Disorders of Aromatic Amino Acids

7/25/2019 Disorders of Aromatic Amino Acids

1/6

DISORDERS OF AROMATIC AMINO ACIDS

Disorder Deficiency Description Pathogenesis Clinical Features Diagnosis

Phenylketonuria Phenylalanine hydroxlase

(Classical)

Tetrahydrobiopterin(BH4)-

new variant

Disorder of aromatic amino

acid metabolism due to a

deficiency in the activity of the

liver enzyme, which catalyzes

the conversion of

phenylalanine to tyrosine.

Phenylalanine and its products

accumulate causing an

imbalance resulting to

neurologic, dermatologic and

behavioral symptoms

Autosomal recessive

2 out of 87,005 neonates were detected

using newborn screening (local data)

Prognosis

Rarely seen because of early detection andsubsequent therapy

Mental deficiency is prevented whentreatment is initiated before 2 months of life

The rule here is you have to continuerestriction in the diet because in the long

term outcome, patient would again

deteriorate in cognitive function

1. Mentally retarded

-

If not detected earlier

- Seen in 90% patients

- Occurs in 99% of untreated patients; 50

points loss from IQ if untreated.

-

Can be prevented if treatment is

initiated before 2 months of life

2. Stunted

- Generally short but weight is normal for

age

3. Light skinned, light colored hair (blond)

many are fair skinned4. Musty smelling(due to accumulation of

phenylacetate)5. Eczematoid rashor intractable itching6. Behavioural disorders hyperactivity,

rhythmic purposeless movements,

stereotypy, tremors and athetosis are

common

Other Manifestations:

Cerebral palsyquadrispastic

- Spastic hypertonic cerebral palsy occurs

in 30%, seizures in 20% and EEG

abnormalities in 80% of pts.

Abnormal movements (stereotypy)

Newborn screening by method oGuthrie or by fluorometrimethods

A positive newborn screen resuwarrants repeat ConfirmatorTesting:

Quantitative phenylalanine an

tyrosine levels in the blood

- Classic PKU is confirmed by:

a.Phenylalanine levels > 120

umol/Lb.low tyrosine level

Ferric Chloride Test

- Another useful diagnostic test-- Urine is tested with 10% ferric

chloride o Positive result: greenprecipitate formed

in the presence of phenyl pyruvic

acid

Residual Phenylalanine

hydroxylase

- in the liver tissue activity of les

than 10% through an assay

Tyrosinemia Fumaryl AcetoacetateHydrolase

-last step in the degradation oftyrosine

-fumaryl acetoacetate builds

up

- Autosomal recessive

-CABBAGE ODOR URINE(TYSON CHICKEN, TYROSINEMIA)

Alkaptonuria Homogentisic Acid Oxidase Relatively benign inborn error of

phenylalanine -tyrosine

catabolism

Homogentisicacid accumulates

AUTOSOMAL RECESSIVE

Discoloration of cartilage and connective

tissues

Ochronoticpigments (ochronosis)

-Often leads to severe arthritis

-Due to oxidation of excess metabolite

May lead to severe arthritis later in life

Darkening of urine on standing

Hawkinsinuria 4-Alpha-

hydroxyphenylpyruvate

hydroxylase deficiency

AUTOSOMAL DOMINANT inborn error of tyrosine metabolism; excretion

of the unusual cyclic amino acid metabolite,

hawkinsin

Deficiency in enzyme that catalyses the

conversion of hydroxyphenylpyruvate tohomogentisate

Inidividuals with this disorder are

symptomatic only during infancy. Symptoms

usually appear after weaning from

breastfeeding with the introduction of a

high-protein diet.

characteristic tyrosine metabolites

by organic acid analysis of the urine


2/6

DISORDERS OF BRANCHED CHAIN AMINO ACID

MSUD branched-chain

alpha ketoacid

dehydrogensae

complex

Dr. Cavans Lec:

