Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency / 浙江大学学报·医学版

Multiple carboxylase deficiency (MCD) includes autosomal recessive holocarboxylase synthetase (HLCS) deficiency and biotinidase (BTD) deficiency, which are caused by and gene mutations respectively. Neonatal screening for HLCS deficiency is based on 3-hydroxyisovaleryl carnitine in dry blood filter paper, and BTD deficiency is based on BTD activity determination. HLCS deficiency and BTD deficiency are characterized by neurocutaneous syndrome and organic aciduria, however, they are different in onset age, neurological symptoms and metabolic decompensation, which needed to be differentiated from acquired biotin deficiency or other genetic metabolic diseases. The diagnosis of the disease requires a combination of biochemical characteristics of hematuria, enzyme activity determination and genetic test. Routine biotin doses are effective for most MCD patients. This consensus is intended to benefit early screening and diagnosis of MCD.

Hipoventilação relacionada ao sono de origem central secundária à deficiência de biotinidase: relato de caso / Sleep-related hypoventilation due to partial biotinidase deficiency: a case repor

RESUMO: A hipoventilação relacionada ao sono de origem central resulta em hipercapnia relacionada ao sono na vigência de condições normais do sistema respiratório e excluindo-se outros fatores. Os pacientes portadores dessa patologia podem se apresentar assintomáticos ou com queixas de cefaleia matinal, déficit cognitivo e fadiga, além de eventos como a observação de respiração superficial. No presente relato, descreve-se o caso de uma paciente de três anos, com exame físico geral e neurológico normais, desenvolvimento neuropsicomotor adequado, apresentando irregu-laridades respiratórias e bradicardia durante o sono. Encaminhada para investigação de distúrbios respiratórios do sono, sendo diagnosticada com hipoventilação relacionada ao sono. Através do estudo genético, evidenciou-se a deficiência de biotinidase como a possível causa da sintomatologia, comprovada por dosagens enzimáticas e teste genético molecular. O tratamento medicamentoso foi iniciado precocemente, determinando resolução dos sintomas descritos. A importância do presente relato se encontra na apresentação da deficiência da biotinidase com quadro cardiorrespiratório isolado em criança neurologicamente normal, ademais trata-se de um caso em que a etiologia de Breath-Holding Spells foi a deficiência dessa enzima. Correspondência sugerida pela resolução da hipoventila-ção central após a introdução da biotina. Além disso, nesse caso, os sintomas Apparent Life-Threatening Events, que aterrorizam o observador e até o profissional, foram solucionados com tratamento simples, a ingesta oral de biotina. Esse relato de caso corrobora com a expansão das possibilidades de manifestações fenotípicas das formas tardias de deficiência de biotinidase, como o fenótipo da Síndrome da Hipoventilação Central. (AU)

ABSTRACT: Idiopathic sleep-related hypoventilation occurs in individuals with hypercapnia during sleep in normal conditions of the respiratory system in the absence of other disorders. Patients with this condition may be asymptomatic or have complaints of morning headache, cognitive deficit and fatigue, and observation of shallow breathing. This report describes the case of a 3-year-old patient with normal physical and neurological exam, appropriate neuropsychomotor development, presenting breathing irregularities, and bradycardia during sleep. The patient was referred to an investigation for sleep respiratory disturbs and was diagnosed with hypoventilation related to sleep. The genetic study, done by enzymatic dosages and molecular genetic tests, showed the deficiency of biotinidase as a possible cause of symptomatology. The drug treatment was initiated early with the resolution of the symptoms. The present clinical report highlights the biotinidase deficiency with an isolated cardiorespiratory condition in a neurologically normal child, which also led to Breath-Holding Spells. This relation was suggested after central hypoventilation resolution following biotin introduction. Besides, Apparent Life-Threatening Events symptoms, which terrify the observer and even professionals, disappeared after the oral intake of biotin. Finally, this case report corroborates the expansion of possibilities for the phenotypic manifestations of late cases from biotinidase deficiency, as the SHC phenotyp. ((AU)

Caracterização bioquímica e genética da deficiência de biotinidase no Programa de Triagem Neonatal de Minas Gerais: estudo prospectivo de cinco anos / Biochemical and genetic characterization of biotinidase deficiency in the Neonatal Screening Program of Minas Gerais: a five-year prospective study

