About one century ago, Garrot defined the first disease of inbron error of metabolism. Many diseases have been classified in this category. ORGANIC ACIDEMIA with multiple manifestation is one of them. A 12 year old boy with several episodes of METABOLIC ACIDOSIS and one attack with loss of conciousness, but with lack of skin manifestation was admitted to the clinic. His diagnosis as METHYL MALONIC ACIDEMIA has definitly been confirmed by sending a sample aboard. Although such diagnosis is difficult to make in Iran, but our information about such case will be helpful in correct diagnosis of any cases with unexplained METABOLIC ACIDOSIS and developmental delay.

Dear Editor: METHYL-MALONIC ACIDEMIAs (MMA) are a group of autosomal recessive disorders caused by diminished activity of METHYL- malonyl-CoA mutase (MCM) enzymes. MCM converts METHYL-malonyl-CoA to succinyl- CoA, which then can be metabolized in the Krebs cycle. Either the defect in the MCM activity or its cofactor 5’-deoxyadenosylcobalamin (AdoCbl) may lead to accumulation of the METHYL-MALONIC acid.

ORGANIC acid occur as physiologic intermediates in variety of intracellular METABOLIC pathways, such as catabolism of amino acid, mitochondrial b oxidation of fatty acids, tricarboxilic acid cycle, and cholesterol and fatty acid biosynthesis. The classical ORGANIC aciduria represent the pursuit of abnormalities of aminoacid degradation beyond deamination Their diagnostic hallmark is an accumulation of characteristic ORGANIC acids. The clinical features result from toxicity of the accumulating methabolites. Treatment involved 1. protein restriction 2. supplementation of amino acids with unimpaired metabolism as well as trace elements and 3. specific measures for detoxification if indicated. Diagnostic tests consist of CBC, FBS, Bun, Cr, uric ORGANIC acid, TG, Cholesterol Ca, P, ALP, VBG, Na, K, Cl, U/A (PH, SG, Ketone), Ammonia, lactate, pyrovate, Ketone body CPK, Aldolase, SGOT, SGPT, BIL, PT, PTT, Plasma amino acid HPLC, Homocysteine, Urine amino acid and carbohydrate chromatography, Acyl carnitine profile, urine ORGANIC acids and for next steps tissue specimen and enzyme activity and gene study. clinical chemical indices of organid aciduria is METABOLIC ACIDOSIS, Increased anion gap, Hyperglycemia and hypoglycemia, Ketosis and Ketonuria, Lactic ACIDOSIS, Hyperammonemia, Hyperuricemia, Hypertriglyceridemia, increase of transaminase Granulocytopenia, thrombocytopenia and Anemia. Acylcarnitine profile and urine ORGANIC acids are two for important tests for differentiation of types of ORGANIC academia.

ORGANIC ACIDEMIAs, also known as ORGANIC acidurias, are a group of disorders characterized by increased excretion of ORGANIC acids in urine. They result primarily from deficiencies of specific enzymes in the breakdown pathways of amino acids or from enzyme deficiencies in beta oxidation of fatty acids or carbohydrate metabolism. ORGANIC acids also are found in the urine of some patients with mitochondrial disease. Most ORGANIC ACIDEMIAs become clinically apparent during the newborn period or early infancy. After an initial period of well-being, affected children develop a life-threatening episode of METABOLIC ACIDOSIS characterized by an increased anion gap. This presenting episode may be mistaken for sepsis, and if unrecognized, is associated with significant mortality. Children with an ORGANIC ACIDEMIA are susceptible to METABOLIC decompensation during episodes of increased catabolism, such as intercurrent illness, trauma, or surgery. Parents and clinicians must be well informed about the initial signs of decompensation and trained in applying an emergency regimen. Surgeons and anesthesiologists should be aware of potential complications and their prevention during anesthesia and surgery. Diagnosis has been facilitated through the use of gas chromatograph-mass spectrometry (GC-MS) and tandem mass spectrometry. Prenatal diagnosis is available for most disorders by detection of diagnostic compounds in amniotic fluid, by analysis of enzyme activities in amniocytes or chorionic villi, by molecular analysis, or by a combination of the three. Diagnosis also may be made through newborn screening by tandem mass spectrometry. Laboratory findings are an essential part of the diagnostic approach to ORGANIC ACIDEMIAs. In most ORGANIC ACIDEMIAs, metabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of the acid-base balance. Hypoglycemia, lactic and/or ketoACIDOSIS, and hyperammonemia of varying severity accompany the overt or compensated ACIDOSIS. In most instances, a definite diagnosis will be achieved by gas chromatography/mass spectrometry (GC/MS) studies of the urine. However sometimes definite diagnosis by clinical and laboratory assessments is not conclusive, in this cae diagnostic approach must be supported by loading tests. The majority of ORGANIC ACIDEMIAs may be treated by limiting the source of intake or removing the toxic intermediary metabolite. In the case of disorders lacking an effective treatment, an early diagnosis could lead to proper genetic counseling of the parents and to the option of reliable prenatal diagnosis of future pregnancies.

