Inborn Errors of Metabolism 1 Flashcards
What is the most typical cause of inborn errors of metabolism and why are they difficult to detect at birth?
Enzyme deficiency - defective enzyme or lack of cofactor
Difficult to detect because patient appears normal initially before getting worse
How are inborn errors of metabolism inherited?
Autosomal recessive, since carriers with around 50% activity are typically asymptomatic
What are typical pathophysiological consequences of enzyme deficiencies?
Accumulation of substrate, deficiency of product, and sometimes accumulation of alternate products
What is a locus heterogeneity for an enzyme deficiency?
Diseases due to deficiencies of multiple enzymes in the same pathway
What can lead to “metabolic crash” in a patient?
Increased metabolic flux through defective pathway, due to fever, illness, or starvation. This leads to clinical decompensation
What is the most common disorder of amino acid metabolism? What accumulates in this disorder?
PKU, mutation in phenylalanine hydroxylase, which converts Phe -> Tyr.
Phenylpyruvic acid accumulates
What are the untreated symptoms of PKU and why, generally?
Severe intellectual disability, seizures, autism, fair skin and hair color. This is because Tyrosine is needed to make T3/T4, NE / E / Dopamine, and melanin pigment
How is PKU diagnosed?
Elevated phenylalanine / tyrosine ratio
What is the cofactor for PAH which some patients respond to supplementation with?
BH4 - tetrahydrobiopterin.
What is classic vs nonclassic PKU?
Classic -> nonsense mutation causing loss of PAH activity
Other -> mutations in BH4 leading to elevated phe levels
What is maternal phenylketonuria and how does this relate to diet for life?
Elevated maternal phe levels can cause birth defects in babies including microcephaly, heart defects, and retardation
-> always keep people on restricted diet for safety
Why is the urea cycle important?
Only major metabolic pathway for removal of waste nitrogen, occurring in liver.
Ammonia is highly neurotoxic, and is readily uptaken via astrocytes
What are the clinical features of urea cycle defects?
- Vomiting
- Tachypnea
- Encephalopathy
- General malaise
- Blurred vision, seizures, coma, slurred speech
What is one urea cycle disorder which can lead to progressive spastic diplegia? What other tidbit is special in this condition?
Arginase deficiency, this will also not lead to elevated blood ammonia (since it leads to storage of ammonia as an amino acid)
Why does a urea cycle disorder cause tachypnea?
Ammonia stimulates the respiratory center
What is the only urea cycle disorder which is not autosomal recessive?
ornithine transcarbamylase deficiency (OTCase)
How are urea cycle defects diagnosed? What is one exception?
Enzyme deficiency leads to an elevation of substrate for that enzyme in blood.
In OTCase, however, orotic acid accumulates however, since carbamoyl phosphate is instead used for pyrimidine synthesis rather than citrulline (OTCase 2)
What is the treatment for urea cycle disorders?
- Protein restriction
2. Increase alternate pathways for NH3 removal, i.e. supplemental arginine or citrulline to “prime the pump”
What are typical features of organic acid disorders?
Disorders of amino acid metabolism which are someone downstream the removal of the amino group so amino acid does not accumulate.
Autosomal recessive, due to enzyme deficiency, characterized by METABOLIC ACIDOSIS
What causes maple syrup urine disease (MSUD)?
Branched chain ketoacid dehydrogenase deficiency
Features - acute neurologic defects, microcephaly, mental retardation
What is used for definitive diagnosis of MSUD and what is the treatment?
Diagnosis - increased BCAA (leucine, isoleucine, valine) or organic acids in urine, followed by molecular / enzyme analysis
Treatment - reduction of protein substrate, avoidance of CATABOLIC state, providing cofactors
What is the most common cause of galactosemia?
Mutations in Galactose-1-phosphate uridyl transferase, but can be caused by any enzyme involved in metabolism of galactose
What is one special consideration for treatment of galactosemia patients?
They are especially susceptible to gram-negative bacterial infection (especially E. coli), but they will have general lethargy, jaundice, hepatomegaly, and vomiting / diarrhea
What is the diagnosis for galactosemia?
Elevated galactose levels in blood or urine
What is the primary treatment for galactosemia?
Removal of lactose from diet, and substituting with soy-based formulas
What is one common longterm difficulty with galactosemia patients who are women?
Premature ovarian failure / infertility
What are the worst effects of the most severe fatty acid oxidation disorders (FAOD)?
Severe cardiomyopathy and hepatopathy from accumulation of toxic products (remember talking to Dr. Feldman after panel about MCAD)
What is one common diagnostic symptom of FAOD’s? Why?
hypoketotic hypoglycemia - during fasting glucose is quickly depleted, and ketone bodies cannot be made from breaking down fats to acetyl-CoA.
What is the most common FAOD? how is the diagnosis made?
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
Hypoketotic hypoglycemia, dicarboxylic aciduria, MC acylcarnitine elevations on plasma acylcarnitine profile, confirm with molecular testing
What are the “episodes” which MCAD patients suffer? What typically triggers them?
Vomiting, lethargy, seizures, coma
Triggered via fasting or infection
How is MCAD treated?
Frequent feedings, with IV glucose as needed. Reduction in dietary fat and carnitine supplementation
What is a typical clinical progression of lysosomal storage diseases?
Patients appear normal at birth, then as material accumulates in lysosomes in target tissue, there is a “plateau” in development, and “regression” into death
What type of disease is Tay Sachs and what causes it?
Sphingolipidosis
Caused by hexosaminidase A deficiency, required for breakdown of GM2 ganglioside.
Who is screened for Tay-Sachs, and why? How is diagnosis made?
Ashkenazi Jewish population - caused by 3 mutations in same gene.
Diagnosis is made via enzyme assay
What is the clinical presentation / diagnosis of Tay-Sachs?
Brain is predominant site of GM2 - neurological deterioration beginning at 6-12 months, with motor weakness and loss of milestones. Death by age 2-5, cherry red spot on macula.
What is a mucopolysaccharidosis?
Glucosaminoglycans accumulate in lysosomes as a result of a deficiency in one of the degradation enzymes
What is the only mucopolysaccharidosis which is not autosomal recessive, and what is its inheritance pattern?
Hunter syndrome - X-linked recessive
What are the clinical features of Hurler syndrome?
Coarse facial features, including large head and tongue, with short stature and claw hand due to mucopolysaccharide buildup.
How is Hurler syndrome diagnosed?
Mucopolysaccharides appear in urine, with enzyme assay being diagnostic.
What is Hurler-Scheie?
Milder form of Hurler syndrome with some residual enzyme activity
What are the two main treatments for Hurler syndrome, and why can intellectual disability not be prevented?
- Bone marrow transplant to slow progression of somatic features
- Enzyme replacement therapy in Hunler-Scheie - enzyme cannot cross blood-brain-barrier
What causes methylmalonic acidemia? What type of disorder is it? What is the treatment?
Failure of conversion of methylmalonyl-CoA to succinyl-CoA via methylmalonyl-CoA mutase in breakdown of isoleucine and valine
- it is an organic acidemia commonly caused by B12 deficiency, in which case it can be treated with B12 supplementation. Otherwise restrict protein and pray for no acidosis
What causes biotinidase deficiency?
Defect in recycling of biotin via the biotinidase enzyme, which cleaves biocytin (biotin attached to protein in holocarboxylases)
What features are really clinically diagnostic of biotinidase deficiency? It can be treated with B7 supplementation. Just know that
- Eczema-like skin rash in skin folds
- Loss of hair on scalp (alopecia)
- Metabolic acidosis + neurologic abnormalities
