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The 8p23.1 duplication syndrome is a rare condition, characterized by dysmorphisms, intellectual disability, congenital cardiac anomalies, and autism spectrum disorder (ASD). The current model for explaining the pathogenesis of this condition postulates that few dosage-sensitive genes within the duplication are sufficient for the core clinical features, although the molecular mechanisms leading to the ASD presentation remain to be solved. Herein, we described clinical and cytomolecular findings of an 8p23.1 duplication in a boy with mild facial dysmorphisms, cardiac anomalies and ASD. Therefore, we investigated the influence of duplicated genes on the pathophysiology of ASD in our patient. We identified four duplicated genes (BLK, GATA4, PINX1, TNKS) connected with proteins previously associated with ASD and involved in significant enriched pathways associated with human neurological conditions. Moreover, the candidate genes are highly expressed in brain regions associated to ASD, such as the hippocampus. Taken together, these results point out crucial interactions among BLK, GATA4, PINX1, and TNKS and genes associated with ASD. We indicate cellular networks perturbations encompassing neuronal development pathways related to our patient's condition. Thus, these findings bring new insights into the genetic basis of ASD in patients with 8p23.1 duplication syndrome.

Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of β-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12 ) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.

RESUMO Objetivo: Avaliar a apresentação clínica inicial dos casos com diagnóstico confirmado de erros inatos do metabolismo (EIM) em um serviço de referência em atendimento pediátrico. Métodos: Estudo clínico, observacional, com delineamento transversal e de coleta retrospectiva em consulta ambulatorial de 2009 a 2013. Critério de inclusão: paciente encaminhado para investigação de EIM. Critério de exclusão: diagnóstico prévio de EIM. Variáveis analisadas: dados de identificação; situação atual da investigação diagnóstica; história familiar; apresentação clínica inicial; alterações laboratoriais. Os dados foram analisados por meio de estatística descritiva Resultados: Incluídos 144 pacientes, sendo 62,5% do sexo masculino. A mediana de idade foi de 2,6 anos e a média de 4,3 ± 4,7 anos. Doze pacientes (8,3%) tiveram o diagnóstico confirmado (três com aminoacidopatias, três com acidemias orgânicas, dois com distúrbios do ciclo da ureia e quatro com doenças de depósito lisossômico). Déficit cognitivo e convulsões foram os sinais e sintomas iniciais; seguidos de retardo de crescimento, atraso do desenvolvimento neuropsicomotor, convulsões e hepatomegalia. As principais alterações laboratoriais encontradas foram hiperamonemia e acidose metabólica. Conclusões: O diagnóstico dos EIM ainda traz desafios à prática pediátrica. Neste estudo foram identificados os seguintes fatores: dificuldade de acesso aos exames laboratoriais específicos, reduzido número de especialistas e pouca difusão do conhecimento nas faculdades da área da saúde. O diagnóstico precoce dos EIM tem impacto fundamental no tratamento e prevenção das sequelas, devendo ser considerado já nas hipóteses diagnósticas iniciais. ABSTRACT Objective: To assess the initial clinical presentation of confirmed cases of inborn errors of metabolism (IEM) at a reference facility for pediatric care. Methods: Cross-sectional, observational and descriptive study with data collection of outpatients, from January 2009 to December 2013. Inclusion criterion: referral to IEM investigation. Exclusion criterion: prior diagnosis of IEM. Analyzed variables: identification data; status of diagnostic investigation; family history of IEM; initial clinical presentation, laboratory abnormalities related to the hypothesis of IEM. Descriptive statistical methods were used in the data analysis. Results: We included 144 patients in the study, of which 62.5% were male. The mean and median ages were, respectively, 4.3 ± 4.7 years and 2.6 years. Twelve patients (8.3%) had a confirmed diagnosis of IEM (three with aminoacidopathies, three with organic acidemias, two with urea cycle disorders and four with lysosomal storage diseases). Cognitive impairment and seizures were the initial signs and symptoms, followed by growth retardation, neuropsychomotor developmental delay, seizures and hepatomegaly. The main laboratory abnormalities in the diagnosis were hyperammonemia and metabolic acidosis. Conclusions: The diagnosis of IEM still creates challenges to the pediatric practice. In this study, we identified the following factors: difficulty to access specific laboratory tests, reduced number of experts and poor dissemination of knowledge among healthcare schools. The early diagnosis of IEM majorly impacts the treatment and prevention of sequelae and should be considered in the initial diagnostic hypotheses.

Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

Background The literature suggests that inflammatory bowel disease (IBD) activity during the periconceptional period is a risk factor for active disease during pregnancy. This study aims to evaluate if there is influence of IBD characteristics (type, classification, duration, activity in the periconceptional period, severity and treatment of disease) on the frequency of active disease during pregnancy and postpartum. Methods Retrospective study that included pregnant women followed in Maternal-Fetal Medicine department at Hospital de Santa Maria diagnosed with IBD, with information on ≥2 of the referred variables and delivery between March 2012 and July 2018 (n = 37; 24 Crohn’s disease, CD and 13 ulcerative colitis, UC). The statistical tests used were chi-square and Fisher’s exact test. Results There was no statistically significant difference between CD and CU in the activity of IBD during pregnancy and postpartum. Diagnosis >5 years and >10 years ago was associated with lower frequency of active disease during pregnancy (15% vs. 78.6%, p < 0.005 and 8.3% vs. 59.1%, p = 0.009, respectively), but did not influence postpartum activity. Age at diagnosis (≤16 years or 17–40 years) did not appear to influence IBD activity. IBD activity during the periconceptional period and pregnancy had a statistically significant association (72.7% with active disease during the periconceptional period and pregnancy and 26.1% with quiescent IBD at the time of conception but active during pregnancy, p = 0.023). There were 3 cases of IBD remission during pregnancy (2 CD and 1 UC). Of the 15 cases of active disease during pregnancy, 6 of them (40%; 4 with CD and 2 with UC) were reactivations. 3 women had active IBD during the postpartum period and all of them already had active disease during pregnancy. Regarding severity, all cases of active IBD were classified as mild disease. The type of therapy (biological, corticosteroids, thiopurines, salicylates, antibiotics or lack of therapy) was not related to disease activity during pregnancy or postpartum. Prior bowel surgery related to IBD (n = 7, all with CD) was associated with a lower frequency of active disease during pregnancy (0% vs. 51.7%, p = 0.027). Conclusion The diagnosis of IBD for more than 5 or 10 years and previous bowel surgery were associated with a lower frequency of active disease during pregnancy. There was a relationship between IBD activity in the periconceptional period and pregnancy, which reinforces the importance of pregnancy planning and prior disease control.

The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity.All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed.Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337TC (p.L446P), c.1466AG (p.N489S) and c.962GA (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183GA, c.-315AG and c.-514CT were present in heterozygosis in 5/17 discordant patients. In addition, c.-183GA and c.-514CT were also present in 10/37 concordant patients.The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.

For some X-linked disorders the expressivity and penetrance in females are almost similar to those ones found in males. For mucopolysaccharidosis type II (MPS II), there are no studies in the literature trying to identify subtle signs and symptoms of this disease in heterozygotes. The objective of this study was to compare heterozygotes and non-heterozygotes for MPS II, in order to test the hypothesis that heterozygotes may present subtle manifestations of the disease. In this observational and transversal study we collected data on 40 Brazilian women with a positive familial history for MPS II that included clinical and physical exam, karyotype, pattern of X-inactivation, iduronate-2-sulfatase (IDS) activity in leukocytes and plasma, urinary glycosaminoglycans levels, computerized tomography scans (CT) of abdomen and spine, and brain magnetic resonance imaging. The Results showed the follow-ing: According to DNA analysis, 22 women were classified as heterozygote and 18 as non-heterozygotes. We did not find any abnormality on physical examination, karyotype, or spine CT. Also the pattern of X-inactivation was not different between the groups. Applying the Bonferroni’s correction, both groups were found to differ only in relation to IDS activity in plasma and in leukocyte, which were lower in heterozygotes. In our investigation we did not find any evidence of subtle clinical manifestations of MPS II in heterozygotes. Our findings suggest there is no relation between the absence of clinical signs in these women and the occurrence of a favorable skewing pattern of X-inactivation.