MSUD: Manifestations

First symptoms in an infant at

about 3-5 days

Poor appetite/feeding

Irritability or high pitched

incessant crying

Characteristic odor of urine

After a few days, the baby:

becomes limp with episodes ofrigidity

has seizures loses his/her sucking reflex

has increased sleeping

become comatose

MSUD: Management -rapid

removal of toxic substances

Temporary removal of CHONfrom diet/ low protein using a

special formula

Ensure that baby hascaloriesfrom other sources

Add VCO (medium chain) todiet for long term mgt

MSUD: management -long term

maintain low levels ofdangerous amino acids - LOW

PROTEIN DIET

balance between growthneeds dietary intake

branched chain amino acidsminimal needs

Artificial formula of the otheressential amino acids

provision of vitamins andminerals

regular monitoring of bloodand acid levels

regular monitoring of growth and

development

Accumulation of 3 branched chain ketoacids o Alpha ketoisocaproic acid

o Alpha ketoisovaleric acid

o Alpha keto B methylvaleric acid

o Derivatives of leucine, valine, isoleucine

(leucine causes more severe neurologic

symptoms)

Accumulation of BCAA ad 2-hydroxy acids in the

plasma, urine, CSF

Leucine and 2-oxoisocaproic acid are the most

toxic to the brain

Brain injury is due to neurotransmitter deficiency

and growth restriction associated with branched

chain amino acid accumulation and energy

deprivation through Krebs cycle disruption

Manifestations

Normal newborn who initially does well for a

few days and suddenly on days 5-7 develops

lethargy and high pitched cry, feeds poorly, and

becomes opisthotonic and comatose

Seizure and hypoglycaemia are also common

Five Clinical phenotypes:

Classic MSUD

a characteristic sweet odor resembling

burnt sugar (maple syrup) can be

detected in the patients urine , sweat,

hair and cerumen

Birth: newborns appear healthy

Overwhelming illness in the first few

days of life. Lethargy, quickly

progressing to convulsions and coma, is

a common manifestation.

5th -7th day: develop lethargy, feedingdifficulty and hypotonia after ingestion

of protein

2nd week: seizures because of cerebral

edema

Within 1 month: coma and death

Intermittent MSUD

Milder manifestation compared to

classic form

Patients are generally well but become

really sick when they are under stress

such as in infection or surgery

Intermediate MSUD

Seen in patients whose enzyme activity

is about 15-25% of normal

Symptoms are milder than the classic

form

Thiamine responsive MSUD

Same clinical features as intermediate

MSUD

Biochemical abnormality maybe

corrected with the intake of high doses

of thiamine

E-3 Deficient MSUD

Patient present with lactic acidosis

Symptomatology may parallel that of

classic MSUD or may show a more rapid

neurologic deterioration

Plasma amino acid analysis

elevated branched ami

acids (leucine, isoleucine a

valine)

Urine Organic Analysis

increased levels of branch

chain keto-acids

Definitive diagnos

measuring the activity

BCKD enzyme of fibrobla

leukocyte or amniotic flu

levels

o Classic forms have 2% residual enzym

activity

Presumptive Diagnos

presence of 2

dinitrophenylhydrazine

(DNPH) which precipitates t

keto-acids in the uri

forming a yellow precipitate

Diagnosis

measurement/ detection oBCAA in urine or plasma

NBS using TMS

Activity of the BCKD enzym

DNA testing for the known

genes

MetylMalonic Aciduria methylmalonyl-

CoA

mutase deficiency

AUTOSOMAL RECESSIVE defects in the metabolic pathway

where methylmalonyl-coenzyme A (CoA) is

converted intosuccinyl-CoA by the

Neonatal ketoacidosis, lethargy,

vomiting and profound hypotonia, and

profound metabolic acidosis

Increased amount of

methylmalonic acid and

metabolites of PA
https://en.wikipedia.org/wiki/Methylmalonyl-coenzyme_Ahttps://en.wikipedia.org/wiki/Succinyl-CoAhttps://en.wikipedia.org/wiki/Succinyl-CoAhttps://en.wikipedia.org/wiki/Methylmalonyl-coenzyme_A


3/6

enzymemethylmalonyl-CoA mutase

Vitamin B12is also needed for the conversion of

methylmalonyl-CoA to Succinyl-CoA. Mutations

leading to defects in vitamin B12metabolism or

in its transport frequently result in the

development of methylmalonic acidemia.

First week of life after onset of protein

feeding

Defect in methylmalonyl CoA mutase

Hematologic: Anemia, leukopenia and

thrombocytopenia

Renal Failure in the second decade

Molecular testing

Isovaleric Acidemia isovaleryl CoA

dehydrogenase

AUTOSOMAL RECESSIVE The deficient enzyme plays an essential role in

breaking down proteins from the diet.

