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Disorders of Amino Acid Metabolism and Transport

Prepared by

Fakhruddin Babiker Ali

Contents
Hyperphenylalaninaemia Disorders of Tyrosine Metabolism Branched-Chain Organic Acidurias/Acidemias Disorders of the Urea Cycle and elated !n"ymes Disorders of #ulfur Amino Acid Metabolism Disorders of Ornithine Metabolism Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism %on&etotic Hyperglycinemia '(lycine !ncephalopathy) Disorders of *roline and #erine Metabolism Transport Defects of Amino Acids at the Cell Membrane+
Cystinuria $ysinuric *rotein ,ntolerance Hartnup Disorder

Hyperphenylalaninaemia
*henylalanine '*H!) '-). an essential aromatic amino acid. is mainly metaboli"ed in the li/er by the *H! hydro0ylase '*AH) system This en"yme re1uires the acti/e pterin. tetrahydrobiopterin 'BH2) 3hich is formed in three steps from (T* BH2 is con/erted to the inacti/e pterin-2a-carbinolamine and reacti/ated again /ia '1BH4) Defects in either *AH or the production or recycling of BH2 may result in hyperphenylalaninaemia as 3ell as in Tyrosine and Tryptophan deficiency #e/ere *AH deficiency 3hich results in a blood phenylalanine '*H!) greater than 54667M 3hen indi/iduals are on a normal protein inta&e. is referred to as classical phenyl&etonuria '*8U) or 9ust *8U Milder defects associated 3ith le/els bet3een :667M and 54667M are termed H*A and those 3ith le/els less than :667M but abo/e 5467M mild H*A

Hyperphenylalaninaemia
Disorders of biopterin metabolism ha/e in the past been called malignant *8U or malignant H*A; Ho3e/er such disorders are no3 best named according to the underlying en"yme deficiency

Hyperphenylalaninaemia

*henylalanine Hydro0ylase Deficiency '*8U) Maternal *henyl&etonuria Hyperphenylalaninaemia and Disorders of Biopterin Metabolism

Hyperphenylalaninaemia

Hyperphenylalaninaemia
The phenylalanine hydro0ylation system including the synthesis and regeneration of pterins and other pterin-re1uiring en"ymes
'BH4) dihydrobiopterin '1uinone) 'BH2) tetrahydrobiopterin 'DH* ) dihydropteridine reductase '(T*) guanosine triphosphate '(T*CH) guanosine triphosphate cyclohydrolase< '%O) nitric o0ide '%O#) nitric o0ide synthase '*) phosphate '*AH) *H! hydro0ylase '*CD) pterin-2a-carbinolamine dehydratase< '*T*#) pyru/oyl-tetra hydrobiopterin synthase< '# ) sepiapterin reductase 'TrpH) tryptophan hydro0ylase 'TyrH) tyrosine hydro0ylase

Hyperphenylalaninaemia
*henylalanine Hydro0ylase Deficiency '*8U) Clinical *resentation
The most important and sometimes the only manifestation of *8U is mental retardation 'intelligence 1uotients usually under =6) >omiting may be a prominent early symptom ,rritability. an ec"ematoid rash. and an unusual odor may also be obser/ed /ery early in life The odor of the phenyl&etonuric patient is that of phenylacetic acid; ,t has /ariously been described as mousy. barny. 3olfli&e or musty 'also noticed in patients 3ith defects in urea cycle treated 3ith *h-acetate) *atients 3ith *8U are often 1uite good loo&ing children The dermatitis is usually mild and patients may complain of intractable itching in the absence of /isible cutaneous lesions %eurological manifestations are not usually prominent

Hyperphenylalaninaemia
*henylalanine Hydro0ylase Deficiency '*8U) Metabolic Derangement
The pathogenesis of brain damage in *8U is not fully understood Tyrosine becomes a semi-essential amino acid 3ith reduced blood le/els leading to impaired synthesis of other biogenic amines including melanin. dopamine. and norepinephrine ,ncreased blood *H! le/els result in an imbalance of other large neutral amino acids '$%AA) 3ithin the brain. resulting indecreased brain concentrations of tyrosine and serotonin The ratio of *H! le/els in blood/brain is about 2+5 *H! impairs the metabolism of tyrosine hydro0ylation to dopamine and tryptophan decarbo0ylation to serotonin

Hyperphenylalaninaemia
*henylalanine Hydro0ylase Deficiency '*8U) Diagnosis
By the addition of ferric chloride a deep green color results indicating the presence of phenylpyru/ic acid

Hyperphenylalaninaemia
*henylalanine Hydro0ylase Deficiency '*8U) (enetics
*henyl&etonuria is an autosomal recessi/e disorder Hundreds of different alleles ha/e been disco/ered o/er ?6 percent of 3hich cause disease. but only fi/e are responsible for most human disease< the rest are rare

Treatment
Treatment of *8U is the pro/ision of a diet sufficiently lo3 in phenylalanine that the serum concentrations are maintained in a reasonable range and metabolites disappear from body fluids This re1uires the pro/ision of enough phenylalanine fre1uent 1uantitati/e assessment of the blood concentration Acceptable range from 5@6 to ?66 7mol/$

Hyperphenylalaninaemia
Maternal *henyl&etonuria Clinical *resentation
High *H! concentrations are associated 3ith 'Maternal *8U syndrome)+ facial dysmorphism. microcephaly. de/elopmental delay and learning difficulties. and congenital heart disease Other malformations cleft lip and palate. oesophageal atresia and tracheo-oesophageal fistulae. gut malrotation. bladder e0trophy and eye defects

