Inborn Errors of Metabolism: Disorder of Adults?
Transcript of Inborn Errors of Metabolism: Disorder of Adults?
Flow chart 1: Classification of IEMs
Section 18 Metabolic Disorders
Group 1It involves cellular organelles and includes lysosomal, peroxisomal, glycosylation and cholesterol synthesis defects. • Mucopolysaccharidosis (Hurler, Hunter, Sanfilippo, Morquio,
Maroteaux,Sly,etc.)• Sphingolipidosis(gangliodosis,Tay-Sachs,Sandhoff)• Lactosylceramidosis (Gaucher, Farber, Niemann-Pick, Krabbe,
sulfatasedeficiency)• Glycoproteinases (fucosidosis,manosidosis, sialidosis,aspartyl-
glucosaminuria)• Defectsinmembranetransport(cystinosis,succinicsemialdehyde
dehydrogenase,Salladisease)• Peroxisomal biogenesis defects (Zellweger syndrome, adreno-
leukodystrophy,Refsum’sdisease,hyperoxaluriaTypeI)• Fabry’sdisease,Shindler,Canavandisease,Pompedisease,acid
lipase deficiency, acid maltase deficiency, cerebrotendinousxanthomatosis,JuvenileBatten’sdisease,Kuf’sdisease,etc.
Group 2ItincludesIEMsthatgiverisetoanacuteorchronicintoxication.• Disorders of amino acids: Cystinuria, phenylketonuria (PKU),
tyrosinemia, homocystinuria, alcaptonuria, maple syrup urine disease, Hartnup’s disease, hyperornithinemia with gyrateatrophy
• Organic acidurias: Beta-ketothiolase deficiency, methyl-glutaconic academia, isovaleric academia, glutaric academia Type I, propionic academia, multiple carboxylase deficiency,methyl malonic academia
INTRODUCTIONInborn errors of metabolism (IEMs) are individually rare, butcollectively numerous.The termwas coined by ArchibaldGarrod,whoin1927presentedtheHuxleylectureatCharingCrossHospital.1 Until recently, IEMs were considered a specialty of pediatricians.Indeed,theterm“inborn”hasmeantforalongtime,adiseasewhichstarts in the newborn period or at least in childhood. Althoughmost IEMs can havemild forms starting in adolescence or late inadulthood, thisconceptof “adultonset IEMs”hasnot reached themedical community until recently. Theyrefertosinglegenedisorderswhereinlossoffunctionofasingle enzyme results in abnormalities in synthesis or catabolismofproteins,carbohydratesorfats,whichresultsinadisruptioninametabolicpathway.Thisresultsintoxicaccumulationsofsubstratesbefore the disruption, intermediates from alternative pathways,and/or defects in energy production and utilization. Nearly everymetabolicdiseasehasseveralformsthatvaryinageofonset,clinicalseverity and mode of inheritance. The mode of inheritance determines the male to female ratio of affectedandmanyIEMshavemultipleformsthatdifferintheirmodeof inheritance.
CLASSIFICATIONA simple method classifies IEMs into disorders involving proteinmetabolism,carbohydratemetabolism,lysosomalstorage,fattyacidoxidation defects, mitochondrial disorders, peroxisomal disorders. AdetailedandwidelyusedclassificationwhichcategorizesIEMsfromapathophysiologicalperspectiveisasfollows(Flow chart 1):2
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Inborn Errors of Metabolism: Disorder of Adults?
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Group II They do not interfere with the embryofetal development andthey present with a symptom-free interval and clinical signs of“intoxication”, which may be acute (vomiting, coma, liver failure,thromboembolic complications etc.) or chronic (failure to thrive,developmentaldelay,ectopialentis,cardiomyopathyetc.).Circum-stances that can provoke acute metabolic attacks include fever,intercurrentillnessandfoodintake.Clinicalexpressionisoftenbothlate in onset and intermittent.
