Márcia Gonçalves Ribeiro

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.

Clinical and epidemiological studies of amniotic deformity, adhesion, and mutilation (ADAM) sequence in a South American (ECLAMC) population.

Amniotic deformity, adhesion, and mutilation (ADAM) sequence is a heterogeneous condition, with a broad spectrum of anomalies, where intrinsic causes, as defect of germ plasm, vascular disruption, and disturbance of threshold boundaries of morphogens during early gastrulation, alternate with extrinsic causes as amniotic band rupture to explain the condition. This study aimed to identify which phenotypes could be considered as ADAM sequence, determine the prevalence rate, and disclose risk factors for this sequence. We identified 270 cases defined as having some skin evidence of constriction band, plus those having limb defects suggestive of ADAM sequence, among 3,020,896 live and stillborns in the years 1982 to 1998 in ECLAMC (Latin American Collaborative Study of Congenital Malformations). Half of the cases presented mutilation (reduction), and deformity (ring constriction) affecting distal parts of fingers or toes bilaterally, without associated defects. Acrania, cephalocele, typical or atypical facial clefts, eyelid coloboma, and celosomia were also observed being significantly associated with the skin lesion. One affected infant in every 11,200 births, was found with stable trends during the last 17 years. There was an excess of cases in populations living at high altitude, stillborns, and neonatal infant dead. Among ADAM cases there was an excess of mothers with a prenatal history of febrile acute illness, medication drug use, or vaginal bleeding during the first trimester of pregnancy. Higher than expected frequencies of first‐born child, premature birth, low birth weight for gestational length, and non‐cephalic fetal presentation were also found. The observed geographic difference in birth prevalence could be a useful indication to study specific genetic and environmental candidate factors to ADAM susceptibility.

Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis?

Mucopolysaccharidoses (MPS) form a group of inherited metabolic disorders characterized by intralysosomal storage of glycosaminoglycans. This study aimed to investigate the path followed by Brazilian patients from birth to diagnosis. An interview was conducted with patients parents or guardians with subsequent review of patients medical records. One hundred thirteen patients with MPS were included (MPS I: 18, MPS II: 43, MPS IIIA: 2, MPS IIIB: 3, MPS IIIC: 1, MPS IVA: 15, MPS IVB: 1, MPS VI: 29, MPS VII: 1) from 97 families. Median age at the onset of signs/symptoms was 18 months (MPS I: 18, MPS II: 24, MPS IVA: 8, MPS VI: 8). Skeletal abnormalities (for MPS IVA and MPS VI), joint contractures (for MPS II), and typical facial features (for MPS I) were the most frequently reported first signs/symptoms. Several health professionals were involved in patients care as of the onset of symptoms until biochemical diagnosis was established. Median age at diagnosis was 76 months (MPS I: 75, MPS II: 95, MPS IVA: 75, MPS VI: 52). Considering the group as a whole, there was a 4.8‐year delay between the onset of signs/symptoms and the establishment of the diagnosis. Considering that specific therapies are available for some of these disorders and that early treatment is likely to change more favorably the natural history of the disease, efforts should be made to minimize this delay. We believe that this situation can be improved by measures that both increase awareness of health professionals about MPS and improve access to diagnostic tests.

A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay

Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, speech delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.