We report on the first case of a child with a de novo 7q terminal deletion [46,XX,del(7)(q35 → qter)] presenting esophageal stenosis. This cytogenetic abnormality was confirmed by FISH, using subtelomeric probes, and by a whole-genome array-CGH assay. The child also had phenotypic features previously described in patients with a similar deletion, as growth retardation, microcephaly, coloboma of papilla, ptosis, hearing loss, urinary tract anomalies, partial agenesis of sacrum, hypotonia and neuropsychomotor delay. The odontoid hypoplasia identified, in similarity with the esophageal stenosis, represents an uncommon finding. This report is also the first clinical description of a patient with an abnormality involving the sonic hedgehog gene and an esophageal alteration. It is discussed the possibility of a specific association between them, according to some results observed in studies with animal models.

BACKGROUND AND PURPOSE: There are no reliable markers to predict neurologic outcome of patients with mucopolysaccharidosis (MPS) II. We hypothesized that brain MR imaging and MR spectroscopy are useful in depicting features related to cognitive impairment (CI) in MPS II. MATERIALS AND METHODS: Nineteen male patients with MPS II were included in this study. They were evaluated through intelligence/developmental tests to be classified in 2 groups: patients with CI (group A) or patients without CI (group B). Brain MR imaging evaluated white matter (WM) lesions, hydrocephalus, and brain atrophy. Voxels from MR spectroscopy (point-resolved spectroscopy TE 30 ms) were positioned in the WM of the deep right frontal lobe and at the gray matter (GM) in the posterior occipital cortex across the midline. Comparison of MR imaging and MR spectroscopy findings between these 2 groups and a control group was performed. RESULTS: The mean age of the patients was 9.6 years (group A, 7.08 years old, 12 patients; group B, 14 years old, 7 patients; P = .076). Brain atrophy and hydrocephalus were more frequently found in group A patients ( P = .006 and P = .029, respectively); these patients also presented more severe WM lesions than patients from group B ( P = .022). Patients from group A also had a higher myo-inositol (mIns)/creatine (Cr) ratio in the GM ( P = .046) and in the WM ( P = .032). The choline/Cr and N- acetylaspartate/Cr ratios were similar in both groups. CONCLUSIONS: Our study showed that severe WM lesions, brain atrophy, hydrocephalus, and elevated mIns/Cr were more common in patients with MPS II and with CI.

OBJETIVO: Avaliar a progressao da mucopolissacaridose II, durante um periodo de 12 meses, em 11 pacientes brasileiros. METODOS: Onze pacientes brasileiros com mucopolissacaridose II foram avaliados prospectivamente no Servico de Genetica Medica do Hospital de Clinicas de Porto Alegre. As avaliacoes realizadas na visita inicial e na de 12 meses foram: anamnese, exame fisico, ressonância nuclear magnetica abdominal, ecocardiograma, teste da caminhada em 6 minutos, audiometria, exames bioquimicos sericos e dosagem urina- ria de glicosaminoglicanos. RESULTADOS: Os principais achados relativos a comparacao entre as duas visitas foram: 1) dois pacientes apresentaram retardo de crescimento; 2) dois pacientes apresentaram variacao negativa em relacao ao peso; 3) um paciente apresentou variacao de obesidade para sobrepeso; 4) tres pacientes desenvolveram alargamento do ventriculo esquerdo; destes, dois aumentaram o numero de lesoes nas valvas cardiacas; 5) nao foi encontrada diferenca estatistica significativa entre a media das distâncias percorridas no teste da caminhada em 6 minutos; 6) houve aumento do volume esplenico; 7) ocorreu aumento dos niveis de gamaglutamiltransferase; 8) nao houve alteracao dos niveis urinarios de glicosaminoglicanos. CONCLUSOES: De uma maneira geral, a unica variavel que apresentou, no periodo estudado, piora com potencial repercussao clinica imediata foram os achados ecocardiograficos. Embora o periodo de 12 meses seja curto para medir alteracoes na maioria dos parâmetros comprometidos na mucopolissacaridose II, sua natureza progressiva deve ser levada em conta na avaliacao da eficacia dos protocolos de tratamento para essa condicao.