Group IIICommon symptoms in this group include hypoglycemia, hyper-lactatemia, hepatomegaly, hypotonia, myopathy, car diomyopathy, cardiac failure, circulatory collapse, and brain involvement. Someof the mitochondrial disorders and pentose phosphate pathwaydefectscaninterferewiththeembryofetaldevelopmentandgiveriseto dysmorphism, dysplasia and malformations. Ingeneral,cliniciansshouldconsiderthepossibilityofanIEMinany patientwith an unexplained neurological disorder. Some brainregionslikebasalgangliaarehighlyvulnerabletoenergymetabolismdefects and metals. In an adult patient with an unexplainedencephalopathy or an unexplained coma, certain features are highly suggestiveofanIEM:(1)whentheencephalopathyistriggeredbyanextrinsic factor—surgery, fasting, exercise, treatments, high-proteinintake, newmedication (Table 1), etc.; and (2)when specific brainlesionsarepresentonbrainmagneticresonanceimaging(MRI). Twomaingroupsof IEMsareresponsible forencephalopathiesinadults:intoxications(mainly,ureacycledisorders,homocysteineremethylationdefectsandacuteporphyrias)andenergymetabolismdefects (respiratory chain disorders, pyruvate dehydrogenasedeficiencyandbiotineresponsivebasalgangliadisease). In the first group, MRI is usually normal or can show poorlyspecificfeatureswhereasinthesecondgroup,MRIisalmostalwaysabnormal,showingbilaterallesionsofbasalganglia(Leighsyndrome)orpseudo-strokes(mainlyinthecaseofrespiratorychaindefects).
DIAGNOSIS AND MANAGEMENTInbornerrorsofmetabolismmaypresentinadolescenceoradulthoodas a psychiatric disorder. In some instances, an IEM is suspectedbecause of informative family history or because psychiatricsymptomsformpartofamorediffuseclinicalpicturewithsystemic,cognitive or motor neurological signs. There are 3 important steps in the diagnosis and management of anIEM.
1. SuspicionThesymptomsandsignsforanIEMareverycommonandnonspecific;therefore, one should think of IEM as an etiology in unexplained/peculiarcasesandtrytoruleoutthepossibility.
• Urea cycle defects: Citrullinemia, argininemia, arginosuccinicaciduria, carbomyl phosphate synthase deficiency, ornithinetranscarbamylasedeficiency
• Sugar intolerance: Galactosemia, epimerase deficiency, heredi-taryfructoseintolerance,galactokinasedeficiency
• Others: Porphyrias, Wilson’s disease, aceruloplasminemia,Lesch-Nyhansyndrome,Sjogren-Larssonsyndrome.
Group 3It includes IEMs that affect the cytoplasmic and mitochondrialenergeticprocesses.Mitochondrialdefectsarethemostsevereandaregenerallyuntreatable(exceptketonebodydefectsandcoenzymeq10defects).Cytoplasmicenergydefectsaregenerallylesssevere.• Fatty acid oxidation defects: carnitine palmitoyl transferase I,
II deficiency, short-chain acyl-CoA dehydrogenase deficiency,medium-chain acyl-CoA dehydrogenase deficiency, verylong chain acyl CoA dehydrogenase deficiency, long-chain3-hydroxyacyl-CoAdehydrogenasedeficiency,glutaricacademiaType II,carnitineuptakedeficiency,hydroxymethylglutarylCoAlyase
• Mitochondrial disorders: pyruvate dehydrogenase complexdeficiency,pyruvatecarboxylasedeficiency,myoclonicepilepsywith ragged red fibers, mitochondrial encephalopathy withlactic acidosis and stroke, phosphoenolpyruvate carboxykinasedeficiency, Leber’s hereditary optic atrophy, neuropathy ataxiaandretinitispigmentosa(NARP)
• Glycogen storage disorders: von Gierke’s disease (Type I),Pompe’s disease (Type II), Cori’s or Forbes’ disease (Type III),Anderson’sdisease(TypeIV),McArdle’sdisease(TypeV),Her’sdisease (Type VI), Tarui’s disease (Type VII), Type IX, FanconiBickel syndrome (Type XI), red cell aldolase deficiency (TypeXII),TypeXIII,Type0.