Metabolic Derangement
-etal *H! concentrations are 5A - 4 times those in the mother. due to acti/e transport from the mother to the fetus *H! competes for placental transport 3ith other large neutral amino acids and affects fetal de/elopment in a /ariety of as yet un&no3n 3ays Maternal blood *H! concentrations 546-B:6 or 566-4=67mol/l

Hyperphenylalaninaemia
Hyperphenylalaninaemia and Disorders of Biopterin Metabolism
Deficiency include (T* cyclohydrolase , '(T*CH) deficiency. :pyru/oyl-tetrahydropterin synthase '*T*#) deficiency. dihydropteridine reductase 'DH* ) deficiency and pterin-2a-carbinolamine dehydratase '*CD) deficiency 'primapterinuria)

Clinical *resentation
Asymptomatic #ymptomatic 3ith neurological deterioration in infancy despite a lo3 *H! diet #ymptomatic 3ith neurological deterioration in infancy on a normal diet

Hyperphenylalaninaemia
Hyperphenylalaninaemia and Disorders of Biopterin Metabolism Metabolic Derangement
Disorders of pterin synthesis or recycling are associated 3ith decreased acti/ity of *AH. tyrosine hydro0ylase. tryptophan hydro0ylase and nitric o0ide synthase Highly /ariable blood *H! concentrations ranging from normal toC 46667mol/l Central ner/ous system 'C%#) amine deficiency is most often profound and responsible for the clinical symptoms

(enetics
All disorders are autosomal recessi/e 333;BH2;org

Hyperphenylalaninaemia

Hyperphenylalaninaemia

Disorders of Tyrosine Metabolism


Tyrosine is one of the least soluble amino acids, and forms characteristic crystals upon precipitation It derives from two sources; diet and hydroxylation of phenylalanine Tyrosine is both glucogenic and ketogenic The first step of tyrosine catabolism is conversion into 4hydroxyphenylpyruvate
By cytosolic tyrosine aminotransferase in liver lso by mitochondrial aspartate aminotransferase in liver and other tissues !minor role under normal conditions"

The penultimate intermediates , maleylacetoacetate and fumarylacetoacetate, can be reduced to succinylacetoacetate, followed by decarboxylation to succinylacetone

Disorders of Tyrosine Metabolism

Hereditary Tyrosinaemia
Type , 'Hepatorenal Tyrosinaemia) Type ,, 'Oculocutaneous Tyrosinaemia. ichner-Hanhart #yndrome) Type,,,

Transient Tyrosinaemia Al&aptonuria Ha3&insinuria Albinism

Disorders of Tyrosine Metabolism

Disorders of Tyrosine Metabolism


The tyrosine catabolic path3ay
'5)Tyrosine aminotransferase 'deficient in tyrosinaemia type ,,) '4) 2-hydro0yphenylpyru/ate dio0ygenase 'deficient in tyrosinaemia type ,,, ha3&insinuria. site of inhibition by %TBC) 'B) homogentisate dio0ygenase 'deficient in al&aptonuria) '2) fumarylacetoacetase 'deficient in tyrosinaemia type ,) '=) aspartate aminotransferase ':) =-aminole/ulinic acid '=-A$A) dehydratase 'porphobilinogen synthase)

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Clinical *resentation Clinically. tyrosinaemia type , may be classified based on the age at onset of symptoms
Acute before : months of age 3ith acute li/er failure #ubacute bet3een : months and 5 year of age 3ith li/er disease. failure to thri/e. coagulopathy. hepatosplenomegaly. ric&ets and hypotonia Chronic after the first year 3ith chronic li/erdisease. renal disease. ric&ets. cardiomyopathy and/or a porphyria-li&e syndrome

Tyosinaemia type ,, is characteri"ed by ocular lesions 'aboutD=E of the cases). s&in lesions '@6E). and neurological complications ':6E). or any combination of these Only 5B cases of tyrosinaemia type ,,, ha/e been described and the full clinical spectrum of this disorder is un&no3n The most common long-term complication is intellectual impairment. found in D=E of the reported cases

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Metabolic Derangement Tyrosinaemia type , is caused by a deficiency of the en"yme fumarylacetoacetate hydrolase '-AH). 3hich is mainly e0pressed in the li/er and &idney Accumulated metabolites ha/e local effects e0cept #A and #AA -AA. MAA and #A disrupt sulfhydryl metabolism by forming glutathione adducts. thereby rendering cells susceptible to free radical damage #econdary deficiency of 2-hydro0yphenylpyru/atedio0ygenase and methionine adenosyltransferase. resulting in hypertyrosinemia and hypermethioninemia Additionally. -AA and MAA are al&ylating agents and can disrupt the metabolism of thiols. amines. D%A and other important intracellular molecules

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Metabolic Derangement ,n tyrosinaemia type , =-A$A. a neuroto0ic compound is belie/ed to cause the acute neurological crises. and also disrupts renal tubular function. heme synthesis and immune function Tyrosinaemia type ,, is due to a defect of hepatic cytosolic tyrosine aminotransferase leading to increased production and accumulation of 2-hydro0yphenyl-pyru/ate. -lactate and Facetate Corneal damage due to crystalli"ation of tyrosine in the corneal epithelial cells The etiology of the neurological manifestations is un&no3n. but it is belie/ed that hypertyrosinaemia may ha/e a role in pathogenesis Tyrosinaemia type ,,, is due to deficiency of 2-hydro0yphenylpyru/ate dio0ygenase 'H*D) 3hich is e0pressed in li/er and &idney