A deficiência da biotinidase (DB) é doença metabólica hereditária, autossômica recessiva, causada por mutações no gene da biotinidase (BTD), localizado no cromossomo 3. Apresenta expressão fenotípica diversa em razão de deficiência variável da atividade da enzima biotinidase. Se não diagnosticada precocemente, pode causar retardo mental e até morte. O tratamento preventivo é simples e de baixo custo, consistindo na ingestão de doses farmacológicas de biotina livre durante toda a vida. Este é um estudo populacional para confirmar a incidência da DB profunda e parcial em recém-nascidos (RN) triados pelo PTN-MG, estabelecer a frequência das variantes identificadas no BTD, estimar a frequência da variante p.D444H na população triada e correlacionar os níveis de atividade enzimática da biotinidase com o genótipo. Todos os testes bioquímicos e moleculares foram realizados nos laboratórios do Nupad-UFMG. Durante os 5 anos de estudo foram triados 1.168.385 RN e 634 apresentaram resultados alterados para triagem em papel filtro. Em 620 RN foi determinada a atividade sérica da biotinidase, sendo confirmados 84 RN com DB (6 com DB profunda e 78 com DB parcial) e 52 RN considerados suspeitos de terem a doença. A incidência combinada da DB foi de 1:13.909 (IC95% - 1:11.235 a 1:17.217). O sequenciamento de BTD nos 136 RN identificou 36 mutações, sendo 9 ainda sem registro em banco de dados. As variantes mais frequentes foram a p.D444H, p.[A171T;D444H], p.D543E, intrônica (c.310-15delT), p.V199M e p.H485Q. A frequência do alelo p.D444H foi estimada em 0,016 e a de indivíduos heterozigotos, 0,031. Observou-se que nem sempre a correlação fenótipo bioquímico e genótipo é consistente dada a variabilidade da atividade enzimática tanto entre pacientes com o mesmo genótipo quanto no mesmo paciente em dosagens consecutivas. Na grande maioria dos pacientes com DB parcial identificou-se a dupla heterozigose de p.D444H com outra variante, sendo observada um contínuo de valores entre 15% e 33% da atividade enzimática de referência. Quando a outra variante era sabidamente patogênica "grave", a variação sempre ocorria dentro da faixa para DB parcial. Quando da segunda variante decorria defeito enzimático mais brando, os valores se aproximavam ou pouco ultrapassavam o ponto de corte superior para DB parcial. Conclui-se que a incidência combinada de DB em MG está entre as mais altas do mundo e que, portanto, a triagem neonatal cumpre papel crucial na identificação precoce da doença, propiciando tratamento preventivo dos sintomas e sequelas. A grande variabilidade genotípica observada nos pacientes reflete a origem multiétnica do estado. A determinação sérica da atividade enzimática é, sem dúvida, o teste mais importante para confirmação do diagnóstico da DB. O sequenciamento do gene BTD, principalmente nos casos com classificação bioquímica duvidosa, cumpre papel relevante na definição do status do paciente e da necessidade de suplementação de biotina. Este estudo demonstra que o programa de triagem neonatal para DB em Minas Gerais é viável, útil e provavelmente efetivo sob o ponto de vista econômico.