Introduction The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. Methods All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. Results Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients. Conclusions The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.

Background: Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase activity, however, may be artifactually low due to enzyme lability, premature birth, and jaundice; this hinders both phenotypic classification and the decision to implement therapy. This study sought to characterize the clinical and genetic profile of a sample of Brazilian patients exhibiting reduced biotinidase activity. Methods: This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene. Results: The sample comprised 38 individuals with biochemical phenotypes defined a priori on the basis of biotinidase activity in serum/plasma (2 with profound deficiency, 9 with partial deficiency, 15 heterozygous, 1 borderline between partial deficiency and heterozygosity, 2 borderline between heterozygous and normal) or dried blood spot sample (n = 9, all with unspecified deficiency). Most patients were from Southern Brazil (n = 29/38) and were identified by neonatal screening (n = 33/38). Parental consanguinity was reported in two cases. The most commonly found genetic variants were c.1330G > C (p.D444H), c.755A > G (p.D252G), and c.[511G > A;1330G > C] (p.[A171T;D444H]), with allele frequencies of 50%, 9.4%, and 5.4% respectively. Three novel pathogenic variants were identified (c.119 T > C or p.L40P, c.479G > A or p.C160Y, and c.664G > A or p.D222N). Twenty-nine patients had two pathogenic variants detected (with cis/trans status ascertained in 26/29), six had only one variant, and three had no pathogenic variants detected. Genotyping confirmed the original phenotypic classification based on enzyme activity in 16/26 cases. Three polymorphic variants were identified in control individuals, of which two were nonpathogenic (c.1171C > T or p.P391S and c.1413 T > C or p.C471C, with a frequency of 1.5% and 5.5% respectively) and one pathogenic (c.1330G > C, frequency 4%). Conclusions: Our findings suggest that partial BD is the most common form of BD in Brazil, and expand current knowledge on the allelic heterogeneity of this condition.

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, inherited disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. As a result of this deficiency, glycosaminoglycans accumulate in lysosomes in many tissues, leading to progressive multisystemic disease. The cardiopulmonary and neurological problems associated with MPS II have received considerable attention. Orthopedic manifestations are common but not as well characterized. This study aimed to characterize the prevalence and severity of orthopedic manifestations of MPS II and to determine the relationship of these signs and symptoms with cardiovascular, pulmonary and central nervous system involvement. Orthopedic manifestations of MPS II were studied using cross-sectional data from the Hunter Outcome Survey (HOS). The HOS is a global, physician-led, multicenter observational database that collects information on the natural history of MPS II and the long-term safety and effectiveness of enzyme replacement therapy. As of January 2009, the HOS contained baseline data on joint range of motion in 124 males with MPS II. In total, 79% of patients had skeletal manifestations (median onset, 3.5 years) and 25% had abnormal gait (median onset, 5.4 years). Joint range of motion was restricted for all joints assessed (elbow, shoulder, hip, knee and ankle). Extension was the most severely affected movement: the exception to this was the shoulder. Surgery for orthopedic problems was rare. The presence of orthopedic manifestations was associated with the presence of central nervous system and pulmonary involvement, but not so clearly with cardiovascular involvement. Orthopedic interventions should be considered on an individual-patient basis. Although some orthopedic manifestations associated with MPS II may be managed routinely, a good knowledge of other concurrent organ system involvement is essential. A multidisciplinary approach is required.