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
(enetics All Hereditary tyrosinaemia are inherited as autosomal recessi/e traits Diagnosis ,n tyrosinaemia type , li/er function tests are usually abnormal !le/ated le/els of succinylacetone indried blood spots. plasma or urine are pathognomonic of tyrosinaemia type , Other metabolite abnormalities< ele/ated plasma le/els of tyrosine. phenylalanine and methionine. reduced erythrocyte =-aminole/ulinate dehydratase acti/ity and increased urinary=-A$A e0cretion Confirmation of the diagnosis re1uires either en"yme assay or by mutation analysis

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Diagnosis ,n tyrosinaemia type ,, *lasma tyrosine concentrations are usually abo/e 5466 7mol/l Ghen the tyrosinaemia is less pronounced adiagnosis of tyrosinaemia type ,,, should be considered Urinary e0cretion of the phenolic acids 2-hydro0yphenylpyru/ate. -lactate. -acetate is highly ele/ated 'also in type ,,,) %-acetyl- tyrosine and 2-tyramine are also increased Confirmation of the diagnosis re1uires either en"yme assay on li/er biopsy or by mutation analysis ,n tyrosinaemia type ,,, *lasma tyrosine concentrations are usually from B66F5B66 7mol/l Confirmation of the diagnosis re1uires either en"yme assay on li/er or &idney biopsy or by mutation analysis

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Treatment Historically tyrosinaemia type , 3as treated 3ith a tyrosine and phenylalanine restricted diet. 3ith or 3ithout li/er transplantation ,n 5??4 a ne3 drug. 4-'4-nitro-2-trifluoromethylben"oyl)-5.Bcyclohe0anedione '%TBC). a potent inhibitor of 2hydro0yphenylpyru/ate dio0ygenase 3as introduced The rationale for the use of %TBC is to bloc& tyrosine degradation at an early step so as to pre/ent the production of to0icdo3n-stream metabolites such as -AA. MAA and #A< the le/els of tyrosine. 2hydro0yphenyl-pyru/ate and -lactate concomitantly increase

Disorders of Tyrosine Metabolism


Hereditary Tyrosinaemia
Treatment Tyrosinaemia type ,, treatment consists of a phenylalanine and tyrosine-restricted diet (ro3th and nutritional status should be regularly monitored At present. tyrosinemia type ,,, appears to be associated 3ith intellectual impairment in some cases. but not in others ,t is reasonable to treat patients 3ith a lo3-phenylalanine and tyrosine diet

,t is recommended to maintaining plasma tyrosine le/els bet3een 466 and 2667mol/l

Disorders of Tyrosine Metabolism


Transient Tyrosinaemia
Transient tyrosinaemia is one of the most common amino acid disorders. and is belie/ed to be caused by late fetal maturation of 2hydro0yphenylpyru/atedio0ygenase ,t is more common in premature infants than full term ne3borns The le/el of protein inta&e is an important etiological factor %o3 /anishing concomitant 3ith a reduction in the protein content of ne3born formula mil&s Asymptomatic Tyrosine le/els are e0tremely /ariable. and can e0ceed 4666 7mol/l esol/es spontaneously by 2F: 3ee&s

Disorders of Tyrosine Metabolism


Al&aptonuria Clinical *resentation
Dar&ening of urine 3hen e0posed to air 'infancy) Clinical symptoms first appear in adulthood Hoint and connecti/e tissue in/ol/ement are most prominent symptoms Cardiac disease and urolithiasis may be detected in the later years

Metabolic Derangement
,t is caused by a defect of the en"yme homogentisate dio0ygenase Accumulation of homogentisate and its o0idised deri/ati/e ben"o1uinone acetic acid. the putati/e to0ic metabolite and immediate precursor to the dar& pigment. 3hich gets deposited in /arious tissues

Disorders of Tyrosine Metabolism


Al&aptonuria (enetics
Al&aptonuria is an autosomal recessi/e disorder

Diagnosis
Al&alinisation of the urine from al&aptonuric patients results in immediate dar& bro3n coloration of the urine (as chromatographyF mass spectrometry '(C-M#) based organic acid screening methods can specifically identify and 1uantify homogentisic acid Homogentisate may also be 1uantified by H*$CI:6J and by specific en"ymatic methods

Treatment
Dietary restriction of phenylalanine and tyrosine inta&e reduces homogentisate e0cretion. but compliance is a ma9or problem

Disorders of Tyrosine Metabolism


Ha3&insinuria Clinical *resentation
are condition. 3hich has only been described in four families characteri"ed by failure to thri/e and metabolic acidosis in infancy

Metabolic Derangement
,t is thought to be caused by an incomplete con/ersion of 2hydro0yphenylpyru/ate to homogentisate due to a defect in 2hydro0yphenylpyru/ate dio0ygenase $eading to abnormal metabolites ha3&insin '4-cysteinyl-5.2dihydro0ycyclohe0enylacetate) and 2-hydro0ycyclo0ylacetate Ha3&insin is thought to be the product of a reaction of an epo0ide intermediate 3ith glutathione. 3hich may be depleted The metabolic acidosis is belie/ed to be due to=-o0oproline accumulation secondary to glutathione depletion

Disorders of Tyrosine Metabolism


Ha3&insinuria (enetics
Unli&e most other inborn errors of metabolism. ha3&insinuria sho3s autosomal dominant inheritance

Diagnosis
,dentification of urinary ha3&insin or 2-hydro0ycyclohe0ylacetate by (C-M# is diagnostic Ha3&insin is a ninhydrin-positi/e compound. 3hich appears bet3een urea and threonine in ion-e0change chromatography of urine amino acids

Treatment
#ymptoms in infancy respond to a return to breastfeeding or a diet restricted in tyrosine and phenylalanine along 3ith /itamin C supplementation 'asymptomatic after the first year of life)

