topical review article: organic acidurias: a review. part 1

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1991 6: 196J Child NeurolPinar T. Ozand and Generoso G. Gascon

Topical Review Article: Organic Acidurias: A Review. Part 1

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Topical Review Article

Organic Acidurias: A Review. Part 1Pinar 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, Kingdom of Saudi Arabia.

Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids,disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resul-tant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolismis the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione,and γ-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic man-ifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervoussystem. The age of presentation and the associated systemic, hematologic, and immune findings provide additionalguidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusualneurologic presentations. (J Child Neurol 1991;6:196-219).

n organic acid is a compound that generatesprotons at the prevailing pH of the humanorganism. The accumulation of an organic acid incells and fluids (plasma, cerebrospinal fluid, or

urine) indicates impaired intermediary metabolismand leads to a disease state called organic acidemiaor organic aciduria. Since isovaleric acidemia, the

oldest known and treated, was described in 1966,12more than 50 phenotypically different organic aci-demias are now known, thanks to gas chromatogra-phy/mass spectrometry (GC/MS).

Pathogenesis

Ketonuria and Hyper- Lactic AcidemiaMany organic acids are produced during the catabo-lism of carbohydrates, lipids, and amino acids. Un-der usual physiologic conditions, the protonsgenerated by these compounds are neutralized bythe buffer systems available in cells and biologic flu-ids. Examples of normally compensated metabolicacidosis are ketone body production in the fastingstate and lactic acid accumulation following vigorous

exercise. An excessive rate of production, however,will lead to overt metabolic acidosis, as in diabeticketoacidosis. Another disorder, glycogen storagedisease type 1, is associated with impaired gluconeo-genesis and produces significant hyper-lactic aci-demia under normal physiologic conditions or

following a load of a sugar, such as fructose.3 3

Excess Organic AcidsBesides ketone bodies and lactate, other organicacids may be produced in excess. While they arebarely detectable under normal physiologic condi-tions, such compounds accumulate in large amountswhen an enzyme activity related to their furtherbreakdown is deficient. Traditionally, the term or-ganic acidemia has been confined to these latterconditions. Good examples are methylmalonic aci-demia,4 propionic acidemia,5 isovaleric acidemia,6 6and 3-hydroxy-3-methylglutaric aciduria secondaryto 3-hydroxy-3-methylglutaryl coenzyme A (CoA)lyase deficiency.’ The accumulation of such organicacids not only causes compensated or overt acidosisbut is usually associated with grave systemic or neu-rologic disease. The primary enzyme deficiency re-sponsible for the generation of these compoundscauses significant derangements of intracellular andmitochondrial metabolism.

Interference With Intracellular MetabolismAn example is the accumulation of glutaric and3-methylglutaric acids in glutaric aciduria type 1.8

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197

These two compounds accumulate because the en-zyme responsible for further metabolism of glutaryl-CoA, glutaryl-CoA dehydrogenase, is deficient.8 Thedisease is diagnosed by the accumulation of thesetwo organic acids in biologic fluids. This accumula-tion is usually associated with compensated meta-bolic acidosis and causes mild overt acidosis onlywhen excessive glutaryl-CoA is produced from a

load of the precursor.’ Nevertheless, glutaric acid-uria type 1 may remain inconsequential, except thatthe intracellular accumulation of glutaryl-CoA inhib-its glutamate decarboxylase,l° ie, the synthesis ofy-aminobutyric acid in the central nervous systemand the malate-aspartate shuttle in the liver.11 Thefirst of these events is possibly responsible for necro-sis of the basal ganglia IO, 12 and the second, for hypo-glycemia.11

Another example is the accumulation of methyl-malonyl-CoA intramitochondrially in patients withmethylmalonic acidemia.4 4 Increased excretion of

methylmalonic acid results from its increased hy-drolysis. Hyperammonemial3 and hypoglycemia 14result from inhibitory effects of methylmalonyl-CoAon ureagenesis and on pyruvate carboxylase (andhence on gluconeogenesis).

These two examples can be extended to other or-ganic acidemias. These disease states lead to accumu-lation of organic acids in biologic fluids that mightcause compensated or overt metabolic acidosis but ex-ert most of their progressive neurologic and systemiceffects as a result of increasing derangements of theintracellular biochemical pathways.

Interference With Energy MetabolismGlycolysis and ketone body and fatty acid utilizationconstitute the bulk of energy metabolism in humans.These pathways culminate in the generation of fourorganic acids: pyruvate, lactate, 3-ketobutyrate (ace-toacetate), and 3-hydroxybutyrate, the turnover andpool of which are large.15,16 The pool size and rate ofmetabolism of these organic acids show significantincrease and decrease under normal physiologicconditions, since they are finely tuned by hormonesthrough secondary messengers. 17,11 It is thereforenot surprising to observe significant increases in

their levels, leading to compensated or overt meta-bolic acidosis when the intracellular pathways arederanged secondary to the accumulation of organicacid intermediates. Therefore, in a large number oforganic acidemias, acidosis occurs not only becauseof the accumulation of the organic acid, but also be-cause of increasing levels of lactate, pyruvate, 3-

ketobutyrate, and 3-hydroxybutyrate.

MitochondriopathiesEnergy is generated by adenosine triphosphate syn-thesis in a specific cellular organelle, the mitochon-drion, while electrons are transported to oxygen.The transport of electrons requires several cofactorsand a complex protein machinery whose synthesis iscontrolled both by cellular and mitochondrial DNA.19Any derangement in this process will lead to the ac-cumulation of lactate or fatty acid intermediates. Bydefinition, such disorders should be included in or-ganic acidemias, since not only do they lead to thegeneration of protons that alters the buffer metabo-lism, but they also lead to progressive disease be-cause of the derangement of intracellular pathwaysaffecting many aspects of normal cell function. How-ever, they are commonly considered as mitochondri-opathies because a distinct cell organelle is

implicated .20 We shall include some mitochondriop-athies in this review because their symptom complexshows significant overlap with other organic aci-demias.

Aminoaciduria Versus Organic AciduriaDisorders of amino acid metabolism are associatedwith the accumulation of organic acids but are notusually classified within the organic acidemias.Branched-chain aminoacidemia or maple syrupurine disease, for example, is caused by the defi-ciency of a dehydrogenase specific for branched-chain 2-keto acids.21 This leads to significantelevation of three branched-chain amino acids-leu-

cine, isoleucine, and valine-as well as significantaccumulation of their 2-keto acids. Maple syrupurine disease can be diagnosed by detection of eitheramino acids or 2-keto acids in urine. Traditionally, itis considered an aminoacidemia, since it is primarilydiagnosed through the increased levels of branched-chain amino acids. A related disorder, dihydrolipoyldehydrogenase (or E3) deficiency, is caused by thedeficiency of one component of the branched-chain2-ketoacid dehydrogenase component, the E3.22 Thisunit is shared by other dehydrogenases, such aspyruvate dehydrogenase, and 2-ketoglutaric dehy-drogenase. Therefore, in E3 deficiency, in additionto a moderate accumulation of branched-chainamino acids and their 2-keto intermediates, derange-ment of several enzymes occurs. E3 deficiency istherefore traditionally classified as an organic aci-

demia. While E3 deficiency is discussed below,branched-chain aminoacidemia is not included in

this review.In disorders such as phenylketonuria, 23 Hawk-

insinuria,24 and tyrosinemia type 1,25 the enzyme



198

deficiency leads to the accumulation of aromatic or-ganic acids in the urine, which are used to diag-nose the disease. However these three disorders are

usually discussed as derangements of phenylala-nine and tyrosine metabolism, despite the fact thatHawkinsinuria and succinylacetonuria are preferablydiagnosed by GC/MS. Another example is N-acety-laspartic aciduria in Canavan disease.26 The com-pound excreted is a substituted amino acid, essential-ly an organic acid. The condition can be diagnosedeither by the increased excretion of N-acetylasparticacid in urine by GC/MS26 or by enzymic determina-tions in cultured fibroblasts or brain 2’ but is ex-

cluded from this review because it is traditionallyconsidered a primary disease of the glia.

Although these preliminary considerations indi-cate that the terms organic acidemia and organic ac-iduria are used arbitrarily, we have decided to keepthem and review those disorders that are tradition-

ally considered within these categories.

Diagnostic AspectsThe diagnostic approach synthesizes clinical and lab-oratory assessments. Clinical assessment considers

presentation and signs. Laboratory assessment (dis-cussed in part 2 of this review) uses clinical bio-chemical screening tests and confirmatory GC/MStechniques.

~ z

Neurologic Clinical Assessment/PresentationThe prototypical presentation of organic acidemias iseither intermittent attacks of acidotic coma or pro-gressive encephalopathy. Less well appreciated arepresentations such as static encephalopathies, braindysgenesis, myelopathy-neuropathy, and myopa-thy.

