Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism.

Importance: Recent advances in newborn screening (NBS) have improved the diagnosis of inborn errors of metabolism (IEMs); however, many potentially treatable IEMs are not included on NBS panels, nor are they covered in standard, first-line biochemical testing. Objective: To examine the utility of untargeted metabolomics as a primary screening tool for IEMs by comparing the diagnostic rate of clinical metabolomics with the recommended traditional metabolic screening approach. Design, Setting, and Participants: This cross-sectional study compares data from 4464 clinical samples received from 1483 unrelated families referred for trio testing of plasma amino acids, plasma acylcarnitine profiling, and urine organic acids (June 2014 to October 2018) and 2000 consecutive plasma samples from 1807 unrelated families (July 2014 to February 2019) received for clinical metabolomic screening at a College of American Pathologists and Clinical Laboratory Improvement Amendments-certified biochemical genetics laboratory. Data analysis was performed from September 2019 to August 2020. Exposures: Metabolic and molecular tests performed at a genetic testing reference laboratory in the US and available clinical information for each patient were assessed to determine diagnostic rate. Main Outcomes and Measures: The diagnostic rate of traditional metabolic screening compared with clinical metabolomic profiling was assessed in the context of expanded NBS. Results: Of 1483 cases screened by the traditional approach, 912 patients (61.5%) were male and 1465 (98.8%) were pediatric (mean [SD] age, 4.1 [6.0] years; range, 0-65 years). A total of 19 families were identified with IEMs, resulting in a 1.3% diagnostic rate. A total of 14 IEMs were detected, including 3 conditions not included in the Recommended Uniform Screening Panel for NBS. Of the 1807 unrelated families undergoing plasma metabolomic profiling, 1059 patients (58.6%) were male, and 1665 (92.1%) were pediatric (mean [SD] age, 8.1 [10.4] years; range, 0-80 years). Screening identified 128 unique cases with IEMs, giving an overall diagnostic rate of 7.1%. In total, 70 different metabolic conditions were identified, including 49 conditions not presently included on the Recommended Uniform Screening Panel for NBS. Conclusions and Relevance: These findings suggest that untargeted metabolomics provided a 6-fold higher diagnostic yield compared with the conventional screening approach and identified a broader spectrum of IEMs. Notably, with the expansion of NBS programs, traditional metabolic testing approaches identify few disorders beyond those covered on the NBS. These data support the capability of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered in the initial evaluation for metabolic disorders.

Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism.

Children with inborn errors of intermediary metabolism (IEiM) must follow special diets that restrict their intake of essential nutrients and may compromise normal growth and development. We evaluated body composition, bone mineral density, physical activity, and food intake in IEiM patients undergoing dietary treatment. IEiM patients (n = 99) aged 5-19 years and healthy age- and sex-matched controls (n = 98) were recruited and underwent dual-energy X-ray absorptiometry to evaluate anthropometric characteristics and body composition. Data on food intake and physical activity were also collected using validated questionnaires. The height z-score was significantly lower in IEiM patients than controls (-0.28 vs. 0.15; p = 0.008), particularly in those with carbohydrate and amino acid metabolism disorders. Significant differences in adiposity were observed between patients and controls for the waist circumference z-score (-0.08 vs. -0.58; p = 0.005), but not the body mass index z-score (0.56 vs. 0.42; p = 0.279). IEiM patients had a significantly lower total bone mineral density (BMD) than controls (0.89 vs. 1.6; p = 0.001) and a higher risk of osteopenia (z-score < -2, 33.3% vs. 20.4%) and osteoporosis (z-score < -2.5, 7.1% vs. 0%), but none presented fractures. There was a significant positive correlation between natural protein intake and BMD. Our results indicate that patients with IEiM undergoing dietary treatment, especially those with amino acid and carbohydrate metabolism disorders, present alterations in body composition, including a reduced height, a tendency towards overweight and obesity, and a reduced BMD.

Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with CPT2D, VLCADD and LCHADD/TFPD.

