arch dis child fetal neonatal ed-2001-chakrapani-f205-10

REVIEW

Detection of inborn errors of metabolism in thenewborn

A Chakrapani, M A Cleary, J E Wraith

It is important for paediatricians and neona-tologists to keep in mind inborn errors ofmetabolism (IEMs) as a cause of illness in theneonatal period, as many disorders are treat-able and, in most cases, successful outcome isdependent on a rapid diagnosis and early insti-gation of therapy. Even with untreatable disor-ders, it is important to establish the diagnosis inthe index case in order to allow prenataldiagnosis in subsequent pregnancies. In des-perately sick neonates for whom no diagnosis isreadily available, IEMs are near the top of thelist of diVerential diagnoses.

IEMs can present in the newborn in a varietyof ways. Typically, an IEM is suspected as aresult of a suggestive combination of acuteclinical symptoms without any prior warning.However, sometimes non-specific clues exist,such as a previous unexplained neonatal deathand, in some families, the risk of an IEM isalready highlighted by the presence of a previ-ously aVected child. IEMs may be detectedthrough the newborn screening programme,though at present phenylketonuria is the onlydisorder for which mass screening is acceptedin the UK. Some IEMs result in dysmorphism,and the investigation of these cases is not com-plete without considering metabolic causes.Finally, disorders that normally manifest inolder children may sometimes cause abnor-malities in the newborn period.

Pathogenesis of IEMs—“placentalprotection”Like all genetic disorders, IEMs are presentfrom conception, and most defective enzymesare active in fetal life. Nevertheless, most con-ditions have no adverse consequences on thefetus, as the placenta provides an eVectivedialysis system for the removal of toxicmetabolites. Thus most babies with an IEM areborn in good condition and of normal birthweight. Some IEMs, such as galactosaemia,manifest only after the substrate for thedeficient enzyme becomes available in the formof feeds. There are some exceptions to thisconcept of “placental protection”; for example,disorders that aVect energy metabolism, suchas the primary lactic acidoses and glutaric aci-duria type II or non-ketotic hyperglycinaemiawhere the primary defect is in cerebralintermediary metabolism and the substrateaccumulation in body fluids represents anoverflow from the brain.

Clinical presentation of IEMsMaintaining a high index of suspicion of meta-bolic disease in an ill neonate is essential, and itmust be borne in mind that some disorders,such as galactosaemia, can predispose to Gramnegative septicaemia.

The first step in the recognition of IEMs is acareful scrutiny of the family history and theobstetric notes. The majority of metabolic dis-orders presenting in the neonatal period areautosomal recessive, and thus a history ofparental consanguinity can be a helpful clue. Afew metabolic conditions are associated withmaternal problems during pregnanciescarrying aVected fetuses. It has recently beenrecognised that some fetal disorders of fattyacid oxidation can predispose the mother todeveloping acute fatty liver of pregnancy(AFLP) and the HELLP syndrome of haemo-lysis, elevated liver enzymes, and low plateletcount.1 2 Steroid sulphatase deficiency cancause prolonged labour as a result of decreasedplacental oestrogen production,3 and condi-tions associated with renal pathology can resultin oligohydramnios.

PATTERNS OF PRESENTATION

Neurological abnormalities—encephalopathy andseizuresTwo general patterns of presentation can bedistinguished. The first is a baby, apparentlyhealthy at birth, who after a symptom freeinterval develops non-specific symptoms suchas lethargy, poor feeding, vomiting, or irritabil-ity. Metabolic acidosis, altered sensorium, con-vulsions, and hyperammonaemic coma be-come apparent soon afterwards. Normalammonia concentrations in neonates are lessthan 65 µmol/l,4 but we have frequentlyobserved concentrations of up to 180 µmol/l insick newborns. Higher ammonia concentra-tions warrant thorough investigation for meta-bolic causes. The organic acidaemias (propi-onic, methylmalonic, and isovaleric acidaemia)and the urea cycle defects classically present inthis manner, and in either case respiratoryalkalosis may be the initial acid–base distur-bance.5 6 Maple syrup urine disease (MSUD) isa possibility when acid–base disturbances andhyperammonaemia are not prominent features.The likelihood of a metabolic disorder is veryhigh in the presence of ketonuria, as neonatesotherwise do not readily produce ketones.