Intermittent Attacks. One clinical presentation ofan organic acidemia is periodic acidosis-a life-

threatening episode of metabolic acidosis that maytake place at any age and may repeat at anytime .28,29 These episodes are preceded by a pro-drome of vomiting, somnolence, hypotonia, andsometimes, seizures. Attacks are precipitated by in-fections, excessive protein intake, surgical proce-dures that lead to increased protein catabolism indisorders related to amino acids or glutathione syn-thesis, and large carbohydrate load in some mito-chondriopathies. When compensated or overt meta-bolic acidosis is not appreciated, the severe episodeof vomiting may lead to erroneous laparotomy forintestinal obstruction or even pyloromyotomy.3o-32

This prodrome rapidly progresses to coma or pyram-idal, extrapyramidal, cerebellar, or brain-stem signs.The primary or secondary derangement of gluconeo-genesis, ketogenesis, and ureagenesis leads to hypo-glycemia, hyperammonemia, and acidosis secondaryto the accumulation of a variety of organic acids. Or-ganic acidemias associated with such episodes ofperiodic acidosis are listed in Appendix A. Isova-leric acidemia,l 3-hydroxy-3-methylglutaryl-CoA ly-ase deficienCY,7 propionic acidemia,5 methylmalonicacidemia,4 pyruvate dehydrogenase deficiency,’ 7pyruvate carboxylase deficiency,33,34 and complex IVdeficiency35 are prototypes. Repeated acidotic epi-sodes lead to severe central nervous system damageand death if left untreated. In this group of disor-

ders, a careful history will often reveal the presenceof central nervous system symptoms that were notappreciated before the acidotic attack. The clinicalsymptoms at and after the time of acidosis indicateglobal involvement of the central nervous system; eg,developmental delay and pyramidal tract signs arecommon. Specific symptoms may be associated withcertain diseases (see following section on specificdisorders). For example, 3-methylglutaconic aciduriawith normal hydratase36 and D-glyceric aciduria

with defective fructose metabolism3~-4o manifest

myoclonus. Infantile-onset pyruvate dehydrogenasedeficiency presents predominantly with cerebellar

signs. 41-47 Impairment of oxidative metabolism

due to severe deficiency of pyruvate dehydroge-nase 41,42,48 or of complex IV49-54 manifests as brain-stem symptoms. Accumulation of fatty acyl-CoA isthought to be detrimental to normal muscle mito-chondrial function and could be responsible for themyopathy observed in fatty acyl-CoA dehydroge-nase deficiencies.55-59

Some organic acidemias present with episodicattacks reminiscent of Reye syndrome, ie, Reye-likesyndrome. An acute accumulation of fatty acyl-CoAesters in medium-chain acyl-CoA dehydrogenasedeficiency often presents as Reye-like syndrome(Appendix B). 57,60-63 The presentation of some pa-tients with 3-hydroxy-3-methylglutaryl-CoA lyasedeficiency is similar to Reye syndrome.

Progressive Neurologic Disease. A much-encountered

clinical presentation in Saudi Arabia is that of anacute or subacute progressive neurologic diseasewithout overt acidosis. An organic acidemia may bediscovered in a child with progressive encephalopa-thy who slowly develops pyramidal, extrapyrami-dal, or cerebellar signs and mental deterioration.There may be preceding motor developmental de-



199

lay, but more striking is impairment of later matur-ing functions like speech and language and bothgross and fine motor coordination. Appendix B liststhese disorders and presenting neurologic signs.The best example is the recognition of glutaric acid-uria type 1 among patients with otherwise asymp-tomatic &dquo;dystonic cerebral palsy. 1165 It is assumedthat a chronic accumulation of glutaryl-CoA is re-

sponsible for necrosis of basal ganglia. 10,66,67 Long-term biotin deprivation, as in biotinidase deficiency,manifests as pyramidal tract and cerebellar symp-toms. 68-70 Cobalamin mutations C,~l-8° D,SI-S3 andF 84-86 present with pyramidal tract signs and abnor-mal eye movements. The later-onset forms of pyru-vate dehydrogenase deficiency due to partialdeficiency of the enzyme lead to extrapyramidal andcerebellar signs. 41,42,45-47 The initial symptom of

myoclonic epilepsy with ragged-red fibers syndromeis that of a seizure disorder with interictal myoclo-nus or tremors. 87-90 Occasionally, disorders charac-terized by periodic acidosis will manifest with onlyneurologic signs. These exceptions are also listed inAppendix B.

Presentation As Static or Slowly Progressive Central Ner-vous System Disease. An organic acidemia may bediscovered during the study of a child with static en-cephalopathy. Good examples are: a patient withisovaleric acidemia,91 a patient with 3-methylgluta-conic aciduria with normal hydratase,92 and a pa-tient with fumaric aciduria93 whose chief complaintsare speech difficulties. A patient with succinic semi-aldehyde deficiency might arrive with autistic fea-tures. 94-97 The development of mental retardation ina patient with glutathione synthetase deficiency is aslowly progressive event..98-100

Congenital Brain Anomalies and Dysmorphia. A recent

report,101 as well as our experience, suggests thatthe fetus with organic acidemia might be affected be-fore birth and might be born with congenital anom-alies of the brain. The brain anomalies may be a partof the dysmorphic features associated with certainorganic acidemias (Appendix C). In these disorders,the derangement of a function vital to the fetuscauses teratogenesis. The absence of riboflavin maybe responsible for dysmorphia in the neonatal form ofmultiple acyl-CoA dehydrogenase deficiency.lo2-l06A normal cobalamin pathway is essential for the fe-tus, since methylmalonic acidemia and cobalamin Cmutation appear with dysmorphic features .76,77,79 Fe-tal metabolism is mainly anaerobic glycolytic;107,108

nevertheless, pyruvate dehydrogenase deficiencycauses significant dysmorphia.41

Spinal Cord Symptomatology and Peripheral Neuropathy.The presenting symptom of an organic acidemia,with or without periodic acidosis, can be with spinalcord symptomatology, eg, methylcrotonyl-CoAcarboxylase deficiency1o9,111 and cobalamin D muta-tion.81-83 Peripheral neuropathy has been docu-mented in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency

Myopathic Presentation. Flavoprotein-linked dis-

eases, 55,58,59,112 oxidative defects such as late-onsetpyruvate dehydrogenase deficiency, 14,47 complex I

and III deficiencies,113,114 and mitochondriopathies,particularly those with large deletions of mitochon-drial DNA will show myopathy or cardiomyopathyin addition to disturbed central nervous systemfunction, vision, and hearing (Appendix B). An ex-ample is Kearns-Sayre syndrome.115-11’

Asymptomatic Organic Acidemias. Rarely, an organicacidemia occurs in an apparently normal individual.This phenotypic variability is documented for propi-onic acidemia,118 methylacetoacetyl-CoA ketothio-lase (3-ketothiolase) deficiency,119,12o methylmalonicacidemia,121,122 medium-chain acyl-CoA dehydroge-nase deficiency,123 and glutathione synthetase defi-ciency.124 These are discovered accidentally whenunaffected siblings and parents of the patient are in-vestigated. Some other organic acidemias, such as2-ketoadipic aciduria,125 usually remain asymptom-matic.

’

Age of Presentation. Many organic acidemias presentdifferent phenotypic expression at different ages.This phenotypic variability is observed even amongaffected members of the same family, eg, with meth-ylmalonic acidemia.126 It is important to recognizethis phenotypic variability, since it carries prognosticimportance. For example, while neonatal-onset

pyruvate carboxylase deficiency is invariably lethal,the late-onset form can be compatible with life. 127-129Appendix D categorizes each disorder according tophenotypes at different ages. When phenotypic vari-ability is encountered, it can be explained by the na-ture of the enzyme defect; eg, different phenotypesof methylmalonic acidemia 130 and isovaleric aci-

demia131 are caused by different types of mutations.The availability of a secondary limited source of thedeficient product will alter the appearance and pro-gression of clinical symptoms, as in biotinidase defi-



200

ciency. 68,132 In some instances, the excessive

production of an organic acid is caused by differentdefects appearing as different phenotypes; eg, 3-

methylglutaconic aciduria with normal hydratase isclinically quite varied and probably represents sev-eral different disorders.36 Organic acidemias causedby mitochondrial DNA defects will manifest at dif-ferent ages with different clinical expression, de-

pending on the degree of heteroplasmic inheritanceof the mitochondrial genome, 19,20,133 for example,complex I113,134 and complex IV49,135 deficiencies.

Nonspecific Symptoms and Signs ofOrganic AcidemiasThe clinical presentation of an organic acidemia withperiodic acidosis or with primarily neurologic symp-toms includes nonspecific symptoms. The pertinentnonspecific manifestations include failure to thriveand associated systemic and immunologic findings.

Failure to Thrive. Malnutrition and frequent infec-tions associated with organic acidemias may explainthe commonly encountered retarded growth. How-ever, some organic acidemias impair normal growthdirectly, and when there is no obvious cause, failureto thrive should alert the clinician to the possibilityof organic acidemia. Infants may be born with signsof intrauterine growth retardation. Examples are

the neonatal form of multiple acyl-CoA dehydro-genase deficiency136,13’ and deficiencies of pyruvatedehydrogenase E1,41,42,48 E2, 138,139 and E3 sub-units 107,140-142 and mevalonate kinase. 143,144 In pa-tients with deletions or mutations of mitochondrial

DNA, eg, mitochondrial encephalopathy lactic aci-dosis with strokelike episodes syndrome145,146 andmyoclonic epilepsy with ragged-red fibers syn-drome, ~’~’~ failure to thrive is universally present.In Kearns-Sayre syndrome, it occurs before the pre-sentation of ophthalmologic, muscular, and cardiacconductive defects.116 In some instances, failure tothrive persists despite adequate therapy, as in meth-ylmalonic acidemia.l4

Systemic Manifestations. In some organic acidemias,other organ systems are significantly involved.