Immidiate Management Infants and children with acute METABOLIC crisis require immediate treatment to prevent further acute deterioration and long-term sequelae. Early and appropriate treatment before confirmation of the diagnosis is life-saving. Eliminate intake of the precursors of possibly toxic metabolites. This applies most often to suspected inborn errors of amino acid or ORGANIC acid metabolism. In both cases, dietary or parenteral intake of protein and amino acids should be eliminated immediately an ORGANIC ACIDEMIA is suspected. Administer glucose a simple source of calories at least 8 mg/kg / min to suppress mobilization of endogenous sources of the metabolites. This is achieved by the intravenous administration of 10% dextrose supplemented by Intralipid. Specific Therapy disease NPO: Minimize intake and endogenous production of toxic metabolites. Hadration: Administer high-calorie, high-carbohydrate intravenous fluids: 10% dextrose in 0.2% NaCl at 1.5 times calculated maintenance, and add KCl .Alkali Therapy: Bicarbonate is generally not indicated unless the plasma bicarbonate is<10 mmol/Lو deficits should be only half corrected. Hemo or peritoneal dialysis: If just described measures fail to induce clinical & biochemical improvement, hemo or peritoneal dialysis is indicated to Accelerate elimination of toxic metabolites. If hyperammonemia exists:1.5×Maintenance D/W 10 % & intravenous lipids 1 g/kg 24 h Sodium benzoate 250 mg/kg to be added to 20 cc/kg of 10% glucose & infused within 1-2 h (priming dose) Continue infusion of sodium benzoate 250-500 mg/ kg / 24 h following the above priming dose & should be added to daily intravenous fluids Initiate peritoneal dialysis or hemodialysis :if above treatment fails to produce an appropriate decrease in plasma ammonia. Peritoneal dialysis is too slow. Exchange transfusion brings the plasma ammonium down quickly, but rebound hyperammonemia occurs just as quickly. It may be useful in some circumstances as an adjunct to hemodialysis.Cofactors Therapy Administration of cofactors may be indicated in ORGANIC ACIDEMIA :Biotin 10 mg/dayCarnitine 100 / mg / kg / day in three divided doses IV or orallyCobalamin (vitamin B12) 1 mg SC or IMB6 100 mg IV or Activated B6 10 mg/kg IV, should be given to neonates with seizures unresponsive to conventional anticonvulsants, if there is no response to B6 and Activated B6 ,folinic acid , should be administered for possible folinic acid responsive seizures.

The deficiency of isovaleryl-CoA dehydrogenase leads to an inborn recessive error of leucine metabolism named isovaleric ACIDEMIA (IVA). Its presentation may be either in the neonatal period as an acute episode of METABOLIC ACIDOSIS or later as a “chronic intermittent form”. Normal development is promoted by early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine. The present case was a 35-day-old boy admitted with seizure whose initial screening test was in favor of ORGANIC ACIDEMIA of the isovaric ACIDEMIA (Ammonia: 200 µmol/L). As the venous blood gas (VBG) analysis revealed no ACIDOSIS, newborn METABOLIC screening was repeated. Typical laboratory findings and elevated levels of C5 and C5/C2 confirmed isovaleric ACIDEMIA again. As the above patient had no ACIDOSIS while the other tests including laboratory and genetic analysis were in favor of IVA, he considered to be a rare case.

ORGANIC ACIDEMIAs are the group of METABOLIC disorders which define by high anion gap METABOLIC ACIDOSIS, hypo or hyperglycemia & hyperammonemia. Because of the severity of disease in children and its fatality in severe form of disease and also need for life long treatment, prenatal diagnosis is an important diagnostic tool. Three approaches to prenatal diagnosis may be possible, including measurement of analytes in amniotic fluid or use of cells obtained by Choronic Villus sampling (CVS) or amniocentesis to either assay enzyme activity or extract DNA for molecular genetic testing. Biochemical genetic testing: Prenatal diagnosis for pregnancies at increased risk for propionic ACIDEMIA, METHYLMALONIC ACIDEMIA, biotin-unresponsive3-METHYLcrotonyl-CoA carboxylase deficiency, glutaric ACIDEMIA type 1, ketothiolase deficiency, METHYLMALONIC aciduria and homocystinuria, cblC type, and isovaleric ACIDEMIA is possible by analysis of amniotic fluid if highly accurate quantitative methods are used to measure the appropriate analytes. Amniocentesis is usually performed at approximately 15 to 18 weeks gestation. Prenatal diagnosis for pregnancies at increased risk for MSUD is possible by measurement of enzyme activity in fetal cells obtained by chorionic villous sampling(CVS) at approximately ten to 12 weeks gestation or amniocentesis usually performed at approximately 15 to 18 weeks gestation.(If cells from CVS are used, extreme care must be taken to assure that they are fetal rather than maternal cells).Molecular genetic testing: Prenatal diagnosis for pregnancies at increased risk for all disorders is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks of gestation or chorionic villous sampling (CVS) at approximately ten to 12 weeks of gestation. Both disease-causing allels of an affected family member must be identified before prenatal testing. Preimplantation genetic diagnosis (PGD) may be available for families in which the disease causing mutation has been identified.

