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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
The penultimate intermediates , maleylacetoacetate and fumarylacetoacetate, can be reduced to succinylacetoacetate, followed by decarboxylation to succinylacetone
Hereditary Tyrosinaemia
Type , 'Hepatorenal Tyrosinaemia) Type ,, 'Oculocutaneous Tyrosinaemia. ichner-Hanhart #yndrome) Type,,,
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
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
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
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
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
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
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
,>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
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
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#
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
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
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
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
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
(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
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
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$KCD deficiency is an autosomal-recessi/e disorder
,nfants
#ymptoms are generally rather less acute and more /ariable anore0ia. lethargy. /omiting and failure to thri/e. 3ith poor de/elopmental progress ,rritability and beha/ioral problems are also common encephalopathy 3ith changes in consciousness and neurological signs
(enetics
The genes for all the urea-cycle en"ymes ha/e no3 been mapped. isolated and fully characteri"ed The most common urea cycle disorder is OTC deficiency. 3as found to be N-lin&ed All the other conditions ha/e autosomal recessi/e inheritance
(enetics
Homocystinuria due to CB# deficiency is inherited as an autosomal recessi/e trait
(enetics
Mutations of the MAT5A gene account for both autosomal recessi/e and autosomal dominant hypermethioninemia
(enetics
Mutations in the (MT gene also occurring in either parent confirm autosomal recessi/e inheritance of this defect
Metabolic Derangement
Deficiency of this en"yme has been pro/en and leads to a bloc& in the degradation and accumulation of #-adenosylhomocysteine as 3ell as increased le/els of #-adenosyl-methionine and methionine
(enetics
,nheritance is autosomal recessi/e
Metabolic Derangement
Deficiency of the *$*-re1uiring Q-cystathionase leads to tissue accumulation of cystathionine !0cretion of cystathionine occur and %-acetylcystathionine is also e0creted
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/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
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
(enetics
,nheritance is autosomal recessi/e
Than& +ou,