Specifically, the enzyme is responsible for the

third step in processing leucine, an essential

amino acid.

If a mutation in the IVD gene reduces oreliminates the activity of this enzyme, the body

is unable to break down leucine properly.

As a result, isovaleric acid and related

compounds build up to toxic levels, damaging

the brain and nervous system.

Stale perspiration, sweaty feet or ripe

cheese odor

First week: acidosis, coma

Infants who survive acute phase will go

on to have the chronic intermittent form

later on in life. Chronic: lethargy, vomiting, ataxia and

ketoacidosis

Death may occur if proper therapy is not

initiated.

Mass spectrometry: screening o

urine of newborns-> early

diagnosis

Elevations ofisovalerylglycinein

urine and ofisovalerylcarnitine

plasma are found

Glutaric Aciduria Glutaryl-CoAdehydrogenase

AUTOSOMAL RECESSIVE body is unable to break down completely

theamino acidslysine, hydroxylysine

andtryptophan.

Excessive levels of their intermediate

breakdown products (glutaric acid,glutaryl-

CoA,3-hydroxyglutaric acid,glutaconic acid)can

accumulate and cause damage to thebrain and

other organs, but particularly thebasal ganglia,

which are regions that help regulate movement

GA1 causes secondary carnitine deficiency,

asglutaric acid,like otherorganic acids,isdetoxified bycarnitine.Mental retardation may

also occur

Neurodegenerative after the first year

of life

Hypotonia, dystonia, choreoathetosis

and seizures

Resemble extrapyramidal cerebral

palsy

Macrocephaly, loss of appetite, profuse

sweating and hypoglycemia

Acrid urine
https://en.wikipedia.org/wiki/Methylmalonyl-CoA_mutasehttps://en.wikipedia.org/wiki/Vitamin_B12https://en.wikipedia.org/wiki/Vitamin_B12https://en.wikipedia.org/wiki/Vitamin_B12https://en.wikipedia.org/w/index.php?title=Isovalerylglycine&action=edit&redlink=1https://en.wikipedia.org/w/index.php?title=Isovalerylcarnitine&action=edit&redlink=1https://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenasehttps://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenasehttps://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenasehttps://en.wikipedia.org/wiki/Amino_acidhttps://en.wikipedia.org/wiki/Lysinehttps://en.wikipedia.org/wiki/Tryptophanhttps://en.wikipedia.org/wiki/Glutaric_acidhttps://en.wikipedia.org/wiki/Glutaryl-CoAhttps://en.wikipedia.org/wiki/Glutaryl-CoAhttps://en.wikipedia.org/w/index.php?title=3-hydroxyglutaric_acid&action=edit&redlink=1https://en.wikipedia.org/wiki/Glutaconic_acidhttps://en.wikipedia.org/wiki/Brainhttps://en.wikipedia.org/wiki/Basal_gangliahttps://en.wikipedia.org/wiki/Glutaric_acidhttps://en.wikipedia.org/wiki/Organic_acidhttps://en.wikipedia.org/wiki/Carnitinehttps://en.wikipedia.org/wiki/Mental_retardationhttps://en.wikipedia.org/wiki/Mental_retardationhttps://en.wikipedia.org/wiki/Carnitinehttps://en.wikipedia.org/wiki/Organic_acidhttps://en.wikipedia.org/wiki/Glutaric_acidhttps://en.wikipedia.org/wiki/Basal_gangliahttps://en.wikipedia.org/wiki/Brainhttps://en.wikipedia.org/wiki/Glutaconic_acidhttps://en.wikipedia.org/w/index.php?title=3-hydroxyglutaric_acid&action=edit&redlink=1https://en.wikipedia.org/wiki/Glutaryl-CoAhttps://en.wikipedia.org/wiki/Glutaryl-CoAhttps://en.wikipedia.org/wiki/Glutaric_acidhttps://en.wikipedia.org/wiki/Tryptophanhttps://en.wikipedia.org/wiki/Lysinehttps://en.wikipedia.org/wiki/Amino_acidhttps://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenasehttps://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenasehttps://en.wikipedia.org/w/index.php?title=Isovalerylcarnitine&action=edit&redlink=1https://en.wikipedia.org/w/index.php?title=Isovalerylglycine&action=edit&redlink=1https://en.wikipedia.org/wiki/Vitamin_B12https://en.wikipedia.org/wiki/Methylmalonyl-CoA_mutase


