Clinical characterization and genetic testing for a patient with creatine deficiency syndrome 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child affected with cerebral creatine deficiency syndrome 1 (CCDS1).@*METHODS@#High-throughput sequencing was carried out to screen pathogenic variant associated with the clinical phenotype of the proband. The candidate variant was verified by Sanger sequencing.@*RESULTS@#High-throughput sequencing revealed that the proband has carried heterozygous c.327delG variant of the SLC6A8 gene, which was verified by Sanger sequencing.Neither parent was found to carry the same variant.@*CONCLUSION@#The de novo heterozygous c.327delG variant of the SLC6A8 gene probably underlay the CCDS1 in this child.

Analysis of L2HGDH gene mutation in a patient with 2-hydroxyglutaric aciduria / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore pathogenic mutation in a family affected with 2-hydroxyglutaric aciduria.</p><p><b>METHODS</b>Exons of 3 candidate genes, including L2HGDH, D2HGDH and SLC25A1, were amplified with polymerase chain reaction and subjected to direct sequencing.</p><p><b>RESULTS</b>DNA sequencing has found that the proband and his affected younger brother have both carried a heterozygous mutation c.845G>A (p.R282Q) in the exon 7 of the L2HGDH gene. The same mutation was not detected in the his sister who was healthy. Pedigree analysis has confirmed that the above mutation was inherited from the mother. No mutation was detected in exons and flanking sequences of the D2HGDH and SLC25A1 genes.</p><p><b>CONCLUSION</b>Mutation of the L2HGDH gene probably underlies the 2-hydroxyglutaric aciduria in this family.</p>

Menkes disease mimicking non-accidental injury in a Filipino child

We report an 11-month-old male who presented with recurrent seizures, subdural bleed, skull fracture, lightly pigmented hair, and fair lax skin. Copper and ceruloplasmin levels were low and gross deletion of ATP7A gene was found confirming the diagnosis of Menkes disease. The presence of subdural bleed and skull fracture prompted a referral to the Child Protection Unit to rule out child abuse.

Carbonic anhydrase II deficiency: A novel mutation.

Carbonic anhydrase II (CA II) deficiency is an extremely rare autosomal recessive disorder, characterised by a triad of osteopetrosis, renal tubular acidosis and cerebral calcifications. A 12-year-old boy with classical features of CA II deficiency is reported who was found to be homozygous for the mutation in CA II gene and parents were heterozygous for the same mutation .To the best of our knowledge this is the first case report of mutation proven CA II deficiency from India.

Inherited metabolic diseases in the urine organic acid analysis of complex febrile seizure patients / 소아과

PURPOSE: Seizure associated with fever may indicate the presence of underlying inherited metabolic diseases. The present study was performed to investigate the presence of underlying metabolic diseases in patients with complex febrile seizures, using analyses of urine organic acids. METHODS: We retrospectively analyzed and compared the results of urine organic acid analysis with routine laboratory findings in 278 patients referred for complex febrile seizure. RESULTS: Of 278 patients, 132 had no abnormal laboratory findings, and 146 patients had at least one of the following abnormal laboratory findings: acidosis (n=58), hyperammonemia (n=55), hypoglycemia (n=21), ketosis (n=12). Twenty-six (19.7%) of the 132 patients with no abnormal findings and 104 (71.2%) of the 146 patients with statistically significant abnormalities showed abnormalities on the organic acid analysis (P<0.05). Mitochondrial respiratory chain disorders (n=23) were the most common diseases found in the normal routine laboratory group, followed by PDH deficiency (n=2 ) and ketolytic defect (n=1). In the abnormal routine laboratory group, mitochondrial respiratory chain disorder (n=29) was the most common disease, followed by ketolytic defects (n=27), PDH deficiency (n=9), glutaric aciduria type II (n=9), 3-methylglutaconic aciduria type III (n=6), biotinidase deficiency (n=5), propionic acidemia (n=4), methylmalonic acidemia (n=2), 3-hydroxyisobutyric aciduria (n=2), orotic aciduria (n=2), fatty acid oxidation disorders (n=2), 2-methylbranched chain acyl CoA dehydrogenase deficiency (n=2), 3-methylglutaconic aciduria type I (n=1), maple syrup urine disease (n=1), isovaleric acidemia (n=1), HMG-CoA lyase deficiency (n=1), L-2-hydroxyglutaric aciduria (n=1), and pyruvate carboxylase deficiency (n=1). CONCLUSION: These findings suggest that urine organic acid analysis should be performed in all patients with complex febrile seizure and other risk factors for early detection of inherited metabolic diseases.

