Inborn Errors of Metabolism 1

Question 1

What is the most typical cause of inborn errors of metabolism and why are they difficult to detect at birth?

Answer 1

Enzyme deficiency - defective enzyme or lack of cofactor

Difficult to detect because patient appears normal initially before getting worse

Question 2

How are inborn errors of metabolism inherited?

Answer 2

Autosomal recessive, since carriers with around 50% activity are typically asymptomatic

Question 3

What are typical pathophysiological consequences of enzyme deficiencies?

Answer 3

Accumulation of substrate, deficiency of product, and sometimes accumulation of alternate products

Question 4

What is a locus heterogeneity for an enzyme deficiency?

Answer 4

Diseases due to deficiencies of multiple enzymes in the same pathway

Question 5

What can lead to “metabolic crash” in a patient?

Answer 5

Increased metabolic flux through defective pathway, due to fever, illness, or starvation. This leads to clinical decompensation

Question 6

What is the most common disorder of amino acid metabolism? What accumulates in this disorder?

Answer 6

PKU, mutation in phenylalanine hydroxylase, which converts Phe -> Tyr.

Phenylpyruvic acid accumulates

Question 7

What are the untreated symptoms of PKU and why, generally?

Answer 7

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

Question 8

How is PKU diagnosed?

Answer 8

Elevated phenylalanine / tyrosine ratio

Question 9

What is the cofactor for PAH which some patients respond to supplementation with?

Answer 9

BH4 - tetrahydrobiopterin.

Question 10

What is classic vs nonclassic PKU?

Answer 10

Classic -> nonsense mutation causing loss of PAH activity

Other -> mutations in BH4 leading to elevated phe levels

Question 11

What is maternal phenylketonuria and how does this relate to diet for life?

Answer 11

Elevated maternal phe levels can cause birth defects in babies including microcephaly, heart defects, and retardation

-> always keep people on restricted diet for safety

Question 12

Why is the urea cycle important?

Answer 12

Only major metabolic pathway for removal of waste nitrogen, occurring in liver.

Ammonia is highly neurotoxic, and is readily uptaken via astrocytes

Question 13

What are the clinical features of urea cycle defects?

Answer 13

1. Vomiting
2. Tachypnea
3. Encephalopathy
4. General malaise
5. Blurred vision, seizures, coma, slurred speech

Question 14

What is one urea cycle disorder which can lead to progressive spastic diplegia? What other tidbit is special in this condition?

Answer 14

Arginase deficiency, this will also not lead to elevated blood ammonia (since it leads to storage of ammonia as an amino acid)

Question 15

Why does a urea cycle disorder cause tachypnea?

Answer 15

Ammonia stimulates the respiratory center

Question 16

What is the only urea cycle disorder which is not autosomal recessive?

Answer 16

ornithine transcarbamylase deficiency (OTCase)

Question 17

How are urea cycle defects diagnosed? What is one exception?

Answer 17

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)

Question 18

What is the treatment for urea cycle disorders?

Answer 18

1. Protein restriction

2. Increase alternate pathways for NH3 removal, i.e. supplemental arginine or citrulline to “prime the pump”

Question 19

What are typical features of organic acid disorders?

Answer 19

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

Question 20

What causes maple syrup urine disease (MSUD)?

Answer 20

Branched chain ketoacid dehydrogenase deficiency

Features - acute neurologic defects, microcephaly, mental retardation

Question 21

What is used for definitive diagnosis of MSUD and what is the treatment?

Answer 21

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

Question 22

What is the most common cause of galactosemia?

Answer 22

Mutations in Galactose-1-phosphate uridyl transferase, but can be caused by any enzyme involved in metabolism of galactose

Question 23

What is one special consideration for treatment of galactosemia patients?

Answer 23

They are especially susceptible to gram-negative bacterial infection (especially E. coli), but they will have general lethargy, jaundice, hepatomegaly, and vomiting / diarrhea

Question 24

What is the diagnosis for galactosemia?

Answer 24

Elevated galactose levels in blood or urine

Question 25

What is the primary treatment for galactosemia?

Answer 25

Removal of lactose from diet, and substituting with soy-based formulas

Question 26

What is one common longterm difficulty with galactosemia patients who are women?

Answer 26

Premature ovarian failure / infertility

Question 27

What are the worst effects of the most severe fatty acid oxidation disorders (FAOD)?

Answer 27

Severe cardiomyopathy and hepatopathy from accumulation of toxic products (remember talking to Dr. Feldman after panel about MCAD)

Question 28

What is one common diagnostic symptom of FAOD’s? Why?

Answer 28

hypoketotic hypoglycemia - during fasting glucose is quickly depleted, and ketone bodies cannot be made from breaking down fats to acetyl-CoA.

Question 29

What is the most common FAOD? how is the diagnosis made?

Answer 29

Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)

Hypoketotic hypoglycemia, dicarboxylic aciduria, MC acylcarnitine elevations on plasma acylcarnitine profile, confirm with molecular testing

Question 30

What are the “episodes” which MCAD patients suffer? What typically triggers them?

Answer 30

Vomiting, lethargy, seizures, coma

Triggered via fasting or infection

Question 31

How is MCAD treated?

Answer 31

Frequent feedings, with IV glucose as needed. Reduction in dietary fat and carnitine supplementation

Question 32

What is a typical clinical progression of lysosomal storage diseases?

Answer 32

Patients appear normal at birth, then as material accumulates in lysosomes in target tissue, there is a “plateau” in development, and “regression” into death

Question 33

What type of disease is Tay Sachs and what causes it?

Answer 33

Sphingolipidosis

Caused by hexosaminidase A deficiency, required for breakdown of GM2 ganglioside.

Question 34

Who is screened for Tay-Sachs, and why? How is diagnosis made?

Answer 34

Ashkenazi Jewish population - caused by 3 mutations in same gene.

Diagnosis is made via enzyme assay

Question 35

What is the clinical presentation / diagnosis of Tay-Sachs?

Answer 35

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.

Question 36

What is a mucopolysaccharidosis?

Answer 36

Glucosaminoglycans accumulate in lysosomes as a result of a deficiency in one of the degradation enzymes

Question 37

What is the only mucopolysaccharidosis which is not autosomal recessive, and what is its inheritance pattern?

Answer 37

Hunter syndrome - X-linked recessive

Question 38

What are the clinical features of Hurler syndrome?

Answer 38

Coarse facial features, including large head and tongue, with short stature and claw hand due to mucopolysaccharide buildup.

Question 39

How is Hurler syndrome diagnosed?

Answer 39

Mucopolysaccharides appear in urine, with enzyme assay being diagnostic.

Question 40

What is Hurler-Scheie?

Answer 40

Milder form of Hurler syndrome with some residual enzyme activity

Question 41

What are the two main treatments for Hurler syndrome, and why can intellectual disability not be prevented?

Answer 41

1. Bone marrow transplant to slow progression of somatic features
2. Enzyme replacement therapy in Hunler-Scheie - enzyme cannot cross blood-brain-barrier

Question 42

What causes methylmalonic acidemia? What type of disorder is it? What is the treatment?

Answer 42

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

Question 43

What causes biotinidase deficiency?

Answer 43

Defect in recycling of biotin via the biotinidase enzyme, which cleaves biocytin (biotin attached to protein in holocarboxylases)

Question 44

What features are really clinically diagnostic of biotinidase deficiency? It can be treated with B7 supplementation. Just know that

Answer 44

1. Eczema-like skin rash in skin folds
2. Loss of hair on scalp (alopecia)
3. Metabolic acidosis + neurologic abnormalities