Arch Dis Child Fetal Neonatal Ed 2001;84:F205–F210 F205

Willink BiochemicalGenetics Unit,Manchester M27 4HA,UKA ChakrapaniM A ClearyJ E Wraith

Correspondence to:Dr [email protected]

Accepted 17 November 2000

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The second pattern of involvement is aneonate who has overwhelming neurologicalillness with unconsciousness, convulsions, andapnoea in the absence of significant hyperam-monaemia and acid–base disturbances, andwithout an apparent symptom free interval.The diVerential diagnosis includes non-ketotichyperglycinaemia, molybdenum cofactor defi-ciency, pyridoxine dependent seizures, and theprimary lactic acidoses. Mitochondrial andperoxisomal disorders can also present in thismanner, and often result in severe hypotonia,with or without dysmorphism and congenitalanomalies.

Metabolic acidosisUnexplained, persistent metabolic acidosis is acommon feature of IEMs that present neonatally.Calculation of the anion gap can be helpful, asconditions that cause acidosis with a normalanion gap are limited to those associated withrenal and intestinal bicarbonate loss. The organicacidaemias and the primary lactic acidosescause metabolic acidosis with a raised anion gapin the early stages. Most metabolic conditionsresult in acidosis in the late stages as encepha-lopathy and circulatory disturbances progress.

Lactic acidosis—Infants with lactic acidosispresent a diYcult diagnostic problem. A highplasma lactate can be secondary to hypoxia,cardiac disease, infection, or convulsions,whereas primary lactic acidosis may be causedby disorders of pyruvate metabolism and respi-ratory chain defects. Some IEMs (fatty acidoxidation disorders, organic acidaemias, andurea cycle defects) may also be associated witha secondary lactic acidosis.7 As venous obstruc-tion by tourniquet, crying, or breath holdingmay increase plasma lactate concentrations bytwo- to threefold, arterial samples are morereliable. Persistent increase of plasma lactateabove 3 mmol/l in a neonate who was notasphyxiated and who has no evidence of otherorgan failure should lead to further investiga-tions for an IEM. The lactic acidoses are a het-erogeneous group of disorders, and manydefects are tissue specific (for example, limitedto muscle or the CNS). Often the infant dieswithout a diagnosis, and it is essential to collectthe correct skin, muscle, and liver samples forenzyme and DNA analyses.

HypoglycaemiaInborn errors of metabolism should be consid-ered in all patients with hypoglycaemia in thenewborn period although most patients willturn out to have a diVerent diagnosis. Samplesshould be collected during an episode ofhypoglycaemia if possible. Fat oxidation de-fects, the hepatic forms of glycogen storagedisease, and disorders of gluconeogenesis suchas fructose-1,6 bisphosphatase deficiency canpresent in this way. An IEM that primarilyaVects liver function (see below) can also resultin secondary hypoglycaemia.

Cardiac diseaseCardiac failure, particularly in the presence ofhypertrophic cardiomyopathy and hypotonia,may suggest a mitochondrial respiratory chain

defect, a long chain fatty acid oxidationdisorder, or Pompe’s disease (GSD II). Otherlysosomal disorders may also be associatedwith cardiac disease, but dysmorphism isusually the revealing symptom (see below).The multisystem congenital disorders of glyco-sylation (CDG) can present soon after birthwith cardiomyopathy and/or pericardial eVu-sion.8 Additional features include failure tothrive, facial dysmorphism, inverted nipples,and abnormal fat distribution.9 X linkeddilated cardiomyopathy and neutropenia(Barth syndrome) is a recently described entitywith characteristic abnormalities on urineorganic acid analysis.10 Cardiac arrhythmias,with or without cardiomyopathy, have beendescribed in most of these conditions.

