topical review article: organic acidurias: a review part 2

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1991 6: 288J Child NeurolPinar T. Ozand and Generoso G. Gascon

Topical Review Article: Organic Acidurias: A Review Part 2

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288

Topical Review Article

Organic Acidurias: A ReviewPart 2

Pinar T. Ozand MD, PhD; Generoso G. Gascon, MD

Received Nov 9, 1990. Received revised Feb 26, 1991. Ac-

cepted for publication March 4, 1991.From the Department of Pediatrics (Drs Ozand and Gascon),

and Biological and Medical Research (Dr Ozand), King Faisal Spe-cialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Address correspondence to Dr Ozand, Department of Pedi-atrics (MBC-58), King Faisal Specialist Hospital and Research Cen-tre, PO Box 3354, Riyadh 11211, Saudi Arabia.

Abstract

Laboratory findings are an essential part of the diagnostic approach to organic acidemias. In most organic acidemias, me-tabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of theacid-base balance. Hypoglycemia, lactic and/or ketoacidosis, and hyperammonemia of varying severity accompany theovert or compensated acidosis. In most instances, a definite diagnosis will be achieved by gas chromatography/mass spec-trometry (GC/MS) studies of the urine. We detail the pattern of excreted organic acids in the major disorders. When thediagnosis reached by clinical and laboratory assessments is not conclusive, it must be supported by loading tests. We listthe available methods of demonstrating the putative enzyme deficiency in the patient’s cells and tissues. The majority oforganic acidemias may be treated by limiting the source of or removing the toxic intermediary metabolite. We providelists of available diets, supplements, and medications. In some instances, residual defective enzyme activity may be stim-ulated. We describe symptomatic management of the disturbed acid-base and electrolyte balance. (J Child Neurol

1991;6:288-303).

Laboratory DiagnosisThe laboratory investigations of a child suspected ofhaving an organic aciduria include stepwise determi-nations of (1) blood gases, pH, base excess, and elec-trolytes ; (2) blood glucose, 3-hydroxybutyrate,acetoacetate, free fatty acids, and ammonia concen-trations, blood count, and blood lactate and pyru-vate levels; and (3) blood and urine amino acids.These studies should be followed by gas chromato-graph/mass spectrometric (GC/MS) identificationand measurement of urinary organic acids. Finally,the preliminary diagnosis must be confirmed byprovocation tests and cellular enzyme assays.

Acid-Base Balance and ElectrolytesThe organic acidemias listed in Appendix A (in part1 of this article) are characterized by periodic epi-sodes of acidosis with dehydration and electrolytedisturbance. In such patients, blood gas determina-tions reveal the acidosis and the extent of base ex-

cess, and electrolyte measurements show the extentof electrolyte and fluid disturbances. 28,29

Blood Glucose and Ketone Bodies

Hypoglycemia is a frequent complication of organicacidemias that can occur with or without associatedketosis (Appendix F). Ketone bodies provide an al-ternative fuel when carbohydrate is in short supplyor when it cannot be used efficiently.&dquo; This alter-nate energy source is particularly important for thecentral nervous system and may explain asympto-matic hypoglycemia in the newborn. Hepatic keto-genesis depends on the availability of fatty acylcoenzyme A (CoA) esters synthesized from fatty ac-ids released from adipose tissue and on the availabil-ity of carnitine.l6 Ketogenesis is regulated by theactivity of carnitine acyltransferase I, which carriesacylcarnitines into mitochondria, and by the level ofmalonyl-CoA, which inhibits this enzyme.18 In thefed state, malonyl-CoA is generated from citrate.The lowered concentration of malonyl-CoA in liverin the fasting state permits ketogenesis to occur. 18However, the physiologic and pathologic forms ofketosis depend primarily on the rate of delivery offree fatty acids to the liver. When this rate is out ofcontrol, ketogenesis is driven to such a high ratethat it exceeds the rate of ketone body utilization-16

at GEORGE MASON UNIV on July 1, 2014jcn.sagepub.comDownloaded from


289

Each step of this pathway (viz, release of fatty acidsfrom peripheral tissues, availability of L-carnitine,and level of malonyl-CoA) may be affected by thedisturbed intermediary metabolism of the organic ac-idemia, leading to different patterns of associated ke-tosis (Appendix F). The severe hypoglycemia of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency’13,111and of medium-chain acyl-CoA dehydrogenase defi-ciency123 is associated with very low to absent ketosisand can lead to rapid death. In phosphoenolpyruvatecarboxykinase deficiency, persistent hypoglycemia insome patients without significant acidosis can causeunnecessary pancreatectomy for treatment of a pre-sumed nesidioblastosis.151,275,276 Patients with propi-onic acidemia,192 methylmalonic acidemia,130,199 andglutaric aciduria type 111 manifest severe hypoglyce-mia during the acidotic attacks.

Blood Ammonia

z

Most organic acidemias impair ureagenesis, causinghyperammonemia (Appendix G). In the acidotic cri-sis of mitochondrial 3-ketothiolase deficiency, nor-mal ammonia levels would make propionic andmethylmalonic acidemia less likely. While dihydroli-poyl dehydrogenase (E3) deficiency and pyruvatecarboxylase or dehydrogenase deficiencies lead to

severe lactic acidosis, the E3 deficiency can be recog-nized by the low or absent hyperammonemia. Propi-onic and methylmalonic acidemias and occasionallyisovaleric acidemial’3 cause severe hyperammone-mia during acidosis. In some organic acidemias, eg,medium- and long-chain acyl-CoA dehydrogenasedeficiencies, and glutaric aciduria type 1, hyperam-monemia can be observed in the absence of signifi-cant acidosis.

Hematopoietic FindingsAppendix H lists the organic acidemias that sup-press hematopoiesis, such as disorders of leucineand isoleucine metabolism.157 Methylmalonic acidinhibits bone marrow stem-cell growth and sup-presses granulopoiesis.15~,15s Propionic acidemiacauses immune deficiency involving T and B lym-phocytes.l6o Major defects of riboflavin 102,236 and vi-tamin B12 metabolism’3,84 impair bone marrow

functions. Absence of glutathione synthesis impairsgranulocyte163 and erythrocyte function.98

Methylmalonic aciduria can occur without acido-sis, due to mutations involving the synthesis of bothadenosylcobalamin and methylcobalamin. Such pa-tients might manifest homocystinuria and other

hematologic abnormalities. In a neurologically im-paired child with methylmalonic aciduria and/or ho-mocystinuria, the disease can be readily diagnosed bythe cluster of symptoms (Table 1).

