In born errors of amino acid metabolism Flashcards
In born errors of amino acid metabolism give rise to class of diseases known as the __________.
aminoacidopathies
Aminoacidopathies are diseases caused by a ________ determined, ______ abnormality in the _________ of amino acids
genetically
Biochemical
metabolic pathway
Aminoacidopathies account for a negligible portion of neonatal and paediatric diseases
T/F
F
non-negligible portion
Phenylketonuria (PKU) is inherited as ____________ trait and occurs in about 1 in 15,000 births.
An autosomal recessive
Phenylketonuria (PKU)
Two forms have been identified:
_______ and _______
Classic PKU and non classic PKU
Classic Phenylketonurea
The metabolic defect in the classic form of PKU is _________ of the enzyme ________ which catalyzes the conversion of ________ to ________
an absence of activity
phenylalanine hydroxylase (PAH),
phenylalanine to tyrosine
Classic Phenylketonurea
In the absence of phenylalanine hydroxylase (PAH), phenylalanine levels are usually greater than ______ mol/L.
1200
PKU
In the newborn, the upper limit of normal for a phenylalanine level is _____ mol/L (2 mg/dL).
120
High levels of phenylalanine and some of its metabolites—e.g.,________ acid, _________ and ______ acid— can cause significant _____ problems.
phenylpyruvic
phenylpyruvate
phenyllactic
brain
phenylpyruvate, also known as _______
phenylketone
PKU
All of these Metabolites are found in both the ____ and the ______ of a PKU patient, giving the urine a characteristic _______ odour.
blood; urine
musty
PKU
In infants and children with this inherited defect, _________ and _______ occur as a result of the toxic effects on the brain of phenylalanine or its metabolic by products.
retarded mental development and microcephaly
Phenylketonurea: Treatment
Brain damage can be avoided if the disease is detected at _______ and the infant is ____________________.
Also, women with PKU who are untreated during pregnancy almost always have babies who are _______ and _________
At birth
maintained on a diet containing very low levels of phenylalanine
microcephalic; mentally retarded.
Phenylketonurea: Treatment
The fetal effects of maternal PKU are preventable if the mother is __________________________ from __________ through ——-.
maintained on a phenylalanine-restricted diet
before conception
term
Hyperphenylalaninemia cases occur that are not the result of the lack of the PAH enzyme.
T/F
T
Non classic forms of PKU
The defect in these cases is a deficiency in the enzymes needed for the regeneration and synthesis of ____________
tetrahydrobiopterin (BH4).
BH4 is a ______ required for the enzymatic _______ of the aromatic amino acids _______,_______, and ______
cofactor
hydroxylation
phenylalanine, tyrosine, and tryptophan.
Non classic forms of PKU
A deficiency of ____ results in elevated blood levels of phenylalanine and deficient production of _______ from _____ and _____
BH4
neurotransmitters
tyrosine and tryptophan.
Non classic forms of PKU
Cofactor defects account for only ______% of all cases of elevated phenylalanine levels
1–5
New born screening program for PKU
In the US, every state now screens the blood phenylalanine level of all newborns at about _____ of age.
If the screening test is abnormal, other tests are needed to confirm or exclude PKU.
3 days
Newborn screening for PKU allows early identification and implementation of treatment.
T/F
T
The goal of PKU treatment is to maintain the blood level of phenylalanine between ____ and ____ mg/dL (120–600 mol/L)
2 and 10
Dietary treatment of PKU
Some phenylalanine is needed for normal growth, so a diet that has some phenylalanine but in ______ than normal is the recommended treatment.
much lower amounts
Some phenylalanine is needed for normal growth
T/F
T
High-protein foods, such as meat, fish, poultry, eggs, cheese, and milk, are preferred for patients with PKU.
