Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants.

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID phenotypes caused by pathogenic variants in the X chromosome. We analyzed the XCI pattern in blood samples of 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 (8%) presented with extreme or total XCI skewing (≥ 90%), which was significantly higher than expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnostic rate of 73% (8/11 patients). All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (an XCI escape gene; two cases), WDR45, and PDHA1, and four variants in the autosomal genes KCNB1, CTNNB1, YY1, and ANKRD11. Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data confirm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants, and point to the possibility of identifying causative variants in autosomal genes with a XCI role.

Rare and intractable fibrodysplasia ossificans progressiva shows different PBMC phenotype possibly modulated by ascorbic acid and propranolol treatment.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare congenital intractable disease associated with a mutation in ACVR1 gene, characterized by skeleton malformations. Ascorbic acid (AA) and propranolol (PP) in combination is reported to minimize flare-ups in patients. FOP leukocyte phenotype may possibly be modulated by AA and PP treatment. In this study, expression of 22 potential target genes was analyzed by RT-PCR in peripheral blood mononuclear cells culture (PBMC) from FOP patients and controls to determine effectiveness of the combination therapy. PBMC were treated with AA, PP and AA+PP combination. Basal expression of 12 of the 22 genes in FOP PBMC was statistically different from controls. ACVR1, ADCY2, ADCY9 and COL3 were downregulated while COL1 was upregulated. ADRB1, ADRB2, RUNX2, TNF-α and ACTB, were all overexpressed in FOP PBMC. In control, AA upregulated COL1, SVCT1, ACTB, AGTR2 and downregulated ADCY2. In FOP cells, AA upregulated ACVR1, BMP4, COL1, COL3, TNF-α, ADCY2, ADCY9, AGTR2 and MAS, while downregulated ADBR2, RUNX2, ADCY1, SVCT1 and ACTB. PP increased ADBR1 and decreased RUNX2, TNF-α, AGTR1, ACTB and CHRNA7 genes in treated control PBMC compared to untreated. PP upregulated ADBR1, ADBR2 and MAS, and downregulated TNF-α and ACTB in treated FOP PBMC versus untreated. AA+PP augmented ADRB1 and ADRB2 expressions in control PBMC. In FOP PBMC, AA+PP augmented ACVR1, COL1, COL3, ADBR1, AGTR2 and MAS expression and downregulated ADBR2, RUNX2, ACTB and MRGD. These data show distinct gene expression modulation in leukocytes from FOP patients when treated with AA and or PP.

Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.

Mucopolysaccharidosis VII in Brazil: natural history and clinical findings.

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

Congenital chromoanagenesis in the routine postnatal chromosomal microarray analyses.

Chromosomal microarray analyses (CMA) have greatly increased both the yield and diagnostic accuracy of postnatal analysis; it has been used as a first-tier cytogenetic test in patients with intellectual disability, autism spectrum disorder, and multiple congenital abnormalities. During the last 15 years, we performed CMA in approximately 8,000 patients with neurodevelopmental and/or congenital disorders, of which 13 (0.16%) genetically catastrophic complex chromosomal rearrangements were identified. These ultrarare rearrangements showed clustering of breakpoints, characteristic of chromoanagenesis events. Al1 13 complex events display underlying formation mechanisms, originating either by a synchronization of the shattering of clustered chromosome regions in which regional asynchrony of DNA replication may be one of the main causes of disruption. We provide an overview of the copy number profiling in these patients. Although several previous studies have suggested that chromoanagenesis is often a genetic disease source in postnatal diagnostic screening, due to either the challenge of clinical interpretation of these complex rearrangements or the limitation of microarray resolution relative to the small size and complexity of chromogenic induced chromosome abnormalities, bringing further attention and to study its occurrence in the clinical setting is extremely important.

Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study.