CLINICAL MANIFESTATIONSInbornerrorsofmetabolism(IEMs)canaffectanyorgansystemandmanifestationsvary from thoseof acute life-threateningdisease tosubacute progressive degenerative disorder. Progression may beunrelenting with rapid life-threatening deterioration over hours,episodic with intermittent decompensations and asymptomaticintervals, or insidious with slow degeneration over decades. Allthreegroupsof IEMscanmanifest inadults,moresowithGroupIdisorders. In neonates and children, manifestations are nonspecific andvery similar to that of septicemia, a major reason why IEMs goundetected. There may be dysmorphic features present at birth(generallywhenfetalenergyisaffected),ordevelopduringthefirstyearoflife(lysosomaldisorders). In adults, the symptomsmay includemild-to-profoundmentalretardation, autism, learning disorders, behavioral disturbances,muscle weakness, progressive paraparesis, hemiparesis, dystonia,chorea, ataxia, ophthalmoplegia, visual deficit, epileptic crisis,hepatosplenomegaly and hypoglycemia. Some manifestations may be intermittent, precipitated by thestressofillness,orprogressive,withworseningovertime.Disordersmanifested by subtle neurologic or psychiatric features often goundiagnosed until adulthood.
Group I Onsetinadulthood(upto>70years).Amongtheorgansimpacted,thenervoussystemisby farmostcommon.Thus, lateonset formsof IEMs often display psychiatric or neurological presentations.These include atypical psychosis or depression, unexplained coma, peripheral neuropathy, cerebellar ataxia, spastic paraparesis,dementia, movement disorders, epilepsy, etc.
TABLE 1 │ Drugs which aggravate inborn errors of metabolism
Disease Drugs Mechanism
Urea cycle disorders Valproate Blockage of urea cycle
Porphyrias Imipramine, meprobamate
Porphyrogenic
Wilson’s disease Neuroleptics Blockage of D2 dopamine receptors
GM2 gangliosidosis Tricyclic antidepressants, phenothiazines
?Increased lipid storage
Respiratory chain disorders
Valproate Blocks the respiratory chain
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2. EvaluationOnce the possibility of an IEM is suspected, how should it beevaluated?TherearefourpartstotheevaluationofanIEM:A. History, family history: One of the most important clue is a history
of deterioration after an initial period of apparent good health rangingfromhourstoweeks.Developmentaldelay,particularlymissingmilestonesmaybepresent.Anotherkeyfeatureischangein the diet and unusual dietary preferences particularly protein or carbohydrateaversion.Thefamilyhistoryisveryimportant.MostIEM are autosomal recessive, so theremay have been siblingswith similar illnessesordeaths from“sepsis”or “sudden infantdeath syndrome (SIDS)”. The parents may be consanguineousor come from a genetic isolate. There are also X-linked, andmitochondrial inherited IEM, so a family historymust includeinformationaboutthemother’ssiblings,theirchildren,etc.
B. Physical examination:The physical examination of patients withIEM is usually normal except for nonspecific findings. Physicalfindingsthatareimportantinclude:facialdysmorphism,cataracts,hepatosplenomegaly and myopathy.
C Initial screening tests: The initial evaluation of an IEM shouldbegin with simple urine and blood analysis. The first step ischeckingforunusualodorsinurine(Table 2),someofwhicharenotspecific,butapositiveresultcandirecttowardoneormorespecifictests.
Thebloodtestsencompasscompletebloodcount,bloodgasesandblood electrolytes.Thepanel of tests should also include lactate,liver function test, cholesterol, pyruvate, urea, creatinine and uric acid.Alowneutrophilcountmaybeindicativeoforganicacidemias.Thelactate/pyruvateratiooflessthan25cancelsthepossibilityoflactic acidosis, organic acidurias, urea cycle defects and fatty acid metabolism. High levels of lactate and pyruvate are symbolic ofmitochondrial defects.3Anelevatedammonialevelinbloodpointstoureacycleabnormalitiesandsomeorganicacidemias.Serumandurineaminoacidanalysesrevealhyperalaninemia.Avalueabove16fortheaniongapissuggestiveoforganicacidurias.Glucoselevelischeckedtoruleouthypoglycemia,whichisacommonfeatureofmanyIEMs.