Blood Lactate and PyruvateThe blood values of lactate, pyruvate, 3-hydroxybu-tyrate, acetoacetate, and free fatty acids are particu-larly valuable for the differential diagnosis of organicacidemias with hyper-lactic acidemia. The lactate/pyruvate and 3-hydroxybutyrate/3-ketobutyrate re-

dox couples are linked through the ratio ofnicotinamide adenine dinucleotide (NAD) to re-

duced NAD (NADH) in cytosol for the former andin mitochondria for the latter. Increased NADH/NAD indicates a more reduced state, and a de-creased ratio indicates a more oxidized state. Undernormal conditions, the prevailing cytosolic NADH/NAD is in equilibrium with a ratio of lactate/pyru-vate around 25; and that in mitochondria with a ratio

TABLE 1Differential Diagnosis of Clinical Conditions Associated With Methylmalonic Aciduria



290

of 3-hydroxybutyrate/3-ketobutyrate > 2. 151,271,275,276The reducing power of NADH is carried from cyto-sol into mitochondria by malate, which is oxidizedinto oxaloacetate, generating NADH intramitochon-drially. In mitochondria, aspartate is formed by trans-amination from oxaloacetate and is transported intocytosol, where it generates oxaloacetate that is re-duced to malate. The transport of malate and aspar-tate is unidirectional, and this pathway is known asthe malate-aspartate shuttle, the primary role ofwhich is to carry electrons from cytosol into mito-chondria. 151,271,275,276 In the neonatal form of pyru-vate carboxylase deficiency, this shuttle is impaired,leading to more oxidized mitochondria but more re-duced cytosol. Therefore, the lactate/pyruvate ratiois > 50, reflecting the reduced cytosol, while the3-hydroxybutyrate/acetoacetate ratio is < 1.33,127 The

lactate/pyruvate ratio is < 25 in other neonatal hyper-lactic acidemic disorders, such as phosphoenolpyru-vate carboxykinase151,2’5 and pyruvate dehydroge-nase deficiencies. 46,48,256,264 Although in E3 defi-

ciencyl07,108,140-142,312 and mitochondrial oxidative

phosphorylative defects, 114,281,284,287,312- 314 the lac-

tate/pyruvate ratio is > 50, the 3-hydroxybutyrate/acetoacetate ratio is also > 2, 141,142,287 since the

malate-aspartate shuttle is not impaired.In organic acidemias caused by defects in fla-

voproteins, the determination of the plasma free

fatty acids/3-hydroxybutyrate ratio yields values > 1

(normal < 1),55,315 since fatty acid oxidation is im-

paired. In medium-chain fatty acyl-CoA dehydrog-enase deficiency, a loading test with 1 to 1.4 g me-dium-chain triglycerides fails to reduce thisratio.241,315

Blood and Urine Amino AcidsSince most organic acidemias lead to increased ami-noacidemia (Appendix I), blood amino acids need tobe determined. Blood glycine is elevated in most or-ganic acidemias. Detection of elevated branched-chain amino acid levels during acidotic attacks

permits rapid diagnosis of E3 deficiency. Blood ala-nine concentrations parallel concentrations of lacticand pyruvic acids, providing additional confirmationof lactic acidemic disorders. In neonatal-onset pyru-vate carboxylase deficiency, citrulline is elevated. Inflavin-linked defects, sarcosine, 2-aminoadipic acid,or saccharopine levels are increased.

Organic acidemias that impair renal tubular

transport systems will cause generalized aminoaci-duria, or de Toni-Fanconi-Debre syndrome as de-scribed in Part 1,49-54,151-155

Urine Organic AcidsA more definite diagnosis of an organic acidemiawill be achieved by the study of the urinary excre-tion pattern of organic acids by GC/MS. Each diseaseyields a characteristic increase in several organic ac-ids, derived from or linked to the defective meta-bolic pathway (Appendix J). Describing the primarypattern of acidosis, ie, lactic, ketotic, mixed, or noneof the above, facilitates the interpretation of theGC/MS pattern. For example, while both biotinidaseand holocarboxylase synthetase deficiency will showsimilar excretory patterns, the former is associatedmainly with lactic acidosis and the latter with mixedketolactic acidosis. In 3-methylglutaconic aciduria,the excretion of 3-methylglutaconic acid and 3-meth-ylglutaric acid in the normal hydratase variant is

usually not more than that observed in the deficientvariant.36 The methylmalonic aciduria is significantlyhigher in methylmalonic acidemia with associatedketonuria than in patients with cobalamin mutations(Table 1 and Appendix J). The patterns of organicacid excretion of short- and medium-chain or

medium- and long-chain fatty acyl-CoA dehydroge-nase show significant overlap. The diagnosis of anorganic acidemia cannot therefore be based solely onGC/MS findings but must include previous clinicaland laboratory observations.

It must be emphasized that increased excretionof urine organic acids can be nonspecific. It is impor-tant to obtain urine samples for GC/MS during theacidosis and after the crisis. These determinationsmust be repeated when results are ambiguous. Ageand maturity influence the normal values of urinaryorganic acids.316 In ketoacidosis caused by condi-tions other than ketotic organic acidemias, 2-methyl-3-hydroxybutyric acid and 3-hydroxyisovaleric acidcan accumulate and lead to erroneous diagnoses. 311Some organic acids might be generated by intestinalbacterial overgrowth.318 Infusion or ingestion offoods with medium-chain triglycerides leads to

increased dicarboxylic aciduria.319 The urinary excre-tion of 3-hydroxy-3-methylglutaric acid is age de-

pendene20 and can occur nonspecifically.321 In-creased urinary excretion of 5-oxoproline has beenobserved in patients receiving special diets and inthose with severe burns, Stevens-Johnson syndrome,homocystinuria, and propionic acidemia.322-324Drugs such as valproic acid cause erroneously highfatty acid metabolic intermediates in the urine. 32-5,326

Loading TestsWhen the GC/MS findings are not specific, a diag-nostic impression must be supported by provocation



291

tests. The excretion of organic acids and, when pos-sible, of their carnitine and glycine esters must bemeasured before and after a loading test (AppendixK). This is particularly true for organic acidemiaswith hyper-lactic acidemia, since few additional or-ganic acids are present in the urine of the majority(Appendix J). Some of these tests should be consid-ered hazardous because they can precipitate an aci-dotic attack (propionic acidemia or methylmalonicacidemia) or death (medium-chain acyl-CoA dehy-drogenase deficiency) (Appendix K). In other dis-eases the provocation tests are not a health hazard.For example, in multiple carboxylase deficiency, bi-otin loading will differentiate between biotin-respon-sive and -resistant conditions. In neonatal hyper-lactic acidemia, an alanine or glucose tolerance test ordichloroacetate loading distinguishes between pyru-vate carboxylase, pyruvate dehydrogenase, and E3deficiencies. In patients with defects of flavoproteinmetabolism, loading tests are performed because thein vitro diagnostic studies are available only in a fewspecialized laboratories. In 3-methylglutaconic aci-duria the two phenotypic variants can be differenti-ated by leucine provocation. When determination offree and esterified carnitine or chromatographic anal-ysis of carnitine esters are available, loading tests withL-carnitine or glycine, with subsequent identificationof the increased excretion of conjugated compounds,should be the choice (Appendix K).