BACKGROUND: The plasma acylcarnitine profile is frequently used as a biochemical assessment for follow-up in diagnosed patients with fatty acid oxidation disorders (FAODs). Disease specific acylcarnitine species are elevated during metabolic decompensation but there is clinical and biochemical heterogeneity among patients and limited data on the utility of an acylcarnitine profile for routine clinical monitoring. METHODS: We evaluated plasma acylcarnitine profiles from 30 diagnosed patients with long-chain FAODs (carnitine palmitoyltransferase-2 (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxy acyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCHAD/TFP) deficiencies) collected after an overnight fast, after feeding a controlled low-fat diet, and before and after moderate exercise. Our purpose was to describe the variability in this biomarker and how various physiologic states effect the acylcarnitine concentrations in circulation. RESULTS: Disease specific acylcarnitine species were higher after an overnight fast and decreased by approximately 60% two hours after a controlled breakfast meal. Moderate-intensity exercise increased the acylcarnitine species but it varied by diagnosis. When analyzed for a genotype/phenotype correlation, the presence of the common LCHADD mutation (c.1528G > C) was associated with higher levels of 3-hydroxyacylcarnitines than in patients with other mutations. CONCLUSIONS: We found that feeding consistently suppressed and that moderate intensity exercise increased disease specific acylcarnitine species, but the response to exercise was highly variable across subjects and diagnoses. The clinical utility of routine plasma acylcarnitine analysis for outpatient treatment monitoring remains questionable; however, if acylcarnitine profiles are measured in the clinical setting, standardized procedures are required for sample collection to be of value.

Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery.

PURPOSE: Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. METHODS: We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. RESULTS: The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. CONCLUSIONS: Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.

Normal vitamin D levels and bone mineral density among children with inborn errors of metabolism consuming medical food-based diets.

A higher incidence of osteopenia is observed among children with inherited metabolic disorders (inborn errors of metabolism, or IEMs) who consume medical food-based diets that restrict natural vitamin D-containing food sources. We evaluated the vitamin D status of children with IEMs who live in the Pacific Northwest with limited sun exposure and determined whether bone mineral density (BMD) in children with phenylketonuria (PKU), the most common IEM, correlated with diet or biochemical markers of bone metabolism. We hypothesized that children with IEMs would have lower serum vitamin D concentrations than controls and that some children with PKU would have reduced bone mineralization. A retrospective record review of 88 patients with IEMs, and 445 children on unrestricted diets (controls) found the 25-hydroxyvitamin D concentrations were normal and not significantly different between groups (IEM patients, 27.1 ± 10.9; controls, 27.6 ± 11.2). Normal BMD at the hip or spine (-2

[GASTROSTOMY POSITIVELY AFFECTS NUTRITIONAL STATUS AND DIMINISHES HOSPITAL DAYS IN PATIENTS WITH INBORN ERRORS OF METABOLISM]. / LA GASTROSTOMÍA AFECTA POSITIVAMENTE AL ESTADO NUTRICIONAL Y DISMINUYE LOS DÍAS DE HOSPITALIZACIÓN EN PACIENTES CON ERRORES INNATOS DEL METABOLISMO.

INTRODUCTION: the nutrition management of patients with inborn errors of metabolism (IEM) requires the permanent use of elemental medical formulas whose organoleptic characteristics sometimes impede oral acceptance. In addition, these patients may have gastrointestinal disorders and require constant use of drugs, that often complicate treatment adherence, thereby committing their nutritional status and disease control. Gastrostomy is an alternative to facilitate feeding and treatment, but its use is controversial. OBJECTIVE: to compare nutrition status and length of hospitalizations before and after gastrostomy surgery in a group of IEM patients. METHODS: retrospective analysis of anthropometric data, number of hospitalizations due to metabolic decompensation and length in pediatric patients with IEM before and after gastrostomy. RESULTS: 16 children were analyzed, 40% with propionate disorders, 25% with abnormal urea cycle and 35% other IEM. After gastrostomy, the number of eutrophic patients increased from 6-56%, and malnutrition decreased from 94 to 44%. After gastrostomy inpatient hospital days significantly decrease from 425 to 131 (p = 0.011), admission numbers pre-gastrostomy decreased from 33 to 17, however this difference was not statistically significant. CONCLUSION: in this sample, gastrostomy improved nutritional status in 56% of EIM patients and significantly reduced hospital days caused by metabolic decompensation.