Biotinidase deficiency (BD) is an autosomal recessive metabolic disorder caused by mutations in the BTD gene, located on chromosome 3. Diverse phenotypic expression is due to variable deficiency of biotinidase enzyme activity. If not diagnosed early in life, BD may cause mental retardation and even death. Preventive treatment is simple and inexpensive, consisting of administration of free biotin at pharmacological doses throughout life. This is a population-based study aiming to confirm the incidence of profound and partial BD in newborns (NB) screened by the PTN-MG, to establish the frequency of mutations identified in BTD gene, to estimate the frequency of p.D444H variant in the screened population, and to correlate levels of biotinidase enzymatic activity with the genotype. All biochemical and molecular tests were performed at Nupad-UFMG laboratories. During the five-year study, 1,168,385 newborns were screened and 634 had abnormal results in the filter-paper screening. Serum biotinidase activity was determined in 620 newborns, and BD was confirmed in 84 NB (6 with profound and 78 with partial BD); 52 NB were suspected of having the disease (upper borderline range). The combined incidence of BD was 1:13,909 (95%CI; 1:11,235 to 1:17,217). BTD sequencing in the 136 NB identified 36 mutations, 9 of which had not yet been registered in a public database. The most frequent variants were p.D444H, p.[A171T;D444H], p.D543E, intronic (c.310-15delT), p.V199M and p.H485Q. The frequency of the p.D444H allele was estimated at 0.016 and for heterozygous individuals, 0.031. Biochemical phenotype and genotype correlation has not been always consistent given some variability of enzymatic activity both between patients with the same genotype and in the same patient in consecutive dosages. In the great majority of patients with partial BD, the double heterozygosis of p.D444H was identified with another variant, being observed a continuum of values between 15% and 33% of the reference enzymatic activity. When the other variant was known to be "severely" pathogenic, the variation always occurred within the range for partial BD. When the second variant was due to a milder enzyme defect, the values approached or slightly exceeded the upper cutoff point for partial BD. In conclusion, the combined incidence of BD in MG is among the highest in the world and, therefore, neonatal screening plays a crucial role in the early identification of the disease, providing preventive treatment of symptoms and avoiding sequelae. The large genotypic variability observed in patients reflects the multiethnic origin of the state of MG. The serum determination of enzymatic activity is undoubtedly the most important test to confirm the diagnosis of BD. The BTD gene sequencing, especially in cases with doubtful biochemical classification, plays a relevant role in defining patient status and the need for biotin supplementation. This study demonstrates that DB screening program is feasible, useful, and probably cost-effective in Minas Gerais.

Auditory Neuropathy/Dyssynchrony in Biotinidase Deficiency

Biotinidase deficiency is a disorder inherited autosomal recessively showing evidence of hearing loss and optic atrophy in addition to seizures, hypotonia, and ataxia. In the present study, a 2-year-old boy with Biotinidase deficiency is presented in which clinical symptoms have been reported with auditory neuropathy/auditory dyssynchrony (AN/AD). In this case, transient-evoked otoacoustic emissions showed bilaterally normal responses representing normal function of outer hair cells. In contrast, acoustic reflex test showed absent reflexes bilaterally, and visual reinforcement audiometry and auditory brainstem responses indicated severe to profound hearing loss in both ears. These results suggest AN/AD in patients with Biotinidase deficiency.

Deficiencia de biotinidasa y malformación de anillo vascular: reporte de un caso / Biotinidase deficiency and vascular ring malformation: case report

La deficiencia de biotinidasa es una alteración metabólica autosómica recesiva, que afecta la escisión de biotina disminuyendo su reciclado. Estudios en familiares del caso índice encontraron que generalmente ambos padres son portadores y los hermanos presentan el gen alterado; solo los homocigotos tienen síntomas que varían según el grado de deficiencia. Las madres pueden tener deficiencia moderada y mantenerse asintomáticas. En un estudio que utiliza células humanas expuestas a deficiencia de biotina, disminuyó el crecimiento celular y contribuyó al desarrollo de paladar hendido. La deficiencia de biotina en embarazadas ocasiona malformaciones en los productos. En recién nacidos, la deficiencia de biotinidasa se ha relacionado con síndrome VACTERL y páncreas anular. Se presenta el caso de una lactante con deficiencia de biotinidasa y defecto congénito de anillo vascular que rodea y comprime tráquea y esófago, alterando la deglución y la respiración. La niña fue suplementada con biotina e intervenida, con excelentes resultados.

Biotinidase deficiency is an autosomal recessive metabolic disorder that affects the cleavage of biotin. Family studies of the index case found that both parents are usually carriers and siblings have the altered gene, but only homozygotes have manifestations that vary depending on the deficiency grade. Mothers may have moderate deficiency and be asymptomatic; biotin deficiency in pregnant women causes defects in children. In a study, using human cells exposed to biotin deficiency, cell growth decreased contributing to the development of cleft palate. In newborns, biotinidase deficiency has been associated with VACTERL syndrome and annular pancreas. The case of an infant with biotinidase deficiency and congenital defect of the vascular ring is presented. This defect surrounds and compresses the trachea and esophagus, disturbing swallowing and breathing. Infant was supplemented with biotin and surgically intervened with excellent results.