Citrobacter freundii infection in glutaric aciduria type 1: adding insult to injury.

Glutaric aciduria type 1 (GA1) is an inborn error of organic acid metabolism, where the brain is the principal organ affected with exposure to toxic metabolic product, 3-hydroxyglutaric acid (3-OHGA). A 2-year-old boy with GA1 and delayed developmental milestones had an acute neurological crisis leading to massive brain abscess with Citrobacter freundi infection, a rare cause of neonatal meningitis and often associated with brain abscess. Both 3-OHGA and C. freundii can damage the blood-brain barrier and can cause significant trauma which demands immediate and appropriate management. Encephalopathic manifestations of GA1 may consequently increase the risk of meningeal infection and it has not been previously documented.

Inherited neurodevelopmental brain diseases: applications of homozygosity mapping to identify new genetic causes of disease

The last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible to arrive at a molecular diagnosis, due in part to lack of knowledge of molecular causes of these tremendously complex conditions. Common genetic disorders of brain development include septo-optic dysplasia, schizencephaly, holoprosencephaly, lissencephaly and hindbrain malformations. For each of these disorders, a critical step in brain development is disrupted. Specific genetic diagnosis is now possible in some patients with most of these conditions. For the remaining patients, it is possible to apply gene-mapping strategies using newly developed high-density genomic arrays to clone novel genes. This is especially important in countries like Iran where large family size and marriage between relatives makes these strategies tremendously powerful

Values of tandem mass spectrometry in etiologic diagnosis of cerebral developmental retardation / 中华儿科杂志

<p><b>OBJECTIVES</b>To investigate the values of tandem mass spectrometry (MS/MS) in etiologic diagnosis and understanding therapeutic effect in cerebral developmental retardation, and to help patients in early diagnosis, treatment and favorable prognosis.</p><p><b>METHODS</b>One hundred and fifty-eight childhood patients with brain heteroplasia were tested from July 2004 to October 2006. The blood was collected on filter paper, punched and extracted into methanol solution with stable isotope labeled internal standards, then derivatized with butanolic-HCl. After preparation, the samples were analysed by tandem mass spectrometry. Eleven MS/MS-positive patients were further analyzed based on gas chromatography/mass spectrometry (GC/MS) analysis of urine, clinical course, and treatment outcome.</p><p><b>RESULTS</b>Eleven of 158 patients (7.0%) with inborn metabolic error were confirmed, including five with methylmalonic acidemia, two with propionic acidemia, one with ornithine transcarbamylase deficiency, one with maple syrup urine disease, one with phenylketonuria, and one with biotinidase deficiency. Among them, five were male, six were female, aged from 4 days to 21 months. The clinical manifestations were diverse, including mental developmental retardation or degradation (11 cases), convulsion (5 cases), coma (4 cases), vomiting (4 cases), malnutrition (4 cases), lethargy (3 cases), repeated infection (3 cases), hypotonia (2 cases), etc. Laboratory findings showed metabolic acidosis, hyperammonemia, hyperlactacidemia, anemia, etc. MRI findings of the brain showed cerebral atrophy, a pattern of bilateral T(2)W high signal intensity or/and T(1)W low signal intensity in cerebral white matter and multiple encephalomalacia or vesicular change, ect. In methylmalonic acidemia patients, the early onset with severe acidosis and coma have had a poor prognosis. Improvement was observed in 8 cases after treatment with vitamin B(12), L-carnitine, special milk, low-protein diet or biotin, etc. However 3 MMA patients died.</p><p><b>CONCLUSION</b>MS/MS was helpful for some patients in etiologic diagnosis and understanding therapeutic effect of cerebral developmental retardation. Early diagnosis and appropriate treatment are essential to improve the prognosis and prevent brain damage.</p>