Enzyme StudiesMethods for the demonstration of the putative en-zyme defect are available for the majority of organicacidemias, and the enzyme deficiency must be es-tablished as soon as possible (Appendix L). Most ofthe procedures depend on the use of cultured fibro-blasts, lymphoblasts, or lymphocytes. Some of thesetests, such as the assays for 3-hydroxy-3-methylglu-taryl-CoA lyase, propionyl-CoA carboxylase, and bi-otinidase, are rapid and simple. Others require abiochemical setting for the study of release, or fixa-

tion of isotope from the substrate, but are not partic-ularly difficult. The determination of flavoprotein-linked enzyme defects, sophisticated mitochondrialstudies, or complementation analysis can be per-formed in only a few laboratories. Electron micro-scopic and histochemical studies of the biopsymaterial for various mitochondriopathies require anexperienced pathologist. Other procedures, such asdetermination of enzymes by immunologic tech-

niques, require antibodies that are not readily avail-able. In some instances, the enzyme activity in

cultured cells is so low that an accurate diagnosismust be based on measurements in biopsy material,eg, pyruvate dehydrogenase.41 Finally, the availabil-ity of DNA probes133,32’-329 is essential for the studyof such complex disorders as myoclonic epilepsywith ragged-red fibers (MERRF),87 mitochondrial en-cephalomyopathy lactic acidodsis with strokelike ep-isodes (MELAS),33o,331 and Kearns-Sayre117,297,332,333syndrome (Appendix L).

Principles of Treatment of Organic AcidemiasOrganic acidemias can be treated by (1) decreasingthe production of toxic metabolites, (2) removingtoxic metabolites, (3) avoiding certain drugs, (4)stimulating the residual enzyme activity, and (5)symptomatic treatment, including hydration and re-storing acid-base balance.

Decreased Production of Toxic MetabolitesRestricting dietary precursors decreases productionof toxic metabolites, eg, restricting a particularamino acid when there is defective catabolism ofamino acids. This is achieved either by restrictingthe protein or by supplying an artificial diet with re-stricted amino acids. The daily requirement of in-fants for amino acids involved in organic acidemiasis listed in Table 2. It is preferable to provide the in-fant with 0.5 to 0.8 g/kg natural protein daily, to

supplement the diet with a mixture of amino acids

TABLE 2 ’

Range of Amino Acid Requirements for Different Age Groups

*Expressed in mg/kg daily.Adapted from Acosta334 and references. ~~183,184,195,201,227,246



292

excluding the amino acid that is the source of the or-ganic acid, and to provide enough nitrogen in theform of nonessential amino acids.&dquo; The optimumcomposition of diets has been extensively studied.334In organic acidemias involving branched-chainamino acids, it is desirable to prevent the break-down of muscle protein. Saudubray et al estimatethat a 3.2-kg newborn can catabolize 7 to 10 g of pro-tein per day, producing 5.4 to 7.7 mmol of leucine.335Provision of enough calories, avoidance of fasting,and aggressive management of intercurrent infec-tions and diarrhea are required particularly in isova-leric acidemia336 and propionic acidemia.192 In

3-methylglutaconic aciduria with normal hydratase,propionic acidemia, and methylmalonic acidemia, anintercurrent illness or excessive protein load will pro-voke an acidotic attack.180,192,195 In medium-chainacyl-CoA dehydrogenase deficiency, it is important toavoid fasting and formulas that contain medium-chain fatty acids and to provide frequent feeding. 337This is also true for E3 deficiency, in which fasting in-duces both lacticacidosis and ketosis. Such patientsshould never be fasted more than 5 to 6 hours andmust be provided a high-carbohydrate diet. 117 Ininfantile- and late-onset pyruvate dehydrogenase de-ficiency, ketogenic diets ameliorate, while carbohy-drate ingestion provokes, symptoms with lacticacidosis. 41,44-47,138,264

The dietary management of organic acidemiasis listed in Appendix M. Disorders for which oth-er forms of treatment are available are excluded,eg, biotinidase deficiency and cobalamin muta-

tions. Chronic ketosis caused by deficiency of thio-lases110,155,249 does not respond to carbohydrate oralanine suppression. Diseases that lack a definite

pathogenic mechanism, such as 3-methylglutaconicaciduria with normal hydratase, D-glyceric aciduria,and mevalonate kinase deficiency, also lack dietarycontrol. Multiple acyl-CoA dehydrogenase, neonatalform with dysmorphia; pyruvate carboxylase andpyruvate dehydrogenase deficiencies with neonatalonset; and phosphoenolpyruvate carboxykinase de-ficiency or mitochondriopathies are lethal diseases,unresponsive to diets. In some organic acidemias,although the clinical response to diet restriction is

variable, it should always be attempted.Approximately half of the organic acidemias can

be managed by diet. In these disorders, early andadequate treatment will provide normal develop-ment and reversal of clinical findings (Appendix M).The restricted diets should be composed accordingto available guidelines.334 The patient’s maximumtolerance to the restricted component must be deter-

mined individually. The diet must provide optimumgrowth and reduce the excretion of organic acids,and it should be palatable. Some diets are simple,eg, diets for glutathione synthetase deficiency areprecautionary measures as applied to glucose-6-phosphate dehydrogenase deficiency.338 In propi-onic acidemia, the use of mitronidazole has beenadvised, to reduce the significant propionic acid pro-duction by intestinal anaerobes.33 In such disordersas isovaleric acidemia, propionic acidemia, methyl-malonic acidemia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, the patient learns to avoidcertain foods by developing conditioned aversion.

Removal of Toxic ProductsVarious metabolites of organic acidemias, producedin excess, are toxic and must be removed. The accu-mulation of acyl-CoA compounds inhibits acetyl-CoA carboxylase, adenine nucleotide translocase,citrate synthase, glutamate and malate dehydroge-nases, lipase, N-acetylglutamate synthetase, pyru-vate carboxylase, and guanosine triphosphate-dependent succinate-CoA ligase. 340 Inhibition of

pyruvate carboxylase and the malate-aspartate shut-tle causes hypoglycemia. Inhibition of pyruvate dehy-drogenase by accumulating acyl-CoA causes

increased accumulation of lactic and pyruvic acids.Low mitochondrial adenosine triphosphate, impairedsynthesis of N-acetylglutamate, and inhibition of themalate-aspartate shuttle or of aspartate utilization, in-terfere with normal ureagenesis, causing hyperam-monemia. Increased blood lactate competes withrenal transport sites of uric acid and causes hyperuri-cemia.34O The accumulation of short-chain fatty acidsand acyl-CoA in metabolic errors of fatty acid oxida-tion uncouples oxidative phosphorylation and inhib-its the malate shuttle, causing hypoglycemia.149

Carnitine functions to facilitate the transport ofacyl-CoA as acylcarnitine across the mitochondrialmembrane, since acyl-CoA compounds do not ordi-narily cross membranes. 218,340,341 When excessive ac-cumulation of intramitochondrial acyl-CoA occurs,excessive acylcarnitine will be formed, crossing themitochondrial and cellular membrane with eventualrenal excretion. In organic acidemias, the generationof acyl-CoA exceeds the endogenous synthesis ofcarnitine, and renal transport is impaired by car-nitine esters, which leads to secondary carnitine de-ficiency.218,340,341 The administration of L-camitine tosuch patients is required to free mitochondrial re-duced CoA- and to normalize the disturbed func-tions. Carnitine acyltransferase is active with mostof the acyl-CoA esters, except those of 2-hydroxy