A clinical presentation of a METABOLIC disorder, often first seen in infants who present with poor feeding, vomiting, tachypnea, ACIDOSIS, hyperammonemia, ketosis, ketonuria, irritability, and convulsions or hypotonia and lethargy, findings that are otherwise suggestive of neonatal sepsis Diseases with OA Isovaleric and propionic ACIDEMIAs, maple syrup urine disease, medium chain acyl dehydrogenase deficiency, glutaric, METHYLMALONIC, formiminoglutamic acidurias.DescriptionThe term "ORGANIC ACIDEMIA" or "ORGANIC aciduria" (OA) applies to a diverse group of METABOLIC disorders characterized by the excretion of non-amino ORGANIC acids in urine. Most ORGANIC ACIDEMIAs results from a dysfunction of a specific step in amino acid catabolism, usually due to deficient enzyme activity. This leads to the accumulation of ORGANIC acids in the biological fluids (blood and urine), which, in turn, produces disturbances in the acid-base balance and causes alterations in pathways of intermediary metabolism. METHYLMALONIC ACIDEMIA occurs when the activity of METHYLmalonyl CoA mutase is defective in the isoleucine, valine, methionine and threonine degradative pathway. Propionic ACIDEMIA occurs when the activity of Propionyl CoA carboxylase isdefective in the isoleucine, valine, methionine and threonine degradative pathway. Isovaleric ACIDEMIA occurs when the activity of Isovaleryl CoA dehydrogenase is defective in the leucine degradative pathway. Glutaric ACIDEMIA type I occurs when the activity of Glutaryl CoA dehydrogenase is defective in the lysine, hydroxylysine and tryptophan degradative pathway.3-Hydroxy-3-METHYLglutaryl CoA (HMG-CoA) lyase deficiency occurs when the activity of HMG CoA lyase is defective in the leucine degradative pathway. 3-METHYLcrotonyl CoA carboxylase deficiency occurs when the activity of 3-METHYLcrotonyl-CoA carboxylase is defective in the leucine degradative pathway. IncidenceWhile each individual disorder is rare, overall incidence of ORGANIC ACIDEMIAs is 1:20, 000.Clinical FeaturesA neonate affected with an ORGANIC ACIDEMIA is usually well at birth and for the first few days of life. The usual clinical symptoms of OA disorders may include vomiting, METABOLIC ACIDOSIS, ketosis, dehydration, coma, hyperammonemia, lactic ACIDOSIS, hypoglycemia, failure to thrive, hypotonia, global developmental delay, sepsis and hematologic disorders. The non-distinct clinical presentation may initially be attributed to sepsis, poor breast-feeding, or neonatal asphyxia. Screening Newborn Screening Laboratory performs a screening test for ORGANIC ACIDEMIAs by tandem mass spectrometry (MS/MS). It is a screening test and not a diagnostic test. Confirmatory TestingA diagnosis must be confirmed using an independent analysis of urinary ORGANIC acids as well as other appropriate tests. It is important to confirm or exclude the diagnosis of an ORGANIC ACIDEMIA in a timely fashion and with a high degree of accuracy to avoid unnecessary testing, to provide appropriate interventions, prognostic and genetic counseling, and to ensure access to specialized medical services. Implications for Genetic Testing The disorders included in this screening are inherited in an autosomal recessive manner. While a family history of neonatal death should prompt consideration of an ORGANIC ACIDEMIA, a negative family history does not preclude the possibility. Interpretations/Recommendations Mandated Disorders: • Expected Results: No elevated markers for C3, C5, C5DC, and C5OH (Acylcarnitine Profile within acceptable limits) • Equivocal Results: Indeterminate results Recommend: Repeat filter paper specimen within 2 days • Presumptive-Positive Results: Elevated acylcarnitine markers indicating a possible ORGANIC ACIDEMIA or repeat equivocal results Glutaric ACIDEMIA type I–C5DC Propionic and METHYLMALONIC ACIDEMIA–C3 Isovaleric ACIDEMIA–C5 3-Hydroxy-3-METHYLglutaryl CoA lyase deficiency–C5OH 3-METHYLcrotonyl CoA carboxylase deficiency–C5OHRecommend: Immediate assessment of the baby's health status and consultation with METABOLIC/genetic specialist strongly recommended. Non-Mandated Disorders: Other acylcarnitine markers detected on MS/MS • Positive Results: An elevated acylcarnitine result that does not match a mandated ORGANIC ACIDEMIA disorder profile Recommend: Immediate assessment of the baby's health status and consultation with a METABOLIC/genetic specialist for appropriate urine and/or serum confirmatory/diagnostic testing and treatment Newborn screening tests are adjuncts to clinical assessment, which is paramount. An ORGANIC ACIDEMIA disorder should be considered in infants with any of the signs/symptoms regardless of newborn screening results.