Introducción: el tratamiento nutricional de los pacientes con errores innatos del metabolismo (EIM) implica el uso permanente de fórmulas modificadas en aminoácidos cuyas características organolépticas pueden dificultar su aceptación por vía oral. Estos pacientes pueden tener alteraciones gastrointestinales y requieren el uso constante de medicamentos, lo cual complica la adherencia al tratamiento, comprometiéndose con ello su estado nutricional y el control de la enfermedad. La gastrostomía es una alternativa para facilitar la alimentación y el tratamiento, pero existen controversias sobre su uso. Objetivo: comparar el estado nutricional y la duración de las hospitalizaciones antes y después de la realización de la gastrostomía en un grupo de pacientes con EIM. Métodos: análisis retrospectivo de datos antropométricos, número de internamientos por descompensación metabólica y su duración en pacientes pediátricos con EIM antes y después de la gastrostomía. Resultados: se analizaron 16 niños; 40% con defectos del propionato, 25% con alteraciones del ciclo de la urea y 35% con otros EIM. Después de la gastrostomía, la proporción de pacientes eutróficos aumentó del 6 al 56% y la desnutrición disminuyó del 94 al 44%. Después de la gastrostomía, la duración de los periodos hospitalarios disminuyó significativamente de 425 a 131 días (p = 0.011); el número de internamientos disminuyó de 33 antes de la intervención a 17, sin embargo, esta diferencia no tuvo significación estadística. Conclusión: en esta muestra, la gastrostomía mejoró el estado nutricional en 56% de los pacientes con EIM, y redujo significativamente los días de hospitalización por descompensación metabólica.

Vitamin A and retinol-binding protein deficiency among chronic liver disease patients.

OBJECTIVE: Vitamin A deficiency (VAD) is associated with the progression of chronic liver disease (CLD). The aim in this study was to assess levels of serum retinol and retinol-binding protein (RBP) as well as liver vitamin A stores in the presence of liver cirrhosis and hepatocellular carcinoma. METHODS: We ascertained the serum retinol and RBP levels of randomly selected CLD patients divided into two groups, one given 1500 UI (n = 89) and the other receiving 2500 UI (n = 89) doses of retinyl palmitate for the relative dose response test. Blood samples were collected in a fasting state and 5 and 7 h after supplementation. RESULTS: The prevalence of VAD was 62.4%. There was a progressive drop in serum retinol (P < 0.001) and RBP (P = 0.002) according to the severity of the liver disease, and a greater prevalence of severe VAD was noted in cirrhosis Child & Pugh C (52.8%). Fifty percent of the patients presented a low availability of RBP relative to retinol concentration, and there was no peak in RBP levels regardless of the dose of retinyl palmitate administered. CONCLUSIONS: Our findings suggest serum retinol and RBP are relevant as indicators of vitamin A nutritional status in the presence of CLD. Liver vitamin A store cannot be evaluated using the RDR test because CLD causes a reduction in RBP synthesis and interferes with the mobilization of endogenous vitamin A. Considering how the patients already showed a drop in RBP relative to retinol concentrations, it is reasonable to assume vitamin A supplementation may trigger harmful effects in CLD patients.

Assessment of quality of life of the children and parents affected by inborn errors of metabolism with restricted diet: preliminary results of a cross-sectional study.

INTRODUCTION: The development in therapeutic strategies has increased survival of children affected by inborn errors of metabolism with restricted diet (IEMRD). These diseases have mild- and long-term consequences on the health. Little is known about the impact on the quality of life (QoL) of children and their families. The aims of this study were: to compare the QoL of the children and parents affected by IEMRD with the QoL of the general population and one pathology associated with long-term consequences. PATIENTS AND METHODS: This cross-sectional study was performed at the French Reference Center for inborn metabolic disorders (Marseille, France). Inclusion criteria were: a child with a diagnosis of organic aciduria, urea cycle defect, or maple syrups urine disease (MSUD). Socio-demographics, clinical data, and QoL were recorded. RESULTS: Twenty-one of 32 eligible families were included during a planned routine visit. Ten (47%, 95% CI 27-69%) children were affected by organic aciduria, six (29%, 95% CI 10-48%) by urea cycle defects, and five (24%, 95% CI 6-42%) by MSUD. Among the younger children, the general well-being was significantly lower in the children with IEMRD than in the leukemia children (58 ± 16 versus 76 ± 15, p = 0.012), and among the older children, the leisure activities were significantly lower in the children with IEMRD than in the leukemia children (29 ± 18 versus 62 ± 22, p < 10-3), while the relationships with teachers were better (76 ± 23 versus 60 ± 23, p = 0.01). The physical QoL score was lower in the parents than in the French norms (66 ± 21 versus 75 ± 1, p = 0.05). Factors modulating QoL were: eating and neurologic disorders, enteral nutrition, and feeding modalities. CONCLUSION: The children and the parents of children affected presented altered 'physical' and 'social' QoL scores compared with the norms and patients with leukemia and their families. Future studies based on larger cohort studies should determine the different weights of potential predictive factors of QoL.

A new case of malonic aciduria with a presymptomatic diagnosis and an early treatment.

