Avaliação das anomalias clínico-funcionais na doença de Pompe: Relato de Caso

The patient was a 15 year-old girl who turned out at the Physical Therapy Clinic presenting progressive scoliosis and angle of 50º Coob by X-Ray. She complained of back pain, headache and weakness of shoulder and pelvid girdle. Physical therapy evaluation came across features of delayed motor development and undermourishment, together with generalized muscle weakness (grade=4) which was observed by the Kendall test. Lung vital capacity was 40,5%. Clinical Changes: studies of the enzymes with acid alpha-glucosidase assay kits used on filter and leukocytes low enzyme activity, suggesting a late form of the Pompe disease. The molecular studies proved that the patient had a mutation associated with late-onset Pompe disease. Acid alpha-glucosidase enzyme assay studies performed in skin fibroblasts showed a reduction of the enzymatic acitivity of the acid alpha-glucosidase, confirming the previous results. On account of the results, Pompe disease induced important changes in clinical and functional, as well as metabolic changes, decreased strength and muscle action potentially, biomechanical changes in the spine and changes in respiratory capacity. Furthemore, this case of Pompe disease illustrates the importance od adequate physical therapy evaluation as it can be the starting point of investigation of serious conditions such as late onset Pompe disease.Paciente do sexo feminino com 15 anos, apresentou-se na Clínica de Fisioterapia, devido à presença de escoliose progressiva com ângulo de Coob de 50º pelo Raio-X. Apresentou queixa de dor na coluna e na cabeça, fraqueza de cintura escapular e pélvica. Na avaliação fisioterapêutica observou-se um quadro semelhante ao atrado do desenvolvimento motor e desnutrição, com fraqueza muscular generalizada (grau=4) observada pelo teste de Kendall. Na função pulmonar a capacidade vital apresentou com 40,5%. Estudos enzimáticos com dosagem da alga-glicosidade ácida em papel-filtro e leucócitos evidenciaram baixa atividade enzimática, sugestivo de forma tardia da doença de Pompe. No estudo molecular, comprovou-se que a paciente possuía mutação associada à forma tardia da doença: estudos enzimáticos da alfa-glicosidade ácida em fibroblastos cultivados a partir de biópsia de pele evidenciaram redução da atividade enzimática da alga-glicosidase ácida, confirmando estudos enzimáticos prévios. Perante os resultados, a doença de Pompe apresentou alterações clínicas e funcionais importantes como alteração do metabolismo, diminuição de força e do potencial de ação da musculatura, alterações biomecânicas na coluna e na capacidade respiratória. Adicionalmente, o caso ilustra a importânica da avaliação fisioteraupêtica adequada, pois ele pode ser o ponto de partida da investigação de doenças graves como o presente caso

Evaluation of 3-O-methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases

Aromatic L-amino acid decarboxylase (AADCD) deficiency is an autosomal recessive neurometabolic disorder, caused by biallelic mutations in the DDC gene, that impairs the synthesis or metabolism of neurotransmitters leading to severe motor dysfunction. The main clinical signs are oculogyric crisis, hypotonia, hypokinesia, and dystonia. The biochemical diagnosis can be performed in cerebrospinal fluid by neurotransmitter analysis, which requires an invasive lumbar puncture, and the sample needs to be shipped frozen to a reference laboratory, usually across a country border. Measurement of AADC activity in plasma is also possible, but available in a few labs globally. 3-O-methyldopa (3-OMD) is a catabolic product of L-dopa and it is elevated in patients with AADC deficiency. The quantification of 3-OMD can be performed in dried blood spots (DBS), a sample that could be shipped at room temperature. 3-OMD levels of AADCD patients and controls were quantified in DBS by liquid chromatography tandem mass spectrometry. DBS samples from 7 Brazilian patients previously diagnosed with AADCD were used to validate the 3-OMD quantification as a screening procedure for this condition. All AADCD patients had at least a four-fold increase of 3-OMD. Thus, 3-OMD seems to be a reliable marker for AADCD, with potential use also in the newborn screening of this disease

Coherence Time Effects on J/psi Production and Suppression in Relativistic Heavy Ion Collisions

Using a coherence time extracted from high precision proton-nucleus Drell-Yan measurements and a nuclear absorption cross section extracted from pA charmonium production experiments, we study J/psi production and absorption in nucleus-nucleus collisions. We find that coherence time effects are large enough to affect the measured J/psi-to-Drell-Yan ratio. The S+U data at 200A GeV/c measured by NA38 are reproduced quantitatively without the introduction of any new parameters. However, when compared with recent NA50 measurements for Pb+Pb at 158A GeV/c, the data is not reproduced in trend or in magnitude.Comment: 8 pages, 2 figure