Liver dysfunctionGalactosaemia is the commonest metaboliccause of liver dysfunction in the newbornperiod. Besides signs of liver disease, earlyonset cataracts are very suggestive. Other rarerIEMs such as hepatorenal tyrosinaemia, á1

antitrypsin deficiency, neonatal haemochroma-tosis, and mitochondrial respiratory chain dis-orders must also be considered in the diVeren-tial diagnosis. Niemann–Pick disease type C(NPC) is a lipid storage disorder that resultsfrom a defect of intracellular cholesterol esteri-fication, and classically presents with neurode-generative manifestations in childhood.11 A sig-nificant proportion of patients, however, haveneonatal manifestations with variable degreesof cholestasis, liver dysfunction, and hepato-splenomegaly, well before the onset of neuro-logical illness.12

DysmorphismBesides CDG, other metabolic conditions canmanifest with dysmorphism; for example,disorders that aVect energy metabolism di-rectly (pyruvate dehydrogenase deficiency, glu-taric aciduria type II) or indirectly (3-hydroxyisobutyric aciduria) can result invarious physical malformations including facialdysmorphism, and cardiac, renal, and skeletaldefects. The disorders of peroxisomal biogen-esis (the “Zellweger spectrum”) can presentwith hypotonia associated with facial featuresresembling Down’s syndrome. Patients withlysosomal disorders usually appear normal inearly infancy, but some conditions (GM1 gan-gliosidosis, I-cell disease, and infantile sialicacid storage disease) can manifest in the firstweeks of life with coarse facies, upper airwayobstruction, and cardiac dysfunction. Severedefects in cholesterol synthesis (Smith–Lemli–Opitz syndrome, X linked chondrodysplasiapunctata, and mevalonic aciduria) can alsopresent with characteristic dysmorphic featuresand multiple anomalies.13 14

Other suggestive abnormalitiesAbnormal body odour is noted in some organicacidaemias, for example, the smell of maplesyrup in maple syrup urine disease, and ofsweaty feet in isovaleric acidaemia and glutaricaciduria type II. Most babies who have an unu-sual or powerful odour, however, do not have

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an IEM. Temperature instability has manycommon causes, but is also an early feature ofMenke’s syndrome. Non-immune hydropsfetalis can be associated with a number ofmetabolic disorders (table 1).15 16 Jaundice andbleeding diathesis occur in disorders that aVectliver function, but may also be a late sign inother IEMs such as the urea cycle defects.

Investigation of a neonate who may havean IEMAs a wide variety of IEMs can present in theneonate, the level of clinical and biochemicalexperience required for their diagnosis andtreatment is substantial. It is essential to discussinvestigations with all the laboratories involvedand to give some indication of urgency. Appro-priate transportation to the metabolic labora-tory must be arranged, and as much clinicalinformation as possible must be provided on therequest cards. The interpretation of manymetabolic investigations can be confounded bymedications and special feeds, hence a full drugand feeding history must be stated.

The approach to diagnosis varies with thenature of severity of symptoms. In some situa-tions, it is possible to make a good guess at thediagnosis clinically and then select the testsmost likely to give the answer (see table 2). In

most cases, however, it is necessary to performa group of tests, as many IEMs can cause verysimilar symptoms.

THE “METABOLIC SCREEN”The scope of metabolic disorders is enormousand constantly expanding. The term “meta-bolic screen” (which would denote a set ofinvestigations to rule out most known meta-bolic causes of illness) is therefore inappropri-ate, and such a request to a laboratory is mean-ingless. Specialised metabolic investigations ina sick neonate must always be dictated by theclinical situation, and directed towards specificconditions (table 3).

Although techniques will vary, most labora-tories will require samples of blood (2–3 mleach in heparinised and EDTA bottles, and adried blood spot on a screening card) and urine(5–10 ml in a sterile container with nopreservatives). It is good practice to save andfreeze all urine passed for future analysis, andto save a heparinised blood sample before thefirst blood transfusion. Occasionally moreunusual investigations, such as CSF analysisfor organic and amino acids may be necessary.17

It is best to discuss such tests with the labora-tory to ensure that the samples are collectedand preserved correctly.

In many cases these investigations willprovide a definitive diagnosis or a highsuspicion of a specific IEM. The completecharacterisation of the particular conditionusually involves more specific studies, such asenzyme assays, DNA analysis, and family stud-ies. Most of such work is performed oncultured skin fibroblasts or transformed lym-phoblast cell lines at supraregional laborato-ries.