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

A decade of molecular diagnosis of Mucolipidosis II and III in Brazil: a pooled analysis of 32 patients

Abstract GlcNAc-1-phosphotransferase is a hexameric complex formed by subunits α, β, and γ, where the first two are encoded by the GNPTAB gene and the third by the GNPTG gene. Pathogenic variants identified in the GNPTAB gene cause the diseases Mucolipidosis II and III alpha/beta, which are severe and characterized by an overflow of lysosomal hydrolases into the extracellular environment, and their absence in lysosomal compartments causes an accumulation of non-degraded macromolecules. Methodology: a retrospective study that included 32 unrelated Brazilian patients with a clinical and genetic diagnosis of Mucolipidosis II/III alpha/beta. The regional frequency of the altered alleles was determined. Results: The patients were from all regions of Brazil. The most prevalent variants were c.3503_3504del, associated with the severe form of the disease, and c.1208T>C, associated with the milder form. Variant c.3503_3504del is the most frequently found in the Midwest, Northeast, and Southeast regions of Brazil. In the South, 42.8% of the alleles present the c.1196C>T variant. Conclusions: From the perspective of all patients diagnosed with Mucolipidosis II/III in Brazil, it is possible to conclude that different regions present allelic frequencies of specific pathogenic variants, which can be explained by the occurrence of a founding effect or high inbreeding rates.

Percepções paternas quanto as suas expectativas sobre o futuro do filho com deficiência mental / Fathers' perceptions of their expectations about the future of children with mental disability

Objetivou-se desvelar as percepções paternas quanto as suas expectativas em relação ao futuro do filho com deficiência mental. A coleta de dados ocorreu a partir de entrevistas semiestruturadas, nos meses de agosto a novembro de 2011. Para tanto, a fenomenologia, sob a perspectiva hermenêutica de Heidegger, foi o referencial teórico escolhido. Mediante o alcance do fenômeno, participaram do estudo doze sujeitos, homens, pais de crianças com deficiência mental. Dos discursos, os temas que emergiram diante do fenômeno investigado foram: 'concebendo o futuro do filho a partir da notícia da deficiência', 'refletindo sobre o futuro no cotidiano', 'percebendo que a criança com deficiência tem seu próprio tempo de desenvolvimento', 'percebendo a dependência do filho' e 'tendo a esperança e a fé como futuro'. O nascimento da criança com deficiência permitiu ao pai uma reflexão diante do fato, ressignificando suas percepções e expectativas quanto ao seu ser-pai. Conclui-se que diante da experiência de ter um filho com deficiência vivenciada pelo pai, ser ouvido é um processo terapêutico, devendo ser uma intervenção proporcionada pelo profissional de saúde. Sugere-se, assim, a capacitação do profissional que presta assistência a essa população, para que seja proporcionado um melhor atendimento aos indivíduos que vivenciam essa experiência.

This study aimed to reveal the paternal perceptions about their expectations for the future of children with mental disability. The data was collected from semi-structured interviews from August to November 2011. Phenomenology, in the hermeneutic perspective of Heidegger, was the theoretical reference chosen. Reaching the phenomenon, twelve subjects participated in the study, men, fathers of children with mental disabilities. Themes emerged from the phenomenon investigated: 'designing the future of the child from the news of disability', 'reflecting about the future in daily life', 'realizing that the child with disability has his own development time', 'realizing the child ́s dependency' and 'having hope and faith as the future'. The birth of children with disabilities allowed the father reflect front the fact, giving new meaning to their perceptions and expectations about being a father. It is concluded that in face of having a child with disability experienced by the father, being heard is a therapeutic process and should be an intervention proportionate by a healthcare professional. It is therefore suggested the training of professionals who provide assistance to this population, so that better care be provided to individuals having this experience

Mucopolysaccharidosis type VI on enzyme replacement therapy since infancy: Six years follow-up of four children.

Clinical and biochemical improvements are reported on Mucopolysaccharidosis type VI (MPS VI) patients on Enzyme Replacement Therapy (ERT) with rhASB (galsulfase, Naglazyme®), and preclinical and clinical studies have shown clinical benefits of early initiation. We report four unrelated MPS VI children who began ERT as infants (ages 5 days­10 months). The three older patients showed the first clinical signs of MPS VI at baseline, also presenting different degrees of dysostosis multiplex, and two had mild heart disease. The two oldest also had mild facial coarseness, one had hearing conduction deficit and sleep disorder and the other corneal clouding at baseline. After six years on ERT, all four patients have normal urinary GAG values. Although they all showed normal motor and mental development, brain and cervical spine MRI images available from two of the older patients showed abnormalities, while the youngest child continues having normal images. The four patients presented slower progression of bone and joint disease when compared to their affected older siblings. It should be noticed that only two patients in this sample are currently below the 3rd percentile for height: the youngest who has a constitutional factor associated and the eldest who already presented frank dysostosis at 10 months of age. These findings confirm previous studies that report that skeletal features of the disease cannot be completely prevented despite early ERT. Heart disease already present in two of the four infants at baseline got worse over time and appeared in another patient, but the youngest child on ERT introduction still has a normal echocardiogram at six years of age; he also is the only one without corneal clouding after six years follow-up. Our results also suggest that early ERT prevented storage in spleen and liver and may also have improved or prevented progression of facial dysmorphic features, corroborating similar findings seen in previous studies. No safety concerns were identified and none of the patients experienced a serious adverse event. The baseline severity of the disorder of these four infants seems related to age and it is tempting to say that severity on the first year of life is progressive and ERT effectiveness is indirectly related to it. Despite being known that MPS VI progresses differently among patients, the fact that these infants had a slower progression than their older siblings speaks in favor of a very early start of ERT. In conclusion, this report confirms the early manifestations of the disease and provides additional evidence on safety and of the beneficial effects of ERT in patients less than 1 year of age.

Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic and multisystem lysosomal storage disease with a wide disease spectrum. Clinical and biochemical improvements have been reported for MPS VI patients on enzyme replacement therapy (ERT) with rhASB (recombinant human arylsulfatase B; galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.), making early diagnosis and intervention imperative for optimal patient outcomes. Few studies have included children younger than five years of age. This report describes 34 MPS VI patients that started treatment with galsulfase before five years of age. METHODS: Data from patients who initiated treatment at <5 years of age were collected from patients' medical records. Baseline and follow-up assessments of common symptoms that led to diagnosis and that were used to evaluate disease progression and treatment efficacy were evaluated. RESULTS: A significant negative correlation was seen with treatment with ERT and urinary GAG levels. Of those with baseline and follow-up growth data, 47% remained on their pre-treatment growth curve or moved to a higher percentile after treatment. Of the 9 patients with baseline and follow-up sleep studies, 5 remained unaffected and 1 patient initially with mild sleep apnea showed improvement. Data regarding cardiac, ophthalmic, central nervous system, hearing, surgical interventions and development are also reported. No patient discontinued treatment due to an adverse event and all that were treatment-emergent resolved. CONCLUSIONS: The prescribed dosage of 1mg/kg IV weekly with galsulfase ERT is shown to be safe and effective in slowing and/or improving certain aspects of the disease, although patients should be closely monitored for complications associated with the natural history of the disease, especially cardiac valve involvement and spinal cord compression. A long-term follow-up investigation of this group of children will provide further information on the benefits of early treatment as well as disease progression and treatment efficacy and safety in this young patient population.

1031-1034delTAAC (Leu125Stop): a novel familial UBE3A mutation causing Angelman syndrome in two siblings showing distinct phenotypes.

BACKGROUND: More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene) have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect. CASE PRESENTATION: We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features. CONCLUSIONS: We hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i) maybe the proband has an additional problem (genetic or environmental) besides the UBE3A mutation; ii) since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii) this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.

Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

UNLABELLED: 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.

[Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts]. / 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 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, 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.

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.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros / Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts

As mucopolissacaridoses (MPS) são doenças genéticas raras causadas pela deficiência de enzimas lisossômicas específicas que afetam o catabolismo de glicosaminoglicanos (GAG). O acúmulo de GAG em vários órgãos e tecidos nos pacientes afetados pelas MPS resulta em uma série de sinais e sintomas, integrantes de um quadro clínico multissistêmico que compromete ossos e articulações, vias respiratórias, sistema cardiovascular e muitos outros órgãos e tecidos, incluindo, em alguns casos, as funções cognitivas. Já foram identificados 11 defeitos enzimáticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauração da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevenção e o cuidado das complicações, aspecto ainda bastante importante no manejo desses pacientes. Na década de 80 foi proposto o tratamento das MPS com transplante de medula óssea/transplante de células tronco hematopoiéticas (TMO/TCTH) e na década de 90 começou o desenvolvimento da Terapia de Reposição Enzimática (TRE), que se tornou uma realidade aprovada para uso clínico nas MPS I, II e VI na primeira década do século 21. Os autores deste trabalho têm a convicção de que um melhor futuro para os pacientes afetados pelas MPS depende da identificação, compreensão e manejo adequado das manifestações multissistêmicas dessas doenças, incluindo medidas de suporte (que devem fazer parte da assistência multidisciplinar regular destes pacientes) e terapias específicas...

