Genetic Disorders of Metabolic Pathways Lecture (Dr. Seidler) Flashcards
Essential Amino Acids
- Arginine
- Histidine
- Isoleucine
- Leucine
- Valine
- Lysine
- Methionine
- Pheynalanine
- Threonine
- Tryptophan
** “PVT TIM HALL” ***
Non- Essential Amino Acids
- Cysteine
- Alanine
- Glycine
- Aspartate
- Asparagine
- Glutamate
- Glutamine
- Proline
- Serine
- Tyrosine
Phenylketouria
A) First case in 1934
B) SEVER INTELLECTUAL DISABILOITY: IQ
Alternate Degradation Pathway in PKU
1) Phenylalanine —–> Phenylpyruvate (Gives off Musty Smell)
2a) Phenylacetate —> Phenylacteyl Glutamine
- Disrupt Neurotransmission and Block Amino Acid transport in the Brain as well as Myelin Formation
2b) Phenylacetate —-> Phenyllactate
- Disrupt Neurotransmission and Block Amino Acid transport in the Brain as well as Myelin Formation
Classic PKU
- Absence of PHENYLALANINE HYDROXYLASE (
Secondary PKU
- 3% of all HYPER-PHENYLALANINE
- Insufficient BH4 leads to BH2 deficiency
- Major Clinical finding: ABNORMAL RESPONSE TO DIET!!!!!!!!!!!
- May respond to BH4 Treatments!!
Consequences of Excess Phenylalanine (And its Metabolites)
- Normal at birth
- Toxic to INFANT NEUROLOGICAL TISSUES
INHIBITION OF:
1) TYROSINASE: Decrease in Pigmentation
2) 5HT DECARBOXYLASE: Decrease in Serotonin Synthesis
3) GLUTAMTE DECARBOXYLASE: Decrease in GABA Synthesis and possible decrease in ALL Catecholamines
***Damage occurs AFTER Birth (0 to 6 Months)
*** Loss of 5 - IQ Units every 10 Weeks of delayed Treatment
Tests for Phenylalanine Levels
PLASMA CONCENTRATIONS:
- NORMAL: approx 1 mg/ dL (0.06 mM)
- PKU: 10 to 60 mg/dL (0.61 - 3.62 mM)
LAB TESTS:
1) Guthrie Test: Bacterial inhibition Assay
2) Mass Tandem Spectrophotometry (MS/ MS)
TARGET CONCENTRATIONS:
- Target: 3 to 15 mg/dL (0.18 to 0.91 mM)
- Commercially available diets
Maternal PKU
MATERNAL PKU:
- Phenylalanine CROSSES the Placenta
- PAH in Fetal Liver is UNABLE to convert PHE to TYR
OFFSPRING:
- 92% Mental Retardation (Intellectual Disability)
- 73% Microcephaly
Alkaptonuria
** Deficiency in HOMOGENTISATE OXIDASE!!!!!!!!!!!!
A) Autosomal Recessive (1st recognized in 1897)
B) Typically presents in 20 to 30s:
- With Discoloration of SCLERA (OCHRONOSIS)
- Dark Colored Urine (Darkens on Standing)
C) Accumulation of Homogentisate:
- Severe degeneration of Cartilage of the Spine and other Major Joints (OSTEOARTHRITIS)
- Kidney Disease
Albinism
*** Deficiency in TYROSINASE!!!!!!!
A) Autosomal Recessive
B) Unable to Synthesize Melanin
C) Hair, Skin, Eyes
D) Associated OCULAR DEFECTS
E) INCREASED RISK OF BASAL CELL and SQUAMOUS CELL CARCINOMAS!!!!!!!!!!!
Tyrosinemias
***** CABBAGE ODOR!!!!!!!
Type I: Deficiency in FUMARYLACETOACETATE HYDROLASE!!!!
Type II: Deficiency in TYROSINE AMINOTRANSFERASE!!!!
Type III (Neonatal): Deficiency in Para- HYDROXYPHENYL PYRUVATE OXIDASE!!!!!
A) Type I is the MOST COMMON!!!
- Infants have a CABBAGE- Like Odor
- LIVER FAILURE!!!
B) Succinylacetone:
- Toxic compound and especially topic to the Kidney
Homocystinuria
Classic: Deficiency in CYSTATHIONE BETA-SYNTHASE!!!!!!
***Cysteine is a precursor for GLUTATHIONE!!!!!!
Alternate Degradation Pathway:
- *Homocysteine Thiolactone:
- reacts with Proteins readily in Lysine residues
Clinical features of Homocystinuria
A) DEEP VEIN THROMBOSIS
B) Stroke
C) Atherosclerosis
D) MARFAN LIKE HABITUS (Tall stature/ Long Finger)
- In MARFAN’S, Subluxation of Lens in UP and OUTWARD!!!!!
- In CS Deficiency, Subluxation of Lens is DOWN and INWARD
E) Mental Retardation (Intellectual Disability)
f) JOINT CONTRACTURES!!!!!
Maple Syrup Urine Disease
** VALINE, LEUCINE, ISOLEUCINE!!!!!!
** Deficiency in BRANCHED CHAIN ALPHA KETO ACID DEHYDROGENASE!!!!!!!!
A) Autosomal Recessive
B) Symptoms appear 3 to 4 days AFTER Birth
- Feeding difficulties, Vomiting, Lethargic
- Progressive Neurodegeneration
- Abnormal Muscle Tone
- Coma, Death
C) ELEVATED BCAAs and ALPHA-KETOACIDS (Urine and Plasma)
- BURNT SUGAR SMELL
D) INCIDENCE:
- Mennonite community: 1/ 176
- United States: 1/ 180,000