Most lysosomal diseases (LD) are inherited as autosomal recessive traits, but two important conditions have X-linked inheritance: Fabry disease and Mucopolysaccharidosis II (MPS II). These two diseases show a very different pattern regarding expression on heterozygotes, which does not seem to be explained by the X-inactivation mechanism only. While MPS II heterozygotes are asymptomatic in most instances, in Fabry disease most of female carriers show some disease manifestation, which is sometimes severe. It is known that there is a major difference among X-linked diseases depending on the cell autonomy of the gene product involved and, therefore, on the occurrence of cross-correction. Since lysosomal enzymes are usually secreted and uptaken by neighbor cells, the different findings between MPS II and Fabry disease heterozygotes can also be due to different efficiency of cross-correction (higher in MPS II and lower in Fabry disease). In this paper, we review these two X-linked LD in order to discuss the mechanisms that could explain the different rates of penetrance and expressivity observed in the heterozygotes; this could be helpful to better understand the expression of X-linked traits.

Mucopolysaccharidosis VI is caused by accumulation of the glycosaminoglycan dermatan sulfate in all tissues due to decreased activity of the enzyme arylsulfatase B. Patients exhibit multisystemic signs and symptoms in a chronic and progressive manner, especially with changes in the skeleton, cardiopulmonary system, cornea, skin, liver, spleen and meninges. Patients usually have normal intelligence. In the past, treatment of mucopolysaccharidoses was limited to palliative medical care. The outcome for affected patients improved with the introduction of new technologies as hematopoietic stem cell transplantation, relegated to specific situations after enzyme replacement therapy (ERT) became available. The specific ERT for MPS VI, galsulfase (Naglazyme®, Biomarin Pharmaceutical) was approved in 2005 by FDA and in 2006 by EMEA, and three clinical studies including 56 patients have evaluated the efficacy and safety. Long-term follow up data with patients treated up to 5 years showed that ERT is well tolerated and associated with sustained improvements in the patients' clinical condition. Intrathecal ERT may be considered in situations of high neurosurgical risk but still it is experimental in humans, as is intra-articular ERT. It is possible that the full impact of this therapy will only be demonstrated when patients are identified and treated soon after birth, as it was shown that early introduction of ERT produced immune tolerance and improved enzyme effectiveness in the cat model. New insights on the pathophysiology of MPS disorders are leading to alternative therapeutic approaches, as gene therapy, inflammatory response modulators and substrate reduction therapy.

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.