Insulin resistance in adolescents with Down syndrome: a cross-sectional study

BackgroundThe prevalence of diabetes mellitus is higher in individuals with Down syndrome (DS) than in the general population; it may be due to the high prevalence of obesity presented by many of them. The aim of this study was to evaluate the insulin resistance (IR) using the HOMA (Homeostasis Model Assessment) method, in DS adolescents, describing it according to the sex, body mass index (BMI) and pubertal development.Methods15 adolescents with DS (8 males and 7 females) were studied, aged 10 to 18 years, without history of disease or use of medication that could change the suggested laboratory evaluation. On physical examination, the pubertal signs, acanthosis nigricans (AN), weight and height were evaluated. Fasting plasma glucose and insulin were analysed by the colorimetric method and RIA-kit LINCO, respectively. IR was calculated using the HOMA method. The patients were grouped into obese, overweight and normal, according to their BMI percentiles. The EPIINFO 2004 software was used to calculate the BMI, its percentile and Z score.ResultsFive patients were adults (Tanner V or presence of menarche), 9 pubertal (Tanner II – IV) and 1 prepubertal (Tanner I). No one had AN. Two were obese, 4 overweight and 9 normal. Considering the total number of patients, HOMA was 1.7 ± 1.0, insulin 9.3 ± 4.8 μU/ml and glucose 74.4 ± 14.8 mg/dl. The HOMA values were 2.0 ± 1.0 in females and 1.5 ± 1.0 in males. Considering the nutritional classification, the values of HOMA and insulin were: HOMA: 3.3 ± 0.6, 2.0 ± 1.1 and 1.3 ± 0.6, and insulin: 18.15 ± 1.6 μU/ml, 10.3 ± 3.5 μU/ml and 6.8 ± 2.8 μU/ml, in the obese, overweight and normal groups respectively. Considering puberty, the values of HOMA and insulin were: HOMA: 2.5 ± 1.3, 1.4 ± 0.6 and 0.8 ± 0.0, and insulin: 13.0 ± 5.8 μU/ml, 7.8 ± 2.9 μU/ml and 4.0 ± 0.0 μU/ml, in the adult, pubertal and prepubertal groups respectively.ConclusionThe obese and overweight, female and adult patients showed the highest values of HOMA and insulin.

Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli–Seip congenital generalized lipodystrophy syndrome

Context  Congenital generalized lipodystrophy, or Berardinelli–Seip syndrome, is a rare autosomal recessive disease caused by mutations in either the BSCL2 or AGPAT2 genes. This syndrome is characterized by an almost complete loss of adipose tissue usually diagnosed at birth or early infancy resulting in apparent muscle hypertrophy. Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present.

Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.

O retardo mental na distrofia muscular de Duchenne

OBJETIVO: Fazer um levantamento da literatura medica destinada ao estudo das disfuncoes cognitivas nos pacientes com distrofia muscular de Duchenne, atraves da descricao dos marcos do desenvolvimento neuropsicomotor e dos testes psicometricos para quantificacao da inteligencia. FONTES DOS DADOS: Revisao nao sistematica sobre os aspectos da cognicao na distrofia muscular de Duchenne nas principais bases medicas cientificas: MEDLINE, LILACS, Biblioteca Cochrane e SciELO. SINTESE DOS DADOS: Os pacientes com distrofia muscular de Duchenne apresentaram atraso para marcha e desenvolvimento da linguagem, os quais se correlacionaram a menores pontuacoes nos testes de inteligencia no futuro. Ha marcante disfuncao nos subtestes das habilidades verbais. CONCLUSOES: A media do coeficiente de inteligencia encontra-se com um desvio padrao abaixo da media populacional. Quanto maior a disfuncao cognitiva, piores serao os aspectos relacionados a morbidade e mortalidade na doenca.OBJECTIVE To survey the medical literature directed to the study of cognitive dysfunction in patients with Duchenne muscular dystrophy through description of the milestones of neurological development and psychometric tests for quantifying intelligence. SOURCES Non-systematic review of aspects of cognition in Duchenne muscular dystrophy in the major medical scientific bases: MEDLINE, LILACS, SciELO and Cochrane Library. SUMMARY OF THE FINDINGS Patients with Duchenne muscular dystrophy exhibited delay in walking and language development, which correlated with lower scores on future intelligence tests. There is marked impairment in the verbal subtests. CONCLUSIONS Average IQ has standard deviation below the average of the population. The greater the cognitive impairment, the worse aspects related to morbidity and mortality in the disease will be.

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.