Long-chain fatty acyl-CoA dehydrogenase, 55,58,59multiple acyl-CoA dehydrogenase, 148,149 and meval-onate kinase143 deficiencies are associated with

chronic liver disease. Fanconi syndrome has beenobserved in isovaleric acidemia, 150 phosphoenol-pyruvate carboxykinase deficiency,151 and complexIV defects.49-54 Methylmalonic acidemia152 and defi-ciencies of glutathione synthetase,153 pyruvate

carboxylase,154 and short-chain acyl-CoA dehydro-genase155 can impair renal tubular function. Renalfailure has been documented in methylmalonic aci-demia156 and glutaric aciduria type 1.12

Immunologic Defects. The deranged organic acid

pathway may impair normal immune function (Ap-pendix E). Organic acidemias related to the path-way of branched-chain amino acids, eg, methyl-malonic acidemia, 157,158 isovaleric acidemia,159pro-pionic acidemia, 160 and mitochondrial 3-ketothiolasedeficiency, 157 are associated with dysfunction ofthe immune system. Suppression of granulopoieticprogenitor-cell proliferation 157 and impaired T- andB-cell function16o,161 have been implicated. Im-

paired availability of biotin and riboflavin accountsfor the association of infections in biotinidase69,111,161and multiple acyl-CoA dehydrogenase deficien-cies.149 Defective glutathione synthesis as in 5-

oxoprolinurial62,163 or impaired oxidative phospho-rylation, as in complex IV deficiency,164,165 will im-pair granulocytic function.

Specific Disorders

Organic Acidemias Related to Branched-ChainAmino Acids

Leucine. Isovaleric acidemia is caused by the deficien-cy of isovaleryl-CoA dehydrogenase and presentswith periodic acidotic attacks in neonatal, 6,166-168 in-fantile, and childhood forms. I, 166, 169-172 The acidoticepisodes are preceded by’69 or associated with infec-tions, 159,169,172,173 since the disease inhibits the mat-uration of hematopoietic cells.159 A &dquo;cheesy&dquo; smellemanates during attacks. Neurologic signs includehypotonia, tremor, 168 pyramidal 170 and extrapyrami-dal signs,

ISO and developmental retardation. 169 Ataxiaand speech problems169 can occur when age of onsetis late.91 Mental retardation is already present whenthe disease is recognized late (20% neonatally versus50% childhood-diagnosed patients).169 Isovaleric aci-demia may present with compensated acidosis andneurologic signs only; eg, unsteady gait,91 spastic di-plegia, mental retardation,1’° and Reye-like syn-drome.169 Despite the dramatic presentation ofisovaleric acidemia in the neonate, death is not a com-mon occurrence (30% ). 169 Rarely, the disease is associ-ated with cerebellar hemorrhage,16~ cataracts,dwarfism, and congenital anomalies 172 and with Fan-coni syndrome and renal tubular acidosis. 150

3-Methylcrotonyl-CoA carboxylase deficiency (methyl-



201

crotonic aciduria)109, 174-178 is characterized by periodicacidosis without specific neurologic signs. 175 An ex-ception is one patient who presented with hypoto-nia, fasciculations, and muscle atrophy withoutacidosis at 4.5 months.109 The earlier-described pa-tients may have been cases of holocarboxylase syn-thetase deficiency. The acidosis can present shortlyafter birth 171 or can be induced by high-protein feed-ing 177 later during childhood.

3-Methylglutaconic aciduria occurs with two differ-ent presentations, one with normal and the otherwith deficient 3-methylglutaconic acid hydratase.

In 3-methylglutaconic aciduria with normal hy-dratase, the defective pathway is unknown.36 It is aprogressive neurodegenerative disease with periodicacidotic episodes179-182 precipitated either by exces-sive protein intake 181 or by severe infections.lso,isiFailure to thrive is prominent. 181 Intrauterine growthretardation 182 and dysmorphic featureslso,~s2 suggestonset before birth. Neurologic signs include hypoto-nia, dyskinesia, choreoathetosis, myoclonus, senso-rineural deafness, optic atrophy, and tapetoretinaldegeneration. 36,179-182 In some cases, the presentingsymptom is infantile spasms syndrome.36,1s2 Neuro-radiologic studies reveal white-matter abnormali-ties. 182 The disease leads to microcephaly, 181 spasticquadriplegia, and eventually, dementia in all pa-tIents, 36, 179-182 with early death.36

3-Methylglutaconic aciduria with deficient hydratasebegins in childhood with developmental retardation,particularly in receptive and expressive language.92

3-Hydroxy-3-methylglutaryl-CoA lyase deficiencyleads to a rapidly progressing acidosis, precipitatedby leucine load and fasting, 183,184 that becomes irre-versible. The patient dies within hours if the diseaseis not recognized and treated, particularly in theneonatal period. 183 Acidotic attacks are associatedwith or preceded by seizures, hypotonia, and pyra-midal tract signs.ls3,1s4 In surviving patients treatedadequately, few neurologic or neuroradiologic se-

quelae remain, with normal physical and mental de-velopment.ls3,ls4

Deficiency of dihydrolipoyl dehydrogenase (E3), a

unit shared by several mitochondrial dehydroge-nases, presents as intermittent metabolic acidosiswith severe failure to thrive and increased suscepti-bility to infections. 107,108,140-142 Neurologic signs in-clude hypotonia, respiratory difficulties, pyramidaltract signs, severe developmental retardation, andoptic atrophy but no seizures. 107,108,140-142

Isoleucine. 2-Methyl acetoacetyl-CoA 3-ketothiolase (mi-tochondrial 3-keto or @-ketothiolase) deficiency usually pre-

sents with intermittent severe acidosis. 31,119,120,185-190Neurologic signs preceding the acidosis include

early developmental delay,119,185,189 hypotonia, 119,189myoclonus,185 unstable gait, 185 ataxia, 120 and diple-gia. 120 A newborn who mistakenly underwent py-loromyotomy at 4 weeks for persistent vomitingshowed hypotonia before the first acidotic attack at12 weeks and developed cardiomyopathy.31 Be-

tween acidotic episodes, patients may show no evi-dence of neurologic involvement. 12~,185-189 Familyhistory may reveal infantile deaths following misdi-agnosed acidotic attacks. 187 However, the diseasehas also been diagnosed in a healthy sibling119 orparent 120 during studies of the index patient’s fam-ily.

Propionic acidemia is a deficiency of propionyl-CoA carboxylase, which requires biotin as cofactor.The incidence is 1 in 350,000 births in the Massachu-setts screening program.191 It causes an infantile on-set metabolic encephalopathy with periodic acidosis.Vomiting, anorexia, dehydration, lethargy, and hy-potonia precede the acidotic attack.192,193 Severe

vomiting may mimic pyloric stenosis.32 Preceding orintercurrent infections, particularly diarrhea, are

common,192 due to a concomitant immune defi-

ciency. 160 Severe malnutrition and chronic muco-cutaneous candidiasisl6o cause dermatitis with wide-spread erythematous patches of scaly skin, particu-larly in the intertriginous areas.194,195

Seizures and myoclonus are associated with orprecede propionic acidemia in approximately 25% ofcases.192 Two children with seizure disorder andmental retardation but without acidosis were subse-

quently diagnosed as having propionic acidemia.194A child with a history of early childhood seizuresbut subsequent normal development was found tohave the disease after a sibling was diagnosed. 118Approximately 60% of patients progress to severefailure to thrive, mental retardation, spastic quadri-plegia, microcephaly, and focal seizures, especiallywhen recognized late.192,194 Propionic acidemia is

among the severest organic acidemias of infancy,leading to death in 40% of patients during anacidotic attack5 and causing severe neurologic mor-bidity in the remaining 60%.32,192,196 When recog-nized and treated promptly, intelligence remainsnormal. 192,195-198

Organic Acidemias Related to Metabolismof VitaminsDerangements of vitamin metabolism lead to defi-ciencies of cofactors shared by several enzymes af-fecting more than one intermediary pathway.



202

Cobalamin-, biotin-, and riboflavin-linked deficien-cies constitute a large percentage of organic aci-demias.

Organic Acidemias Related to Cobalamin Metabolism.

Dietary cobalamin is converted in steps to its cofac-tors adenosylcobalamin and methylcobalamin,which are involved in amino acid and nucleic acidmetabolism. An interruption at any step leads to dis-eases sharing the clinical symptoms of cobalamin de-ficiency.

Methylmalonic acidemia is caused by the absenceor deficiency of methylmalonyl-CoA mutase or byabnormal intramitochondrial metabolism of cobal-

amin, ie, a deficiency of adenosylcobalamin (cobal-amin A or B mutants). 130 Its incidence is 1 in 48,000.126In classic methylmalonic acidemia, attacks of ketoac-idosis and hyperammonemia are precipitated byheavy protein feeding65 or viral, bacterial, or fungalinfections. 4,157,158 Metabolic acidosis at the time ofinitial investigation may be absent, particularly inmethylmalonyl-CoA mutase deficiency and cobal-amin B genotypes.

