Metabolics - General - Investigations (TRANSFERRED)

Question 1

Reference: Genetics residents in-training examination – Fall 2020

A patient presents with the following clinical picture. What two non-molecular tests (laboratory or imaging) would you order to help clarify the diagnosis and specify why you would choose each test or what results you expect.

A. 6 month old female with hair loss, eczema-like rash, progressive hypotonia, and hearing loss.

B. Neonate with profound hypotonia, large anterior fontanelle, seizures, and liver dysfunction.

C. 30 year old man with progressive lower limb spasticity, sphincter control issues, and erectile dysfunction.

D. 3 month old male with seizures, hypotonia, developmental regression, skin laxity, fragile hair. There was a large cephalohematoma at birth.

E. 1 year old female with coarse facial features, recurrent AOM, short stature, and mild developmental delay.

Answer 1

A)

1. Biotinidase level – low (profound likely)
2. Urine organic acids – expect metabolites of propionic acid (PA, 3OH-PA, methylcitric), metabolites of 3-MCC (3HIVA, 3methylcrotonylglycine), lactate
3. Acylcarnitine profile – expect elevated C3 and C5OH

B)

1. VLCFA – elevated (best answer is elevated C26:0 and elevated ratio C26:0 to C22:0
2. Brain MRI - leukodystrophy or neuronal migration disorder
3. AUS – renal cysts
4. Skeletal survey – epiphyseal stippling

Note: would accept low plasmalogens, elevated pipecolic acid, elevated THCA and DHCA on bile acid profile, but would not accept elevated phytanic and pristanic acid as a neonate would not have these in their diet

C)

1. VLCFA – elevated (best answer is C26:0 and elevated C26:0 to C22:0 ratio)
2. Adrenal studies – X-ALD is associated with adrenal insufficiency
3. Brain MRI – progressive white matter changes

D)

1. Copper – low
2. Ceruloplasmin – low
3. Brain MRI with MRA – atrophy, defective myelination, and vascular tortuosity
4. Skull ray – Wormian bones

E)

1. Urine MPS spot (positive) or urine MPS fractionation – increased excretion of heparan and dermatan sulfate
2. Skeletal survey – dysostosis multiplex
3. Urine oligosaccharides – may see increased excretion
4. ECHO – valvular disease

Question 2

Reference: Genetics residents in-training examination – Fall 2020

List 3 causes of abnormal patterns on transferrin isoelectric focussing.

Answer 2

Congenital disorders of glycosylation (N-linked specifically)
Hereditary fructose intolerance
Galactosemia
Chronic alcoholism