293

or 2-keto compounds.110 This accounts for the ab-sence of a carnitine effect clinically in mitochon-drial 3-ketothiolase deficiency and the absence ofcarnitine ester formation with its metabolites.185At present, a large number of organic acidemiasare treated with oral administration of L-carnitine in100- to 200-mg/kg daily doses, as shown in Appen-dix N,1~0,218,245,341-349 Although no toxic effect ofL-carnitine is known, doses larger than 150 mg/kgmay cause diarrhea.169

A second detoxification mechanism involves the

cytosolic glycine N-acylconjugase. The substrate pref-erence of this enzyme is not well documented. It is ac-tive with isovaleryl-CoA,35o,351 propionyl-CoA, 345and ti~lyl-CoA350,351 but not with 3-methylcrotonyl-COA.1 4 In isovaleric acidemia and propionic aci-

demia, the administration of glycine will normalizebiochemical findings in as little as 3 days, with even-tual normalization of central nervous system and he-matologic findings within 2 or 3 weeks. 166,345,352 Theorganic acidemias managed by the administration ofglycine are listed in Appendix N. Although no clinicaltrial exists, the excretion of glycine conjugates inthe urine of patients with medium-chain acyl-CoA de-hydrogenase deficiency suggests a place for glycineuse.55

Avoidance of Certain DrugsCertain medications should be avoided. Benzoic acidand acetylsalicylic acid compete with acyl-CoAfor glycine conjugation.353 Valproic acid is conju-gated to carnitine, decreasing the availability of thelatter.325,326 Patients with glutathione synthetase de-ficiency should not be given the medications re-

stricted in glucose-6-phosphate dehydrogenase defi-ciency. 338

Stimulation of Residual ActivityVarious organic acidemias respond favorably to

medications that stimulate the residual enzyme ac-

tivity. A depleted precursor might be replenishedexogenously. For example, pharmacologic doses ofvitamins may increase the synthesis of related cofac-tors.354 The compounds that have been successfullyused are listed in Appendix N. Loading tests, eg, bi-otin loading in multiple carboxylase deficiency2o4-210or in vitro studies to demonstrate the enzyme activa-tion by large concentrations of cofactor, may revealthe cofactor responsiveness,355 but are not alwaysreliable. A patient with organic acidemia should beconsidered cofactor- or precursor-responsive if sub-stantial clinical and biochemical improvement occursthrough the use of such a substance.355 A trial of di-

agnostic therapy, with long-term follow-up indicat-ing fewer and less severe crises, adequate growthand development, and eventual tolerance of a nor-mal diet,355 may be the best indicator of an effectivedietary supplement.

In some organic acidemias, such measures re-main ineffective because no cofactors are known orthe defective enzyme cannot be activated. In others,although a biochemical response can be observed,no clinical improvement occurs.56 In some diseases,such as mitochondrial disorders and succinic semial-

dehyde dehydrogenase deficiency, the defective

pathway cannot be stimulated or replaced.Some organic acidemias respond partially or

variably to dietary supplements. In cobalamin muta-tions and in multiple acyl-CoA dehydrogenase defi-ciency, some of the biochemical and clinical derange-ments may improve, but not others. In other condi-tions, some patients respond while others fail, eg,glutaric aciduria type 1 and pyruvate dehydrogenasedeficiency. The observation by Hommes et a1356 thatthiamine pyrophosphate stabilizes the pyruvate de-hydrogenase complex prompted the use of largedoses of thiamine (Appendix N). In one study, 13 pa-tients with infantile onset of the disease received largedoses of thiamine, with only three patients subse-quently dying.41 Although thiamine supplementa-tion is considered to be without effect in severe formsof this disease, it should nevertheless be tried in verylarge doses in all patients. 354,357 Dichloroacetate inhib-its the phosphorylase that inactivates pyruvate dehy-drogenase, thereby stabilizing a defective enzyme. Itssuccess in some patients and low tOXlc1ty358,359 war-rants its use as trial therapy in pyruvate dehydroge-nase deficiency.

The other half of the organic acidemic syn-dromes responds favorably to such therapies, al-

though prolonged follow-up is not available in mostinstances. Because of the gratifying results obtainedduring the treatment of acute acidotic attacks, werecommend a mixture of megavitamins in a seri-

ously ill child thought to have organic acidemia.36oAlthough no contraindication exists to such an initialintervention, a rapid presumptive diagnosis can bereached in most instances. In multiple carboxylasedeficiency due to defective holocarboxylase syn-thetase, most patients respond favorably to largedoses of biotin. 132,203 Some patients with biotin re-sponsive 3-methylcrotonyl-CoA carboxylase defi-

ciency may instead have holocarboxylase synthetasedeficiencies.69,132,1’5 Biotin is without effect in thetreatment of pyruvate carboxylase deficiencybut has been variably successful in propionyl-CoA



294

carboxylase deficiency.192 In biotinidase deficiency,the continuous vitamin loss is easily replaced bypharmacologic doses of biotin.21o,361 The defectivedihydrolipoyl dehydrogenase can be successfullystimulated by large doses of lipoic acid. 140 In pa-tients with methylmalonic acidemia, some mutationsinvolving the generation of mitochondrial adenosyl-cobalamin will respond favorably to large doses ofvitamin B12. The response to vitamin B12 must be de-termined in all patients initially, by following theurinary levels of methylmalonic acid. 14,201,202,362 Ri-boflavin is a precursor of flavin adenine dinucleotide

(FAD), which is involved in various dehydroge-nases, and large doses have been effective in somepatients with fatty acid oxidation defects. The symp-toms of pyruvate carboxylase deficiency, if caused

by loss of citric acid intermediates, can be reversedby large amounts of precursor amino acids. Menadi-one and ascorbic acid have been used in the treat-ment of complex I and III deficiencies, since theirredox potential fits between the components of com-plex III.354 Exogenous supplementation of coenzymeQ has been recommended for complex III defi-

ciency.354

Treatment of SymptomsThe management of a patient with organic acidemiais complicated by anorexia, vomiting, and refusal tofeed, resulting in malnutrition. The chemical en-cephalopathy created by the disease, particularlyimpairment of central nervous system autonomicfunction, might be responsible for these symptoms363and usually leads to an acidotic episode, with leth-argy, tachypnea, and rapid dehydration.

A patient with an organic acidemia characterizedby periodic episodes of acidosis (Appendix A, Part1) will often arrive with varying degrees of acidosisand dehydration. Such an attack should be treatedvigorously by administration of appropriateamounts of fluids, electrolytes, and buffers such assodium bicarbonate or tromethamine.28,29,335 Electro-lytes, particularly potassium and phosphate, mustbe monitored closely because their levels decreaserapidly with the correction of acidosis. Between aci-dotic attacks, such a patient must be prescribed ap-propriate amounts of alkalinizing solutions ofbicarbonate or citrate to be taken orally. The com-pounds listed in Appendix N should be added to thetreatment as required. In a rapidly progressive crisisof multiple acyl-CoA dehydrogenase deficiency or ofcomplex I deficiency, repeated intravenous injec-tions of methylene blue may be lifesaving, since thisprovides the flow of electrons from the accumulated

intermediates directly into the oxidative chain.354,3~In severe episodes of acidosis, exchange transfusionand peritoneal dialysis have been used successfully,despite the risk of infection in an immunocompro-mised patient. 335,365 In disorders involving branched-chain amino acids, large amounts of glucose with in-sulin should be tried.366 Total parenteral nutritionwith commercial or individually mixed amino acids ina patient with a prolonged acidotic attack is anotheralternative.195