130

Hypotonia without overt acidosis may be theonly presenting sign of methylmalonic acidemia. 4,199Developmental retardation, 130,199,200 hypotonia, 130,199and sensorineural deafnessl3o result when the dis-ease is untreated. Developmental retardation, butnot growth retardation ’65 can be reversed by appro-priate diet2ol and cobalamin administration. 130,199,202Renal proximal tubular acidosis and chronic renalfailure can be associated.152,156 The death rate in

methylmalonyl-CoA mutase absence is higher thanin other genotypes. 130 Infants with mutase deficiencyand methylmalonic aciduria may remain asymp-tomatic.121 Two adults lived to old age without overtdisease.122

Cobalamin mutations C, D, and F are associatedwith severe neurologic symptomatology and methyl-malonic aciduria but occur without ketoacidosis and

hyperammonemia, differentiating them from classicmethylmalonic acidemia. Defects in the cytosolic ox-idation of Co++ to Co+++ (cobalamin C and D mu-tations) or of its lysosomal pathway (cobalamin Fmutation) simultaneously prevent the synthesis ofboth adenosylcobalamin and methylcobalamin. Thedefective synthesis of adenosylcobalamin leads to

methylmalonic aciduria and of methylcobalamin tohomocystinuria.

Cobalamin C mutation is an early-onset neurologicdisease presenting with severe failure to thrive,feeding difficulties, hypotonia, and developmentalretardation.71-8o Neurologic symptoms and signs

include seizures,’6 myoclonus ’72 pyramidal tract

signs,’6 microcephaly,’1 abnormal vision 72,75,77 withmacular and retinal abnormalities,72,75 and hearingloss?7

Cobalamin D mutation is a late-onset disease81-83presenting with ataxia,81,82 abnormal eye move-

ments or nystagmus,82,83 mental retardation,82,83and psychosis.83 Seizures,82 hypotonia,82 pyramidaltract signs,83 and spinal cord signs81,83 in a child oradolescent should prompt a search for this disease.

Cobalamin F mutation was described in an infantwith seizures, hypotonia, abnormal eye movements,and opisthotonus.84-86

Organic Acidemias Related to Biotin Metabolism. Bio-tin is a cofactor for carboxylases. It is convertedinto biotinyl-5-adenosine monophosphate and thenbound to the E amino group of a lysine in the activecenter of different carboxylases by a single enzymeholocarboxylase synthetase. The breakdown of car-boxylases liberates lysine-bound biotin (biocytin),which is cleaved by biotinidase to yield free biotin.The endogenous pool of biotin is large compared tothat provided by the diet or gut synthesis by intesti-nal flora.68 The deficiency of either holocarboxylasesynthetase or biotinidase leads to biotin deficiency,an organic acidemia known as multiple carboxylasedeficiency. Biotin deficiency impairs the pathways ofvarious carboxylases; therefore, the clinical picturecombines features of propionic acidemia and defi-ciencies of 3-methylcrotonyl-CoA carboxylase, pyru-vate carboxylase, and acetyl-CoA carboxylase. Holo-carboxylase synthetase deficiency presents as a moresevere condition than deficiency of biotinidase, sincesmall amounts of biotin are always available throughdietary intake or intestinal bacterial synthesis. 68’132

Holocarboxylase synthetase deficiency causes peri-odic acidotic attacks203-208 associated with anorexia,stupor, hypotonia,2o6,20’ myoclonus, seizures, and

developmental delay. 204-208 In most instances, theenzyme deficiency is due to its decreased affinity tobiotin. Therefore, some clinical response will be ob-tained on administration of pharmacologic doses ofbiotin. 206,207

Biotinidase deficiency presents initially with neuro-logic symptoms.68,209,21 Metabolic acidosis appearslater during the course of the disease and in only60% of patients.69,209 Seborrheic or atopic dermatitis,alopecia, and conjunctivitis are each present in 20%of cases. Susceptibility to Candida infections 69,111,161is caused by the associated T- and B-cell immune de-fects.111,161 Symptoms occur earlier in breast-fed in-fants, since human breast milk contains less biotin



203

than formulas.209,21O Seizures, myoclonus or tremor(60%), sensorineural hearing loss (40%), develop-mental delay (40%), hypotonia (30%), visual difficul-ties with optic atrophy, stridor and episodes of

apnea, impaired gross and fine motor function, andimpaired speech with echolalia, precede the acidosisby months or years. 68-70,209-213 In its late-onset

form, ataxia and cerebellar signs are the predomi-nant neurologic findings, forming a triad with ery-thematous skin rash and alopecia. 69,111,209,211,212,214Wolf et al recommend biotin treatment in all infantsand children exhibiting a progressive neurodegener-ative disease, cutaneous manifestations, alopecia, can-didiasis, and immune deficiency, singly or in

combination, until biotinidase deficiency can beruled out.69 Death occurs in only 20% of cases.69,209

Organic Acidemias Related to Flavoprotein Metabolism.Flavoproteins are mitochondrial dehydrogenasesthat contain flavin adenine dinucleotide (FAD) asthe cofactor. Dehydrogenases specific for short-, me-dium-, and long-chain fatty acids, glutaryl-CoA, andsarcosine are examples of such FAD-containing pro-teins.55 The E3 subunit of pyruvate, 2-ketoglutarate,and branched-chain ketoacid dehydrogenases alsocontain FAD.20,22,215 These matrix proteins pass theelectrons from their substrates to a dimer electron

transport flavoprotein (ETF). Another FAD dehy-drogenase (ETFQO) transports electrons from ETF tocoenzyme Q (CoQ). The electrons from CoQ arethen transported into the main electron transportchain.55 Inborn errors of these flavoproteins impairthe utilization of these compounds as well as oflysine and tryptophan, which are normally catabo-lized to glutaryl-CoA and sarcosine.55

Short-chain acyl-CoA dehydrogenase deficiency is a

rare disease with different phenotypic expressions:severe metabolic acidoSiS,56 petechiae in infancy,216childhood-onset nonketotic hypoglycemia, and Reye-like syndrome. 217 Another presentation is with de-velopmental deterioration after 6 months of age,with subsequent acidosis at 13 months.216 Thedownhill course proceeds with increasing muscleweakness,218 intercurrent infections,56,216,21’ spasticdiplegia, and death.56,216

Medium-chain acyl-CoA dehydrogenase deficiency(MCAD) presents primarily as a Reye-like syndromewith intermittent hypoglycemic attacks5’-63,21s butwith a mild ketosis inappropriately low for the de-gree of hypoglycemia. Acidosis, when present, ismild and due to the accumulation of lactic acid.61

Symptoms are attributed to the severe neurotoxicity

of elevated medium-chain fatty acids, which are

known to inhibit neuronal Na-K-ATPase.219 Pro-

longed fasting in these patients leads to unexpecteddeath caused by increased lipolysis.55 Howat et a122°and Allison et al221 detected MCAD and long-chainfatty acyl-CoA dehydrogenase deficiencies in tissuesof 1% to 10% of children dying from sudden infantdeath syndrome. This disease should be consideredin families with multiple cases of sudden infantdeath syndrome. 57,60,123 In any child younger than 2years with a Reye-like syndrome, MCAD is the

prime diagnosis, since Reye syndrome is rare in thisage group. 57,60 It must be ruled out in any olderchild with Reye-like syndrome and pernicious vom-iting, absence of agitation or disorientation beforecoma, and particularly in the absence of increasedintracranial pressure. 57,60 Despite the severity andfrequency of hypoglycemic attacks, intelligence isnormal in 80% of the surviving patients. 55,61,222,223MCAD is the most common cause of nonketotic hy-poglycemia in childhood and leads to death if unrec-ognized. 55,224 It also can occur without symptoms,having been detected in the father of three suddeninfant death syndrome patients.

123 Loading tests arediagnostic in asymptomatic members of a familywith sudden infant death syndrome.6o

Long-chain acyl-CoA dehydrogenase deficiency pre-sents as a nonacidotic episodic hypoglycemia, as inMCAD, 55,218,225 with additional features of cardiomy-opathy and hepatic fibrosis and cirrhosis. 55,58,59,218The nonketotic hypoglycemic episodes are triggeredby infection or fasting. 55,58,59 Patients may experi-ence repeated infections.58,59 Hypotonia is the mainneurologic sign and may be explained by mitochon-drial damage caused by accumulating long-chainfatty acyl-CoA esters.226 Mortality is 40%, and sur-viving patients have severe to moderate mental re-tardation and microcephaly. 55,59,218

Glutaric aciduria type 1 is caused by deficiency ofglutaryl-CoA dehydrogenase, a flavoprotein that ox-idizes the glutaryl-CoA generated from lysine andtryptophan breakdown. 12 Its clinical presentation isheterogeneoUS,227 with intermittent acidosis or ex-trapyramidal signs. 65,228-230 Acidosis is rare, is an

associated rather than a presenting symptom,9, 12,228and can appear late in the disease.231 The associatedketosis and hypoglycemia have been explained byinhibition of the malate-aspartate shuttle by glutaryl-CoA.ll Other organs affected are myocardium, kid-ney, and liver.12 Intercurrent infections232 are notcommon.229