Dystonia is a clinically and genetically heterogeneous disorder of movement characterized by involuntary and sustained muscle contractions and rigid postures affecting one or more sites of the body. It can be classified according to the distribution of affected body parts, age of onset and etiology 1 . Up to now, at least 15 different loci (DYT1–DYT15) have been described in this condition 1,2 . Adult-onset idiopathic torsion dystonia affecting specific parts of the body, such as the eye (blepharospasm), neck (cervical dystonia), and hand (writer’s cramp) has been associated with the DYT7 locus, located in the short arm of chromosome 18 1-3 . Autoimmune diseases have been considered conditions associated with reactions of the immune system against selfantigens or body systems. They are disorders often associated with severe and chronic morbidity. In spite of recent advances, much of their etiology is still unknown 4 . We describe a rare case of a patient with 18p deletion syndrome presenting focal dystonia, Hashimoto thyroiditis, vitiligo and cerebral white matter abnormalities. CaSe The patient is a 30 year old white woman, the fourth child of a non-consanguineous couple, without any history of similar cases in the family. The patient was born full-term, with a Cesarean section, after a pregnancy without intercurrences. During her first year of life, she had several episodes of infection (oti tis and tonsillitis) as well as constipation where laxative use was needed. At 3 months, she had a convulsive crisis during fever. In relation to her neuropsychomotor development, the mother recalls she supported her own head at 6 months and pronounced her first words at the age of three. The patient was also unable to accompany normal school, failing several grades. After a long period without intercurrences, she began with blepharospasm together with cervical dystonia. She presented telarche at the age of 12 and menarche at 13, and at around 20 she began with menstrual irregularity. The hormonal evaluation conducted later diagnosed hypothyroidism due to Hashimoto thyroiditis. During the physical exam at the age of 30, she presented obesity (weighing 70 kg, between the 90–97 percentiles), short stature (149 cm, under the 3 percentile), brachycephaly, but without microcephalia (head circumference of 53 cm – between the 2–50 percentiles), rounded face, ocular hypertelorism (interpupillary distance higher than the 97 percentile), ptosis, blepharospasm, corneal opacification, hypoplasia of the middle third of the face, broad nasal bridge, high palate, short and broad neck, low posterior hairline, broad thorax and accentuated cervical kyphosis (Figs 1A and B). She also had dextroconvex thoracic scoliosis, small hands and feet with hyperconvex nails (Figs 1C and D) and achromic spots of different sizes, spread about the body (thorax, dorsum and members), and vitiligo was diagnosed. The face remained in a fixed position, always turned to the right and downwards (Figs 1A and B). Nuclear magnetic resonance of the skull revealed a dilated ventricular system, with the presence of multiple hypersinal foci at T2 and DP in the semi-oval centers, without gadolinium impregnation, suggestive of demyeliminating lesions, and around the lateral ventricles and third ventricle, suggestive of periependimal leukomalacia (Fig 2A). Electroencephalograph assessment was normal. The thorax radiograph revealed hyperkyphosis with a reduction in body height at the seventh thoracic vertebra and dextroconvex thoracic scoliosis. Ophthalmological evaluation verified the presence of intense photophobia, bilateral keratocone with lower conjunctival pannus in the right eye and the entire left eye. Chromosomal analysis through GTG banding karyotype revealed a deletion involving the short arm of chromosome 18: 46,XX,del(18)(p11.1) (Figs 2B and 2C). The karyotype of the parents was normal.

The aim of the study was to characterize clinically and biochemically mucopolysaccharidosis type II (MPS II) heterozygotes. Fifty-two women at risk to be a carrier, with a mean age of 34.1 years (range 16–57 years), were evaluated through pedigree analysis, medical history, physical examination, measurement of iduronate sulfatase (IDS) activities in plasma and in leukocytes, quantification of glycosaminoglycans (GAGs) in urine, and analysis of the IDS gene. Eligibility criteria for the study also included being 16 years of age or older and being enrolled in a genetic counselling programme. The pedigree and DNA analyses allowed the identification of 40/52 carriers and 12/52 non-carriers. All women evaluated were clinically healthy, and their levels of urinary GAGs were within normal limits. Median plasma and leukocyte IDS activities found among carriers were significantly lower than the values found for non-carriers; there was, however, an overlap between carriers’ and non-carriers’ values. Our data suggests that MPS II carriers show lower plasma and leukocyte IDS activities but that this reduction is generally associated neither with changes in levels of urinary GAGs nor with the occurrence of clinical manifestations.