Management while awaiting resultsThe management should be dictated by theseverity of symptoms. Very mild symptoms mayrequire no change to the management. As milkfeeds are often the source of the toxic metabo-lites, these should be stopped, if the symptomsare more than very mild, while preliminaryresults are awaited. Generally, intravenous 10%dextrose with added electrolytes should beused. In more severe cases, intravenous bicar-bonate may be necessary to correct metabolicacidosis. Other additives should be dictated bythe blood biochemistry with the aim ofmaintaining glucose and electrolyte homoeo-stasis.

The extremely ill or rapidly deteriorating infantwill require more aggressive therapy. Care mustbe taken to avoid overhydration in the presenceof impaired renal function. Adequate correc-tion of acidosis often requires very large dosesof sodium bicarbonate (up to 20–30 mmol/kgin some organic acidaemias) which may causehypernatraemia, sometimes necessitating dialy-sis. Blood electrolytes should be checkedfrequently (4–6 hourly) during correction ofthe acidosis. If hyperammonaemia is present,treatment with sodium benzoate should becommenced (250 mg/kg loading dose, followedby an infusion of 250 mg/kg/24 hours). Thelong term neurological outcome of the urea

Table 1 Metabolic conditions associated with hydrops fetalis

Lysosomal disordersMucopolysaccharidosis types IV and VIIGaucher disease type IIGM1 gangliosidosisNiemann–Pick disease type CFarber diseaseInfantile free sialic acid storage diseaseSialidosisGalactosialidosisMucolipidosis II (I cell disease)

RBC enzyme abnormalitiesGlucose-6-phosphate dehydrogenase deficiencyPyruvate kinase deficiencyGlucosephosphate isomerase deficiency

Neonatal haemochromatosisRespiratory chain disordersCongenital disorders of glycosylationGlycogen storage disease type IV

Table 2 Investigations for the diagnosis of an IEM

First line investigationsFull blood countUrea and electrolytesAnion gapBlood gasesGlucoseLactateAmmoniaLiver function testsUrine reducing substancesUrine ketonesCSF lactate

Second line investigationsUrine organic acidsUrine amino acidsPlasma uric acidPlasma amino acidsPlasma carnitine and acylcarnitine profileBiotinidaseGalactosaemia screening tests (e.g. Beutler)CSF amino acids

Third line or specialised investigationsEnzyme assays on skin fibroblasts or blood cellsDNA mutation analysisSpecial metabolite assays (e.g. VLCFA, transferrin isoelectric

focusing, etc)

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cycle defects depends on the rapidity of resolu-tion of the initial hyperammonaemic coma.The use of medications alone is rarely suYcientin this situation, and dialysis is usuallynecessary. Haemodialysis and haemodiafiltra-tion are more eVective than peritoneal dialysis,and if available, should be the methods ofchoice in the initial treatment of urea cycledefects, MSUD, and the organicacidaemias.18–20 Exchange transfusion is notuseful, except in desperate situations whendialysis is not immediately available.

Secondary carnitine deficiency is common inmany metabolic conditions, especially theorganic acidaemias and fatty acid oxidationdefects. Carnitine supplementation (100 mg/kg/day in four divided doses) is therefore usefulin infants with suspected metabolic diseasewhile awaiting results.

Respiratory depression and cerebral oedemacaused by direct toxic eVects of accumulatingmetabolites are commonly present. Ventilatorysupport should therefore be used early andcontinued until the baby is breathing vigor-ously. Clinical recovery to a degree suYcient towithdraw ventilatory support can be delayedtwo to three days after correction of the meta-bolic abnormality. Maintainance of good hy-dration and tissue perfusion may necessitatethe use of inotropes and colloid infusions.