In the early-onset9, 11,228 and late-onset231 forms,the child presents acutely with dystonia, choreo-



204

athetoid movements, grimacing, dysarthria,65 sub-dural hematoma,11,231 seizures,9, 229 or hypotoniaand quadriparesis.22’ Macrocephaly can be pres-ent.228,230,231 White-matter changes around lateral

ventricles, striatal and lenticular necrosis, and bilat-eral frontotemporal atrophy are detected at necropsyor on computed tomographic scan. 66,67,227,233 Thedecreased 4-aminobutyric acid content in putamenand caudate nucleuS22’ has been explained by the in-hibitory effect of glutaric acid on y-aminobutyric acidsynthesis.10 Bilateral striatal necrosis is seen in mostpatients. 66,67,233 The clinical picture is more severethan the neuroradiologic findings, suggesting thatneuronal dysfunction precedes neuronal death. 230Glutaric aciduria can present with only dyskinesia,as first reported in five choreoathetotic cerebral

palsy patients by Brandt et al .65 Three infantile met-abolic errors manifest primarily with dystonia: glu-taric aciduria type 1, o-glyceric aciduria, and sulfiteoxidase deficiency.65,231 A patient described byGregersen et al232 presented with ataxia and diffi-

culty walking. Despite severe neurologic impair-ment, 60% of patients show normal intellect.229Eighty percent of those patients who manifest withonly choreoathetosis are of normal intelligence.65Death occurs in approximately 15% .5,229,230

Multiple acyl-CoA dehydrogenase deficiency (glutaricaciduria type 2) is a family of disorders in which theelectron transport chain linking flavoproteins ETFand ETFQO are defective, creating distinctly differ-ent phenotypes: a neonatal form, an infantile form,and childhood and late-onset forms.55 Different de-fects occur among patients with the severe infantileform, such as absent ETF, ETFQO, and other CoQcoupling proteins.234 Heterogeneity of the enzymicdefect may explain why riboflavin may be therapeu-tic, particularly in the second and third phenotypes.55Although the disease is autosomal recessive, an

X-linked inheritance proposed in one family withthe neonatal form235 suggests different mechanisms.Since the defect commonly affects fatty acyl-CoA,glutaryl-CoA, and sarcosine dehydrogenases, theclinical and laboratory features include those of re-lated organic acidurias.

The neonatal form is a disease with multisysteminvolvement and with dysmorphic features reminis-cent of peroxisomal disorders at birth, leading to

rapid death.236 The dysmorphic features and con-genital brain anomalies may be due to absent ribo-flavin function in the fetus, since experimentalriboflavin deficiency causes similar findings. Theseare cerebral dysgenesis, abnormal gyrus formation,cerebral degeneration with fibrous gliosis of caudate

and putamen, abnormal formation of bile ducts, gas-trointestinal tract abnormalities, kidney cysts, con-genital heart disease, and craniofacial dysmor-phia.lo2-l06 A fetus can be stiIlborn.104 The survivingnewborn shows severe hypotonia, superimposed in-fections, 102,235,237 and resistant hypoglycemia andacidosis, 102,104,236,238-240 but the disease is incompat-ible with life.

The nature of the enzyme defect in the infantileform is unknown, despite laboratory evidence for mul-tiple flavoprotein deficiencies .241-244 Following a pe-riod of severe developmental delay, failure to thrive,and anorexia, 136,137 the infant experiences an attackof severe hypoglycemia with acidosis. Frequent in-fections,242 cardiomyopathy,136 and hair loss136 havebeen described. Two patients were normal until hy-poglycemic acidotic attacks at 6 weeks and 9 monthsof age.242 Another showed repeated seizures but anotherwise normal clinical appearance for 4 years.241This infantile form may be responsive to riboflavintreatment,245 which may permit normal develop-ment.241,242

The childhood- and late-onset form manifests withsystemic involvement but mild or absent acidosis.One child experienced repeated episodes of mild hy-poglycemia and compensated acidosis, with gradu-ally increasing hepatomegaly and worsening of liverfunctions until 3 years of age, when his symptomsdisappeared on riboflavin administration.246 A 19-year-old patient who previously manifested re-

peated attacks of hypoglycemia, infections, and

hepatic dysfunction, was diagnosed after she devel-oped proximal myopathy.149 Another 17-year-oldgirl was diagnosed following 2 years of progressivelipid storage myopathy.112 None of the patients hadmental retardation.

Organic Acidemias Related toLipid Metabolism

Acetyl-CoA Carboxylase Deficiency. Acetyl-CoA car-

boxylase is a biotin-dependent enzyme that initiatesfatty acid synthesis. One infant with this deficiencypresented with severe failure to thrive, hypotonicmyopathy, and respiratory difficulties. 241

Mevalonic Aciduria. Mevalonic acid is formed from

3-hydroxy-3-methylglutaryl-CoA and converted to

mevalonate-5-phosphate by a kinase that is the firstintermediate in cholesterol synthesis.143 A patientwith mevalonate kinase deficiency had dysmorphicfeatures and acidosis at birth, cataracts at 2 months,repeated systemic and gastrointestinal infections, re-



205

current anemia with hepatosplenomegaly, seizures,and growth and developmental retardation untildeath at 2 years of age.143,1~ Mevalonic aciduria wasdiscovered in a 6-year-old boy with cerebellar ataxiaand elevated serum creatine kinase.248

Cytosolic Acetoacetyl-CoA Thiolase Deficiency. Two pa-tients presented with severe developmental delay,abnormal electroencephalograms, brain atrophy,and liver disease.155,24 Both infants had continuousketonuria and compensated acidosis.155 The patientdescribed by Bennett et a1155 remained profoundlyretarded.

Mitochondrial Acetoacetyl-CoA Thiolase Deficiency. A

5-year-old patient had growth retardation, severe

progressive neuropathy, and ataxia.110 Motor nerveconduction velocities were slow. She eventually wasunable to walk but had normal mentation, vision,and hearing She was continuously ketotic withcompensated acidosis. 110

Organic Acidemias Related to Glycolysis

Pyruvate Dehydrogenase Deficiency. This deficiency isthe most common cause of neonatal-, infantile-, and

early childhood-onset primary lactic acidosis. Pyru-vate dehydrogenase is a mitochondrial enzyme con-sisting of three subunits with different catalyticfunctions, El, E2, and E3, and a protein X.250,251 Allunits are coded in the nuclear genome .250,251 The Elsubunit contains two E1a and two E1~ componentsand decarboxylates pyruvate (pyruvate decarbox-

ylase). The E1a component is coded on chromo-some X p22.1, and the E1~ component on chromo-some 3.25° Thiamine pyrophosphate is the cofactor forE1. Most deficiencies of pyruvate decarboxylase arecaused by mutations of the E1a component. 250-252Varied phenotypic expression of E1a defects can be ex-plained by selective inactivation of the X chromo-some.251 The activity of the El subunit is controlled byacetyl-CoA/free reduced CoA and reduced nicotin-amide adenine dinucleotide (NADH)/nicotinamideadenine dinucleotide (NAD) ratios and thus is subjectto different metabolic regulations. 17 El is inactivatedby a kinase that phosphorylates the enzyme and acti-vated by a phosphatase that cleaves this phosphateester.253 The deficiency of phosphatase causes a simi-lar clinical picture to that of El deficiency.253 Pyru-vate, thiamine pyrophosphate, and dichloroacetatestabilize the enzyme by inhibiting the kinase. 17 The E2

subunit is a lipoamide transacetylase, and the E3 sub-unit is a dihydrolipoyl dehydrogenases

Pyruvate dehydrogenase El subunit (pyruvate decar-boxylase) deficiency occurs in three different pheno-types with decreasing severity: neonatal, infantile,and childhood forms. Severity inversely correlateswith residual activity in tiSSUeS.251 The enzyme is

unevenly distributed in the central nervous system,and the symptoms may reflect the most actively de-

eloping region at a particular time of brain develop-ment.25 Some mutations of a or J3 subunits may bemore deleterious than others.252,255 Nevertheless, Eldeficiency causes atrophy and patchy white-matterchanges affecting cerebrum, basal ganglia, cerebel-lum, and brain stem in all phenotypes.41 Thesechanges are responsible for seizures, hypotonia,exaggerated deep-tendon reflexes, dystonia,choreoathetosis, ataxia, abnormal eye movements,respiratory difficulties, and apnea. The disease af-fects the fetus, since dysmorphia and brain dysgen-esis are observed in 50% of the cases, regardless ofphenotype.41