T/F
F
They are avoided
Instead, calculated amounts of cereals, starches, fruits, and vegetables, along with a milk substitute, are usually recommended
Mass spectrometry is an analytical technique that measures the _________ of ______ particles.
mass-to-charge ratio
charged
Mass spectrometry is most generally used to ___________ by generating a ________ representing the masses of the sample’s components.
find the composition of a sample
mass spectrum
Tandem mass spectrometry
The sample in an MS is first _____ and then ______ to form _________ and _______ that are separated according to their mass-to-charge (m/z) ratio;
The sample is then measured by a ____, which gives the ____ of the _______ for each species.
volatilized
ionized
charged molecular ions and fragments
detector; intensity; ion current
components that are standard in all mass spectrometers: the _______,________ ,________ and ______
the sample inlet, ionization source, mass analyzer, and ion detector
In tandem mass spectrometry applications, the detector is a __________
second mass spectrometer
Tandem mass spectrometry
The MS/MS method has a greater sensitivity, detecting lower levels of phenylalanine and allowing for diagnosis of PKU as early as _____________
The first day of life.
Because MS/MS has the ability to detect more than ____ different genetic disorders with a single specimen, this method is replacing the multiple procedures currently used in newborn screening programs.
25
The reference method for quantitative serum phenylalanine is ________________________
high-performance liquid chromatography (HPLC)
Molecular methods
PKU results from multiple independent mutations (more than _____ identified) at the PAH locus.
400
Albinism results from deficiency of ________ in ________ resulting in inability to form the pigment _____.
tyrosinase
melanocytes
melanin
Albinism
It is _____________ disorder
There is reduced ________ of the _____ and _____
an autosomal recessive
pigmentation
Iris and skin.
Albinism
Patients have _______ and increased incidence of certain ____ cancer.
photosensitivity
skin
Albinism
A mutation in the ____ gene causes deficient ______ production.
TYR
tyrosinase
Albinism
Tyrosinase is required for the conversion of ______ to _______ in the pathway for ______ production.
tyrosine to DOPA
melanin
People with albinism have either a partial or complete _________, or ______, in their _____,_____ or ______
lack of pigment
coloring
eyes, skin or hair.
Tyrosinemia
These are inborn metabolic disorders of _________
tyrosine catabolism
Tyrosinemia
They are characterized by the _____ of ______ and ________ in urine.
excretion
tyrosine and tyrosine catabolites
Tyrosinemia
There are ______ types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme.
three
Type ___ tyrosinemia is the most severe form of this aminoacidopathy and is found in about 1 in 100,000 births.
1
Type I tyrosinemia
Type I tyrosinemia is caused by low levels of the enzyme __________, the ____ of ____ enzymes needed to break down tyrosine.
fumarylacetoacetate hydrolase
fifth
Type I tyrosinemia: Clinical features
Symptoms of type I tyrosinemia include ________ , diarrhea, vomiting, ______ , _____-like odor, ______ abdomen, _____ of legs, and increased predisposition for ______.
failure to thrive
jaundice
cabbage; distended; swelling
bleeding
Type I tyrosinemia: Clinical features
Type I tyrosinemia can lead to ____ and ——- organ failure, problems affecting the ____ system, and an increased risk of _____ or ______ later in life.
liver and kidney
nervous
cirrhosis or liver cancer
Type II tyrosinemia is caused by a deficiency of the enzyme _____________
tyrosine aminotransferase.
Type II tyrosinemia
Tyrosine aminotransferase is the ____ in a series of _____ enzymes that converts tyrosine to (smaller or larger?) molecules, which are excreted by the kidneys or used in energy producing reactions.
first
five
Smaller
Type II tyrosinemia: Clinical features
About half of individuals with type II tyrosinemia are ________ and have symptoms of excessive _______, _____phobia , ___ pain and redness, and painful skin lesions on the palms and soles of the feet.
mentally retarded
tearing
Photo; eye
Type III tyrosinemia is a (common or rare?) disorder caused by a deficiency of the enzyme ____________
Rare
4- hydroxyphenylpyruvate dioxygenase.
Type III tyrosinemia , caused by a deficiency of the enzyme 4- hydroxyphenylpyruvate dioxygenase.