Malonyl-CoA decarboxylase deficiency (MLYCD) is a rare autosomal recessive inborn error of metabolism presenting a variable clinical phenotype. We report an affected Italian male receiving an early diagnosis (8days after birth) and a timely dietary therapy (high carbohydrate, low long chain fatty acid and medium chain triglyceride supplemented diet with l-carnitine supplementation). The boy was born at term and presented normal function of the heart (except for a tricuspid Ebstein-like dysplasia) and neurodevelopmental status. Genomic sequencing of MLYCD gene revealed two point mutations (c.672G>A, c.869C>T) not listed in the Human MLYCD Allelic Variant Database nor in Human Gene Mutation Database, responsible for a deleterious effect on protein structure and function according to a computational analysis (MuPro, SIFT, ConSEQ v1.1). At the age of 2years he only showed a mild language and psychomotor delay, while heart functioning became normal. Brain MRI examination was normal. Thirty-five cases, including our patient, have been described to date. This is the first report concerning a malonic aciduria patient diagnosed on newborn screening and treated in a presymptomatic stage of the disease.

Nutritional management of patients with urea cycle disorders.

The nutritional management of patients with urea cycle disorders (UCDs) involves restriction of dietary protein along with provision of adequate protein-free energy, essential amino acid supplements, and vitamins and minerals in combination with nitrogen-scavenging drugs. The present paper discusses nutrition therapy for a range of circumstances: during an acute hyperammonaemic episode and at hospital discharge; before, during, and after surgery; and for lifelong chronic management of UCDs.

[Diagnosis and treatment of methylmalonic aciduria: a case report]. / Diagnóstico y tratamiento de la aciduria metilmalónica: a propósito de un caso.

The methylmalonic aciduria is an organic acidemia, inherited as autosomic recessive trait, caused by a deficiency of the methylmalonyl-CoA mutase, or by defects in the biosynthesis of the cofactor adenosylcobalamin. Regarding the enzymatic defect, there are two forms: mut(o) with no detectable enzymatic activity and mut(-) with reduced activity. Its clinical presentation may vary from a severe neonatal form with acidosis and death, up to a progressive chronic form. Here we describe the case of a four year-old boy, with diagnosis of methylmalonyl-CoA mutase deficiency type mut(-) with an acute presentation. Molecular analysis of MUT gene identified two mutations c.607G>A (G203R) and c.2080C>T (R694W), later confirmed in the parents. The aim of this report is to highlight the importance of including the organic acid analysis in urine among the first line exams in acutely and severely ill children with undefined etiology. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the secuelae.

Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study.

BACKGROUND AND PURPOSE: Brain creatine (Cr) deficiencies (BCr-d) are rare disorders of creatine biosynthesis and transport. We performed consecutive measures of total Cr (tCr) and of its phosphorylated fraction, phosphocreatine (PCr), in the brains of children affected by Cr synthesis defects during a long period of therapy. The aim was to identify the optimal treatment strategy for these disorders. MATERIALS AND METHODS: Two patients with guanidinoacetate methyltransferase defect (GAMT-d) were treated with different amounts of Cr and with diet restrictions aimed at reducing endogenous guanidinoacetate (GAA) synthesis. Three patients with arginine:glycine amidinotransferase defect (AGAT-d) were treated with different Cr intakes. The patients' treatments were monitored by means of (1)H- and (31)P-MR spectroscopy. RESULTS: Cr and PCr replenishment was lower in GAMT-d than in AGAT-d even when GAMT-d therapy was carried out with a very high Cr intake. Cr and especially PCr replenishment became more efficient only when GAA blood values were reduced. Adenosine triphosphate (ATP) was increased in the baseline phosphorous spectrum of GAMT-d, and it returned to a normal value with treatment. Brain pH and brain P(i) showed no significant change in the AGAT-d syndrome and at any Cr intake. However, 1 of the 2 GAMT-d patients manifested a lower brain pH level while consuming the GAA-lowering diet. CONCLUSIONS: AGAT-d treatment needs lower Cr intake than GAMT-d. Cr supplementation in GAMT-d treatment should include diet restrictions aimed at reducing GAA concentration in body fluids. (1)H- and especially (31)P-MR spectroscopy are the ideal tools for monitoring the therapy response to these disorders.

Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet.

The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

Glutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography-mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L: -carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

Choline- and betaine-defined diets for use in clinical research and for the management of trimethylaminuria.