D. Advanced screening tests:Therearenumerousbiomarkersusedin many laboratories that specialize in biochemical genetics.
These include carnitine, acylcarnitines, lysosomal enzymes, etc (Table 3).4ThesetestsarekeytoexclusionorinclusionofanIEM.Magnetic resonance spectroscopy of brain shows high lactatelevelsinindividualswithmitochondrialdisorders.5
3. TreatmentThe basic principle for treatment of the acute inborn errors isreductionofthesubstratethataccumulatesduetocatabolicenzymedeficiency.Thespecifictreatmentofindividualmetabolicdiseaseistoovasttobedescribedindetail.Thetreatmentstrategiescommonlyemployed are discussed. In general, Group III are considereduntreatable, and the following strategies apply on most part toGroupsIandII.Thebriefapproachesareasfollows:
Prevent catabolism: Administration of calories is used in acuteepisodestoslowdownthecatabolism.
Limit the intake of the offending substance: Simple restriction ofcertain dietary components such as galactose and fructose form the basis of treatment in galactosemia and fructose intolerance.Neonates with PKU should be given a protein substitute that isphenylalanine-free.PatientswithGroupIarecommonlyconsideredfor this line of treatment.
Increase excretion of toxic metabolites: Rapid removal of toxicmetabolites (in IEM’s Group II) can be achieved by exchangetransfusion, dialysis, forced diuresis, using alternative pathwaysfor the excretion of toxic metabolites.6 For example, carnitineis useful in elimination of organic acids in the form of carnitine esters, sodium benzoate and phenylacetate are useful in treatinghyperammonemia, etc.
Enzyme replacement therapy: Patients with Group I IEMs havevariousformsofenzymedeficienciesandareconsideredforenzymereplacement. For example, human alphaglucosidase enzyme issafe andeffective inPompe’sdisease.7 Laronidase isdevelopedasa treatment strategy for mucopolysaccharidoses I,8 recombinantalpha-Gal A for Fabry’s disease,9 imiglucerase in management of Gaucherdisease,10 etc.
Increase the residual enzyme activity: People with Group II IEMscanbenefitbyincreasingtheresidualenzymeactivity.Thisisdonebyadministrationofpharmacologicdosesof the vitamincofactorfor the defective enzyme (Table 4). If the enzyme is reasonablyfunctional, increasing the vitamin concentration will increaseenzyme activity via amass action effect. A study showed that B12 decreases the urinary levels of methyl malonate by enhancingactivityoftranscobalaminII.11
Reduce substrate synthesis: In glycolipid lysosomal storage disease, glycohydrolase that catalyzes glycosphingolipid (GSL) is defectiveleading to accumulation of GSL in lysosome and precipitation ofthe disease. The imino sugar N-butyldeoxynojirimycin (NB-DNJ)inhibitsthefirststepinGSLsynthesis12andbalancestherateofGSLsynthesiswiththeimpairedrateofGSLbreakdown.
