disorders of aromatic amino acids
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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
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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 -
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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 -
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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
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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 -
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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