Deficiencia de la actividad de biotinidasa en la población de recién nacidos del Hospital Materno Infantil Ramón Sardá / Deficiency biotinidase activity in the newborn population of Maternity Hospital Ramón Sardá

La deficiencia de biotinidasa es una enfermedad autosómica recesiva del metabolismo provocado por la ausencia o deficiencia de esta enzima. Clínicamente se caracteriza por síntomas neurológicos: convulsiones, ataxia, pérdida de la audición, atrofia óptica retardo del desarrollo, alopecia, problemas dermatológicos y alteraciones metabólicas (acidemia orgánica cuya descompensación puede llevar al coma o a la muerte). La importancia de tener un método cuantitativo en suero o plasma es importante para confirmar esta patología. Objetivo: Obtener valores de referencia de actividad de biotinidasa en la población de recién nacidos (RN) en una maternidad pública aplicando un método colorimétrico para la cuantificación de la enzima en suero. Material y métodos: Se obtuvieron muestras de pesquisa neonatal y sueros de una población de 238 RN. La actividad de la biotinidasa fue determinada utilizando un método colorimétrico (a partir de una modificación del kit Umtest Biotinidasa de Tecnosuma). Los valores de referencia obtenidos en nuestra población fueron compatibles con los hallados en la bibliografía. La población patológica testigo presentó valores concordantes con su clasificación diagnóstica.

Biotinidase’s Deficiency is an autosomal recessive disorder of metabolism caused by the absence or deficiency of the enzyme. The clinical setting characterizes for neurological (convulsions, ataxia, auditive loss, optic atrophy, development delay), alopecia, skin rash and metabolic alterations (organic acidemia whose decompensation can produce coma or death). The availability of a quantitative technique in blood serum is vital to confirm this pathology. Objective: To obtain reference values for a population of newborns at Public Maternity applying a colorimetric quantitative method in serum blood. Material and methods: Dried blood samples and sera were obtained from a population of 238 newborns. The activity of Biotinidase was measured by using a colorimetric method (from a modification of the Umtest Bionitidase kit of Tecnosuma). We obtained reference values in the analysed population, which are compatible with the bibliographic values used until now. The control pathological population had results according to its diagnostic classification.

Biotinidase deficiency: An atypical presentation.

Biotinidase deficiency is a rare metabolic disorder which can cause dermatological manifestations and lead to severe neurological sequelae if untreated. Holocarboxylase synthetase deficiency also has similar manifestations and needs to be differentiated. We present a neonate who had atypical early onset symptoms and was diagnosed to have biotinidase deficiency.

Diagnosis, treatment and follow-up in four children with biotinidase deficiency from Pakistan

Biotinidase deficiency is an inherited disorder in which the vitamin biotin is not recycled. If untreated, affected individuals develop neurological and cutaneous symptoms. Untreated individuals with biotinidase deficiency either succumb to disease or are left with significant morbidity. We describe clinical course and follow-up of 4 children from Pakistan. All 4 presented with classical symptoms of biotinidase deficiency and responded dramatically to oral biotin within days to weeks. Biotinidase deficiency is reported in Pakistani children from different part of world, however; there is no such report from Pakistan. This highlights lack of awareness of biotinidase deficiency among physicians in Pakistan.

Biotina para o tratamento da deficiência de biotinidase / Biotin for the treatment of biotinidase deficiency