Background: METHYLMALONIC ACIDEMIA is a rare autosomal recessive disease in which there is a deficiency of intracellular cobalamin. This study aimed to assess the effectiveness of parenteral hydroxylcobalamin in the treatment of children with METHYLMALONIC ACIDEMIA. Method: This is a quasi-experimental study without a control group. The participants included under-18-year-old children with confirmed METHYLMALONIC ACIDEMIA. There were only 17 patients with the inclusion criteria, all of whom were included in the study. They received 1mg hydroxylcobalamin injection for 3 or 7 days based on their clinical status. Data was gathered by a demographic questionnaire, along with laboratory tests of urine-MMA, and plasma homocysteine, measured before and after the intervention. Data analyses were performed using SPSS v. 26. Results: The samples included 17 patients, most of whom were males (52. 9%). They had various clinical manifestations consisting of hypotonia, seizure, verbal disorders, movement disorders, organomegaly, hematologic disorders, and ophthalmic disorders. The parenteral hydroxylcobalamin had a borderline significant effect on urine-MMA (p=0. 05),this seems to be due to the sample shortage and can become strongly significant with sample increase. Conclusion: The results revealed the effectiveness of parenteral hydroxylcobalamin in MMA patients. However, there is no standard guideline to suggest the perfect dose of it to acquire the optimum result,so it is suggested to conduct more clinical trials or cohort studies to be done.

Clinical differential Diagnosis The ORGANIC ACIDEMIAs are important in the differential diagnosis of METABOLIC and neurologic derangement in the neonate and of new-onset neurologic signs in the older child.A-ORGANIC aciduria Several disorders, not classified as primary disorders of ORGANIC acid metabolism, have a characteristic urinary ORGANIC acid profile that suggests the appropriate diagnosis.• Mevalonicaciduria, a disorder of cholesterol biosynthesis, shows mevalonic acid in the urine.• GlutaricACIDEMIA type II, a disorder of fatty acid oxidation, has multiple ORGANIC acids in abnormal concentration in urine. These ORGANIC acids include ethylMALONIC acid, glutaric acid, dicarboxylic acids, and glycine conjugates of medium chain dicarboxylic acids.• The fatty acyl CoA-glycine conjugates that signal incomplete fatty acid oxidation and serves as signals to the diagnosis of MCAD defeciency and other disorders of fatty acid oxidation and transport.• Biotinidase deficiency, a disorder of biotin recycling, results in the urinary excretion of several unusual ORGANIC acids, including 3-hydroxy-isovaleric, 3-hydroxypropionic, 3-hydroxybutyric acids, and acetoacetate. Propionyl glycine may also be seen.• Mitochondrial diseases with disordered oxidative phosphorylation often demonstrate the presence of abnormal ORGANIC acids in the urine.B-ACIDOSIS Non-genetic conditions, such as shock, sepsis, DKA, liver and kidney failure, thiamine deficiency, RTA, some drug intoxication cause ACIDOSIS- genetic conditions are include: inherited METABOLIC disorders of lactate and pyruvate metabolism and oxidative phosphorylation, disorders of the Krebs cycle such as fumarase deficiency.C-Hyperammonemia Disorders of the urea cycle and the hyperammonemia-hypoglycemia syndrome. Neuroimaging• A variety of MRI abnormalities have been described in the ORGANIC academia, including distinctive basal ganglia lesions in glutaricACIDEMIA type I (GA I), white matter changes in maple syrup urine disease (MSUD), and abnormalities of the globus pallidus in METHYLMALONIC ACIDEMIA. Macrocephaly is common in GA I.• Some differential agnosis of MRI findings in ORGANIC academia is consist of: HIE, mucopolysacaridosis, middle fossa arachnoid cyst, leigh disease, hexachlorophene toxicity in neonates, myelin splitting disorders.• Some ORGANIC aciduria such as L-2-Hydroxyglutaricaciduria may suggest leukodystrophy in MRI.