Other symptomatic treatments of organic aci-demias are not specific (Appendix N). Baclofen hasbeen used to treat dystonia in glutaric aciduria type1.227 Nalorphine has been used in pyruvate dehy-drogenase deficiency, and prednisone in mitochon-drial disorders. 354

APPENDIX F

Hypoglycemia Associated With Organic Acidemias

Nonketotic or Hypoketotic Hypoglycemia3-Hydroxy-3-methylglutaryl-CoA lease deficiency (significantlactic acidosis also present)183,1

16,1773-Methylcrotonyl-CoA carboxylase deficiencyl’6,i&dquo;Medium-chain acyl-CoA dehydrogenase deficiency (90% of

the attacks),55Long-chain acyl-CoA dehydrogenase deficiency (under

metabolic streSS)55,58,5VMultiple acyl-CoA dehydrogenase deficiency, neonatal,

infantile, and late-onset forms23s,34’Phosphoenolpyruvate carboxykinase deficiency (40% have

severe lactic acidosis; the remainder have mild lacticacidosis)lsi,z~4-z~b

Ketotic Hypoglycemia 367Mitochondrial 3-ketothiolase deficiency36’

Propionic acidemia (during crisis) 192Methylmalonic acidemia 4,AGlutaric aciduria type 1 (during crisis)11Multiple acyl-CoA dehydrogenase deficiency neonatal,

infantile, and late-onset formsllz,’36,z4o

APPENDIX G

Hyperammonemia Associated With AcidoticEpisodes of Organic Acidemias

Absent or Low HyperammonemiaMitochondrial 3-ketothiolase deficiency367Cobalamin mutants C, D, and F~-73,~79,84Multiple acyl-CoA dehydrogenase deficiency, late-onset

form’ 12,149Succinic semialdehyde dehydrogenase deficiency96,97,368Dihydrolipoyl dehydrogenase (E3) deficiency107, 108, 140, 142

Mild Hyperammonemia (Usually <150 ~,mol/L)3-Methylcrotonyl-CoA carboxylase deficiency 178

224Medium-chain acyl-CoA dehydrogenase deficiencyzz4Long-chain fatty acyl-CoA dehydrogenase deficiency58Fumaric aciduria with fumarase deficiency277



295

Moderate Hyperammonemia (150-400 J1mol/L)Isovaleric acidemia 166,173,3523-Methylglutaconic aciduria with normal hydratase1803-Hydroxy-3-methylglutaryl-CoA lyase deficiency183,184Holocarboxylase synthetase deficiency2°3-206Biotinidase deficiency 69,209Short-chain acyl-CoA dehydrogenase deficiencys6,z16Multiple acyl-CoA dehydrogenase deficiency, neonatal

f~~~102, 36,237,241,242Glutaric aciduria type 111Pyruvate carboxylase deficiency, neonatal form 34,127,128,268,269Pyruvate dehydrogenase El subunit deficiency, neonatal

forM258Glutathione synthetase deficiency&dquo;

Severe Hyperammonemia (Usually >400 J1mol)Propionic acidemia32

13,130Methylmalonic acidemia13,130

APPENDIX H

Organic Acidemias Associated With Pancytopeniaor Depression of Bone Marrow Cells

Isovaleric acidemials9Mitochondrial 3-ketothiolase deficiency157,367Propionic acidemia32,160Methylmalonic acidemia13,13o,1s7,lsaCobalamin C mutation (30% have thrombocytopenia)’3Multiple acyl-CoA dehydrogenase deficiency, neonatal

type 102,236 Glutathione synthetase deficiency9s (most patients have

hemolytic anemia)

APPENDIX I

Increased Blood or Urine Amino Acids in Various

Organic Acidemias

Generalized Hyperaminoacidemia and AminoaciduriaIsovaleric acidemia 1503-Methylglutaconic aciduria with normal hydratase180,181Propionic acidemias

2 S361Holocarboxylase synthetase 0’ and biotinidase deficiencies361Short-chain acyl-CoA dehydrogenase deficiency56Pyruvatecarboxylase deficiency, neonatal form33,34, 127, 128,268,269Glutathione synthetase deficiency (in red blood cells291 but

not always true369)

Elevated Branched-Chain Amino Acids in Blood

3-Methylcrotonyl-CoA carboxylase deficiency176,370Dihydrolipoyl dehydrogenase (E3) deficiency (periodic, during

attacks ?67, 108, 140-142Elevated Glycine ,

Isovaleric acidemia 150Propionic acidemias

5

Methylmalonic acidemia’99Glutaric aciduria type 16sD-Glyceric aciduria with defect in fructose metabolism3s,s’1Succinic semialdehyde dehydrogenase deficiency (50%)~’~

Elevated Alanine

Generally observed in diseases with hyperlacticacidemia41,2s6Dihydrolipoyl dehydrogenase (E3) deficiency 107,108,140-142Holocarboxylase synthetase 204 and biotinidase deficiencies361

Phosphoenolpyruvate carboxykinase deficiency 151Pyruvate carboxylase deficiency, neonatal forM33,34,127,269Pyruvate carboxylase deficiency, infantile form129,154,271-273Pyruvate dehydrogenase El subunit deficiency, neonatal

form~’256Pyruvate dehydrogenase E1 subunit deficiency, infantile

form44.48,262,357Pyruvate dehydrogenase E2 subunit deficiency139Pyruvate dehydrogenase phosphatase deficiency2s3

Pathognomonic Amino Acid ElevationsPyruvate carboxylase deficiency, neonatal form: citrulline,

’

lysine, prolinè3,34,127,128,268,269 244Multiple acyl-CoA dehydrogenase deficiency: sarcosine244

Glutaric aciduria type 1: 2-amino adipic acid andsaccharopinelz,6

APPENDIX J

Major Organic Acids in the Urine in VariousOrganic Acidemias

Predominantly Lactic Acidotic Organic Acidemias(Increased Lactic- and Pyruvic Aciduria)

Pyruvate carboxylase deficiency (neonatal and infantileforms), mitochondrial phosphoenolpyruvate carboxykinase defi-ciency, complex I, III, and IV deficiencies and mitochondrial en-cephalomyopathy lactic acidosis with stroke-like episodes (MELASsyndrome) are not associated with other organic acids in the urine.



296

Predominantly Ketoacidotic Organic Acidemias(Increased 2-Ketobutyric Aciduria and 2-HydroxybutyricAciduria)

Cytosolic acetoacetyl-CoA thiolase deficiency, succinyl-CoA3-ketoacyl-CoA transferase deficiency, and glycerol kinase defi-ciency are not associated with additional organic acids in theurine.

Mixed Ketolactic Acidotic Organic Acidemias (IncreasedLactate, Pyruvate, 2-Ketobutyric Aciduria and2-Hydroxybutyric Acid)

Mitochondrial acetoacetyl-CoA thiolase deficiency is not as-sociated with other organic acids in the urine.