Replacement of the end product:Hypoglycemiaisafrequentfindingin patients with glycogen storage diseases, and can be preventedby frequent feeds.Rawcornstarch(2g/kgevery6hours)hasbeenshowntobeeffectiveinpreventinghypoglycemiainglycogenstoragediseaseTypeIasalsodecreasinghyperlipidemia,hyperuricemiaandlactic acidemia.13
Transplantation and gene therapy:Hematopoieticcelltransplantation(HCT)hasbeenusedaseffectivetherapyforIEMs,mainlylysosomalstorage diseases and peroxisomal disorders. The main rational for HCT in IEMs is based on the provision of correcting enzymes bydonorcellswithinandoutsidethebloodcompartment.14
TABLE 2 │ Urine odor in different inborn errors of metabolism
Disorder Odor Compound
Phenylketonuria Musty Phenyl acetate
Tyrosinemia CabbageRancid butter
Hydroxybutyric acidOxomethylbutyric acid
Maple syrup urine disease
Maple syrup Burnt sugar
Oxoisocaproic acid oxomethyl valeric acid
Isovaleric acidema, glutaric academia type II
Sweaty feet Isovaleric acid
Methylcrotonyl-CoACarboxylase deficiency
Cat urine Hydroxyisovaleric acid
Multiple carboxylase deficiency
Cat urine Hydroxyisovaleric acid
Methylmalonic academia
Acid smell Methylmalonic acid
Cystinuria Sulfurus Hydrogen sulfide
Hydroxy methyl glutaric acidurias
Cheesy Cheesy
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TABLE 3 │ Inborn errors of metabolism according to symptom groups
Disease Clinical symptoms Investigation
Muscle weakness or exercise intolerance
Fatty acid oxidation defects Cardiomyopathy, hypoglycemia, liver disease, myoglobinuria
Urine organic acids (fasting)
Glycolytic pathway disorders Anemia, liver disease, muscle weakness, cardiomyopathy, endocrinological disorders, ptosis
Red cells or muscle biopsy for enzyme assays
Glycogen storage disease(a) Type II (acid maltase deficiency) Respiratory difficulties due to diaphragmatic
weaknessLymphocyte acid á-glucosidase
(b) Type III (Cori’s disease) History of early hypoglycemia and hepatomegaly Leukocyte glycogen debrancher enzyme assay
(c) Type V (McArdle’s disease) Myoglobinuria, exercise intolerance, cramps Ischemic exercise test
(d) Phosphorylase b kinase deficiency Cardiomyopathy, liver disease Erythrocyte or liver phosphorylase b kinase assay
Motor neuron disease
Adult polyglucosan storage disease Dementia, neurogenic bladder, sensory loss Leukocyte glycogen brancher assay
Tay-Sach’s and Sandhoff’s disease Slow progressive disorder, pyramidal signs, cerebellar degeneration
Leukocyte total hexosaminidase and hexosaminidase A
Chorea and/or dystonia
Glutamic aciduria type 1 Reye’s syndromeHypoglycemia, slow progressive disorder, gait, disturbance, dysarthria
Urine organic acidsBlood spot for acyl carnitines
Lesch-Nyhan syndrome Renal stones, gout Plasma urate and urine, urate/creatinine ratio
Methylmalonic aciduria with homocystinuria
Anemia Urine organic acids and amino acids, urine, and plasma homocystine
Niemann-Pick disease type C Supranuclear ophthalmoplegia, ataxia, psycho-motor retardation, dementia, splenomegaly
Bone marrow aspirate fibroblast cholesterol incorporation and staining
Wilson’s disease Cataracts, Kayser-Fleischer rings, liver disease, dementia, renal failure, parkinsonian features, dysarthria, loss of coordination of voluntary movement
Plasma copper and ceruloplasmin, urine, copper, liver copper
Leukodystrophy
Krabbe’s leukodystrophy Pes cavus, hemiparesis, spastic tetraparesis Leukocyte â-galactocerebrosidase
X-linked adrenoleukodystrophy In males, gait disturbance, spastic paraparesis, rarely dementia, Addison’s disease. In females, onset >30 y, spastic paraparesis, vibration sense loss, long tract signs, peripheral neuropathy
Plasma very long chain fatty acids
Ataxia
Abetalipoproteinemia Muscle weakness, fat malabsorption, retinitis pigmentosa
Plasma cholesterol and triglycerides, blood film (acanthocytes), lipoproteins
Aceruloplasminemia Presenile dementia, diabetes mellitus, retinal dystrophy
Plasma and urine copper
Cerebrotendinous xanthomatosis Spasticity, cataracts, tendon xanthomas Urine cholesterol
Hartnup disease Skin lesions, dementia Plasma and urine amino acids
Pyruvate dehydrogenase deficiency (X-linked)
Episodes in males triggered by carbohydrate feeding
Pre and postprandial blood lactate, CSF lactate, fibroblast pyruvate dehydrogenase
Sialidosis (mucolipidosis type I) Type I: Visual defect with lens or corneal opacity, ataxia, myoclonus, generalized seizures sometimes with nystagmus, ataxia, dementia, cherry red spot Type II: Mycoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma
Urine oligosaccharides fibroblast alpha-neuraminidase
Strokes and stroke-like episodes
Febry’s disease Angiokeratoma, renal disease, development delay Leukocyte alfa-galactosidase A
Homocystinuria Lens dislocation, occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation
Urine and plasma homocystine and methionine
Contd...