As most metabolic conditions are aggravatedby tissue catabolism, nutritional support in theacute phase requires careful attention. Initially,10% dextrose is suYcient, but more concen-trated solutions (up to 20%) should be used viaa central line to induce mild hyperglycaemia(blood glucose 7–12 mmol/l) if feeds cannot becommenced within 24 hours. Anabolism can

Table 3 Metabolic investigations according to patterns of presentation

Presentation Condition Specific investigations

Encephalopathy Urea cycle defects Urine amino acidsOrganic acidaemias and MSUD Urine organic acids

Plasma amino acidsBlood carnitine and acylcarnitine profileSkin biopsy for enzyme analysis

Fatty acid oxidation defects As above, plus:Blood DNA mutation analysis

Primary lactic acidoses (e.g. pyruvate dehydrogenase CSF lactatedeficiency, pyruvate carboxylase deficiency and Mitochondrial DNA—blood and musclerespiratory chain defects) Muscle biopsy—histology and electron microscopy

Skin biopsy—enzymes of pyruvate metabolismNon-ketotic hyperglycinaemia Plasma and CSF amino acids

Enzyme analysis on transformed lymphoblastsMolybdenum cofactor deficiency Urine sulphite (dipstick)

Urine amino acidsPlasma uric acidSkin biopsy for enzyme analysis

Pyridoxine dependent seizures Trial of pyridoxine under EEG observationHypoglycaemia Fatty acid oxidation defects As under encephalopathy

Hypopituitarism Hormone levels (growth hormone, cortisol, ACTH, insulin, and C peptide)Adrenal dysfunctionHyperinsulinismGluconeogenic defects (e.g. fructose-1,6 bisphosphatasedeficiency)

Blood gases (metabolic acidosis)Plasma lactateUrine organic acids (for glycerol)Enzyme assay—leucocytes or liver biopsy

Glycogen storage disease (types I, III, VI, IX) Plasma lactateEnzyme assay—leucocytes or liver biopsyHistology on liver biopsy

Secondary to organic acidaemias or disorders aVecting the liver As stated under respective sectionsLiver disease Galactosaemia Beutler test

Red cell galactose-1-phosphateDNA mutation analysisOphthalmology assessment for cataracts

Tyrosinaemia type I Plasma amino acidsUrine organic acidsInvestigations for renal Fanconi’s syndrome

á1 Antitrypsin deficiency Serum á1 antitrypsinProtease typing

Neonatal haemochromatosis Serum ferritinLiver biopsy

Niemann–Pick C Foam cells on bone marrow aspitrate, blood film, liver biopsyFilipin staining on skin biopsy

Mitochondrial (respiratory chain) defects CSF lactateMitochondrial DNA—blood and muscleMuscle and liver biopsy—histology and electron microscopy

Cardiomyopathy Pompe’s disease (GSD type II) Enzyme assay on lymphocytes or skin fibroblastsFatty acid oxidation defects As stated under encephalopathyMitochondrial (respiratory chain) defects As stated under liver diseaseCDG 1a syndrome Serum transferrin isoelectric focusing

Enzyme assay on skin biopsyLysosomal storage disorders White cell enzymes

Urine oligosaccharides and mucolpolysaccharidesSkin biopsy

Dysmorphism Lysosomal storage disorders As under cardiomyopathyDisorders of sterol synthesis Urine organic acids

Plasma 7-dehydrocholesterolSkin biopsy

CDG syndrome Serum transferrin isoelectric focusingEnzyme assay on skin biopsy

Glutaric aciduria type II Urine organic acidsBlood carnitine/acylcarnitine profileSkin biopsy




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be further promoted by infusing small doses ofinsulin (0.05 U/kg/h).

After stabilisation, subsequent dietary man-agement will vary depending on the specificdiagnosis, and should be supervised by a dieti-cian with experience in managing metabolicdisease.

Some metabolic disorders have vitaminresponsive forms and in the past, a combina-tion of vitamins and cofactors were adminis-tered to sick newborns while results wereawaited. Nowadays, this blind vitamin treat-ment is not justified, as most metabolic condi-tions can be diagnosed fairly rapidly. Once thediagnosis is made, appropriate cofactor therapycan be used in therapeutic doses (approxi-mately 100 times the daily requirement).