This article describes the development of a series of choline- and betaine-controlled diets that were served to research subjects as part of an ongoing study of diet requirements in humans. These diets were developed based on the analysis of choline and betaine in individual foods. The calculated diets were compared with analyses of all foods combined into a single sample for each day. The laboratory analyses of choline and betaine in the whole-diet aliquots matched the estimated amounts in the diets that were calculated from the analyses of individual foods. These diets were adjusted for several levels of choline and betaine and were well accepted by research subjects who consumed them for a time period of up to 2 months. This article describes applications of this diet for use in clinical research on methyl-group requirements in humans and for use in clinical practice for counseling the client who requires a choline-controlled diet.

Dietoterapia en errores innatos del metabolismo / Nutritional treatment of inborn errors of metabolism

Dependiendo del defecto enzimático, algunos errores innatos del metabolismo (EIM) responden satisfactoriamente a la manipulación de la dieta. Según la alteración metabólica, se han identificado siete formas de tratamiento nutricional, las que permiten reestablecer el balance metabólico. Una de ellas es a través de la reducción del sustrato acumulado causado por la deficiencia primaria de una enzima o por la inhibición secundaria de una de ellas. Un ejemplo ampliamente descrito en la literatura es la fenilquetonuria en la que se ha demostrado que gracias al diagnóstico neonatal temprano, seguido de un tratamiento basado en una dieta restringida en fenilalanina revierten su acumulación previniendo con ello el da¤o neurológico que la enfermedad causa al no ser tratada temprana y adecuadamente. Otra forma de tratamiento es la suplementación de una sustancia nutritiva en déficit debido al defecto metabólico, como ocurre en los defectos del ciclo de la urea, en los cuales donde la arginina debe entregarse como fármaco. Algunos EIM con defecto parcial de la enzima tienen la posibilidad de estimular vías alternas para detoxificar o evitar la síntesis de sustancias nocivas a través drogas o megadosis de vitaminas, un ejemplo es la homocistinuria donde la betaína y piridoxina reducen la producción de homocisteína. Otros defectos enzimáticos abren vías metabólicas alternas, las que generan metabolitos tóxicos, el tratamiento en estos casos, consiste en proporcionar cofactores o megadosis de vitaminas para formar complejos no tóxicos que sean excretados por vía urinaria. Es importante se¤alar que el diagnóstico precoz y el seguimiento estricto a largo plazo, permite que un ni¤o con un EIM se desarrolle normalmente.

Dietary management of inborn errors of metabolism.

Inborn errors of metabolism are individually rare but are an important cause of mortality and morbidity in infants and children. Dietary therapy is the mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia and glycogen storage disease (Type I/III). Some disorders like urea cycle disorders and organic acidurias require dietary modification in addition to other modalities. Certain basic principles of dietary management should be clearly understood for proper management of these disorders. Commercially available diets are very expensive and modification in routine Indian diet may be tried based on content of different nutrients but the desirable fine control is not achieved.

[Treatment of inborn metabolic disorders]. / Behandling af arvelige stofskiftesygdomme.

Biochemical knowledge about inborn errors of metabolism has increased considerably and new biochemical technology has improved our diagnostic possibilities. Therapy includes diet with substrate restriction and supplementation of deficient metabolites, medical reduction of substrate, inhibition of catabolic pathways, vitamins, enzyme substitution, enzyme stabilisation, and transplantation. A future possibility is somatic gene therapy. Treatment of many metabolic disorders is now possible, but it is important to establish both national and international expertise for proper use of new therapies and their evaluation.

Deficiência da 3-0H-3-metil-glutaril-Coa-Liase como causa de coma no período neonatal: relato de caso / 3-hydroxy-3-methyglutaryl-CoA-lyse deficiency as coma etiology in the neonatal period: case report

Estudamos um paciente que apresentou dois episódios de coma no primeiro mês de vida, com descompensaçao metabólica, nos quais se observou hipoglicemia e acidose metabólica acentuada, sem cetonúria. O estudo dos ácidos orgânicos urinários demonstrou elevaçao acentuada de 3-OH-3-metil-glutárico, 3-metil-glutacônico, 3-metil-glutárico e 3-OH-isovalérico. Os sinais e sintomas clínicos associados às alteraçoes metabólicas citadas permitiram o diagnóstico da deficiência da 3-OH-3-metil-glutaril-CoA-liase, entidade de origem autossômica recessiva, passível de ser tratada, como no caso estudado, com dieta hipoproteica, restrita em leucina, hipogordurosa e rica em carboidratos, associada a L-carnitina e evitando-se períodos prolongados de jejum.