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Disease Clinical symptoms Investigation
Mitochondrial myopathy, encephalopathy with lactic acidemia and stroke-like episodes (MELAS)
Seizures, developmental delay, sensorineural hearing loss, diabetes mellitus
Blood of mtDNA analysis
Urea cycle defects Postprandial vomiting, coma, confusion Blood ammonia, plasma, and urine amino acids
Epilepsy
Electron transport chain disorders Any combination of symptoms CSF and blood lactate, blood mtDNA analysis, muscle biopsy for enzyme assay
Juvenile Batten’s disease Visual loss, retinitis pigmentosa Skin or rectal biopsy for histological analysis, DNA for the common mutation
Myoclonic epilepsy with ragged red fibers (MERRF)
Myoclonus Blood for mtDNA analysis
Pyridoxine dependent seizures Persistent seizures responsive to pyridoxine Pyridoxine response trial (primary defect not known)
Behavioral and/or psychiatric disorders and/or dementia
Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis
Leukocyte b-glucosidase, bone marrow aspirate
Ornithine transcarbamylase deficiency Episodic symptoms (often postprandial), sleep disorders, comatose episodes
Plasma ammonia (1 h postprandial), plasma amino acids, urine amino acids and orotic acid
Porphyrria Limb, neck, or chest pain, muscle weakness, abdominal pain, photosensitivity
Urine and fecal porphyrins, urine delta aminolevulinic acid and porphobilinogen
Eye disorders
Galactokinase deficiency Cataracts Postprandial urine sugar, chromatography
Hyperornithinemia with gyrate atrophy of the retina
Optic atrophy Plasma and urine amino acids (ornithine)
Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis
Leukocyte b-glucosidase
Juvenile Batten’s disease Seizures, visual loss, retinitis pigmentossa, dementia
Skin or rectal biopsy for histological analysis, blood for DNA analysis for the common mutation
Leber’s hereditary optic atrophy Bilateral optic atrophy (may be alcohol or tobacco triggered)
Blood for mtDNA analysis
Neuropathy ataxia and retinitis pigmentosa
Retinitis pigmentosa, ataxia, neuropathy Blood for mtDNA analysis
Niemann-Pick disease type C Psychomotor retardation leading to dementia ataxia with dystonia, vertical supranuclear ophthalmoplegia
Bone marrow aspirate, fibroblast cholesterol uptake and staining
Refsum’s disease Peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia
Plasma phytanic acid
Sialidosis Cherry red spot Urine oligosaccharides, fibroblast alfa-neuraminidase
Tyrosinemia type II Cataracts, skin lesions, slight development delay Plasma and urine amino acids
Wilson’s disease Cataract, Kayser-Fleischer rings, liver disease, dementia, renal failure, parkinsonian features, dysarthria, loss of coordination of voluntary movement
Plasma copper and ceruloplasmin, urine copper, liver copper
Contd...
CONCLUSION
The most common mistake made in the management of IEM isdelayed diagnosis or misdiagnosis. In unexplained cases, the possibility of an IEM should be entertained, as many disorders
are treatableand, inmost cases, successfuloutcome isdependenton rapid diagnosis and early instigation of therapy. Even withuntreatable disorders, it is important to establish the diagnosis inthe index case in order to allow prenatal diagnosis in subsequentpregnancies.
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TABLE 4 │ Vitamins in treatment of inborn errors of metabolism
Disorder Vitamin used in the treatment
Maple syrup urine disease Thiamine
Homocystinuria Pyridoxine, folic acid and vitamin B12
Propionic academia Biotin
Methylmalonic academia Hydroxycobalamin
Glutaric academia Riboflavin
Biotinidase deficiency Biotin
Hartnup disease Nicotinic acid
Pyruvate dehydrogenase deficiency/Leigh’s disease
Thiamine
Respiratory chain disorders Riboflavin