Albinism

Absence of normal pigmentation in the s&in and hair. translucent irides. hypopigmented ocular fundus. nystagmus. photophobia. misdirection of optic chiasmatic fibers. and in the classic form of oculocutaneous albinism. absent acti/ity of tyrosinase in the melanocytes

Albinism
There are t3o ma9or melanin pigments+
!umelanin 'Melanin). the blac& or bro3n *heomelanin. the red or yello3

!ach is produced subse1uent to the formation of DO*A1uinone Both types of melanin may be synthesi"ed in a single melanocyte. and mi0tures of the t3o types of melanin may occur Albinism is clinically and genetically heterogeneous; Oculocutaneous albinism is distinguished from ocular albinism in 3hich only the eye is included ,n oculocutaneous albinism a number of specific types ha/e been distinguished

Albinism

Albinism

Albinism
Metabolic Derangement
,t is caused by mutations in tyrosinase gene and abnormality of melanocyte tyrosinase

(enetics
All forms of oculocutaneous albinism are transmitted as autosomal recessi/e traits

Treatment
A/oidance of solar radiation Medications

Branched-Chain Organic Acidurias/Acidemias


The three essential branched-chain amino acids 'BCAAs). leucine. isoleucine and /aline. are initially cataboli"ed by a common path3ay The first reaction. 3hich occurs primarily in muscle. in/ol/es re/ersible transamination to 4-o0o 'or &eto) acids and is follo3ed by o0idati/e decarbo0ylation to 'CoA) deri/ati/es by branched-chain o0o- 'or &eto-) acid dehydrogenase 'BC8D);; #imilar to *yru/ate dehydrogenase $eucine is cataboli"ed to acetoacetate and acetyl-CoA 3hich enters the 8rebs cycle ,soleucine in/ol/es clea/age into acetyl-CoA and propionyl-CoA. 3hich also enters the 8rebs cycle /ia con/ersion into succinylCoA >aline is also ultimately metaboli"ed to propionylCoA Methionine. threonine. fatty acids 3ith an odd number of carbons. the side chain of cholesterol. and bacterial gut acti/ity also contribute to the formation of propionyl-CoA

Branched-Chain Organic Acidurias/Acidemias


Maple #yrup Urine Disease. ,so/aleric Aciduria. *ropionic Aciduria. Methylmalonic Aciduria B-Methylcrotonyl (lycinuria B-Methylglutaconic Aciduria Type , #hort/Branched-Chain Acyl-CoA Dehydrogenase Deficiency 4-Methyl-B-Hydro0ybutyryl-CoA Dehydrogenase Deficiency ,sobutyryl-CoA Dehydrogenase Deficiency B-Hydro0yisobutyric Aciduria Malonic Aciduria

Branched-Chain Organic Acidurias/Acidemias

Branched-Chain Organic Acidurias/Acidemias


*ath3ays of branched-chain amino acid catabolism
'5) Branched-chain 4-&eto acid dehydrogenase comple0 '4) iso/aleryl-coen"yme A 'CoA) dehydrogenase 'B) B-methylcrotonyl-CoA carbo0ylase '2) B-methylglutaconyl-CoA hydratase '=) B-hydro0y-B-methylglutaryl-CoA lyase ':). short/branched-chain acyl-CoA dehydrogenase 'D) 4-methyl-B-hydro0ybutyryl-CoA dehydrogenase '@) 4-methylacetoacetyl-CoA thiolase '?) isobutyryl-CoA dehydrogenase '56) B-hydro0yisobutyryl-CoA deacylase '55) B-hydro0yisobutyric acid dehydrogenase '54) methylmalonic semialdehyde dehydrogenase '5B) acetyl-CoA carbo0ylase 'cytosolic) '52) propionyl-CoA carbo0ylase '5=) malonyl-CoA decarbo0ylase< '5:) methylmalonyl-CoA mutase

Branched-Chain Organic Acidurias/Acidemias


Maple #yrup Urine Disease. ,so/aleric Aciduria. *ropionic Aciduria. Methylmalonic Aciduria
The most commonly encountered BCAA. others are rare

Clinical *resentation
#e/ere neonatal form of metabolic distress Acute. intermittent. late-onset form Chronic progressi/e form presenting as hypotonia. failure to thri/e. and de/elopmental delay

#e/ere neonatal form of metabolic distress


To0ic encephalopathy 3ith either &etosis or &etoacidosis The first signs are poor feeding and dro3siness. follo3ed by une0plained progressi/e coma %eurological signs. dehydration and mild hepatomegaly

Branched-Chain Organic Acidurias/Acidemias


Maple #yrup Urine Disease. ,so/aleric Aciduria. *ropionic Aciduria. Methylmalonic Aciduria
#ign Odor BCAAs in urine Metabolic acidosis Dehydration Hyperlactatemia Hyperammonemia M#UD #3eet. malty. caramel-li&e Kes %o %o %o %o ,>A. *A and MMA Unpleasant s3eaty feet Odor in ,>A %o Kes Kes Kes Kes

Branched-Chain Organic Acidurias/Acidemias


Acute. intermittent. late-onset form
Onset of an acute attac& may arise during catabolic stress %eurological signs. hepatic signs. hematologic and immunolgic signs

Chronic progressi/e form


(astrointestinal symptoms. Chronic %eurological signs

Complications
Acute cererebral oedema and encephalopathy Acute or progressi/e e0trapyramidal syndrome enal tubular acidosis associated 3ith hyperuricemia $arge. superficial des1uamation. alopecia. and corneal ulceration may de/elop Acute or chronic pancreatitis Acute cardiac failure due to cardiomyopathy