A deficiência de biotinidase é um erro inato do metabolismo, de herança autossômica recessiva. Na deficiência de biotinidase, a biotina não pode ser liberada a partir de pequenos biotinilpeptídeos e da biocitina. Assim, pacientes com esta deficiência são incapazes de reciclar a biotina endógena ou de usar a biotina ligada às proteínas da dieta, conseqüentemente a biotina é perdida na urina. Os pacientes com deficiência de biotinidase apresentam uma grande variabilidade de manifestações clínicas da doença, bem como na idade de apresentação dos sintomas. O quadro clínico completo já foi relatado a partir de 7 semanas de vida, mas sintomas neurológicos mais discretos podem ocorrer mais cedo, ainda no período neonatal; no entanto, algumas crianças podem não desenvolver sintomas até a adolescência. As manifestações neurológicas como hipotonia muscular, letargia, crises convulsivas mioclônicas e ataxia são os sinais clínicos iniciais mais freqüentes. Com base no nível da atividade de biotinidase, os pacientes são classificados em três grupos principais: 1. Pacientes com deficiência de biotinidase profunda: possuem menos de 10% da média atividade sérica normal de biotinidase. 2. Pacientes com deficiência de biotinidase parcial: com 10-30% da média atividade sérica normal de biotinidase. 3. Pacientes com diminuição da afinidade da biotinidase pela biocitina: esses pacientes tem atividade enzimática normal aos testes, usualmente realizados; mas a testagem com substratos mais específicos evidencia a diminuição de afinididade. A TECNOLOGIA: Biotina - A biotina (ou vitamina H) é um composto pertencente ao grupo de vitaminas hidrossolúveis do complexo B, necessária em diversas funções metabólicas. EVIDÊNCIAS CIENTÍFICAS: Além da análise dos estudos apresentados pelo demandante, a Secretaria-Executiva da CONITEC realizou busca na literatura por artigos publicados até o dia 01/05/2012. Busca na base de dados Medline/Pubmed(26): utilizando-se os termos "Biotinidase deficiency" [Mesh] e "Therapeutics" [Mesh], restringindo-se para estudos em humanos, identificou-se 9 estudos. Quando se utilizou os termos "Biotinidase deficiency" [Mesh] e "Treatment" [Mesh], restringindo-se para estudos em humanos, identificou-se 138 estudos. Busca na base de dados Embase(27): utilizando-se os termos "Biotinidase deficiency" e "Treatment", restringindo-se para estudos em humanos, identificou-se 155 estudos. Busca na base de dados Cochrane(28): utilizando-se o termo "Biotinidase deficiency", foram identificados 3 trabalhos: uma revisão sistemática sobre triagem neonatal de erros inatos do metabolismo, um estudo de custo-utilidade sobre estratégias de triagem neonatal, uma avaliação econômica sobre programas de triagem neonatal sistemática. Nenhuma metánalise sobre tratamento de Deficiência de Biotinidase foi identificada. Foram encontrados apenas relatos e série de casos, portanto nenhuma revisão sistemática ou ensaio clínico randomizado (ECR), que seriam as melhores evidências para avaliar a eficácia de uma tecnologia usada para tratamento. Foram revisados todos os artigos clínicos em língua inglesa, espanhola e portuguesa, sem restrição de data, que se referissem à abordagem terapêutica da Deficiência de Biotinidase em humanos (independente do sexo e idade). DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 1ª reunião extraordinária do dia 04/07/2012, por unanimidade, ratificaram a deliberação de recomendar a incorporação da Biotina para o Tratamento da Deficiência de Biotinidase, conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. DECISÃO: PORTARIA SCTIE/MS N° 34, de 27 de setembro de 2012 - Torna pública a decisão de incorporar o medicamento Biotina para o Tratamento da Deficiência de Biotinidase no Sistema Único de Saúde (SUS).

La importancia de una ley a tiempo: Presentación de un caso de deficiencia de biotinidasa no diagnosticado por pesquisa neonatal / The importance of a law on time: presentation of a girl with biotinidase deficiency who was not picked up through the neonatal screening

En agosto de 2008, la Provincia de Buenos Aires no había adherido a la Ley Nacional 26279, que establece la obligatoriedad de la pesquisa neonatal para la deficiencia de biotinidasa, entre otras enfermedades. En esa fecha, nace en la Provinciade Buenos Aires una niña que derivan desde una terapia intensiva pediátrica al Hospital Nacional de Pediatría Dr. Prof. J. P. Garrahan, a los 58 días de vida, por alteración del sensorio, acidosis metabólica, hiperlacticoacidemia, alopecia, conjuntivitis y erupción cutánea eritematosa escaldada. Por estaclínica (de 13 días de evolución) se mide la actividad plasmática de biotinidasa, que resultó baja. Se inicia tratamiento con biotina y revierten rápidamente las alteraciones bioquímicas que presentaba. Si se hubiera hecho la pesquisa neonatal, estaniña no hubiera estado expuesta a riesgo de muerte por la enfermedad y se hubiese asegurado (por el inicio presintomático del tratamiento), un desarrollo normal, ya que las lesiones neurológicas no siempre retrogradan o no lo hacen ad integrum.

Hipoglicemia neonatal refractaria como presentacion de deficit parcial de biotinidasa / Neonatal refractary hypoglicemia as clinical presentation of partial deficit of biotinidase

La hipoglicemia es el problema metabólico más común en el neonato, sin embargo, en la gran mayoría de los casos es transitoria, y solo en un pequeño porcentaje se hace refractaria a concentraciones elevadas de glucosa. se describe el caso de un neonato con clínica caracterizada por hipoglicemia desde las primeras horas de vida ameritando aporte de glucosa por vía endovenosa a dosis elevadas. Se inicia una investigación diagnóstica que concluye, al analizar la combinación de síntomas junto a las alteraciones análíticas, error innato del metabolismo tipo déficit parcial de biotinidasa, el cual constituye un trastorno perteneciente al grupo de las acidurias orgánicas, de herencia autosómica recesiva, poco frecuente, que depende de un déficit en la actividad de la enzima biotinidasa. Se evidencia mejoría al iniciar el aporte exógeno de biotina con corrección sostenida de la hipoglicemia.