Management when no diagnosis can bemadeOccasionally no clear diagnosis can be made onthe initial investigations. Every eVort must bemade to keep such neonates alive until allinvestigations are completed. A sick neonatewith hyperammonaemia merits full biochemi-cal correction by dialysis, even if the initial bio-chemical tests are negative, as transient hyper-ammonaemia of the newborn (THAN) may bethe underlying diagnosis. The majority ofpatients with THAN have been preterm infantswho have mild respiratory distress syndrome.21

Plasma ammonia concentrations may begreatly increased, but the plasma and urineamino acid analyses are not characteristic ofany of the urea cycle defects. If treated aggres-sively, THAN is compatible with a good longterm neurological outcome, and hyperammo-naemia does not recur even on a normalprotein diet.22 The aetiology of this condition isunknown.

Management when death is inevitableSome patients will not survive, despite inten-sive treatment. In such cases, establishing adiagnosis is very important for genetic counsel-ling and for later prenatal diagnosis. A fullautopsy is preferable for internal anomalies,but it is uncommon to arrive at a metabolicdiagnosis based on routine autopsy findingsalone. It is therefore essential to collect the rel-evant specimens and biopsy specimens beforeor shortly after death. It is useful to discuss theinfant’s poor prognosis frankly with the parents

and to obtain their permission for autopsy andbiopsies before the infant dies. In our experi-ence, it is unusual not to obtain at least theminimum specimens required for a metabolicdiagnosis, even if full autopsy is refused. Theseinclude a blood spot on a screening card, alithium heparin, and an EDTA blood sample(3–5 ml each), all possible urine frozen in plainsterile containers, and a skin biopsy refriger-ated in culture medium (table 4). If possible,muscle and liver biopsy specimens should alsobe obtained. Open liver biopsy is preferable,but needle biopsy is also of use if an openbiopsy cannot be performed. One piece of eachshould be immediately frozen in liquid nitro-gen or dry ice for enzyme analysis, and anotherstored in an appropriate medium (for example,gluteraldehyde) for electron microscopy.

Management when an IEM is anticipatedSometimes the diagnosis of an IEM can beknown or suspected in advance: there may be apreviously aVected sibling, specific antenataltesting may have established the diagnosis, or amother may be a proven carrier of an X linkedcondition. The optimal management should beestablished prior to delivery. The choice iswhether to treat the baby as aVected whileawaiting tests, or to investigate promptly andcommence appropriate treatment when resultsare available. The decision will vary dependingon the disorder in question, but should bemade in collaboration with the paediatrician,obstetrician, and metabolic specialist.

Many disorders (such as fatty acid oxidationdefects and organic acidaemias) can be readilydiagnosed by analysis of cord blood specimensusing tandem mass spectrometry, and discus-sion with a metabolic laboratory before deliv-ery should enable a rapid diagnosis.

Withdrawal of treatmentIf clinical improvement does not occur within afew days, the infant is unlikely to recover nearnormal cerebral function. In such a situation, itis reasonable to discuss withdrawal of intensivelife support measures with the parents. This isnot diYcult if the diagnosis is known and theprognosis can be explained with some cer-tainty. Even if the exact diagnosis is not known,it is often possible to give the parents some ideaof the likely group of conditions (for example,disorders of pyruvate metabolism or respira-tory chain defects) that their child might have.Occasionally, a gravely ill neonate may survivewithdrawal of intensive care against all expecta-tions. Such infants are likely to have frequentacute episodes of deterioration, and dependingon the degree of brain damage and the under-lying condition, a decision to not undertakeextraordinary measures to prolong life duringthe next episode may be made in discussionwith the parents.

1 Ibdah J, Bennett MJ, Rinaldo P, et al. A fetal fatty acid oxi-dation disorder as a cause of liver disease in pregnantwomen. N Engl J Med 1999;340:1723–31.

2 Innes AM, Seargeant LE, Balachandra K, et al. Hepatic car-nitine palmitoyl transferase I deficiency presenting asmaternal illness in pregnancy. Pediatr Res 2000;47:43–5.