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

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

In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy

Clinical, Biological and Genetic Analysis of Prepubertal Isolated Ovarian Cyst in 11 Girls

BACKGROUND: The cause of isolated gonadotropin-independent precocious puberty (PP) with an ovarian cyst is unknown in the majority of cases. Here, we describe 11 new cases of peripheral PP and, based on phenotypes observed in mouse models, we tested the hypothesis that mutations in the GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX may be associated with this phenotype. METHODOLOGY/PRINCIPAL FINDINGS: 11 girls with gonadotropin-independent PP were included in this study. Three girls were seen for a history of prenatal ovarian cyst, 6 girls for breast development, and 2 girls for vaginal bleeding. With one exception, all girls were seen before 8 years of age. In 8 cases, an ovarian cyst was detected, and in one case, suspected. One other case has polycystic ovaries, and the remaining case was referred for vaginal bleeding. Four patients had a familial history of ovarian anomalies and/or infertility. Mutations in the coding sequences of the candidate genes GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX were not observed. CONCLUSIONS/SIGNIFICANCE: Ovarian PP shows markedly different clinical features from central PP. Our data suggest that mutations in the GNAS1, NR5A1, LHCGR, FSHR StAR, DMRT4 and NOBOX genes are not responsible for ovarian PP. Further research, including the identification of familial cases, is needed to understand the etiology of ovarian PP

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Erros inatos do metabolismo confirmados no Hospital das Clínicas de Ribeirão Preto-SP no período de 2000 a 2008

Os Erros Inatos do Metabolismo (EIM) vêm sendo cada vez mais identificados nos últimos anos. A preocupação com o diagnóstico precoce decorre do foco na prevenção de deficiências, especialmente a mental. Este estudo descritivo teve por objetivo verificar diagnósticos confirmados e modalidades de tratamento utilizadas de janeiro de 2000 a dezembro de 2008. Método: foi realizada busca ativa de casos confirmados nos serviços que atendem esse tipo doença: neurologia (neuropediatria e doenças neuromusculares), pediatria (serviço de gastrologia e hepatologia) e genética clínica, além de levantamento no Serviço de Arquivo Médico do HCFMRP-USP. Foram confirmados 165 pacientes com EIM, com idades de um dia a 22 anos (mediana de um ano); 50 casos foram defeitos na síntese ou catabolismo de moléculas complexas, 65 no metabolismo intermediário, e 50 na produção ou utilização de energia. O tratamento foi instituído para 12 dos 50 pacientes do grupo I sendo reposição enzimática em 11 e transplante de medula óssea em um; todos do grupo II e III receberam orientação  nutricional; 60 do grupo II receberam fórmula dietética industrializada; dos 50 do grupo III, 43 com mitocondriopatias receberam L-carnitina e coenzimas e aqueles com glicogenose, orientação sobre aporte de carbohidratos. A formação de novos recursos humanos, integração com a Rede EIM Brasil e linhas de pesquisa na área são prioridades para melhorar a acuidade na detecção e tratamento de erros inatos do metabolismo.Inborn Errors of Metabolism have been increasingly identified in recent years. The early diagnosis focuses on prevention of disabilities, especially mental retardation. This descriptive study aims to verify confirmed diagnosis and treatment modalities in HCFMRP-USP cases from January of 2000 to December of 2008. A total of 165 patients with ages ranging from one day to 22 years (median one year) were detected. Fifty patients had synthesis or catabolism of complex molecules (group I), 65 intermediary metabolism (group II), and 50 had production or use of energy (group III) defects. Among the patients of group I, 11 had enzyme replacement therapy, and one bone marrow transplantation; for group II and III, in addition to daily nutritional guidance for all of the patients, 60 from group II received industrialized diets; from group III, 43 with mitochondrial diseases received L-carnitine and coenzymes, and those with glycogenosis were focused mainly on the intake of carbohydrates. New human resources, integration with the Network EIM Brazil and lines of research in the area are priorities for improving the accuracy in the detection and treatment of inborn errors of metabolism

SLC35A2â CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Pathogenic de novo variants in the Xâ linked gene SLC35A2 encoding the major Golgiâ localized UDPâ galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2â congenital disorders of glycosylation (CDG; formerly CDGâ IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin Nâ glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2â CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2â dependent UDPâ galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wildâ type to mutant alleles in fibroblasts from affected individuals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/1/humu23731_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/2/humu23731-sup-0001-Supp_Mat__2019.2.10_.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/3/humu23731.pd