This enzyme is found mainly in the _____ with lesser amounts found in the _____.
liver
kidneys
The clinical picture of type III tyrosinemia patients includes mild ________, seizures, and periodic _______ and coordination.
mental retardation
loss of balance
type III tyrosinemia
Diagnostic criteria include an elevated tyrosine level using ______ technique coupled with a confirmatory test for an elevated level of the abnormal metabolite __________ .
MS/MS
succinylacetone
Treatment for tyrosinemia is a _____________
low-protein diet;
Treatment for tyrosinemia
the drug ______, which prevents the formation of ________ and _______, which can be converted to _____, a toxin that damages the ______ and _______
nitisinone
maleylacetoacetic acid and fumarylacetoacetic acid
succinyl acetone
liver and kidneys
Treatment for tyrosinemia
________
________
_________
A low protein diet
the drug nitsinone
full or partial liver transplant.
Alkaptonuria is an inborn metabolic disease transmitted as __________ gene.
an autosomal recessive
Alkaptonuria
The deficient enzyme is _______, which is needed in the metabolism of ______ and ———-
homogentisate oxidase
tyrosine and phenylalanine.
Alkaptonuria Clinical features
A predominant clinical manifestation of alkaptonuria is that the patient’s urine turns _________ when it mixes with air.
brownish-black
Alkaptonuria Clinical features
This phenomenon is due to an accumulation in the urine of __________, which ________ to produce this dark pigment.
homogentisic acid (HGA)
oxidizes
Alkaptonuric patients have no immediate problems
T/F
T
Alkaptonuria- clinical features
Alkaptonuric patients have no immediate problems; however, late in the disease, the high level of HGA gradually accumulates in ____________, causing ________ (pigmentation of these tissues), an ______-like degeneration from the buildup of _______ in the ______, _____ on the sclera (white of the eye), and deposition of pigment in the cartilage of the ears, nose, and tendons of the extremities.
connective tissue
ochronosis; arthritis
homogentisic acid; cartilage
dark spots
Alkaptonuria Laboratory test
_________ is done to test for alkaptonuria.
When _____ is added to the urine, it will turn the urine ______ in patients with alkaptonuria.
Urinalysis
ferric chloride
black
Alkaptonuria Laboratory test
Treatment
Treatment for alkaptonuria is _________, which has been shown to decrease the buildup of brown pigment in the cartilage and may slow the development of ________.
high-dose vitamin C
arthritis
Maple syrup urine disease (MSUD) results from an absence or greatly reduced activity of the enzyme __________, blocking the normal metabolism of the three essential _______ amino acids: ____,_____, and _______
branched-chain -ketoacid decarboxylase
branched- chain
leucine, isoleucine, and valine.
MSUD is an autosomal dominant genetic inherited disorder.
T/F
F
autosomal recessive
Maple Syrup Urine Disease: Clinical features
The result of this enzyme defect is an accumulation of the ______ amino acids and their corresponding _____ in the blood, urine, and cerebrospinal fluid (CSF).
branched-chain
ketoacids
Maple Syrup Urine Disease Clinical features
The most striking feature of this hereditary disease is the characteristic _____ or ______ odor of the urine, breath, and skin
maple syrup or burnt sugar
Maple Syrup Urine Disease Clinical features
Infants with MSUD seem ____ at birth but, within _____, develop _____, vomiting, lack of appetite, and signs of _______
normal
a week
lethargy
failure to thrive.
Maple Syrup Urine Disease
If treatment is not given, the disease can lead to death.
T/F
T
Maple Syrup Urine Disease: Laboratory investigations
________________ is also being used in screening for MSUD.
Tandem mass spectrometry (MS/MS)
Maple Syrup Urine Disease : Laboratory investigations
Prenatal diagnosis of MSUD is made by testing the _______ concentration in cells cultured from _______
decarboxylase enzyme
amniotic fluid.