Branched-Chain Organic Acidurias/Acidemias


Metabolic Derangement M#UD
Caused by a deficiency of the branched-chain 4-&eto acid dehydrogenase 'BC8D) comple0 esults in mar&ed increases in the branched-chain 4-&eto acids in plasma. urine and cerebrospinal fluid 'C#-) Three catalytic components
Decarbo0ylase !5 'L M) e1uiring T** Dihydrolipoyl acyltransferase !4 Dihydrolipoamide dehydrogenase !B M#UD D$AD '!B) deficiency

,>A
Caused by a deficiency of iso/aleryl-CoA dehydrogenase ',>D) esults in the accumulation of deri/ati/es of iso/aleryl-CoA. including free iso/aleric acid. B-hydro0yiso/aleric acid 'B-H,>A). and %iso/alerylglycine iso/alerylcarnitine

Branched-Chain Organic Acidurias/Acidemias


Metabolic Derangement *A
Caused by a deficiency of propionyl-CoA carbo0ylase '*CC) Biotin ,ncreased concentrations of free propionic acid in blood and urine. and the presence of multiple organic acid byproducts. among 3hich propionylcarnitine. B-hydro0ypropionate. and methylcitrate are the ma9or diagnostic metabolites

MMA
Caused by a deficiency of methylmalonyl-CoA mutase 'MCM) B54 $eads to the accumulation of methylmalonyl-CoA. resulting in greatly increased amounts of methylmalonic acid in plasma and urine

Branched-Chain Organic Acidurias/Acidemias


(enetics M#UD. ,>A and *A
Autosomal recessi/e disorders

MMA
Caused by mutations in the MUT locus. encoding the methylmalonyl CoA mutase 'MCM) apoen"yme or by those in genes re1uired for pro/ision of its cofactor. =c-deo0yadenosylcobalamin 'AdoCbl)

Diagnosis
Only M#UD can be diagnosed by using plasma amino acid chromatography alone ,>A. *A and MMA are diagnosed by their specific urinary organic acid profiles using (C-M# or abnormal acylcarnitines on tandem M#

Branched-Chain Organic Acidurias/Acidemias


B-Methylcrotonyl (lycinuria Clinical *resentation
The clinical phenotype ranges from neonatal onset 3ith se/ere neurological in/ol/ement and e/en death to completely asymptomatic adults

Metabolic Derangement
$eucine catabolism is bloc&ed by deficiency of B-methyl crotonyl-CoA carbo0ylase 'B-MCC) Biotin B-methylcrotonyl-CoA and B-methylcrotonic acid accumulate Con9ugated to glycine B-MC( Accumulation of B-methylcrotonylglycine also occurs in multiple carbo0ylase deficiency but in contrast to B-MCC is found together 3ith lactic acid and deri/ati/es of propionylCoA B-Hydro0yiso/alerate 'B-H,>A) is another ma9or metabolite

Branched-Chain Organic Acidurias/Acidemias


B-Methylcrotonyl (lycinuria (enetics
The B-MCC is a heteromeric en"yme consisting of D-'biotincontaining) and !-subunits; B-MCC deficiency results from loss of function mutations in the MCCAand MCCB genes encoding these subunits

Diagnosis
The diagnosis relies on a characteristic urinary profile of organic acids

Treatment
$ong term treatment of symptomatic infants based on a mildly proteinrestricted diet (lycine and carnitine therapies directed at increasing the e0cretion of glycine and carnitine con9ugates

Branched-Chain Organic Acidurias/Acidemias


B-Methylglutaconic Aciduria Type , Clinical *resentation
,dentified in /ery fe3 indi/iduals

Metabolic Derangement
Defecti/e acti/ity of the en"yme B-M(C-CoA hydratase 3hich metaboli"es B-Methylglutaconyl 'M(C)-CoA to B-hydro0y-Bmethylglutaryl-CoA 'B-HM(-CoA) $eads to urinary e0cretion of B-M(C and B-methylglutaric acids a hydrolytic and dehydrogenated products 'respecti/ely) of BMethylglutaconyl 'M(C)-CoA

Branched-Chain Organic Acidurias/Acidemias


#hort/Branched-Chain Acyl-CoA Dehydrogenase Deficiency Clinical *resentation
Brain lesions due to early neonatal hypoglycemia

Metabolic Derangement
Caused by short/branched-chain acyl-CoA dehydrogenase '#BCAD) deficiency ,solation of 4-methylbutyrylglycine '4-MB() and 4methylbutyrylcarnitine '4-MBC) from body fluids 4-methylbutyrylglycinuria

(enetics
Autsomal recessi/e disorder of isoleucine metabolism Caused by a mutation '55:=AC() in the #BCAD gene

Branched-Chain Organic Acidurias/Acidemias


4-Methyl-B-Hydro0ybutyryl-CoA Dehydrogenase Deficiency
#ince 4666 4-methyl-B-hydro0ybutyryl-CoA dehydrogenase 'MHBD) deficiency has been described in appro0imately 56 males aged 4 to @years and in one male adult

Clinical *resentation
Unusual neurodegenerati/e disease

Metabolic Derangement
MHBD deficiency is a defect of isoleucine degradation Mar&ed ele/ations of urinary 4-methyl-B-hydro0ybutyrate and tiglyl glycine 3ithout ele/ation of 4-methylacetoacetate

(enetics
MHBD deficiency is caused by mutations in the N-chromosomal HADH4 gene

Branched-Chain Organic Acidurias/Acidemias


,sobutyryl-CoA Dehydrogenase Deficiency Clinical *resentation
The first patient 3ith isobutyryl-CoA dehydrogenase ',BD) deficiency 3as a 4 year old female 3ho de/eloped anemia and dilated cardiomyopathy in the second year of age. 3ith ery lo3 total plasma carnitine; Urine organic acids 3ere normal !le/ated butyrylcarnitine/isobutyrylcarnitine Tandum M#

