clinical characteristics between patients with different sizes of the deletion and parental origin. METHODS: We studied 97 patients with clinical diagnosis of Williams-Beuren syndrome using five microsatellite markers: D7S1870, D7S489, D7S613, D7S2476 and D7S489_A. RESULTS AND DISCUSSION: Using five markers together, the result was informative in all patients. The most informative marker was D7S1870 (78.4%), followed by D7S613 (75.3%), D7S489 (70.1%) and D7S2476 (62.9%). The microdeletion was present in 84 (86.6%) patients and absent in 13 (13.4%) patients. Maternal deletions were found in 52.4% of patients and paternal deletions in 47.6% of patients. The observed size of deletions was 1.55 Mb in 76/84 patients (90.5%) and 1.84 Mb in 8/84 patients (9.5%). SVAS as well as ocular and urinary abnormalities were more frequent in the patients with a deletion. There were no clinical differences in relation to either the size or parental origin of the deletion. CONCLUSION: Using these five selected microsatellite markers was informative in all patients, thus can be considered an alternative method for molecular diagnosis in Williams-Beuren syndrome.

Schinzel-Giedion Syndrome in Two Brazilian Patients: Report of a Novel Mutation in SETBP1 and Literature Review of the Clinical Features

Schinzel–Giedion syndrome is a rare autosomal dominant disorder comprising postnatal growth failure, profound developmental delay, seizures, facial dysmorphisms, genitourinary, skeletal, neurological, and cardiac defects. It was recently revealed that Schinzel–Giedion syndrome is caused by de novo mutations in SETBP1, but there are few reports of this syndrome with molecular confirmation. We describe two unrelated Brazilian patients with Schinzel–Giedion syndrome, one of them carrying a novel mutation. We also present a review of clinical manifestations of the syndrome, comparing our cases to patients reported in literature emphasizing the importance of the facial gestalt associated with neurological involvement for diagnostic suspicion of this syndrome.

Proteus syndrome: report of a case with recurrent abdominal lipomatosis

Proteus syndrome (PS) is an extremely rare congenital hamartomatous syndrome that was first delineated by Cohen and Hayden (1). The estimated prevalence is less than 1 per 1,000,000 live births (2). It is a sporadic disorder that causes overgrowth of multiple tissues, especially bone, fat, and other connective tissues in a patchy or mosaic pattern. Subcutaneous as well as internal lipomas that may grow to an enormous size are frequently observed. Nevertheless, among the internal lipomas, abdominal lipomatosis is rare (3), with less than 15 cases reported. Herein, we report the first patient described with this distinctive syndrome associated with lipomatosis involving the epiploon.

Dental Evaluation of Kabuki Syndrome Patients

Kabuki syndrome is a genetic disorder of unknown etiology characterized by mental retardation, growth deficiency, and peculiar face (i.e., long palpebral fissures, eversion of the lateral third of the lower eyelids, prominent ears, and broad and depressed nasal tip). Oral manifestations commonly observed in Kabuki syndrome may comprise cleft lip/palate, bifid tongue and uvula, malocclusion, and dental abnormalities. We evaluated the dental findings of eight patients with Kabuki syndrome. One presented cleft palate; three presented caries; and seven had missing teeth, with the upper lateral incisors and inferior central incisors being the most commonly absent. All missing teeth were permanent, and there was no alteration of dental chronology or morphology. Because most patients had mixed dentition, the presence or absence of primary teeth was assessed through the parents’ reports. One patient presented an absent upper canine, which had not been reported previously in the literature. Dental findings may be helpful for clinical diagnosis, or they may be an additional finding to substantiate the diagnosis of Kabuki syndrome in children with mild phenotype.