Isovaleric acidemia is __________ metabolic disorder from a deficiency of the enzyme ____________, preventing normal metabolism of the _________________
an autosomal recessive
isovaleryl-CoA dehydrogenase
branched- chain amino acid leucine.
Isovaleric acidemia
It is caused by mutations in the _______________ gene.
isovaleryl- CoA dehydrogenase (IVD)
Isovaleric Acidemia Clinical features
A characteristic feature of isovaleric acidemia is a distinctive odor of ________ caused by the buildup of _________
sweaty feet
isovaleric acid.
Isovaleric Acidemia Clinical features
Health problems related to isovaleric acidemia range from very mild to life-threatening, but when severe, it can damage the ______ and ______
brain and nervous system.
Isovaleric Acidemia Treatment
Treatment includes a _______ diet to lower the levels of accumulating isovaleric acid, which is toxic to the ____.
protein-restrictive
CNS
Isovaleric Acidemia Treatment
Oral administration of ______ and ______ supplementation may be prescribed because ____________________________________
glycine and carnitine
they interact with isovaleric acid to form nontoxic, readily excreted products.
Homocystinuria
Homocystinuria is yet another ________________ disorder of amino acid metablolism.
inherited autosomal recessive
Homocystinuria
In homocystinuria, it is the lack of the enzyme _________, necessary for the metabolism of the amino acid _____, that results in elevated plasma and urine levels of ______ and of the precursor ______.
cystathionine- synthetase
methionine
methionine
homocysteine
Homocystinuria is asymptomatic in infancy
T/F
T
Homocystinuria
Clinical features
Associated clinical findings in late childhood include _____, ________ in the eye resulting from the lack of ________ essential for collagen formation, and, frequently, ________
osteoporosis
dislocated lenses
cysteine synthesis
mental retardation.
Homocystinuria Clinical features
This defect leads to a multisystemic disorder of the _________,_____,______ , thinning and weakening of ____, and ______ resulting from the toxicity of homocysteine to the vascular endothelium if it goes untreated
connective tissue
muscles
CNS; bones
thrombosis
Homocystinuria Clinical features
Treatment is a _________________________, as well as high doses of ________
dietary restriction of methionine (low protein)
vitamin B6.
Elevations of homocysteine are also of interest in the investigation of cardiovascular risk
T/F
T
Approximately ___% of individuals with untreated homocystinuria and significantly elevated levels of plasma homocysteine (200–300 mmol/L) experience a ______ event before the age of ____.
50
thromboembolic
30
Furthermore, mild homocysteine elevation (15 mmol/L) occurs in ___%– __% of patients with ______ disease.
20
30
atherosclerotic
______ is the end product of amino acid metabolism
Urea
Urea Cycle Disorders
During amino acid metabolism, (toxic or non-toxic?) ______ is generated which is then excreted as urea.
Toxic
ammonia
The urea cycle is a metabolic sequence that takes place in _____ cells to process _______ that is generated when ____ is used by the body.
liver
excess nitrogen
protein
Urea Cycle
______ + ______ = _____ + ______ = ______
Which then looses _____ to become _____
And that is further ______ into ____ and ____
Carbamoyl phosphate
Ornithine
Citruline
Aspartate
Argininosuccinate
Fumarate
Arginine
Hydrolyzed
Urea and ornithine
____________ formation in mitochondria is a prerequisite for the urea cycle
By _______ enzyme
Carbamoyl phosphate
Carbamoyl phosphate synthetase
Citrulline formation from ______ and _____
By _________ enzyme
carbamoyl phosphate and ornithine
ornithine transcarbamoylase
Aspartate provides the additional ______ to _____ to form ______ in _____
By ________ enzyme
nitrogen
Citrulline
argininosuccinate; cytosol
Argininosuccinate synthase
Argininosuccinate looses _____ to form arginine
By __________ enzyme
fumarate
Argininosuccinate lyase
Final step
______ of arginine to urea and _____
By ______ enzyme
Hydrolysis
ornithine
Arginase
Disorders of the Urea Cycle
Hyperammonemia type I
Enzyme defect: _____________
Carbomoyl phosphate synthase 1
Hyperammonemia type I: Treatment
((1))Give conjugating agents like benzoate, phenylacetate, phenylbutyrate to _________ and _______.