Organic Acidurias With Acidotic Episodes but WithoutAssociated Lactic Acidosis or Ketoacidosis

Organic Acidurias Without Significant Acidosis

APPENDIX K

Provocation Tests That Can Confirm the Diagnosisin Various Organic Acidemias

Isovaleric AcidemiaLeucine loading (25 mg/k~,166,353 50 m~/kg,342 or 100 mg/kg) withor without ~lycine (150 or 250 166,35 mg/kg) or with benzoate(200 mg/kgl 6,3s3) or with L-carnitine (200 mg/kg170) leads to in-creased excretion of metabolites.

3-Methylglutaconic Aciduria With Normal HydrataseLeucine loading (75 mg/kg/d in 4 equal doses179 or 200 to 300mg/kg180) fails to raise the metabolites since only 2% to 20% of thedose is converted into organic acids. 179,182

Dihydrolipoyl Dehydrogenase (E3) DeficiencyL-Alanine loading (500 mg/kg 142 or 1 g/kg108) as an intravenous bo-lus raises blood glucose, which differentiates this disorder frompyruvate carboxylase deficiency.

Mitochondrial 3-Ketothiolase DeficiencyIsoleucine loading (75 mg/kg120,187,189,19ð that can be repeated onconsecutive days or 100 mg/kg single dose185) leads to increased



297

excretion of metabolites; identical doses of valine and leucineserve as control.

Propionic Acidemia g32), 32),Isoleucine loading (200 mg/kg3z), valine loading (100 mg/kg3z), or

methionine loading (150 mg/kgl9’) results in increased excretionof metabolites. These measures also provoke acidotic attacks andare not recommended.

Glycine loading (200 mg/k g345) leads to increased excretion ofpropionylglycine.

g3ll,31L-Carnitine loading (100 mg/kg344,345) leads to increased ex-cretion of propionylcarnitine, hippurate, and 4-hydroxyhippurate.

Methylmalonic AcidemiaValine or isoleucine loading (300 mg/kg/d in 4 divided doses36z)increases the metabolites. These measures also provoke acidoticattacks and are not recommended.

L-Carnitine loading (200 mg/kg343) decreases the excretion ofmethylcitrate and methylmalonic acid, with increased excretion ofacylcarnitines.

Multiple Carboxylase Deficiency (HolocarboxylaseSynthetase and Biotinidase Deficiencies)Biotin loading (3.5 mg/kg/d 361 or 10 mg/d in a single dose69,zo9)suppresses the excretion of related organic acids within days inbiotin-responsive types (holocarboxylase synthetase mutants andbiotinidase deficiency).

Isoleucine loading (100 mg/kgz°8) increases the excretion ofrelated organic acids.

Medium-Chain Acyl-CoA Dehydrogenase DeficiencyMedium-chain triglyceride loading (150 mg/kg) given togetherwith glycine (250 mg/kg) increases the metabolites and differenti-ates this disorder from short-chain acyl-CoA dehydrogenase defi-ciency (no response).&dquo; A 1.0 to 1.4-g/kg load fails to raise3-hydroxybutyric acid but causes significant excretion of octanoicacid, hexano glycine, suberylglycine, and octanoylcarnitine. 241,315

Fasting- 5,224,383,384 and ketogenic diet223 increase metabolites.Fasting has been reported to cause death in a patient with me-dium-chain acyl-CoA dehydrogenase deficiency. 55,337 L-Carnitineloading385 (100 mg/kg) increases urinary octanoylcarnitine.

Glutaric Aciduria Type (1)Lysine loading (100 mg/k g231) increases metabolites.

Multiple Acyl-CoA Dehydrogenase DeficiencyLysine loading (60 mg/kg/d in 3 equal doses2 1,386) increases me-tabolites ; leucine (100 mg/kg) serves as control. 211

Medium-chain triglyceride loading (150 mg/kg) given to-

gether with glycine (250 mg/kg) causes increased excretion of me-tabolites. 241

Mitochondrial Acetoacetyl-CoA Thiolase Deficiency andCytosolic Acetoacetyl-CoA Thiolase DeficiencyGlucose loading (500 mg/kg iv) or alanine loading (200 mg/kg iv)or feeding fails to suppress ketosis.llo,lss

Pyruvate Carboxylase Deficiency, Infantile FormL-Alanine loading (100 mg/kg iv) increases lactic acid without in-creasing blood glucose; glucose loading (1 to 2 g/kg iv) increasesblood lactate. 172,273

Pyruvate Dehydrogenase El and E2 Subunit andPhosphatase DeficienciesGlucose loading (1 g/kg iv) or L-alanine loading (110 to 200 mg/kg1V4’,139,262,265) leads to sustained hyperlactic acidemia.

APPENDIX L

Diagnostic Procedures Based on Cellular Studies inVarious Organic Acidemias

These studies are based on enzyme measurements through cata-lytic activity or immune methods (EB), through use of substratesor accumulation of products in cells (OB), through genetic com-plementation (CB), or through DNA-dependent diagnosis (DB).The cells involved are fibroblasts (F), lymphoblasts or lympho-cytes (W), or tissues obtained by biopsy or necropsy.

Isovaleric AcidemiaEB-F,387 OB-Wl

MethVIcrotonyl-CoA Carboxylase DeficiencyEB-F,i75,177 ,~,, B-W 177

3-Methylglutaconic Aciduria With Normal HydrataseEB-F ’38~ OB-Fl$o,181

3-Hydroxy-3-Methylglutaryl-CoA Lyase DeficiencyEB-F and EB-W183,1

Dihydrolipoyl Dehydrogenase (E3) DeficiencyEB-F107, 140, 14~,389 EB-llVer,107,108,142,373 EB-kidney’ 101,3’ EB-brain,los,373 EB-heart, 108 EB-muscle,107,108 OB-F 107

Mitochondrial 3-Ketothiolase DeficiencyEB-F 119,120,185,189 OB-F187

Propionic AcidemiaEB-F,194 EB-W,192 EB-liver, 390 OB-F,32,37S,379,391 CB-F.392-395 Alsosee holocarboxylase deficiency.

Methylmalonic AcidemiaEB-F, 3,396-398 OB-F, 399-402 CB-F. 403 Also see cobalamin muta-tions.

Cobalamin C, D, and F Mutations ’

EB-F so,s5,404 EB-W, 80 EB_liver,79’85 OB-F, 73,76,80,83,84,86,404,405GB-F 79,80,404,406

’ ’ ’

Holocarboxylase Synthetase DeficiencyFB-F 33,175,203,207,407-412 EB-W ’33 (-~r:_p206,413

Biotinidase DeficiencyEB-serum6g’414-417 ,

Flavoprotein-Related MeasurementsSee Vianey-Liaud et alss for a review.

Short-Chain Acyl-CoA Dehydrogenase DeficiencyEB-muscle,41$ OB-F,55,56,217 DB-F 19,420

Medium-Chain Acyl-CoA Dehydrogenase DeficiencyEB-F,63,222,421,422 EB_W,57 EB-liver,224,423 EB-heart,221OB-F,123,223,384,424-426 CB-F, 427 DB-F.428,429 Also see Vianey-Liaudet alss and Gregersen 381 for reviews.