3 Walter JH. Inborn errors of metabolism and pregnancy. JInherit Metab Dis 2000;23:229–36.

Table 4 Investigations if death is inevitable and a metabolic cause is suspected

Specimen Sampling details

Plasma 3–5 ml lithium heparin sample, plasma separated andfrozen

Whole blood for DNA analysis 3–5 ml EDTA sample kept refrigerated (should not befrozen) (other whole blood samples can also be used)

Blood spot for acylcarnitine analysis 2–3 spots on filter paper or Guthrie cardUrine Frozen in a plain sterile containerSkin biopsy for fibroblast culture Collected using aseptic technique, stored in a skin biopsy

medium (if this is not available, viral culture medium ornormal saline in a sterile container may be used) (shouldnot be frozen)

Muscle biopsy 1 cm3 piece immediately frozen in liquid nitrogen or dryice for enzymology, histology, and DNA analysis; onepiece preserved in gluteraldehyde for electron microscopy

Liver biopsy 1 cm3 piece immediately frozen in liquid nitrogen or dryice for enzymology, histology, and DNA analysis; onepiece preserved in gluteraldehyde for electron microscopy

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4 Cooke RJ, Jensen RL. Plasma ammonia concentrations dur-ing the first 6 postnatal months, as measured with anammonium selective electrode. Clin Chem 1983;29:1563–4.

5 Maestri NE, Clissod D, Brusilow SW. Neonatal onset orni-thine transcarbamylase deficiency: a retrospective analysis.J Pediatr 1999;134:268–72.

6 Walter JH, Wraith JE, Cleary MA. Absence of acidosis in theinitial presentation of organic acidaemias. Arch Dis ChildFetal Neonatal Ed 1995;72:F197–9.

7 Poggi-Travert F, Martin D, de Villemeur TB, et al.Metabolic intermediates in lactic acidosis: compounds,samples and interpretation. J Inherit Metab Dis1996;19:478–88.

8 Kristiansson B, Stibler H, Conradi N, et al. The heart andpericardial eVusions in CDGS-I (carbohydrate deficientglycoprotein syndrome type I). J Inherit Metab Dis1998;21:112–24.

9 Imtiaz F, Worthington V, Champion M, et al. Genotypes andphenotypes of patients in the UK with carbohydrate defi-cient glycoprotein syndrome type I. J Inherit Metab Dis2000;23:162–74.

10 Barth P, Wanders RJ, Vreken P. X-linked cardioskeletalmyopathy and neutropenia (Barth syndrome—MIM302060). J Pediatr 2000;135:273–6.

11 Nyhan WL, Ozand P. Niemann Pick type C disease/cholesterol processing abnormality. In: Atlas of metabolicdiseases. London: Chapman and Hall Medical, 1998:575–81.

12 Kelly DA, Portmann B, Mowat AP, et al. Niemann-Pick dis-ease type C: diagnosis and outcome in children, with par-ticular reference to liver disease. J Pediatr 1993;123:242–7.

13 Clayton PT. Disorders of cholesterol biosynthesis. Arch DisChild 1998;78:185–9.

14 Ryan AK, Bartlett K, Clayton P, et al. Smith-Lemli-Opitzsyndrome: a variable clinical and biochemical phenotype. JMed Genet 1998;35:558–65.

15 Van Maldergem, Jauniaux E, Fourneau C, Gillerot Y.Genetic causes of hydrops fetalis. Pediatrics 1992;89:81–6.

16 Stone DL, Sidransky E. Hydrops fetalis: lysosomal disordersin extremis. Adv Pediatr 1999;46:409–40.

17 HoVman GF, Surtees RAH, Wevers RA. Cerebrospinalinvestigations for neurometabolic disorders. Neuropediat-rics 1998;29:59–71.

18 Falk MC, Knight JF, Roy LP, et al. Continuous venovenoushaemofiltration in the acute treatment of inborn errors ofmetabolism. Pediatr Nephrol 1994;8:330–4.

19 Schafer F, Straube E, Oh J, et al. Dialysis in neonates withinborn errors of metabolism. Nephrol Dial Tranplant1999;14:910–18.

20 Wong KY, Wong SN, Lam SY, et al. Ammonia clearance byperitoneal dialysis and continuous arteriovenous hemodia-filtration. Pediatr Nephrol 1998;12:589–91.

21 Hudak M, Jones MD Jr, Brusilow S. DiVerentiation of tran-sient hyperammonaemia of the newborn and urea cycledefects by clinical presentation. J Pediatr 1985;107:712–19.

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newbornDetection of inborn errors of metabolism in the

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