((2))_________/______ ——-.
reduce the nitrogen pool and facilitate excretion
Hemo/peritoneal dialysis
Hyperammonaemia is not a medical emergency.
T/F
F
Disorders of the Urea Cycle
Hyperammonemia Type 2
Deficiency Of ___________
Increased _________ and _______
ornithine transcarbomoylase
glutamine and ammonia.
Disorders of the Urea Cycle
Hyperammonemia Type 2 is an autosomal recessive disease
T/F
F
X-linked
Disorders of the Urea Cycle
Citrullinemia
is the metabolic defect caused by the lack of the enzyme __________, which causes a buildup of the amino acid citrulline as well as _____ in the blood.
argininosuccinic acid synthetase
ammonia
Argininosuccinic aciduria is inherited in __________ pattern.
an autosomal recessive
Disorders of the Urea Cycle
Argininosuccinic Aciduria
The babies lack the enzyme _______, and that prevents the conversion of ______ into _________
argininosuccinic acid lyase
argininosuccinic acid into arginine.
Elevated levels of argininosuccinic also cause buildup of the amino acid citrulline and also ammonia in the blood.
T/F
T
Ammonia is especially damaging to the ______ system, as well as causing eventual damage to the _____.
nervous
liver
Cystinuria is caused by a deficiency of ________ enzyme
None
Cystinuria is caused by a defect in the amino acid transport system rather than a metabolic enzyme deficiency.
Cystinuria is characterized by the ________ of cystine during the _______ in the kidneys, resulting in an excessive concentration of this amino acid.
inadequate reabsorption
filtering process
Cystine _____ out of the urine and forms _____ in the kidneys, ureters, or bladder.
precipitates
stones
Cystinuria
The kidney stones often __________
recur throughout a patient’s lifetime
_________ are directly or indirectly responsible for all of the signs and symptoms of cystinuria
The kidney stones
Signs and symptoms of Cystinuria
_______ , ____ pain, and ______
hematuria
loin
urinary tract infection
Treatment for cystinuria is to prevent ______________
the formation of cystine stones.
Treatment for cystinuria
This is mainly accomplished by _______________ to reduce the _________ in the urine and reduce its precipitating from the urine and forming stones.
High fluid intake means an absolute minimum of ______ of water per day
increasing the volume of urine
concentration of cystine
4 liters
All COPDs cause (alkalosis or acidosis?)
Acidosis
Deficient enzyme
PKU: __________
Albinism: _______
Type 1 tyrosinemia : _______
phenylalanine hydroxylase
tyrosinase
fumarylacetoacetate hydrolase
Deficient enzyme
Type 2 tyrosinemia :______________
Type 3 tyrosinemia : _______________
Alkaptonuria: _______________
tyrosine aminotransferase.
4- hydroxyphenylpyruvate dioxygenase.
homogentisate oxidase
Deficient enzyme
MSUD: ___________
Isovaleric acidemia: __________
Homocystinuria : ______________
branched chain ketoacid decarboxylase
isovaleryl-CoA dehydrogenase
cystathionine- synthetase
Deficient enzyme
Hpa1: ___________________
Hpa 2 : _______________
Citrullinemia: _____________
Argininosuccinic Aciduria: _____________
carbomyl phosphate synthetase
ornithine transcarbomoylase
argininosuccinic acid synthetase
argininosuccinic acid lyase
Incidence rate
PKU- 1: _______
MSUD: 1:________
Homocystinuria: 1:_______
Alkaptonuria: 1:_______
Isovaleric acidemia: 1: ________
15000
150000
200000
250000
250000
Incidence rate
TYR1- 1: ________
TYR2: 1: ________
TYR3: 1:________
100000
250000
too rare