(enetics
,BD catalyses the third step in the degradation of /aline ,t is encoded by the ACAD @ gene OOO The possible clinical implication of this en"yme defect is not &no3n and careful follo3 up is necessary

Branched-Chain Organic Acidurias/Acidemias


B-Hydro0yisobutyric Aciduria
A fe3 patients 3ith increased e0cretion of B-hydro0yisobutyric acid 'BH,BA). an intermediate of the catabolic path3ays of /aline and thymidine. ha/e been identified

Clinical *resentation
Heterogeneous '/omiting. lethargy. &etoacidosis. hypotonia and e/en myopathic features. hypertrophic cardiomyopathy and e/en C%# in/ol/ement is highly /ariable)

Metabolic Derangement
#e/eral en"yme defects malonic. methylmalonic and ethylmalonic semialdehyde dehydrogenase 'MM#DH) Uni1ue patient 3ith B-hydro0yisobutyryl-CoA deacylase deficiency has been identified

Branched-Chain Organic Acidurias/Acidemias


Malonic Aciduria
Only a fe3 patients 3ith malonic aciduria ha/e been described

Clinical *resentation
*rogressi/e lethargy. hypotonia. and hepatomegaly associated 3ith metabolic acidosis and mild hyperammonemia %eonatal Acute episodes of gastroenteritis. febrile sei"ures. une0plained lethargy associated 3ith metabolic acidosis. and hypoglycemia $ate onset

Metabolic Derangement
Due to deficiency of malonyl-CoA decarbo0ylase 'M$KCD) The physiological role of this cytsolic en"yme is some3hat unclear

(enetics
M$KCD deficiency is an autosomal-recessi/e disorder

Branched-Chain Organic Acidurias/Acidemias


Malonic Aciduria Diagnosis
elies on a characteristic profile of urinary organic acids. in 3hich malonic and methylmalonic acids are constant finding

Disorders of the Urea Cycle and elated !n"ymes


The Urea Cycle
,n its complete form. it is only present in the li/er ,t is the main path3ay for the disposal of e0cess of nitrogen $ocali"ed in part in the mitochondria and in part in the cytosol Con/erts the to0ic ammonia and other nitrogenous compounds into the non-to0ic product. urea. 3hich is e0creted in the urine (enetic defects of each en"yme of the urea cycle are recogni"ed and all are responsible for hyperammonaemia (enetic defects of other metabolic path3ays may also lead to secondary inhibition of the urea cycle Alternati/ely. con9ugation of glycine 3ith ben"oate and of glutamine 3ith phenylacetate can be e0ploited in the treatment of patients 3ithdefecti/e ureagenesis

Disorders of the Urea Cycle and elated !n"ymes

Disorders of the Urea Cycle and elated !n"ymes


The urea cycle and alternati/e path3ays of nitrogen !0cretion !n"ymes+
'5) carbamoyl phosphate synthetase< '4) ornithine transcarbamoylase 'B) argininosuccinate synthetase< '2) argininosuccinatelyase '=) arginase ':) %-acetylglutamate synthetase 'D) glutamine synthetase '@) Citrin 'mitochondrial aspartate-glutamate carrier) P denotes stimulation

Disorders of the Urea Cycle and elated !n"ymes


Clinical *resentation
*atients 3ith urea-cycle disorders may present at almost any age
%eonates
*oor feeding. /omiting. lethargy and/or irritability and tachypnoea Transient mild respiratory al&alosis %eurological and autonomic problems Untreated. most babies 3ill die due to cerebral or pulmonary haemorrhage

,nfants
#ymptoms are generally rather less acute and more /ariable anore0ia. lethargy. /omiting and failure to thri/e. 3ith poor de/elopmental progress ,rritability and beha/ioral problems are also common encephalopathy 3ith changes in consciousness and neurological signs

Children and Adults ob/ious neurological signs


Acute encephalopathy. chronic neurological illness. arginase deficiency. glutamine synthetase deficiency. and citrin deficiency

Disorders of the Urea Cycle and elated !n"ymes


Metabolic Derangement
The plasma ammonia concentration is raised as a result of metabolic bloc&s in the urea cycle The concentrations of the amino acids in the metabolic path3ay immediately pro0imal to the en"yme defect 3ill increase. and those beyond the bloc& 3ill decrease ,n addition. plasma alanine and particularly glutamine accumulate in all the disorders Orotic acid and orotidine are e0creted in e0cess in the urine if there is a metabolic bloc& distal to the formation of carbamoyl phosphate. as is the case in OTC deficiency. citrullinaemia. argininosuccinic aciduria and arginase deficiency Carbamoyl phosphate accumulates. lea/es the mitochondrion to the cytosol. enters the path3ay for the synthesis of pyrimidines The urea cycle is lin&ed to many other path3ays of intermediary metabolism

Disorders of the Urea Cycle and elated !n"ymes


To0icity of Ammonia
Ammonia increases the transport of tryptophan across the bloodbrain barrier. 3hich then leads to an increased production and release of serotonin base for symptoms anore0ia Ammonia induces many other electrophysiological. /ascular and biochemical changes in e0perimental systems (lutamine accumulation increases osmolality cellular s3elling and cerebral oedema

(enetics
The genes for all the urea-cycle en"ymes ha/e no3 been mapped. isolated and fully characteri"ed The most common urea cycle disorder is OTC deficiency. 3as found to be N-lin&ed All the other conditions ha/e autosomal recessi/e inheritance