The neonatal form presents at or before birth. Theinfant shows severe failure to thrive (60%), hypoto-nia, seizures, dysphagia, tremors, abnormal eyemovements, respiratory difficulties, stridor, and ap-nea, in association with severe lactic and pyruvicacidosis. 41,42,48 The dysmorphic features are reminis-cent of fetal alcohol syndrome.41,48 Four infants alsohad agenesis of corpus callosum, and one infant hadagenesis of olivary nuclei.41 Autopsy findings revealcystic white- and gray-matter changes. The diseaseleads to severe retardation and microcephaly.41,42Approximately 50% of the patients expire because ofrespiratory difficulties and irretractable acidosis be-fore 6 months of age, and the remainder before 3

years of age.41,48,250, 56-259The infantile form is three times more com-

mon than the early infantile form and is less se-

vere. 41-44,48,260-263 This is the classic Leigh diseaseor subacute necrotizing encephalomyelopathy, al-

though other enzyme deficiencies can result in thesame clinical syndrome. All infants have severe fail-ure to thrive. 1,42,48 Approximately 50% will showdysmorphia such as narrow head with frontal boss-ing, wide and depressed nasal bridge, upturnednose, long filtrum, and flared nostrils.41 Findingsinclude developmental delay, seizures,43,44,262 hypo-tonia or spasticity,43,262 ataxia,43,44 dystonic postur-ing or choreoathetosis,41,42,48 ophthalmoplegia,~·260purposeless eye movements, 44,260 bulbar paresis,~irregular respirations, stridor, apnea, 260 and periph-eral neuropathy. 41,42,48 At necropsy, myelin loss,



206

cavitation of basal ganglia and brain stem, and path-ologic findings of encephalomyelopathy are ob-served.43,263 Neuroradiologic studies show brain

atrophy and brain-stem, basal ganglia, cerebral, andcerebellar hypodensities with cystic lesions.41 Deathoccurs between 10 and 36 months. 41,42,48,260-263 Ageof death is inversely related to the residual activityof pyruvate decarboxylase in fibroblasts.41,42

The childhood form was seen in six boys present-ing between 3 and 13 years of age.41,42,45,46,264 Pre-senting symptoms were ataxia, 41,42,45-47,264 choreo-athetosis with dystonic posturing,46 and muscle

weakness, with periodic exacerbations related to

consumption of a high-carbohydrate diet. 47 Seizuresand dysmorphia were uncommon.41,42 All patientsshowed growth and psychomotor delay and somehad microcephaly, impaired external ocular motil-ity, 47 and muscle atrophy.264 Lactic and pyruvic aci-dosis was mild, becoming prominent when the pa-tient was given a carbohydrate load. 47 The residualenzyme activity in this group was usually greaterthan 30% .41,42,46,47 All patients were alive when re-ported.

Pyruvate dehydrogenase E2 subunit deficiency wasdiagnosed in four patients who showed severe

developmental delay, failure to thrive with hypoto-nia, hyperreflexia, spastic tetraparesis, nystagmoideye movements, optic atrophy, and dystonic rigid-ity. 138,139 Dysmorphia included bilateral epicanthicfolds.138 Moderate lactic and pyruvic acidosis was ex-acerbated by the administration of carbohydrates.139

All four patients described with pyruvate dehy-drogenase phosphatase deficiency 253,260,265,266 had neona-tal onset Leigh encephalomyelopathy, one with un-remitting acidosis253 and death within the first year.

D-Glyceric Aciduria. The enzyme deficiencies associ-ated with two different phenotypes are unknown.One type presents with severe neonatal acidosis,with subsequent moderate mental retardation. Load-ing with L-serine increases urine and plasma levelsof D-glyceric acid, suggesting a defect in the serinemetabolic pathway.26 The second phenotype pre-sents at birth or early infancy with myoclonus,dystonia, spastic tetraparesis, and severe encepha-lopathy leading to early death .37-40 Here, D-glycericaciduria is associated with a defect in fructose me-tabolism.

Organic Acidemias Related to Gluconeogensis

Pyruvate Carboxylase Deficiency. There are two phe-notypes : neonatal and infantile forms. The neonatal

form manifests at birth with severe metabolic acido-sis. Despite the key role of pyruvate carboxylase ingluconeogenesis, hypoglycemia is rare and was ob-served in only three patients .34,268 Neurologic symp-toms include hypotonia and lethargy or hypertonia,seizures, and hepatomegaly.34 Death occurs within10 days to 3 monthS.33,34,127,128,268,269

In the infantile form, patients manifest with epi-sodes of acidosis, severe developmental delay, andhypoglycemia (40%). 129,154,270-273 Neurologic symp-toms include respiratory difficulties, axial hypotonia(50%),271-273 seizures (50%),270,271-273 and micro-

cephaly (10%).272,273 Neuroradiologic studies273 or

necropsy272 reveal brain atrophy and dysmyelina-tion. Fifty percent of patients die during an acidoticattack 33,34,129,154,270-273

Phosphoenol Pyruvate Carboxykinase Deficiency. It

manifests with hypotonia (60%), developmental de-lay (60%), and difficult-to-control hypoglycemia, butmild to moderate lactic acidosis. 151,274-276 It is easilyconfused with nesidioblastosis and diagnosed whenpancreatic surgery or diazoxide treatment fail to con-trol the hypoglycemia .227-230 Sixty percent of pa-tients die.15i,274-276

Organic Acidemias Related to the CitricAcid Cycle

Fumaric Aciduria. Five patients have been reportedwith primary fumaric and succinic aciduria and mildor absent acidosis. 93,277,278 Three infants had hypoto-nia, developmental delay, and microcephaly, 277,278or failure to thrive and hepatic fibrosis.2 Profound

deficiency of both cytosolic and mitochondrial fuma-rases were found. 277,278 In two siblings 19 and 25years old, fumaric aciduria was associated withnormal childhood developmental milestones, but

speech delay and global mental retardation ap-peared later.93

2-Keto Glutaric Aciduria. The partial deficiency of2-ketoglutaric acid dehydrogenase, possibly involv-ing the E2 component of the enzyme, was associatedin two siblings from one family, with massive 2-

ketoglutaric aciduria and early developmental delayfollowed by choreoathetosis at 2 years of life, lead-ing to loss of language skills and dystonic postur-ing. 280



207

Organic Acidemias Related to Defects ofOxidative PhosphorylationA large number of muscle and central nervous sys-tem diseases are caused by mitochondrial abnormal-ities. The mitochondrion is the primary oxidativephosphorylation organelle of the cell. It performsthis function through five multienzyme complexesembedded within the inner membrane of a doublemembrane structure and through two low molecularweight redox carriers, CoQ and cytochrome c.133These are complex I: NADH-CoQ oxidoreductase;complex II: succinate-CoQ oxidoreductase; complexIII: CoQ-cytochrome c oxidoreductase; complex IV:cytochrome c oxidase; and complex V: adenosinetriphosphate synthetase. Specific diseases of the oxi-dative phosphorylative chain associated with lacticand pyruvic acidemia are as follows:

Complex I (NADH-CoQ Reductase) Deficiency. Four

phenotypes have been reported: oculoskeletal myop-athy, progressive encephalopathy, fatal infantileform, and myopathy with exercise tolerance. Thelatter two are diseases of childhood and early ado-lescence. The fatal infantile form manifests with se-vere lactic acidosis and neonatal hypotonia, followedby delayed motor development, respiratory difficul-ties, apnea, and sJiasticity, leading to death by 4months of age.134,2 1 Myopathy with exercise intolerancewas observed in a 10-year-old patient with tiredness,shortness of breath, and muscle aches and crampsfollowing exercise, which induced lactic acidosis.l 3

Complex III (Ubiquinol-Cytochrome c Reductase) Defi-ciency. The clinical presentation in a girl with onsetat 9 years was similar to complex I deficiency.114

Complex IV (Cytochrome c Oxidase) Deficiency. Three

phenotypes exist: infantile mitochondriopathy, sub-acute necrotizing encephalomyelopathy, and partialdeficiency. Only the first two occur during child-hood. Infantile mitochondriopathy can be either fa-tal or benign. The fatal form has three distinct

phenotypes: with Fanconi syndrome, without renalinvolvement, and with cardiomyopathy. Fatal infan-tile mitochondriopathy with Fanconi syndrome has beendescribed in seven patients. 49-54 Its onset at birth iswith severe lactic acidosis and hypotonia, whichleads to increased impairment of respirations andswallowing and to death by 4 months of age. Gluco-suria, aminoaciduria, phosphaturia, and calciuria arepresent. Fatal infantile mitochondriopathy without renalinvolvement but presenting with the same clinical pic-ture has been described. g2-2~ Mutations involving

the mitochondrially encoded polypeptides of com-plex IV can lead to milder and different phenotypicexpressions within the same family. 284 Complex IVdeficiency with cardiomyopathy has been described inthree girls with onset at 2.5 to 4 months of age, withsevere hypotonia, myopathy, cardiomyopathy, mac-roglossia, and neutropenia, but no renal involve-ment. 164,165 Benign infantile mitochondriopathy or

reversible cytochrome c oxidase deficiency has been re-ported in two patients. The onset at 2 to 6 weeks ofage was with severe lactic acidosis, myopathy, mac-roglossia, and respiratory difficulties. The diseaseand muscle pathology improved by 6 to 12 monthsof age, with minimal residual damage, as confirmedby biochemical and pathologic findings.285,286 Cy-tochrome c oxidase deficiency was found in nine pa-tients with Leigh encephalomyelopathy. 115,287,288 Theonset was with respiratory difficulties, weak cry,loss of vision and hearing, and seizures, with even-tual dementia and death. In one patient with onsetat 2 years, the presenting symptom was ataxia. 287

Myoclonic Epilepsy With Ragged-Red Fibers (MERRF),Mitochondrial Encephalomyopathy Lactic Acidosis WithStrokelike Episodes (MELAS), and Kearns-Sayre Syn-dromes. The phenotypic expression of these mito-chondriopathies, which show variable lactic acido-sis, is listed in Table 1.