Hypoglycemia is the most common metabolic problem in the neonate, however, in most cases is transient, and only a small percentage is refractory to high concentrations of glucose. We describe the case of a neonate with clinically characterized by hypoglycemia during the first hours of life merit contribution of glucose by intravenous route at high doses. Begins a diagnostic investigation concludes that, when considering the combination of symptoms with alterations analytical, inborn error of metabolism rate of partial biotinidase deficiency, which is a disorder belonging to the group of organic acidurias, inherited as an autosomal recessive rare that depends on a deficit in the activity of the enzyme biotinidase. improvement is evident when you start providing exogenous biotin with sustained correction of hypoglycemia.

Biotinidase deficiency with hypertonia as unusual feature.

We report 3 cases of biotinidase deficiency presenting in early infancy with neurological and cutaneous manifestations. All of them had hypertonia (spasticity). Response to oral biotin was excellent. One of the cases showed 7D3I biotidase deficient mutation.

Gene mutation analyses in Chinese children with multiple carboxylase deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To confirm the diagnosis of multiple carboxylase deficiency (MCD) on the gene level and explore the mutations in Chinese children with MCD.</p><p><b>METHODS</b>Biotinidase (BT) and holocarboxylase synthetase (HLCS) genes were analyzed by PCR and direct sequencing for the 4 BT deficiency patients and 8 HLCS deficiency patients, respectively. The identified mutations in the parents of the patients and 50 normal controls were screened by PCR-restriction fragment length polymorphism and direct DNA sequencing.</p><p><b>RESULTS</b>Total detection rate of gene mutation is 100% in the 12 children with MCD. Six mutations were detected in the 4 children with BT deficiency, they were c. 98-104del7ins3, c. 1369G>A (V457M), c. 1157G>A(W386X), c. 1284C>A(Y428X), c. 1384delA and c. 1493_1494insT. The last four were novel mutations. Four mutations were found in the 8 children with HLCS deficiency. They were c. 126G>T (E42D), c. 1994G>C (R665P), c. 1088T>A (V363D) and c. 1522C>T (R508W). The last two were hot-spot mutations [75%(12/16)], and c. 1994G>C (R665P) was a novel mutation.</p><p><b>CONCLUSION</b>This study confirmed the diagnosis of 12 patients with MCD on the gene level. Six mutations were found in the BT gene and 4 in the HLCS gene, including 5 novel mutations. Two mutations of the HLCS gene are probably hot-spot mutations in Chinese children with HLCS deficiency.</p>

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.

Biotinidase deficiency.

A three month old baby presented with refractory seizures, dermatosis and persistent metabolic acidosis. Biotinidase deficiency was diagnosed on enzyme assay. Patient responded dramatically to biotin supplementation.

Organic acidemias in Korea: Eight years experience of organic acid analysis / 소아과

PURPOSE: We have done this retrospective study to know the relative incidence and clinical manifestations of organic acidopathies in Korea during 8 years(from Jul. 1997 to May 2005). This results of organic acid analysis of 1,787 patients were compared with the results of organic acid analysis that were published three years ago. METHODS: The results of quantitative organic acid analysis of samples of 1788 patients, referred from Jul. 1997 to May 2005, were analyzed retrospectively according to four age group(-2 mon, 3 mon-2 years, 3-12 years) and major clinical manifestations. Quantification of 83 organic acids was done with gas chromatography and mass spectometry. RESULTS: We diagnosed 470 patients with 27 diseases of organic acid metabolism during this study period. Diseases found more than 10 cases are cytosolic 3-ketothiolase deficiency, mitochondrial respiratory chain disorders, PDHC deficiency, mitochondrial 3-ketothiolase deficiency, glutaric aciduria type II, biotinidase deficiency, methylmalonic aciduria and propionic aciduria. Other diseases were diagnosed in less than 10 cases. CONCLUSION: Though the incidence of individual organic acidemia is low, the overall incidence of organic acidemia as a whole seems to be relatively high in Korea. Compared with the results of organic acid analysis that were reported three years ago, we couldn't find a new disease and the difference of the relative incidences of high incident diseases. We were apprehensive of the errors that was owing to the short study period(3 years), but the relative incidences of our study(8 years) were similar to the results of organic acid analysis that were reported three years ago.