Estudo das interfaces da genética médica com a saúde pública-o indivíduo como fenilcetonúria e o Programa Nacional de Triagem Neonatal / Study of the interfaces of the medical genetics with the health public it individual with phenylketonuric and the National Program of Neonatal Selection

Este trabalho objetivou captar e analisar a compreensão dos responsáveis por pacientes fenilcetonúricos triados pelo "Programa Nacional de Triagem Neonatal", no Estado do Rio de Janeiro, a respeito do modo pelo qual o surgimento e a incorporação de novas tecnologias de diagnóstico e tratamento pela nova genética, aplicadas ao rastreamento populacional, vêm influindo nas atitudes de indivíduos e famílias.Para tanto, foram realizados levantamento das características clínicas e demográficas referentes a um grupo de pacientes fenilcetonúricos em acompanhamento ambulatorial no Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione (IEDE) e,também, entrevistas com os respectivos responsáveis visando detectar suas noções e entendimentos sobre o Programa.Os resultados finais demonstraram inserção dos procedimentos de triagem, diagnóstico e tratamento nas recomendações governamentais atuais. As percepções dos responsáveis verbalizadas nas entrevistas sobre elementos relacionados à genética médica e à saúde pública, em suas interfaces, puderam ser alocadas em cinco categorias analíticas, a saber: as metáforas da edificação, da impressão digital, da vigilância/ da infância,das outras doenças e os "novos cidadãos genéticos".Tais resultados reforçam a necessidade da contínua integração entre os vários segmentos da atenção e cuidados à saúde e a implementação de políticas públicas de saúde, sobretudo as dirigidas para as doenças genéticas.

Glutaric aciduria type I associated with learning disability.

The authors report a 7-year-8-months-old boy with glutaric aciduria type I who had associated dyslexia, dysgraphia and dyscalculia. The diagnosis of glutaric aciduria type I was confirmed on the basis of characteristic neuroimaging and biochemical findings. Axial T1-weighted magnetic resonance imaging scan of the brain showed fronto-temporal atrophy, open opercula and bat-wing dilatation of the sylvian fissures. Axial T[2]-weighted and FLAIR imaging showed hyperintense signal abnormality in both putamen and in the fronto-parietal deep white matter. Urinary aminoacidogram by thin layer chromatography revealed a generalized aminoaciduria. Urinary organic acid analysis by gas chromatography- mass spectroscopy revealed a marked excretion of glutaric acid. Psychoeducational testing was used to diagnose the learning disability. We postulate that the accumulation of glutaric acid and other metabolites was responsible for the child developing the associated learning disability.

Anomalias de desenvolvimento e retardo mental provocados pela exposição às radiações ionizantes: atenção à gestante e criança / development abnormalities and mental retardation caused by the exposure to ionizing radiation: attention to pregnant women and children