Organic Acidemia Related to ,

Glutathione Metabolism

Glutathione Synthetase Deficiency (5-Oxoprolinuria, Py-roglutamic Aciduria). Nineteen patients have beenreported up to 1989.9s-100,124,13,162,163,296-298 Themajority manifested the disease neonatally withmild to severe hemolytic anemia, increased suscepti-bility to infections due to neutropenia and defectiveneutrophil function,162,163 and moderate to severeintermittent acidosis occurring as early as 20 hoursafter birth,297 initially confused with renal tubularacidosis.153 The patients remain asymptomatic be-tween crises. Some patients never manifest acidosisexcept during stress, such as surgery-99 Mental retar-dation is followed by slowly progressive ataxia, in-tention tremor, dysarthria, and pyramidal tract signsduring adolescent years.98,9<’,124, s

Organic Acidemia Related to 4-AminobutyricAcid Metabolism

Succinic Semialdehyde Dehydrogenase Deficiency (4-

Hydroxybutyric Aciduria). Acidosis is rare and is de-



208

TABLE 1

Comparative Symptomatology of MERRF, MELAS, andKearns-Sayre Syndromes*- - --- - - - --- .-

*References reviewed: MERRF syndrome, 87-90,147,289-291 MELAS syndrome, 145,146,153,292-294and KSS. 116,117,295MERRF = myoclonic epilepsy with ragged-red fibers; MELAS = mitochondrial encephalo-myopathy lactic acidosis with strokelike episodes; KSS = Kearns-Sayre syndrome; NR = notreported; EEG = electroencephalogram; VER = visual-evoked response; SSER = somatosen-sory-evoked response; CNS = central nervous system; CT = computed tomographic; CSF =cerebrospinal fluid.

scribed only in one patient.96 This is a slowlyprogressive neurologic disorder with mental retarda-tion, autistic features, hypotonia, truncal and limbataxia, intention tremors, and ocular dyspraxia.94-9’Its onset can be as early as 6 months95 or as late as11 years of age, 97 but it generally manifests early.

Laboratory diagnosis and principles of treatmentof organic acidemias will be discussed in Part 2 ofthis review, which will appear in the October 1991issue of the Journal of Child Neurology.

AcknowledgmentsWe are grateful for the administrative monetary, and hu-

manitarian support of Drs Fahad Al Abdul Jabbar, Chief Execu-tive Director, and Abbass H. Al-Marzouky, Executive Director,

Research Centre of King Faisal Specialist Hospital and ResearchCentre. The project was realized through a grant donated bySheik Rafiq Al Hariri (85-0030).

We would like to thank Mrs Lilia Fernandez for the article

preparation.

APPENDIX A

Organic Acidemias Characterized by PeriodicEpisodes of AcidosisIsovaleric acidemia16s,1693-Methyl crotonyl-CoA carboxylase deficiencyl°9,~’6,1&dquo;3-Methylglutaconic aciduria with normal hydratase 179-1113-Hydroxy-3-methylglutaryl-CoA deficiency 183,184Dihydrolipoyl dehydrogenase (E3) deficiency 107,108,140-1422-Methylacetoacetyl-CoA ketothiolase (mitochondrial 3-ketothio-

lase) deficiency’, 116-190 192)Propionyl-CoA carboxylase deficiency (propionic acidemia192)



209

Methylmalonic acidemia 14,201,202 Cy2ll-206Holocarboxylase synthetase deficient

*56,218Short-chain acyl-CoA dehydrogenase deficiency*s6,zlsGlutaric aciduria type 1*lz,2z’Multiple acyl-CoA dehydrogenase deficiencyNeonatal form with dysmorphialoz,lo4,2s6, ss-z4oInfantile form without dysmorphia 245

Malonyl-CoA decarboxylase deficiency&dquo;Mevalonate kinase deficiency 143Pyruvate dehydrogenase deficiencyEl subunit deficiency 41,43,44, 48,250,255-263E2 subunit deficiencyl3s,ls9

y253,265,266Pyruvate dehydrogenase phosphatase deficiencyIsolated glycerol kinase deficiency and glycerol intolerance 301-303D-Glyceric aciduria with defect in serine metabolism3’,z6’Pyruvate carboxylase deficiencyNeonatal forM33,34,127,128,268,Z69Infantile formI29,154,270-273

Phosphoenolpyruvate carboxykinase deficiency 151,276Fumaric aciduria with deficient fumarasez&dquo;,z’Complex I deficiency, fatal infantile form134,281Complex IV (cytochrome c oxidase) deficiencyWith Fanconi syndrome 49-54Without renal dysfunction 282,284With benign reversible infantile myopathyl3s,zs6With cardiomyopathy&dquo;, 165,299Presenting as Leigh encephalomyelopathyl’s,zs7,2ssMitochondrial encephalopathy, lactic acidosis with strokelike

episodes syndrome115, 5,146,292-294Glutathione synthetase deficiency98

APPENDIX B

Presenting Neurologic Symptoms and Signsof Organic Acidemias Manifesting PrimarilyWith Neurologic Disease

The following neurologic signs and symptoms, singly or in com-bination, might be present at the time of initial presentation be-fore acidotic attack or in organic acidemias that may manifestwithout acidosis.

Developmental Dela 170Isovaleric acidemia~I,170

3-Methylglutaconic aciduria with normal hydratase 92Mitochondrial 3-ketothiolase deficiency’ 19,185,189Cobalamin C mutation 72,74-79Cobalamin D mutations2,s3Biotinidase deficiency69,209

217

.

Short-chain acyl-CoA dehydrogenase deficiency2l’Long-chain acyl-CoA dehydrogenase deficiencyss,s9Glutaric aciduria type 19,1 ,228Multiple acyl-CoA dehydrogenase deficiency, late-onset

form112,14’9,246Cytosolic acetoacetyl-CoA thiolase deficiencylss,249Pyruvate dehydrogenase El subunit deficiency, childhood

form41,42,45-47,2aGlycerol kinase deficiency with adrenal hypoplasia with-ou~-306 and with 307-309 Duchenne muscular dystrophy

Fumaric aciduria932-Ketoglutaric aciduria 280Glutathione synthetase deficiency98-100

*Some patients will manifest without acidosis and with neu-rologic symptoms or will manifest the acidosis after the neuro-logic symptoms.

Succinic semialdehyde dehydrogenase deficiency (autistic fea-tures)94-9’

Psychotic EpisodesIsovaleric acidemia9lCobalamin D mutation 83 .

Speech DifficultiesIsovaleric acidemia9’

3-Methylglutaconic aciduria with normal hydratase’Biotinidase deficiency69Glutaric aciduria type 16sFumaric aciduria932-Ketoglutaric aciduria 280Glutathione synthetase deficiency94,98,99,124Succinic semialdehyde dehydrogenase deficiency9s,9’

Reye-Like Syndrome3-Hydroxy-3-methyl glutaryl-CoA lyase deficiency’4Medium-chain acyl-CoA dehydrogenase deficiency 5760Long-chain acyl-CoA dehydrogenase deficiency55, 18,225

Seizure Disorder

Propionic acidemia118,194Cobalamin C mutation’6Cobalamin F mutation’Biotinidase deficiency69,209Glutaric aciduria type 19,229

18,89Myoclonic epilepsy with ragged-red fibers syndromess,s9

Myoclonus or TremorsMitochondrial 3-ketothiolase deficiency&dquo;Cobalamin C mutationBiotinidase deficiency 69,175D-Glyceric aciduria associated with defect in fructose metabo-

lism3’-4oMyoclonic epilepsy with ragged-red fibers syndrome88,&dquo;9

Pyramidal Tract Signs Such As Central Hypotoniaor Spastic Paresis or Plegia

Isovaleric acidemia 170Mitochondrial 3-ketothiolase deficiency 121Methylmalonic acidemia 4,199Cobalmin C mutation’6Cobalamin D mutation 82,83Cobalamin F mutations4Biotinidase deficiency69,z°9

nay56,217Short-chain acyl-CoA dehydrogenase deficitGlutathione synthetase deficiency94,98,99,124

95,91Succinic semialdehyde dehydrogenase deficiency,9’,

Extrapyramidal Symptoms Such As Dystonic Posturingand Choreoathetosis

Glutaric aciduria type 19·11,66,227,228·231,233Pyruvate dehydrogenase El subunit deficiency, late childhood~~41,42,48

D-Glyceric aciduria with defect in fructose metabolism 37-402-Ketoglutaric aciduria 280

Cerebellar Signs With Truncal and Extremity AtaxiaIsovaleric acidemia9lMitochondrial 3-ketothiolase deficiency 120,185Cobalamin D mutation 81,82Mevalonic aciduria 248Mitochondrial acetoacetyl-CoA thiolase deficiencylloPyruvate dehydrogenase El subunit deficiency, late childhood

~~41,42,45-47Glutathione synthetase deficiency94,98.99,124

Cy94,91,97Succinic semialdehyde dehydrogenase deficient



210

Myoclonic epilepsy with ragged-red fibers syndrome88,89Kearns-Sayre syndrome’ 15-117,295