Long-Chain Fatty Acyl-CoA Dehydrogenase DeficiencyEB-F ’59,225 OB-F, CB-F 427

Glutaric Aciduria Type (1)EB-F,232,430-432 EB-W,9,232,432 OB-liver 12

Multiple Acyl-Coa Dehydrogenase DeficiencyEB-liver,z43,4:30,434 EB-muscle,112 OB-F,104.149,241-243,246,437 OB-mus-cle. 112 See medium-chain acyl-CoA dehydrogenase deficiency and



298

glutaric aciduria type 1.243,433-436 Also see reviews by Vianey-Li-aud et al55 and Gregersen. 381

Acetyl-CoA Carboxylase DeficiencyEB-F,247 EB-W.33 Also see holocarboxylase synthetase deficiency.

Malonayl-CoA Decarboxylase DeficiencyEB-F,3 ° EB-W311

Mevalonate Kinase DeficiencyEB-F, W, and liver143

Cytosolic Acetoacet~yl-CoA Thiolase DeficiencyEB-F,lss,367 OB-F 155,367

Mitochondrial Acetoacetyl-CoA Thiolase DeficiencyEB-liver110

Pyruvate Dehydrogenase E1 Subunit DeficiencyEB-F,41,46,48,13 ,139,2 2,256,257,260,266,281,438 EB-muscle, 42,43,262 EB-

l~g~’42,262,265 gp~~~~42.254,262.265 EB-kidney,z6z OB-F 42,46,48,138,256,259,265 OB-F.255 Also see Stansbie et a117 and Robin-son et a141 for reviews.

Pyruvate Dehydrogenase E2 Subunit DeficiencyEB-F 250

Pyruvate Dehydrogenase Phosphatase DeficiencyEB-liver, muscle, and brain253

Glycerol Kinase DeficiencyEB-F,302,306 EB_W 302 OB-F,301,306 DB-F301,306

Pyruvate Carboxylase DeficiencyEB-F ’34,129,154,268,272,439,440 EB-W, 33,439,441 EB-liver,129,273 EB-kid-

ney, 127,272,273 EB-muscle,314 EB-brain.272 Also see holocarboxylasesynthetase deficiency.

Phosphoenolpyruvate Carboxykinase DeficiencyEB-F,151,395,43&dquo;-441 EB_W~4s9,441 EB-liver,275,442 EB-muscle314

Fumarase DeficiencyEB-F,278 EB-liver and muscle277

2-Ketoglutarate Dehydrogenase DeficiencyEB-F.280 See also E3 deficiency.

Complex I Deficiency 113,313,314EB-muscle mitochondria,lls,s13,s14 EB-liver mitochondria,~&dquo;

EB-F 281

Complex III DeficiencyEB-F,281 EB-muscle’ 14

Complex IV (Cytochrome c Oxidase) DeficiencyEB-F, 281,2 88 EB-muscle, 42,49,50,54,135,283,286,287,443 EB-liver, 42,284,287,288EB-brain/2.288 EB-kidney,2111,2114,287,288 EB-heart2ss

Myoclonic Epilepsy With Ragged-Red Fibers (MERRF)SyndromeDB87,ss

Mitochondrial Encephalomyopathy Lactic Acidosis WithStrokelike Episodes (MELAS) SyndromeDB330,331

Kearns-Sayre SyndromeDB’ 17

Glutathione Synthetase DeficiencyEB-erythrocyte,153,291,444,445 erythrocyte glutathionez9o,z91,s69

Succinic Semialdehyde Dehydrogenase DeficiencyEB-W96,372

APPENDIX M

Dietary Management of Organic Acidemias

Organic Acidemias Not Responsive to DietaryRestrictions or No Information Available

3-Methylglutaconic aciduria with normal hydratase180-182Short-chain acyl-CoA dehydrogenase deficiency56,418Multiple acyl-CoA dehydrogenase deficiency, neonatal form

with dysmorphla102,104,148,238-240Acetyl-CoA carboxylase deficiencyz47Mevalonate kinase deficiency 143Cytosolic acetoacetyl-CoA thiolase deficiency&dquo;’

0Mitochondrial acetoacetyl-CoA thiolase deficienc 11Pyruvate dehydrogenase E2 subunit deficiencyl3 ,1s9 ’

Pyruvate dehydrogenase phosphatase deficienCy113D-Glyceric aciduria 37-39,267

121,111Pyruvate carboxylase deficiency, neonatal form127,154Phosphoenolpyruvate carboxykinase deficiencylsl,z7s,z76Fumarase deficiency277

CY2112-Ketoglutarate dehydrogenase deficiency2soComplex I deficiency314

14Complex III deficiency’14

54,135,165,288Complex IV deficiency50,54,135,165,288Myoclonic epilepsy with ragged-red fibers (MERRF)

syndrome 88Mitochondrial encephalomyopathy lactic acidosis with

strokelike episodes (MELAS) syndrome 299Kearns-Sayre syndrome 87,1164-Hydroxybutyric aciduria94-97

Organic Acidemias With Variable Response to DietaryRestrictions

3-Methylcrotonyl-CoA carboxylase deficiency: No response toprotein restriction.lo9,’T Response to dietary leucine

restriction.175 A ~rotein level of 0.5 to 2.0 g/kg/d isrecommended. 1

Glutaric aciduria type 1: No response to protein restriction.349Response to lysine 227 and tryptophan restriction.334

Pyruvate dehydrogenase El subunit deficiency, neonatal form:No response to carbohydrate restriction 41 (but seeexception 357).

Organic Acidemias Responsive to Dietary Management .

Isovaleric acidemia: Protein restricted to 0.8 to 2.0 g/kg/d 168,169 ; normal diet with precautions to prevent proteincatabolism.336

3-Methylglutaconic aciduria with deficient hydratase.Response to leucine restriction (no prolonged follow upwas reported).92

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency: Avoidfasting.’s3,1s4 Diets with restricted leucine and fat(30% ).183,184,446

Dihydrolipoyl dehydrogenase (E3) deficiency: Avoid fasting;high-carbohydrate diet

Mitochondrial 3-ketothiolase deficiency: Protein restricted to0.7 to 2.0 g/kg/d.119,1zo,las,ls7,ls9

Propionic acidemia: Protein restricted to 0.6 to 2.0 0. g/kg/d. 118,193,196 Normal diet and total parenteral nutrition

with precautions to prevent protein catabolism. 195Metronidazole, 5 mg/kg/d.33Methylmalonic acidemia: Determine maximal protein tolerable



299

by following urinary methylmalonic acid excretion.&dquo; Inpatients with low protein tolerance, diets restricted inisoleucine, valine, methionine, and threonine aresupplemented with mixture of other essential aminoacids. 14,195,201 Prevent protein catabolism.’9s

Holocarboxylase synthetase deficiency: Protein restricted to0.5 to 3 g/kg/d.175,178

Medium-chain acyl-CoA dehydrogenase deficiency;Avoid fasting, medium-chain triglycerides, and ketogenicdiets. 55,63,222,380 Frequent feedin . z,zz3 Low-fat (20%) andhigh-carbohydrate (> 60%) diet.~384,385

Long-chain acyl-CoA dehydrogenase deficiency: Low-fat(< 20%) diet,s9 supplemented with medium-chaintriglycerides. 58

Multiple acyl-CoA dehydrogenase deficiency infantile formwithout dysmorphia: High-carbohydrate (75%), low-fat(< 20% or 3 g/kg/d) diet with protein (1.5 g/kg/d, or 10%to 15% ).137,24 ,35 In acute metabolic crisis, large amountsof glucose with insulin.366

Multiple acyl-CoA dehydrogenase deficiency, adult form:High-carbohydrate (> 60%), low-fat (< 20%) diet. 112

Malonyl-CoA decarboxylase deficiency: Low-fat,high-carbohydrate diet. 300

Pyruvate dehydrogenase El subunit deficiency, infantile andlate-onset forms: High-fat or ketogenic diet as tolerated,with restriction of carbohydrates4~44,46,262,354 (one patientfailed to respond139).