4/6

DISORDERS OF UREA CYCLE ENZYMES

Urea Cycle Defects 5 BiochemicalReactions and

catalyzed by a different enzyme

1.Carbamyl palmytoyl

synthetase deficiency (CPS)

2.Ornithine transcarbamylase

deficiency (OTC)

3.Arginosuccinate synthetase

deficiency (Citrullinemia)

4.Arginosuccinase defieciency

(arginosuccinic aniduria)

5.Arginase (Ornithemia)

Prognosis

92% 1 year survival rate

The IQ however is severely

affected

The duration of coma

correlates with the severity

of mental deficiency

Patients who remain in

hyperammonemic coma

beyond 5 days are more

developmentally

handicapped

All are Autosomal recessive

inheritance (except OTC

deficiency which is X-linked

recessive)

Clinical Manifestations

In the neonatal period, signs and symptoms are mostly related to brain

dysfunction, and are similar regardless of cause of hyperammonemia

Patients do well in the immediate postnatal period until 2-4 days of life when

regular milk intake is established

Become sick and deteriorate fast unless therapy is instituted

Progressive lethargy, apnea, and/or seizures

Hyperammonemia without metabolic acidosis can trigger increased

intracranial pressure that may be manifested by bulging fontanel and dilated

pupils

In patients with partial enzyme deficiencies, the presentation is episodic and

occurs beyond the neonatal period

Unexplained vomiting, intermittent headaches, behavioural changes or acute

encephalopathy

Due to ammonia intoxication

After 1st day of delivery and even before initiation of protein feeding:

o Progressive lethargy

o Vomiting

o Hypotonia

Subsequent days:

o progressive loss of consciousness

o Seizures

Presentation is episodic and patients in partial enzyme deficiency

Occurs late in infancy, childhood and adulthood

The oldest reported patient with partial OTC deficiency was 58 years old

Unexplained or cyclic vomiting, intermittent headache, behavioral changes and

acute encephalopathy

Suspect in a newborn with hypermmonemia without organic acidemia

Clinical presentation a

presence

hyperammonemia

Specific plasma amino ac

and urine organic acid profil

Plasma ammon

concentration of 150 mm

per Liter or higher

Associated with a norm

anion gap Vs Organic acidu

abnormal anion gap

Normal serum gluco

concentration Definitive Diagnosis: enzym

activity assay done on liv

tissue (Liver Biopsy)

DISORDERS OF FATTY ACID OXIDATION

Fatty Acid Oxidation Defects 3 clinical presentations:

1. Hepatic presentation

-Uric acid

-Liver enzymes dehydrogenase

(MCAD) deficiency

-Characterized by acute life

threatening attacks of coma

precipitated by fasting

-Anion gap and acidosis may be

present

-Biochemical abnormalities:

a. Hypoketotic hypoglycemia

b. Hyperammonemia

c. Elevations in serum urea, uric

acid and liver enzymes

Diagnosis

Urinary organic acid analys

- C6-C10 dicarboxylic

acids and absence of

ketosis

Definitive diagnosis:

- Measurement o

specific enzyme activity

in liver tissue


5/6

2. Symptoms referable to the muscles

-Carnitine palmitoyl-transferase II

deficiency

-Sudden muscle weakness in young

adults associated with

myoglobinuria and renal failure

following strenuous exercise

3. Cardiac manifestations

-Patients present with

progressive heart failure

between ages 2-3 years

-Cardiomyopathy may

accompany acute hepatic

syndrome-Exemplified by the muscle-kidney

plasma membrane carnitine

transporter defect

DISORDERS OF SULFUR CONTAINING AMINO ACIDS

Homocystinuria cystathionine beta synthase

deficiency

Autosomal recessive

Homocystinuria represents a

group of hereditarymetabolic

disorders characterized by an

accumulation of the amino

acidhomocysteine in

theserum and an increased

excretion of homocysteine in

theurine.Infants appear to

be normal and early

symptoms, if any are present,

are vague.

Pathogenesis

primary defect defect is in the

enzyme cystathionine B

synthetase which catalyzes the

formation of cystathionine from

homocysteine and serine

Accumulation of homocysteine

and other cysteine

homocysteine residues causes

symptoms referable to the

connective tissue and vascular

systems.