Respiratory Difficulties, Apnea, or StridorBiotinidase deficiency69,z CyN7Acetyl-CoA carboxylase deficient

Abnormal Eye Movements, Nystagmus,Dyspraxia, StrabismusCobalamin D mutation 82,83Cobalamin F mutation84Succinic semialdehyde dehydrogenase deficiency94,9s,9’

Disturbed Vision and Retinal DegenerationCobalamin C mutation72,75,77Biotinidase deficiency69,z°9Kearns-Sayre syndrome’ 16,117,295

Sensorineural Hearing LossCobalamin C mutation&dquo;Biotinidase deficiency69,z°9Myoclonic epilepsy with ragged-red fibers syndrome88,89Kearns-Sayre syndrome’16,117,295

Spinal Cord Symptomatology 09

Methylcrotonyl-CoA carboxylase deficiency’°9Cobalamin D mutation 81,83

Peripheral NeuropathyMitochondrial acetoacetyl-CoA thiolase deficiency&dquo;o

Myopathy or CardiomyopathyLong-chain acyl-CoA dehydrogenase deficiency (cardiomyopa-thy)5,5, 58,59

12,149,246Multiple acyl-CoA dehydrogenase deficiency, late onset’Acetyl-CoA carboxylase deficiency4’Pyruvate dehydrogenase El subunit deficiency, childhood on-

set44,46, 264Glycerol kinase deficiency associated with Duchenne muscular

dystrophy3o’,3’0Complex I deficiency with exercise intolerance&dquo;3Complex III deficiency&dquo;4

194Myoclonic epilepsy with ragged-red fibers syndrome90,294Kearns-Sayre syndrome (ocular + facial)&dquo;’- 117,295

APPENDIX C

Dysmorphic Features and Congenital BrainAnomalies Associated With Various OrganicAcidemias

3-Methylglutaconic aciduria with normal hydrataseFacial dysmorphia with long featureless filtrum, malformed

ears, penile hypospadias, undescended testicles, talipes equi-novarus 36,182

Mitochondrial 3-ketothiolase deficiencyFacial dysmorphia with epicanthic folds’85

Methylmalonic acidemiaEpicanthic folds, prominent forehead, dysplasia of the midface,high arched palate. 201

Cobalamin C mutation

Hatchet-shaped head, arachnodactyly, facial dysmorphia, hy-pospadias~-~

Multiple acyl-CoA dehydrogenase deficiency, neonatal formDysmorphic features generally observed with Zellweger syn-

drome, 103,104,238,239 cerebral dysgenesis, abnormal gyrus for-mation, cerebral degeneration with fibrous gliosis’° -’06

Mevalonic aciduria

Dolicocephaly, cataracts, triangular face, posteriorly rotatedlow-set ears, down-slanted eyes 143,144

Glycerol kinase deficiency associated with adrenal hypoplasia andDuchenne muscular dystrophyShort stature, strabismus, wide-set eyes, drooping mouth, ab-normal genitalia 311-309

Pyruvate dehydrogenase El subunit deficiencyFeatures reminiscent of fetal alcohol syndrome in early infantile

onset form,41 frontal bossing, wide and depressed nasalbridge, upturned nose, flared nostrils, long filtrum in late-onset form, 41 agenesis of corpus callosum and of olivary nu-clei4l

Pyruvate dehydrogenase E2 subunit deficiencyDysmorphic face, epicanthic foldsl3s

APPENDIX D

The Initial Age of Presentation in VariousOrganic Acidemias

Birth to 2 Weeks of LifeIsovaleric acidemia (7O%)6,167,168

)174,1753-Methylcrotonyl-CoA carboxylase deficiency (isolated) (40%)1’4,1’s3-Hydroxy-3-methylglutarvl-CoA lyase deficiency (50%)~’~Propionic acidemia (40%) ,z32,193,196Methylmalonic acidemia (80% of methylmalonyl-CoA mutase ab-

sence genotype) 130 Cy2O5Holocarboxylase synthetase deficiency

Cy56Short-chain acyl-CoA dehydrogenase deficiency56Multiple acyl-CoA dehydrogenase deficiency, neonatal

form’o2,104,1 2,148,236’238-240Pyruvate dehydrogenase El subunit deficiency, neonatal form

(60% )41,42,48,256 3,265,266Pyruvate dehydrogenase phosphatase deficiencf53,265,266

o-Glyceric aciduria with defect of serine metabolism3’,26’Pyruvate carboxylase deficiency, neonatal form33,34,127,128,268,269Phosphoenolpyruvate carboxykinase deficiency (40% )276Complex I deficiency fatal infantile form’~,z81Cytochrome c oxidase deficiency, neonatal form with renal in-

volvement49-s3,zssGlutathione synthetase deficiency~-~~3,i62,i63,296-298

Infancy (2 Weeks to 2 Years of Age)Isovaleric acidemia (30% )169-1723-Methylcrotonyl-CoA carboxylase deficiency (60%)1773-Methylglutaconic aciduria with normal hydratase 179-1823-Hydroxy-3-methylglutaryl-CoA lyase deficiency (50%)~’~Dihydrolipoyl dehydrogenase (E3) deficiencyl07, 108, 140-142Mitochondrial 3-keto thiolase deficiency3’,11 ,18s,186Propionic acidemia (60% )194,197,198Methylmalonic acidemia (66% of methylmalonyl-COA mutase de-ficiency and cobalamin A and B genotypes)1 0Methylmalonic aciduria due to cobalamin C and F muta-

tions’z-8°,90-92Holocarboxylase synthetase deficiencyz°6,zo’Biotinidase deficiency69,175,209

Cy2l7 ,

Short-chain acyl-CoA dehydrogenase deficiencyMedium-chain a7l-CoA dehydrogenase deficiency (90% between1 and 2 years)sLong-chain acyl-CoA dehydrogenase deficiency55Glutaric aciduria type 1, infantile or late-onset pheno-

types9, 66,227,229,231Multiple acyl-CoA dehydrogenase deficiency, infantile

form 136,137,241-244Malonyl-CoA decarboxylase deficiency300Mevalonic aciduria143,1Cytosolic acetoacetyl-CoA thiolase deficiencylss,z49



211

Pyruvate dehydrogenase El subunit deficiency, neonatal form

(40% < 8 mo)~~-~-~-~Pyruvate dehydrogenase El subunit deficiency, infantile

forM41,44,261-263Pyruvate dehydrogenase E2 subunit deficiency13s,139Glycerol kinase deficiency associated with microdeletion syn-

dromes306,307,309D-Glyceric aciduria with defect of fructose metabolism37-40Pyruvate carboxylase deficiency, infantile form33,34,129,1S4,270,271Phosphoenolpyruvate carboxykinase deficiency (40%)~’~’~Fumaric aciduria with deficient fumarase 277,279Cytochrome c oxidase deficiency, neonatal form without renal in-

volvement282-2114Cytochrome c oxidase deficiency, neonatal form with cardiomyo-

pathyl64,165Cytochrome c oxidase deficiency, neonatal form with benign re-

versible myopathy135,286Cytochrome c oxidase deficiency, with Leigh encephalomyelopa-

thy115,287,288

Childhood to Adult (2 to 18 Years of Age)3-Methylglutaconic aciduria with deficient hydratase9’Mitochondrial 3-keto thiolase deficiency 120,185,187-190Methylmalonic aciduria due to cobalamin D mutation 81-83Biotinidase deficiency69Multiple acyl-CoA dehydrogenase deficiency late-onset form149,246Malonyl-CoA decarboxylase deficiency311Mevalonic aciduria 248Mitochondrial acetoacetyl-CoA thiolase deficiencylloPyruvate dehydrogenase El subunit deficiency, childhood

form41,42,45-4 ,264Isolated glycerol kinase deficiency or associated with Duchennemuscular dystrophy3°2,303

Fumaric aciduria932-Ketoglutaric aciduria 280

13Complex I deficiency myopathic form with exercise intolerance’Complex III deficiencyl 4

294Myoclonic epilepsy with ragged-red fibers syndrome294Mitochondrial encephalomyopathy lactic acidosis with strokelike

episodes syndromel4s,z93,z94Kearns-Sayre syndromel6,294

Cy94,98,99,124Glutathione synthetase deficiency94,9s,99,124 (90%)94-97Succinic semialdehyde dehydrogenase deficiency (9O%)94-97

APPENDIX E

Organic Acidemias Associated With Susceptibilityto Serious Infections

Isovaleric acidemia 159,169,172,1733-Methylglutaconic aciduria with normal hydratasel80,181Dihydrolipoyl dehydrogenase (E3) deficiency 107Mitochondrial 3-ketothiolase deficiency12o,1 ls~-~9oPropionic acidemia 160,192

158Methylmalonic acidemié,158Biotinidase deficiency69,111,161

Cyl6,211,211Short-chain acyl-CoA dehydrogenase deficiency56,216,217 .

Long-chain acyl-CoA dehydrogenase deficiencyss,s9Glutaric aciduria type 123Multiple acyl-CoA dehydrogenase deficiency, neonatal

form, 102,192,237 infantile form,242 and late-onset form 149

Cytochrome c oxidase deficiency with cardiomyopathy 164,165Glutathione synthetase deficiencyl62,163

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topical review article: organic acidurias: a review. part 1

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