Clinical Genetics - General = Neurodevelopmental Disorders (TRANSFERRED)

Question 1

Reference: Genetics residents in-training examination - March 2020 (Spring 2020)

A 30-year-old woman presents with unexplained liver cirrhosis and increased liver copper content on biopsy (300 ug per g of dry weight, normal 20-50 ug per g). You are asked to evaluate her for possible Wilson disease.

1) Name 3 other clinical manifestations of Wilson disease that you would look for in this patient (3 points).

2) Serum ceruloplasmin, serum copper, and 24-hour copper excretion are measured. Please fill out the following table with your answers to the following questions:
- for each of these tests, would a low, normal, or high result be typically expected in Wilson disease (0.5 point per line). Explain the pathophysiological mechanism (0.5 point per line)
- for each of these tests, name an acquired condition that could cause similar results (0.5 point per line)
- for each of these tests, name another genetic disorder of metal metabolism that could cause similar results (0.5 point per line).

3) Name the gene associated with Wilson disease (1 point) and the pattern of inheritance (1 point)
4) Name and describe the mechanism of action of two pharmacological treatments for Wilson disease (2 points)

Answer 1

1) 
psychiatric symptoms
movement disorder
hemolytic anemia
Keiser-Fleischer rings
renal involvement

2)
See Genetics residents in-training examination
March 2020 - Page 1

3)

• ATP7B
• AR

4)
- copper chelators (or name specific agents, e.g. penicillamine, trientine): bind copper in blood and tissues and facilitate its urinary excretion
- zinc oxide: reduce copper intestinal absorption

Question 2

Reference: Genetics residents in-training examination - March 2020 (Spring 2020)

An 18-year-old woman presented with color and temperature changes in her hands, intermittent tremor of the hands since the age of 15 years, involuntary right arm movements and difficulties with concentration.

Neurologic examination revealed dystonia of the right arm, a postural tremor of her arms and legs, mild dysphagia and dysarthria, and bradykinesia.

Laboratory tests revealed elevated serum levels of alanine aminotransferase and aspartate aminotransferase. Magnetic resonance imaging of the patient’s brain revealed atrophy in the basal ganglia and brainstem.

See: Image and clinical details from: Schrag A, Schott JM. N Engl J Med 2012;366:e18

Which one of the following tests would be the most likely to reveal the diagnosis?

1) Sequencing of the mitochondrial genome including analysis of duplications and deletions, in a liver biopsy specimen.
2) Measurement of copper in a 24-hour urine sample.
3) Assay of very long chain fatty acids in plasma.
4) A sequencing panel for corneal dystrophy in leukocyte DNA.
5) Measurement of expression levels of type I interferon (IFN) regulated genes in blood (“interferon signature”)
6) Transferrin isoelectric focussing in plasma

Answer 2

2) Measurement of copper in a 24-hour urine sample.