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 primnarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, 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...

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.

[Investigation of neurodevelopment delay etiology: resources and challenges]. / Investigação das causas de atraso no neurodesenvolvimento: recursos e desafios.

To verify the reach of development delay investigation, we brought the experience in the pediatrics, infantile neurology and clinical genetics diagnoses, with resources of a tertiary health care, in 73 children, from 1 to 47 months age, between 1999 and 2001, attending a Stimulation Program of the Association of Parents and Friends of Exceptional Children of Batatais-SP. With a transversal and prospective method, six groups were identified: motor disturbances, dysmorphisms, malnutrition, macrocephaly, microcephaly and motor delay. In the analysis of the contribution of the antecedents, physical or laboratory exams to the diagnosis, it stands out the brain image in the groups "motor disturbances" and "macrocephaly"; and for the remaining groups, the physical examination and maternal data. The causes were detected in 48 (66%), being 38.4% of environmental and 24.6% genetics origin. It is emphasized the specialist evaluation, and the need of appropriate flow of information in the net of health.

Investigação das causas de atraso no neurodesenvolvimento: recursos e desafios / Investigation of neurodevelopment delay etiology: resources and challenges

Com o objetivo de verificar o alcance da investigação de causas do retardo no desenvolvimento neuromotor (RDNM), apresenta-se a experiência no atendimento em Pediatria, Neurologia Infantil e Genética Clínica, em nível terciário, de 73 crianças de 1 a 47 meses, do Programa de Estimulação da APAE de Batatais-SP, entre 1999 e 2001. Utilizando-se método transversal, prospectivo, inicialmente identificaram-se 6 grupos, segundo a semiologia clínica dominante - distúrbios motores, dismorfias, desnutrição, macrocefalia, microcefalia e unicamente atraso motor. Analisando-se a proporção com que os antecedentes e exames contribuíram para o diagnóstico, nos grupos "distúrbios motores" e "macrocefalia" destacaram-se os exames de imagem; nos demais grupos, o exame físico na criança e antecedentes maternos. As causas do RDNM foram detectadas em 48 crianças (66 por cento), sendo de origem ambiental 38,4 por cento e genética 24,6 por cento. Ressalta-se a relevância da avaliação especializada e necessidade de fluxo adequado de informações na rede de saúde.

Splenopancreatic field abnormality is not unique to trisomy 13.

Splenopancreatic fusion is an uncommon finding, usually only seen as part of the splenopancreatic field abnormality associated with trisomy 13. It may present itself either as ectopic splenic tissue in the cauda pancreatis, as ectopic pancreatic tissue in the spleen or accessory spleen, or as fusion of the cauda pancreatis and splenic hilum. In this study, we report four unrelated congenital anomaly cases presenting trisomy 21, osteocraniostenosis syndrome, isolated congenital heart defect, and oligohydramnios sequence due to prune belly syndrome, in which fusion was observed. This demonstrates that, although it may be more common in trisomy 13, this phenomenon should not be interpreted as pathognomonic to that syndrome.

Caudal dysplasia sequence: severe phenotype presenting in offspring of patients with gestational and pregestational diabetes.

The association of maternal diabetes mellitus and congenital anomalies is well established. Children of insulin-dependent diabetic women have an increased risk of congenital malformations, especially major multiorgan defects. The cardiovascular, central nervous, gastrointestinal, genitourinary and musculoskeletal are the most affected body systems. Studies also show that offspring of women with gestational diabetes (specially those with fasting hyperglycaemia) tend to have higher rates of congenital anomalies. We report two cases of infants born to unrelated mothers: one with diabetes mellitus first detected during pregnancy (gestational diabetes) and the other with pregestational diabetes. Both infants had amelia of the lower limbs (suggestive of caudal dysplasia sequence), together with cardiovascular, skeletal, urinary and gastrointestinal defects. While pregestational diabetes seems to leave no doubt about its teratogenicity, the association of gestational diabetes and fetal/newborn malformations is still under discussion. Complete absence of the lower limbs has not been reported in association with gestational diabetes, but it may represent a spectrum of the caudal dysplasia sequence. The presentation of two cases with the same clinical phenotype of mothers with gestational and pregestational diabetes supports the evidence that gestational diabetes can be responsible for the development of the most severe form of the caudal dysplasia sequence.