Inherited Disorders Of Amino Acid Catabolism Flashcards
What is the significance of inherited disorders of amino acid catabolism?
- Enzyme deficiencies involved in amino acid metabolism result in accumulation of toxic substances
- Greater enzyme deficiencies = increased toxicity
- Brain, liver and kidneys most affected
- Acute symptoms typically during catabolic state
• Most aminoacidopathies are identified by newborn screening
“The day after being discharged from the hospital the parents of a new-born baby receive an emergency phone call telling them to not feed their baby, but to report to their physician immediately”
Describe the disorders of amino acid catabolism
Phenylalanine and Tyrosine
- Phenylketonuria, albinism, alkaptonuria, tyrosinosis
Branched chain amino acids (Valine, isoleucine, leucine)
- Maple syrup urine disease, methylmalonic aciduria
Sulfur containing amino acids (Methionine and cysteine)
- Homocystinuria
How does mass. Spectrometry work?
- Amino acid concentration in blood quantitated from blood spot
- Other organic molecules can also be quantitated from blood spot
- Molecular profile based upon the mass / charge ratio of the fractured molecule
What is phenylketonuria?
- Relatively common of the rare disorders
- Autosomal recessive disorder
• Responds very well to dietary treatment
Phenylalanine
- Detected during the first week of life by neonatal screening:
- The Guthrie test (historical)
- Mass Spec (current use)
- If test is positive
- Immediately - place infant on low Phenylalanine (Phe) diet
- Then - test again, in case of false positive
- Some centers test infants twice
- First test might be false negative due to maternal clearance
How does phenylketonuria affect children?
- Children confirmed to have PKU, have to be put on a low Phe diet
- Medical food that is modified to have low Phe
- Low protein diet
- Avoid aspartame (artificial sweetener; i.e., Diet Coke, etc)
- Dietary restriction of Phe to be started immediately on diagnosis
- Blood Phe levels have to be frequently monitored
- If treated, children lead a normal life
- Except for the dietary restrictions
• Recommended lifelong adherence, but after development, patients often stray from the diet (not recommended)
• First successfully treated inborn error of metabolism by dietary
restriction was in the 1950s (Bickel, 1953
Explain the defect in PKU I
This is classic PAH is absent and cannot convert phenylalanine to tyrosine
Phenylaline still converted to phenylpyruvic acid —>phenylpyruvic acid excreted in urine (mousey odor)
What are the characteristics of PKU I (classic PKU) in untreated patients?
- CNS symptoms: child has a delay in milestones and a low IQ (if not treated immediately). Seizures if blood Phe are higher than the recommended level
- Phe is metabolized to phenylpyruvate, phenylacetate & phenyllactate (excreted in urine) resulting in mousey odor of urine
- Phe levels in blood are elevated
- Decreased pigmentation of skin and hair as tyrosine conversion to melanin is inhibited by the elevated Phe levels (inhibits tyrosinase)
Most untreated patients have lighter coloring then parents/siblings from reduced melanin synthesis
What were the symptoms of PKU nefore tratm3nt 2as known?
- Intellectual disability
- Seizures
- Spasticity
- Autistic behaviors
- Hypopigmentation
- Skin rashes
The sibling treated at birth develops normally
How is PKU treated?
• Avoidance – dietary treatment – reduction in phenylalanine (careful monitoring of Phe intake during growth of the patient)
- Sapropterin (synthetic form of BH4) may help some PKU patients
- Typically mild or moderate forms of the disease
- These patients may have a mutant form of the enzyme that has a lower affinity for the cofactor qBH2/BH4
- Considered the first non-dietary treatment for PKU
Describe maternal PKU syndrome
Women with PKU must maintain low Phe levels
before conception and during pregnancy.
• Strict adherence must be maintained prior to conception and throughout pregnancy
- High maternal blood Phe leads to fetal defects:
- Microcephaly
- Lack of mental development, severe neurological problems
- Congenital heart defects
- Facial dysmorphology- long philtrum, epicanthal folds, micrognathia, short nose, microphthalmia, flat midface, facies similar to fetal alcohol syndrome
- Elevated phenylalanine has teratogenic properties
Most people are…
homozygous for normal alleles of PAH gene
Offspring of a person with PKU
All children, once born, will be normal (heterozygous). But during fetal development, the high circulating levels of maternal serum PHE would be teratogenic if the mother is not under strict dietary control of phenylalanine consumption
What causes alkaptonuria?
- Relatively benign inborn error of phenylalanine - tyrosine catabolism
- Deficiency in Homogentisic Acid Oxidase
- Homogentisic acid accumulates, may lead to severe arthritis later in life
- Dietary restriction of Phe & Tyrosine may reduce deposition of homogentisic acid
What are the symptoms of alkaptonuria?
– Darkening of urine on standing
– Discoloration of cartilage and connective tissue
– Ochronotic pigments (ochronosis)
– Often leads to severe arthritis
– Due to oxidation of excess homogentisic acid
What is the effect of tyrosinemia type 1?
Build-up of fumarylacetoacetate • Causes kidney and liver damage • Metabolized to another compounds • Contributes cabbage like smell to urine
Nitisinone (NTBC) inhibits 4-OH- phenylpyruvate dioxygenase (PDO) to prevent accumulation of toxic metabolites
What are the cayses of tyrosinosis (tyrosinemia type 1)?
- Inborn error of phenylalanine-tyrosine catabolism
- Deficiency of fumarylacetoacetate hydrolase
• Manifestations are severe and usually fatal • Liver failure
• Renal failure
• Cabbage like odor of the urine
Nitisone
- Dietary restriction of Phe & Tyr
- Difficult to accomplish as two essential amino acids must be limited
- Tyrosine is required for neurotransmitter synthesis
