20.04.08 Biochemical genetics - inborn errors of metabolism

Question 1

What are inborn errors of metabolism

Answer 1

• Genetically and phenotypically heterogeneous group of disorders caused by alterations in a metabolic pathway.
• Symptoms arise either due to accumulation of a toxic substrate, deficiency of a product or activation of an alternative metabolic pathway.
• Successful treatment usually involves metabolic stabilisation (dietary intervention, supplementation of deficient metabolites)

Question 2

Why is genetic testing important in metabolic disorders

Answer 2

• Metabolic imbalances can be detected by biochemical testing. However, these tests are not specific enough for familial testing.
• Genetic testing allows reproductive options, determine carrier status, exact diagnosis, avoids the need for invasive procedures (liver biopsies to confirm glycogen storage disorders), faster diagnosis, enables use of specific therapies (nonsense mutation suppression), used for prognostic information.

Question 3

Review of Zellweger Syndrome Spectrum

Answer 3

• Incidence 1 in 50,000
• 3 phenotypes depending on severity
• Hypotonic infants, seizures, liver cysts with hepatic dysfunction, bony stippling of patella and other bones. When older they may have retinal dystrophy, sensiorneural hearing loss, dev delay.

Question 4

How is Zellweger syndrome diagnosed

Answer 4

• Biochemical analysis of blood and urine. Measures very-long-chain fatty acids (VLCFA).
• Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 are consistent with a defect in peroxisomal fatty facid metabolism

Question 5

Review of the genetics of Zellweger syndrome (ZS)

Answer 5

• 13 different PEX genes
• Encode proteins required for normal peroxisome assembly.
• PEX1 mutations most common cause of ZS. 60.5% cases.
• AR

Question 6

Review of ornithine transcarbamylase deficiency (OTC)

Answer 6

• Incidence is 1 in 14,000 live births.
• Can be severe neonatal-onset in males or post-neonatal onset (partial deficiency) in males and females.
• Hyperammonemia, leading to coma. Other complications can be dev delay, ADHD.
• X linked inheritance. Mutations in OTC gene.

Question 7

How is ornithine transcarbamylase diagnosed

Answer 7

-Biochemical testing to detect elevated orotic acid excretion after an allopurinol challenge test or decreased OTC enzyme activity in liver.

Question 8

Pathogenesis of ornithine transcarbamylase

Answer 8

• Involved in urea cycle
• OTC converts ornithine to citrulline
• Principle mechanism for the clearance of waste nitrogen and metabolism of nitrogenous metabolic compounds (adenosine monophosphate)
• Also the source of endogenous arginine, ornithine and citrulline.

Question 9

Review of Smith-Lemli-Optiz Syndrome

Answer 9

• 1 in 20,000/40,000
• AR, mutations in DHCR7 gene.
• 7-dehydrocholesterol reductase (7-DHC) converts 7-dehydrocholesterol to cholesterol.
• Defects lead to elevated serum 7-DHC, low serum cholesterol.
• Pre/postnatal growth retardation, microcephaly, dev delay, cleft palate, cardiac defects.

Question 10

Review of Wilson disease

Answer 10

• 1 in 30,000
• AR, mutations in ATP7B gene.
• ATP7B is a copper-transporting P type ATPase. Transports copper out of cells.
• Biochemical tests identify low serum copper and increased urinary copper excretion
• Jaundice, hepatitis, psychiatric disturbance, tremors, chorea, Kayser-Fleischer rings (copper deposition in Descemet’s membrane).

Question 11

Review of Pompe disease

Answer 11

• 1 in 100,000 (infantile onset)
• AR. GAA mutations.
• Alpha-glucosidase is essential for degradation of glycogen to glucose in lysosomes.
• Severe: hypotonia, cardiomegaly, HCM, failure to thrive, hearing loss
• Late onset: proximal muscle weakness, respiratory insufficiency. Often residual enzyme activity.
• Treated with enzyme replacement.