Este estudo objetiva uma análise das anomalias de desenvolvimento e retado mental provocados pelas radiações ionizantes, no intuito de orientar os profissionais de saúde quanto aos riscos das radiografias de diagnóstico em gestantes e crianças. É universalmente conhecido que as radiações ionizantes tem grande potencial nocivo aos tecidos vivos e os estudos a respeito de seus efeitos foram realizados a partir de acidentes nucleares ambientais. O maior problema em se avaliar o risco dos efeitos é que não se conhece um método de distinção entre os efeitos induzidos pela radiação daqueles provenientes de outras fontes. O feto, que se encontra em fase de organogênese, e as crianças, apresentam grande radiossensibilidade, pois estão em processo de crescimento e desenvolvimento, sendo que distúrbios podem ocorrer durante esta fase, acarretando anomalias de desenvolvimento. Retardo mental pode ser observado em embriões que sofreram irradiação na época de desenvolvimento do sistema nervoso central (durante a 8ª e a 25ª semana gestacional). Os efeitos biológicos provenientes das radiações ionizantes variam de acordo com diversos fatores (dose, radiossensibilidade tecidual) e o conceito de altas e baixas doses é subjetivo. Apesar das tomadas radiográficas odontológicas serem consideradas de baixo risco, seu efeito pode não ser considerado insignificante, pois radiações têm ação cumulativa. Pelo exposto, são necessários cuidados para minimizar o risco, utilizando filmes ultra-rápidos, avental de chumbo, indicação e técnicas radiográficas precisas, principalmente quando se de crianças e gestantes. Observa-se necessidade de padronização das unidades de radiação mencionadas na literatura, para facilitar uma comparação entre trabalhos científicos

Agravos peri-gestacionais em pacientes atendidos em centros de referência para deficientes do Recife e zona metropolitana / Gestacional insults in patients cared for at Referenc Centers for handicapped child in Recife and Metropolitan area

Foi objetivo deste estudo avaliar a possível relação da presença de agravos peri-gestacionais e a presença de múltiplas deficiências em pacientes atendidos em centros de referência do Recife e sua região metropolitana. Realizou-se um estudo observacional transversal com componente analítico, em 309 pacientes atendidos em centros de referência em reabilitação de deficiências do Recife e região metropolitana, no período de junho a setembro de 2004. Foi aplicado aos genitores dos pacientes um questionário estruturado quanto ao uso na gestação de medicações, chás, álcool, fumo, drogas; além de presença de infecções. Analisaram-se estes dados relacionando-os com a deficiência apresentada pelo paciente. O material coletado foi arquivado em banco de dados Excel. Foi utilizado o teste de qui-quadrado (x²), para avaliação de possíveis diferenças em frequências. Dos genitores entrevistados 274/309 (89,9our cento) eram responsáveis por portadores de múltipla deficiência identificaram-se algum insulto gestacional; farmacológico, infeccioso, álcool, tabaco ou drogas em 103/309 casos (33,3por cento). O uso de chás medicinais foi o mais comum 33/309 (10,6 por cento), sguido do uso de misoprostol 7/309 (2,2por cento). Os insultos infecciosos estavam presentes no período peri-gestacional em 10,0por cento das pacientes entrevistadas. Historia de aborto prévio foi relatado em 23,3por cento das genitoras. O uso de álcool e de tabaco na gravidez foram identificado em 50/309 (16,2por cento) e 48/309 (15,1por cento), respectivamente. Na amostra estudada o uso de substâncias abortivas e o aparecimento de deficiências não puderam ser estabelecidas, não se podendo apresentar dados conclusivos. O período perigestacional é muito frágil e susceptível a insultos, podendo ser vulnerável a diversos fatores, o que dificulta atribuição das deficiências encontradas a um único evento. Verificou-se elevada frequência de pacientes com paralisia cerebral, na grande maioria das vezes associada a hipóxia ou anóxia cerebral perinatal