Pyruvate carboxylase deficiency, late onset: Diet with fat(40%), protein (10%), and carbohydrate (50% ).271

Glycerol kinase deficiency: Low-fat diet. 301Glutathione synthetase deficiency: Same dietary precautions

as used for glucose-6-phosphate dehydrogenasedeficiency.3

APPENDIX N

Supplemental Medications, Vitamins, or CofactorsUsed in the Management of Organic Acidemias

Organic Acidemias Not Responsive to Supplements3-Methylglutaconic aciduria with or without hydratase

deficiency36, 92,181 Cyl85,l87,189Mitochondrial 3-ketothiolase deficient

Short-chain acyl-CoA dehydrogenase deficiency (glycinecauses biochemical but not clinical response)56

Cytosolic acetoacetyl-CoA thiolase deficiency’ -15Mitochondrial acetoacetyl-CoA thiolase deficiencylloMalonyl-CoA decarboxylase deficiency300,311Mevalonate kinase deficiencyGlycerol kinase deficiency T302,309

138,139Pyruvate dehydrogenase E2 subunit deficiency 21,21Phosphoenolpyruvate carboxykinase deficiency151,274,275Fumarase deficiency277

2802-Ketoglutarate dehydrogenase deficiency.Complex IV deficiency5o>t, 135,165,288Myoclonic epilepsy with ragged-red fibers (MERRF)

syndrome&dquo;Mitochondrial encephalomyopathy lactic acidosis with

strokelike episodes (MELAS) syndrome299Kearns-Sayre syndromel’6

94-974-Hydroxybutyric aciduria94-9’

Organic Acidemias With Variable Response toSupplements

Methylmalonic aciduria due to cobalamin C mutation: Nobiochemical and hematologic response to 1 mg/dvitamin B12. 71-74 Good response without improvement ofretinal findings. 1,78

Cobalamin D mutation: One patient responded to 1 mg/dvitamin B12 81; in another, questionable response.83

Cobalamin F mutation: Response to 1 mg/d vitamin Blz wasquestionable

Glutaric aciduria type 1: Good clinical response to riboflavin,25 to 100 mg/kg, and L-carnitine, 100 mg/kg .227,234 Goodresponse to baclofen. 121

Multiple acyl-CoA dehydrogenase deficiency, neonatal form:Riboflavin, 40 mg/kg/d, and L-carnitine, 300 mg/kg/d,improves organic acid excretion without clinicalresponse 364; good clinical response.’3’ In acute crisisrepeated intravenous methylene blue 2 mg/kg.364

Pyruvate dehydrogenase El subunit deficiency, neonatalform: No response to thiamine and lipoic acid, 41,48,257 butone patient responded clinically. 357 Thiamine should betried in all patents. 447

Pyruvate dehydrogenase El subunit deficiency, infantile form:no response to thiamine 41,260,262,265 ; clinical response tothiamine. 41,447 One patient responded to nalorphine. 260Good clinical response to dichloroacetate, 30 to 100mg/kg/d, in partial deficiency,zs9,3s4 but only biochemicalresponse in others

Pyruvate dehydrogenase El subunit deficiency, late-onset form:300 to 1800 mg/d thiamine produces clinical response, 41,48,447except in one patient.43 L-Carnitine stimulates theenzyme,~9 and should be tried. 31

Organic Acidemias Responsive to SupplementsIsovaleric acidemia: Glycine, 250 mg/kg/d168,169,351,353;

L-carnitine, 100 mg/kg/d 169,342 ; or used in combina-tion. 170,171

3-Methylcroton~-CoA carboxylase deficiency will not respondto biotin176,1 ; phenotypes responsive to 5 to 30 mg/d biotinmight be multiple carboxylase deficiencies. 17’ L-Carnitine100 mg/kg/d. 17

3-Hydroxy-3-methyl~lutaryl-CoA lyase deficiency: L-Carnitine,100 mglkg/day.18~184,446 6Dihydrolipoyl dehydrogenase (E3) deficiency: DL-a-lipoic acid,

25 mg/kg/d.l4oPropionic acidemia: Biotin, 10 to 100 mg, causes variable

success 192 ; glycine, 200 mg/kg/d345; and L-carnitine, 100mg/kg/d. 344,345,350

Methylmalonic acidemia: Some of the mutations will notrespond to vitamin B12 treatment. In each patient, theefficacy of vitamin Blz must be investigated by followingthe urinary excretion of methylmalonic acid. Responsivepatients must receive daily or every other day 1 mgvitamin B12.14,202,362 L-carnitine, 100 mg/kg/d. 43

Holocarboxylase synthetase deficiency: Biotin, 0.5 mg/kg/d to20 mg/d.203,205,::107,412 L-carnitine, 100 mg/kg/d.391

Biotinidase deficiency: Biotin 1.5 to 5 mg/kg/d. 209,361Medium-chain acyl-CoA dehydrogenase deficiency:

Riboflavin380,450; L-carnitine, 100 mg/kg/d. 55,63,2~4,385,450Long-chain acyl-CoA dehydrogenase deficiency: L-carnitine,

100 mg/kg/d.58,59Multiple acyl-CoA dehydrogenase deficiency, infantile form

without dysmorphia: Riboflavin, 10 to 300mg/d137,24~,246,3s4,45B L-carnitine, 100 mglkg/d.245,347,354

Multiple acyl-CoA dehydrogenase deficiency, late form:Riboflavin, 30 mg/d; L-carnitine, 2 g/d.llPyruvate carboxylase deficiency: Supplement the precursors of

Krebs cycle intermediates in the form of asparagine, 50 to175 mg/kg/d, plus aspartic acid, 300 mg/kg/d, plusglutamine, 50 to 350 mg/kg/d, plus glutamic acid, 300 to2000 mg/kg/d.127,154 No response to thiamine andbiotin.3’3,12’1

Complex I deficiency: Particularly late-onset forms willrespond to riboflavin, 120 mg/d; thiamine, 400 to 800 mg/d;menadione, 80 to 160 mg/d; ascorbic acid, 2 g/d; andprednisone.134,354 No response to L-carnitine and biotin.314



300

Acute metabolic crisis responds to repeated intravenousinjections of methylene blue, 2 mg/kg. 354,364

Complex III deficiency: Coenzyme Q, 80 to 160 mg/d;menadione, 80 to 160 mg/d; and ascorbate, 2 g/d.354 Noresponse to riboflavin and thiamine.114

References*

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topical review article: organic acidurias: a review part 2

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