Disorders of the Urea Cycle and elated !n"ymes

Disorders of the Urea Cycle and elated !n"ymes

Disorders of #ulfur Amino Acid Metabolism

Disorders of #ulfur Amino Acid Metabolism


Metabolism of the sulfur-containing amino acids+
'5) cystathionine !-synthase '4) =-methyltetrahydrofolate-homocysteine methyltransferase 'B) betaine-homocysteine methyltransferase '2) methionine #-adenosyltransferase '=) glycine %-methyltransferase ':) #-adenosylhomocysteine hydrolase 'D) H-cystathionase '@) sulfite o0idase

Disorders of #ulfur Amino Acid Metabolism


Homocystinuria due to Cystathione M-#ynthase Deficiency Metabolic Derangement
Deficiency of cystathione M-synthase CB# leads to tissue accumulation of methionine. homocysteine. and their #-adenosyl deri/ati/es. 3ith lac& of cystathionine and lo3 le/els of cysteine The -#H group of homocysteine is /ery reacti/e number of disulfide products $eading to generali"ed /ascular damage and thromboembolic complications Other deleterious effects homocysteine may cause abnormal crosslin&ing of collagen. leading to abnormalities of the s&in. 9oints. and s&eleton in patients

(enetics
Homocystinuria due to CB# deficiency is inherited as an autosomal recessi/e trait

Disorders of #ulfur Amino Acid Metabolism


Methionine #-Adenosyltransferase Deficiency Metabolic Derangement
This disorder is characteri"ed by a deficiency of the hepatic form of the en"yme MAT,/,,, 'but not the e0tra hepatic form. MAT,,). leading to ele/ated methionine concentrations in tissues and physiological fluids Alternati/e metabolism of methionine seems to occur resulting in the formation of the transamination product 2methylthio-B-o0obutyrate and dimethyl sulfide

(enetics
Mutations of the MAT5A gene account for both autosomal recessi/e and autosomal dominant hypermethioninemia

Disorders of #ulfur Amino Acid Metabolism


(lycine %-Methyltransferase Deficiency Metabolic Derangement
High methionine. ele/ated #-adenosylmethionine in plasma 3ithout ele/ated #-adenosylhomocysteine and sarcosine. pro/ides strong e/idence of deficiency of glycine%-methyltransferase '(MT)

(enetics
Mutations in the (MT gene also occurring in either parent confirm autosomal recessi/e inheritance of this defect

Disorders of #ulfur Amino Acid Metabolism


#-Adenosylhomocysteine Hydrolase Deficiency
A single patient 3ith this disorder 3as recently reported

Metabolic Derangement
Deficiency of this en"yme has been pro/en and leads to a bloc& in the degradation and accumulation of #-adenosylhomocysteine as 3ell as increased le/els of #-adenosyl-methionine and methionine

(enetics
,nheritance is autosomal recessi/e

Disorders of #ulfur Amino Acid Metabolism


Q-Cystathionase Deficiency
This is considered to be a benign disorder

Metabolic Derangement
Deficiency of the *$*-re1uiring Q-cystathionase leads to tissue accumulation of cystathionine !0cretion of cystathionine occur and %-acetylcystathionine is also e0creted

(enetics
,nheritance is autosomal recessi/e

Disorders of #ulfur Amino Acid Metabolism


,solated #ulfite O0idase Deficiency Metabolic Derangement
Catalyses the last step in the o0idation of the sulfur atom of cysteine into inorganic sulfate Accumulation of the suspected to0ic compound sulfite together 3ith its deto0ification products. #-sulfocysteine and thiosulfate. 3ith reduced formation of sulfate

(enetics
,nheritance is autosomal recessi/e

Disorders of Ornithine Metabolism


Ornithine is an important intermediate in se/eral metabolic path3ays The pyrido0al phosphate re1uiring en"yme ornithine-Raminotransferase 'OAT) plays a pi/otal role in its metabolism During the neonatal period the flu0 of theOAT reaction is in thedirection of ornithine synthesis Ornithine is then con/erted to citrulline and arginine /ia the urea cycle $ater. at appro0imatelyBF2 months of age. theOAT reaction is re/ersed to cataboli"e e0cess ornithine generated from arginine hydrolysis Ornithine also plays an important role in urea synthesis

Disorders of Ornithine Metabolism


Hyperornithinemia due to Ornithine Aminotransferase Deficiency '(yrateAtrophy of the Choroid and etina) The Hyperornithinemia. Hyperammonemia. and Homocitrullinuria 'HHH) #yndrome S5-*yrroline-=-Carbo0ylate #ynthase Deficiency

Disorders of Ornithine Metabolism

Disorders of Ornithine Metabolism


Ornithine metabolic path3ays
'*i) inorganic phosphate '5) ornithine-R-aminotransferase 'OAT) '4) S5-pyrroline-=-carbo0ylate synthase '*=C#) 'B) S5-pyrroline-=-carbo0ylate dehydrogenase '2) ornithine transcarbamoylase 'OTC) '=) S5-pyrroline-=-carbo0ylate reductase ':) lysine transcarbamoylase 'the step indicated by the bro&enline is not 3ell defined) 'D) mitochondrial ornithine transporter '@) arginase

Disorders of Ornithine Metabolism


Hyperornithinemia due to Ornithine Aminotransferase Deficiency '(yrateAtrophy of the Choroid and etina)
Metabolic Derangement
Deficiency of OAT acti/ity 'alternati/ely. ornithine &etoacid transaminase. O8T) (yrate atrophy of the choroid and retina '(A) ha/e mar&ed hyperornithinemia