This defect leads to a multi-

systemic disorder of

the connective

tissue,muscles,central nervous

system (CNS), andcardiovascular

system.

Clinical Manifestations

Developmental delay and mental

retardation between 18-24 months

Eye problems: glaucoma, cataracts,

optic atrophy, myopia or astigmatism

Bony Changes: spinal osteoporosis and

pectus excavatum

Malar flush

Vascular systems: Arteriovenous

thromboembolism phenomenon iscommon and usual cause of death

stroke-like symptoms, later onset

Diagnosis

Cyanide nitroprusside test

oUsed to screen the urine

oA red purple color develo

in the presence

homocysteine

Plasma amino acid analysis

used to document the elevated

homocysteine and methionine

levels

Enzyme activity can be measure

in the fibroblast, liver and brain

tissue

Newborn screening: elevated

blood methionine as marker for

the disorder

Prenatal diagnosis available by

assay of cystathione synthase in

amniocytes

DISORDERS INVOLVING DEGRADATION PATHWAYS

Mucopolysacchridoses Autosomal recessive trait

except for Hunter syndrome(MPS II) which is x-linked

recessive

abnormal accumulation of

glycosaminoglycans (GAG) ormucopolysaccharides (MPS)

secondary to a basic defect in their

sequential degradation in

Hurler syndrome: (MPS IH) from

deficiency of alpha-L-iduronidaseprototype of MPSrapidly deteriorating

look physically normal at birth but

develops course features by the 18th

Indirect way of screenin

o Look for presence dyostosis multiplex

o Long bones of the

upper extremities look
https://en.wikipedia.org/wiki/Metabolic_disorderhttps://en.wikipedia.org/wiki/Metabolic_disorderhttps://en.wikipedia.org/wiki/Homocysteinehttps://en.wikipedia.org/wiki/Blood_plasmahttps://en.wikipedia.org/wiki/Urinehttps://en.wikipedia.org/wiki/Connective_tissuehttps://en.wikipedia.org/wiki/Connective_tissuehttps://en.wikipedia.org/wiki/Musclehttps://en.wikipedia.org/wiki/Central_nervous_systemhttps://en.wikipedia.org/wiki/Central_nervous_systemhttps://en.wikipedia.org/wiki/Cardiovascular_systemhttps://en.wikipedia.org/wiki/Cardiovascular_systemhttps://en.wikipedia.org/wiki/Cardiovascular_systemhttps://en.wikipedia.org/wiki/Cardiovascular_systemhttps://en.wikipedia.org/wiki/Central_nervous_systemhttps://en.wikipedia.org/wiki/Central_nervous_systemhttps://en.wikipedia.org/wiki/Musclehttps://en.wikipedia.org/wiki/Connective_tissuehttps://en.wikipedia.org/wiki/Connective_tissuehttps://en.wikipedia.org/wiki/Urinehttps://en.wikipedia.org/wiki/Blood_plasmahttps://en.wikipedia.org/wiki/Homocysteinehttps://en.wikipedia.org/wiki/Metabolic_disorderhttps://en.wikipedia.org/wiki/Metabolic_disorder


6/6

lysosomes

GAG are major components of

connective tissue mainly in

cartilage, bone, skin, tendon,

cornea, heart valves, less in liver

and brain

GAG are polymeric carbohydrates

composed of more than a single

type of building block: a

carbohydrate backbone with

amino acid or sulfate residues

month of life: large bulging

scaphocephalic head with frontal

bossing, hypertelorism (increased orbital

distance), depressed nasal bridge, wide

nostrils, large tongue, and thickened lips.

Patients are hirsute. Clouding of cornea

is characteristic. Nystagmus and

strabismus occur later. Deafness is

common. Spine is kyphotic with lumbar

gibbus. Rib cage is broad. Cardiac

valvular disease leads to CHF, angina

pectoris and MI.

short and stubby with

tapering ends and

enlarged middle shaft

portions

Indirect way

screening: skelet

survey radiographs

o Look for the presence

dyostosis multiplex

o Large skull with a

shaped sella turcica an

shallow orbits

Confirmatory:

o Specific enzyme assa

on fibroblasts

leukocytes

Documents

Disorders of Aromatic Amino Acids