Inborn Errors of Metabolism in Korea

Diseases of inborn errors of metabolism (IEMs) are very rare but the overall prevalence of IEMs is not low, and in the United States, about 5~10% of admitted patients have some genetic predispositions. Clinical manifestations of IEMs are very diverse, but most frequent manifestations are neurological symptoms and signs. IEMs in Korea have been underestimated because of prejudice, underdevelopment of diagnostic tools and ignorance. The Korean Pediatric Society has done a retrospective study in order to know the relative incidence of IEMs in 2001. All hospitals with over 100 beds participated in the study. The most frequent disease was Wilson disease (201 cases for 10 years) followed by phenylketonuria (98 cases for 10 years) and Hunters disease (69 cases for 10 years). Disorders of mineral metabolism were the most frequently diagnosed disease groups (252 cases for 10 years) followed by organic acidopathies (220 cases), aminoacidopathies (139 cases), mucopolysaccharidosis (131 cases), disorders of carbohydrate metabolism (84 cases), sphingolipidosis (69 cases), urea cycle disorders (39 cases), peroxisomal disorders (27 cases), porphyrias (16 cases), disorders of purine and pyrimidine metabolism (14 cases), disorders of membrane transport (13 cases), fatty acid oxidation disorders (9 cases), oligosaccharidosis (2 cases), and mucolipidosis (1 case). Clearly, Koreans are not protected from IEMs and a systematic approach is needed to make diagnosis more easy and accurate.

Clinical evaluation and emergency management of inborn errors of metabolism presenting in the newborn.

Close to 500 biochemically diverse genetic metabolic disorders have been identified. Despite their diversity, these diseases share a number of features. First, the majority of patients with an inborn error present clinically with one of five general phenotypes; acute encephalopathy, progressive encephalopathy, primary muscle disease, primary liver disease or primary renal disease. Encephalopathy is by far the most common clinical manifestation of inborn errors of metabolism, and may be acute, intermittent, chronic (progressive), or even non-progressive. Although the five major phenotypes are a useful clinical guide, other clinical presentations of course occur, and some are virtually specific to a single disease or group of disorders. Second, almost all inborn errors are recessive in inheritance, and most of these conditions map to one of the 22 autosomes. Third, specific and effective treatment of inborn errors is often made possible by our understanding of their biochemical bases. Because inborn errors are genetic diseases, families with affected children can be made aware of the risk of recurrence, through genetic counselling. In many instances, presymptomatic treatment of affected relatives, carrier testing, and prenatal diagnosis can be offered. The types of inborn errors and their mode of presentation in the newborn are discussed, along with a schema permitting their rapid diagnosis. The principles of emergency and long term management are also discussed, with particular emphasis on those disorders that present in the newborn period with an acute encephalopathy, the so-called "small molecule" disorders.

Chromosomal and genetic forms of primary skeletal short stature

Fifty patients [25 males and 25 females with age ranging between three months and 18 years] with primary skeletal short stature were chosen for genetic assessment. Personal [prenatal and natal] and family histories were taken including those of abortions and stillbirths. The patients were clinically examined and their head circumference, weight and heights [US/LS] were measured. Karyotype, skeletal surveys, hormonal, biochemical and metabolic assays were carried out. The results showed that 17 cases had a growth failure associated with chromosomal aberrations, 12 cases suffered from inborn errors of metabolism, 11 cases had osteochondrodysplasias, while those associated with syndromes constituted ten cases. Consanguinity was present in 62%, similar cases in the family in 34%, history of abortions in 40%, disproportion in 30% and subnormal mentality in 72%

Wilson's disease: clinical and radiological features.

BACKGROUND: Wilson's disease is a treatable movement disorder with autosomal recessive inheritance which is associated with severe morbidity and mortality if not treated early. MATERIAL AND METHODS: The clinical and radiological features of 22 cases of Wilson's disease seen during January 1984 to December 1993 were analysed for clinical presentation and common radiological features. RESULTS: Among all the patients extrapyramidal features were the commonest (19/22 patients), followed closely by impaired higher mental functions (17/22 patients) and cerebellar signs (11/22 patients). In patients with onset of symptoms before 20 years, the common presentations were impaired higher mental functions, speech disturbance, dystonia and choreo-athetosis; whereas in patients with onset after 20 years cerebellar signs were commonest. The commonest CT head abnormality was basal ganglion hypodensity (10 patients) followed by brain stem hypodensity (6 patients). CONCLUSIONS: The clinical and CT scan features are evaluated and compared with reported series. Hypodensities of brain stem earlier reported a rarity, was seen in 6 out of 22 cases.