Disorders of amino acid metabolism Flashcards
Newborn screens for inborn errors of
Amino acid metabolism (6)
Tyrosinemia
Arginosuccinic Aciduria
Citrullinemia
Phenylketonuria
Maple Syrup Urine disease
Homocystinuria
Newborn screens for inborn errors of
Organic Acid metabolism
Propionic acidemia Glutaric acidemia type 1 Isovaleric acidemia Methylmalonic aciduria Mathylmalonyl-coA mutase deficiency
Newborn screens for inborn errors of
fatty acid metabolism
Long chain hydroxyacyl-CoA dehydrogenase deficiency
Medium chain acyl-CoA dehydrogenase deficiency
Very long chain acyl coa dehydrogenase deficiency
Trifunctional protein deficiency
Carnitine uptake defect
Newborn screens for inborn errors of
other miscelaneous systems
Cystic fibrosis
Congenital hypothyroidism
Biotinidase deficiency
Congenital adrenal hyperplasia
Galactosemia
SCID
What enzyme defect causes alkaptonuria?
HGD, homogentisate dioxygenase.
What amino acid degradation pathways are impaired in alkaptonuria?
Homogentisate is downstream of both Tyrosine and Phenylalanine metablism, when it accumulates it is excreted in urine in its oxidized form, Alcaptone.
Symptoms of alkaptonuria?
Ochronosis. Black pigment deposition of homogentisate in the connective tissue.
Dense black pigment in the intervertebral discs, synovial cartilage, tendons and ligaments, ear and nose cartilage, skin.
Dark/black urine especially after protein rich meal.
Joint and bone pain develops after age 30 and can be debilitating.
Bone density can be low, fractures.
Tendons and ligament tears also increase.
Galstones,
Kidney stones increased rate.
Valvular heart disease at increased rates.
What is the most frequent inborn metabolic disease?
Phenylketonuria
What is the Guthrie assay?
A drop of blood is obtained from an infant and collected on a piece of filter paper. A disk is punched out and placed on an agar gel plate containing Bacillus subtilis and B-2-thienylalanine. The agar gel is able to support bacterial growth but the B-2-thienylalanine inhibits bacterial growth. However, in the presence of extra phenylalanine leached from the impregnated filter paper disk, the inhibition is overcome and the bacteria grow.
What are the two types of Phenylketonuria?
Classical PKU - Phenylalanine hydroxylase defect
Cofactor deficient PKU - Dihydrobiopterin reductase defect.
Symptoms of PKU
Mental retardation, correlates strongly with the load of phenylalanine in blood during infancy
Seizures
Hypertonic muscles
Musty urine and sweat
Fair hair and skin
High plasma phenylalanine
How is phenylalanine metabolized in PKU
aminotransferase generates
phenylpyruvate and alanine
Phenylpyruvate converted to
Phenylacetate and Phenyllactate which makes urine smell.
What transports phenylalanine into neurons?
LAT1 the neutral amino acid transporter
How does extremely high phenylalaline levels affect neurons?
Causes abnormal myelination
Abnormal protein synthesis and neurotransmitter production.
Phenylketnouria treatment
Very strict control of phenylalanine intake
Tyrosine and Tryptophan supplementation (Phenylalanine is a precursor)
Phenylalanine ammonia lyase enzyme substitution therapy.
Essential amino acids
PVT TIM HALL
What is missing in cofactor deficient PKU?
Dihydropteridin Reductase (DHPR) usually,
Therefore Tetrahydrobiopterin cannot be regenrated from Dihydrobiopterin.
or
A defect in de novo synthesis of biopterin (synthesized from from GTP)
How is cofactor deficient PKU diagnosed?
Administering THB, tetrahydrobiopterin decreases plasma Phenylalanine levels and increases Tyrosine levels
How is cofactor deficient PKU treated?
strict control of phenylalanine in diet.
L-DOPA 5-OH-tryptophan, and tetrahydrobiopeterin supplementation.
What enzyme is defective in Albinism?
Tyrosinase. preventing Melanin synthesis from tyrosine.
What are the symptoms of albinism
Light sensitivity
Vision defects
Skin cancer
What causes Maple Syrup Urine Disease?
Branched Chain Ketoacid Dehydrogenase defect. BCKD
What amino acids are involved in maple syrup urine disease?
Leucine Isoleucine Valine
What subunits are involved in oxidative decarboxylation by BCKD,
what are the cofactors for each
E1 Ketoacyl dehydrogenase TPP, thiamine pyrophosphate
E2 Dihydrolipoyl transacetylase FAD
E3 Dihydrolipoyl dehydrogenase NAD
What subunit of the BCKD enzyme is common to other enzymes and what are they?
E3
BCKD
Pyruvate dehydrogenase
alpha ketoglutarate dehydrogenase.
Symptoms of BCKD deficiency
Growth retardation Ketoacidosis Brain edema Seizures Maple Syrup urine
Increased Branched chain amino acids and keto acids in plasma
Leucine and ketoisocaproic acid especially.
How does leucine cause brain toxicity?
Edema
Impaired myelination
Impaired protein and neurotransmitter synthesis
What transporter brings leucine into neurons
LAT1 .
Neutral amino acid transporter
How is ketoisocaproic acid toxic to the brain?
ketoisocaproic acid + glutamate
makes
leucine + alpha-ketoglutarate
It reduces glutamate and GABA availability.
Causes a defect in transport of reducing equivalents
What transporter brings ketoisocaproic acid into neurons?
MCT1 monocarboxilate transporter.
What is the GABA shunt?
a-KG from the TCA cycle shunted to produce succinate and NADH via a GABA intermediate.
a-Ketoglutarate –> glutamate –> GABA –> GABAT –> Succinic semialdehyde –> succinate.
What reducing equivalents are transported in/out of the mictochondrial membrane?
Malate/aKG
Aspartate/Glutamate.
Malate aspartate shuttle
Where is the defect in thiamine responsive MSUD
In the E 1 subunit of the BCKD, which uses TPP as a cofactor.
Therapy for BCKD defeciency?
Diet control of Leu Ile Val.
Hemodialysis during crises
Liver transplant.
What happens if there is a defect in the E3 subunit
Pyruvate dehydrogenase
aKG dehydrogenase
BCKD
are all deficient
Lactic acidosis and severe ketoacidosis.