Organic acidemias in Korea / 한양의대학술지

Since we started organic acid analysis in July 1997, we have collected data about organic acidemias in Korea. The data presented herein constitute our 3 years experience in organic acid analysis. We have collected 712 samples from major university hospitals in all over Korea, which are large enough for relatively accurate estimation of incidence of organic acid disorders. We used solvent extraction method with ethylacetate, MSTFA for derivatization and simultaneously quantitation of 83 organic acids. Out of 712 patients sample, 498 samples (70%) showed no evidence of organic acid abnormalities. Out of the 214 remaining samples, we found very diverse disorders such as methylmalonic aciduria (6), propionic aciduria (10), biotinidase deficiency (6), maple syrup urine disease (3), isovaleric aciduria (4), tyrosinemia type II (4), tyrosinemia type IV (1), glutaric aciduria type I (1), glutaric aciduria type II (22), 3-methylglutaconic aciduria type I (3), 3-methylglutaconic aciduria type III (7), HMG-CoA lyase deficiency (1), hyperglyceroluria (2), cytosolic 3-ketothiolase deficiency (55), mitochondrial 3-ketothiolase deficiency (3), 3-hydroxyisobutyric aciduria (2), L-2-hydroxyglutaric aciduria (2), fumaric aciduria (2), lactic aciduria with combined elevation of pyruvate (most likely PDHC deficiency) (28), lactic aciduria without combined elevation of pyruvate (most likely mitochondrial respiratory chain disorders) (35), SCAD deficiency (3), MCAD deficiency (1), 3-methylcrotonylglycineuria (1), orotic aciduria (most likely urea cycle disorders) (7) and 2-methylbranched chain acyl-CoA dehydrogenase deficiency (1). In conclusion, although the incidence of individual organic acidemia is low, the incidence of overall organic acidemia is relatively high in Korea. Most of the patients showed some signs of neurological dysfunction. Therefore, organic acid analysis should be included in the diagnostic work up of all neurological dysfunctions.

Biotinidase deficiency presenting with dermal manifestations of acrodermatitis enteropathica

Biotin is a water-soluble vitamin and co-factor for activation of carboxylases apoenzymes. Biotinidase enzyme is essential for release of biotin from apoenzymes. Absence of biotinidase is an autosomal recessive trait with a prevalence of 1 in 60000. Clinical manifestations of biotinidase deficiency include dermatitis, alopecia, seizures, hypotonia, developmental delay, hearing loss, visual impairment and immunodeficiency. With early diagnosis and treatment with biotin supplements, it is possible to prevent clinical manifestations and neurological deficits. We report a case of biotinidase deficiency with seizures, developmental delay, acrodermatitis enthropathica manifestations and mild compensated acidosis

Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations

Biotinidase deficiency is an inherited metabolic disorder characterized by neurological and cutaneous symptoms. Fortunately, it can be treated and the symptoms prevented by oral administration of the vitamin biotin. Using dried blood-soaked filter paper cards, biotinidase activity was determined in the sera of 225,136 newborns in Brazil. Mutation analysis performed on DNA from 21 babies with low serum biotinidase activity confirmed that 3 had profound biotinidase deficiency (less than 10 percent of mean normal sera biotinidase activity), 10 had partial biotinidase deficiency (10 to 30 percent of mean normal serum activity), 1 was homozygous for partial biotinidase deficiency, 4 were heterozygous for either profound or partial deficiency, and 3 were normal. Variability in serum enzyme activities and discrepancies with mutation analyses were probably due to inappropriate handling and storage of samples sent to the laboratory. Obtaining an appropriate control serum at the same time as that of the suspected child will undoubtedly decrease the false-positive rate (0.09 percent). Mutation analysis can be used to confirm the genotype of these children. The estimated incidence of biotinidase deficiency in Brazil is about 1 in 9,000, higher than in most other countries. Screening and treatment of biotinidase deficiency are effective and warranted. These results strongly suggest that biotinidase deficiency should be included in the newborn mass screening program of Brazil.