BACKGROUND: Poland syndrome has been attributed to a process of vascular disruption, and exposure to misoprostol at 6–8 weeks of gestation has been shown to produce defects attributed to vascular disruption. Herein we report the first case of a patient with Poland syndrome associated with an aberrant subclavian artery and vascular abnormalities of the retina, whose mother used misoprostol during pregnancy. CASE: A White boy of 1 year and 7 months of age, whose mother used misoprostol during the second month of pregnancy, presented with bilateral epicanthal folds, aplasia of the sternocostal head of the pectoralis major muscle with a hypoplastic nipple on the right side, and asymmetry between the upper limbs. The results of an angiotomographic study showed the presence of an aberrant right subclavian artery. Ultrasonographic evaluation showed turbulence and a high peak in the diastolic velocity in both carotid arteries, suggesting stenosis. Ophthalmologic assessment disclosed an intense bilateral tortuosity of the retinal blood vessels, with arterialnarrowing and rarefaction of the retinal pigment epithelium. CONCLUSIONS: This case suggests that the mechanism of vascular disruption of misoprostol could be related to the aberrant subclavian artery and the observed Poland syndrome. His retinal findings are different from those in cases described thus far in the literature, and this pattern of anomaly has never been associated with a gestational exposure to misoprostol. The possibility of a relationship of the aberrant right subclavian artery and the pattern of blood flow verified in the carotid arteries with the eye fundus abnormalities could be causally related or simply coincidental. Birth Defects Research (Part A), 2007. © 2007 Wiley-Liss, Inc.

We report a 3-year-old boy with isolated 3-methylcrotonyl-coenzyme A deficiency with unexpectedly severe presentation, seizures and history of cerebral ischae-mic episode.

BACKGROUND The concomitant occurrence of breast cancer and pregnancy is relatively uncommon. We report the case of a patient with syndactyly, cleft hands, and absence of distal finger phalanges associated with maternal exposure to chemotherapeutic agents during the first trimester of pregnancy. These associations have not been previously described. CASE The patient was born by normal delivery after 38 weeks of pregnancy. His mother became pregnant while receiving chemotherapy (cyclophosphamide, 5-fluorouracil, and adriamycin) for breast cancer, and the fetus was exposed to these drugs from conception to the 16th week of pregnancy. At birth, anomalies were observed, including a high-arched palate, microcephaly, a flat nasal bridge, bilateral syndactyly in the first and second fingers with a hand cleft between the second and third fingers and hypoplasia of the fifth fingers, and dystrophic nail of the fourth finger of the left hand. The patient's growth and development were deficient. CONCLUSIONS The malformations associated with in utero exposure to these chemotherapeutic agents are highly variable, but growth deficiency and anomalies of the craniofacial region and limbs are the most common. The pattern of malformations in children who were congenitally exposed to chemotherapeutic agents appears to be directly related to the age at and duration of exposure, rather than to the specific drug itself. Effective contraception is essential for the safe use of a potential teratogen in nonpregnant women of reproductive age. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.

Objective: to report a case of a patient diagnosed with Wolfram Syndrome and brachydactyly type E. Wolfram Syndrome is characterized by the presence of diabetes mellitus, diabetes insipidus, atrophy of the optic nerve, alterations of the urinary tract, deafness and neurologic and psychiatric disorders. However, not all manifestations are present at diagnosis, indicating the necessity of long-term follow-up of these patients. This long-term follow-up should be extended to the patients' closest relatives, having in mind the increased risk of occurrence of psychiatric disorders and diabetes mellitus among the heterozygous carriers of Wolfram Syndrome. Description: male, white patients, only child of non-consanguineous parents, was healthy until four years of age, when he presented with polydipsia and polyuria, being diagnosed with diabetes mellitus type I. Since then, he has needed regular insulin use, but has followed an inadequate diet due to socioeconomic problems. He was evaluated by the genetic service when he was 11 years old. Brachydactyly was observed on physical examination. In the course of the complementary investigation, bilateral atrophy of the optic nerve was observed; the visual evoked potential and the electroretinogram were compatible with extensive optic nerve injury. Both retinas were normal. The presence of insulin-dependent diabetes mellitus together with atrophy of the optic nerve is a sufficient criterion for the diagnosis of Wolfram Syndrome. The molecular investigation confirmed the diagnosis of Wolfram Syndrome. Comments: the aim of the present report is to alert physicians about the association between diabetes mellitus and monogenic syndromes, such as Wolfram Syndrome.