The pathophysiological mechanism of the retinal degeneration is unclear (enetics


,nheritance is autosomal recessi/e

Disorders of Ornithine Metabolism


The Hyperornithinemia. Hyperammonemia. and Homocitrullinuria 'HHH) #yndrome
Metabolic Derangement
!le/ated plasma ornithine associated 3ith hyperammonemia and increased urinary e0cretion of homocitrulline 'HHH #yndrme) ,t is a disorder of compartmentation and its defect is in the import of ornithine into the mitochondrion esulting in a functional deficiency of both OTC and OAT acti/ities The deficiency lead to utili"ation of carbamoylphosphate /ia alternate path3ays+ formation of homocitrulline from lysine and formation of orotic acid

(enetics
,nheritance is autosomal recessi/e

Disorders of Ornithine Metabolism


S5-*yrroline-=-Carbo0ylate #ynthase Deficiency
Metabolic Derangement
Mild hyperammonemia. hypoornithinemia. hypocitrullinemia. hypoargininemia and hypoprolinemia. a pattern of metabolic abnormalities consistent 3ith impaired proline and ornithine synthesis Due to deficiency of S5-pyrroline-=-carbo0ylate synthase '*=C#)

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


Hyperlysinemia/#accharopinuria Hydro0ylysinuria 4-Amino-/4-O0o-Adipic Aciduria (lutaric Aciduria Type , '(lutaryl-CoA Dehydrogenase Deficiency) $-4-Hydro0yglutaric Aciduria D-4-Hydro0yglutaric Aciduria %-Acetylaspartic Aciduria 'Cana/an Disease)

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


Hyperlysinemia/#accharopinuria
Metabolic Derangement
Caused by deficiency of the bifunctional protein 4-aminoadipic semialdehyde synthase. the first en"yme of the main route of lysine degradation The t3o functions. lysine-4-o0oglutarate reductase and saccharopine dehydrogenase. may be differently affected by mutations esulting predominantly in hyperlysinemia and hyperlysinuria. accompanied by relati/ely mild sacccharopinuria 'hyperlysinemia,) ,n hyperlysinemia,, predominant e0cretion of sacccharopine

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


Hydro0ylysinuria
Hydro0ylysinuria and concomitant hydro0ylysinemia 3ith some degree of mental retardation Assumed to be caused by a defect of hydro0ylysine &inase

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


4-Amino-/4-O0o-Adipic Aciduria
%o clinical significance 'A &no3n cases asymptomatic) #ymptoms include psychomotor retardation. muscular hypotonia. epilepsy. ata0ia and failure to thri/e

Metabolic Derangement
The metabolic profile is heterogeneous 4-aminoadipic aciduria probably caused by a deficiency of 4aminoadipate aminotransferase Combined 4-amino/4-o0oadipic aciduria by a deficiency of the 4-o0o adipate dehydrogenase comple0 4-Aminoadipic acid sho3s a comple0 e0citatory amino acid synaptic pharmacology. 3hich may be related to the neurological symptoms

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


(lutaric Aciduria Type, '(lutaryl-CoA Dehydrogenase Deficiency)
Metabolic Derangement
Caused by deficiency of glutaryl-CoA dehydrogenase *art of the accumulating glutaryl-CoA is esterified 3ith carnitine esulting in increased ratio of acylcarnitines to free carnitine in plasma and urine '#econdary carnitine deficiency) ,ncreased urinary e0cretion of dicarbo0ylic acids. 4-o0oglutarate and succinate ,n hyperlysinemia ,, predominant e0cretion of sacccharopine

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


$-4-Hydro0yglutaric Aciduria
Metabolic Derangement
Caused by defecti/e -AD-dependent $-4-hydro0yglutarate dehydrogenase !le/ation of $-4-hydro0yglutaric acid in C#- than in plasma Also there is an increase of lysine in blood and C#-

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


D-4-Hydro0yglutaric Aciduria
Metabolic Derangement
Caused by deficiency of adeficiency of D-4-hydro0yglutaric acid dehydrogenase esulting in ele/ated le/els of D-4-hydro0yglutaric acid in all body fluids

(enetics
,nheritance is autosomal recessi/e

Cerebral Organic Acid Disorders and Other Disorders of $ysine Catabolism


%-Acetylaspartic Aciduria 'Cana/an Disease)
Metabolic Derangement
Caused by deficiency of the aspartoacylase esulting in the accumulation of %-acetylaspartic acid in brain. C#-. plasma. and urine

(enetics
,nheritance is autosomal recessi/e

%on&etotic Hyperglycinemia '(lycine !ncephalopathy)

%on&etotic Hyperglycinemia '(lycine !ncephalopathy)


*ath3ays of glycine metabolism
CH4-TH-. =.56-methylene tetrahydrofolate (C#. glycine clea/age system #HMT. serine hydro0ymethyl transferase TCA. tricarbo0ylic acid TH-. tetrahydrofolate

%on&etotic Hyperglycinemia '(lycine !ncephalopathy)

Disorders of *roline and #erine Metabolism


,nborn !rrors of *roline Metabolism
*roline O0idase Deficiency 'Hyperprolinemia Type ,) S5-*yrroline =-Carbo0ylate Dehydrogenase Deficiency 'Hyperprolinemia Type ,,)

,nborn !rrors of #erine Metabolism


B-*hosphoglycerate Dehydrogenase Deficiency *hosphoserine *hosphatase Deficiency #erine Deficiency 3ith ,chthyosis and *olyneuropathy

Transport Defects of Amino Acids at the Cell Membrane


Cystinuria $ysinuric *rotein ,ntolerance Hartnup Disorder

Than& +ou,