Metabolics - Approach to Acute Presentation (TRANSFERRED)

Question 1

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

You are called to do a consult on a four-day-old newborn male on NICU. The child was well until day 2 then had progressive vomiting, lethargy and acidosis originally believed to be sepsis but did not improve with antibiotics. You look for routine laboratory results in the patient’s chart:
Sodium= 135 (135-145 mmol/L), Potassium = 5 (3.7-5.9 mmol/L), Anion gap = 23 (normal < 15)
Blood gas: pH= 6.9 ( 7.36-7.44), CO2 = 22 (41-51 mmHg), Bicarbonate = 5 (21-25 mmol/L)
Glucose = 4.1 (2.8-4.4 mmol/L) but the patient received IV DW5%NS
Urine ketones large (5+)
Lactate = 3.3 (1.4-3.4 mmol/L)
Creatinine = 60 (29-94 μmol/L )
Ammonia = 700 μmol/L (normal < 100 μmol/L for a newborn)
AST = 50 (23-186 U/L) ALT = 80 (14-54 U/L)
WBC 2.0 (4.5-13 X109/L) with 20% neutrophils
Hemoglobin = 104 (135-215 g/L), Hematocrit 33 (42-66%), platelets 25 (140-440 X109/L)

a) Name four (4) specific disorders in your differential diagnosis at this point.
b) List 4 features on the personal and family history that you would look for. For each feature, explain what the presence of the feature would tell you in regard to differential diagnosis.
c) List 4 features of the physical examination that are of most interest to you.
d) Describe 4 laboratory tests (other than molecular/DNA), which may help you make the specific diagnosis. Explain how each laboratory test would help you reach a diagnosis.

Answer 1

a)
Organic acidurias:
Most likely because of metabolic acidosis with bone marrow suppression and ketosis (PA, MMA)
• Propionic acidaemia
• Methylmalonic acidaemia (including Cobalamin metabolism disorders, CblA, CblB, CBlC, CblF)
• Isovaleric aciduria
• Maple Syrup Urine Disease
• Others

Urea cycle disorders:
• Ornithine transcarbamoylase deficiency
• Argininosuccinate synthetase deficiency (Citrullinaemia)
• Argininosuccinate lyase deficiency (Argininosuccinic aciduria)
• N-acetylglutamate synthetase deficiency
• Carbamoyl phosphate synthetase deficiency
• Hyperammonaemia – hyperornithinaemia –homocitrullinuria (HHH) syndrome

Fatty acid oxidation disorders (Glutaric aciduria type 2, LCHADD/TFP, MCADD…)

Others: Succinyl-CoA:3-ketoacid-CoA transferase (SCOT)

b)
Pregnancy, delivery, anomalies seen at ultrasound, others?
Consanguinity – likely recessive
Ethnicity – risk group
Neonatal deaths
Spontaneous abortion
Lethargy with minor illnesses
Unexplained, mental retardation, developmental delay, seizure, sepsis
Neuropsychiatric features
Prematurity -> transient hyperammonemia of the newborn (THAN)
Affected male relative eg uncle – X linked eg OTC
Protein aversion (UCD)
Migraines
Cyclic vomiting (MSUD, UCD)
Others

c) 
Mental status and vital signs
Dysmorphic features
Eyes (cataracts) and skin (jaundice)
Special odor (IVA, MSUD…)
Pulmonary and cardiac exam
Abdominal examination (Hepatosplenomegaly?)
Neurological exam (Axial hypotonia, hyperreflexia, clonus, abnormal movements)

d)
- Plasma Amino acid Profile: MSUD (increase in leucine, valine, isoleucine and allo-isoleucine, look for increased glycine (ketotic hyperglycinemia), proline and Alanine (lactic acidemia), rule out Urea Cycle Disorders,

• Urinary organic acid profile (to investigate organic acidurias IVA, MMA, PA, MSUD)
• Acylcarnitine profile : to investigate organic acidurias
• Total homocysteine (differential diagnostic of MMA)
• DNPH testing
• Others

Question 2

Reference: Genetics residents in-training examination – Fall 2020

A 3 day old male infant presents to the ER with food refusal, progressive lethargy, gasping, and tachypnea. He looks unwell, poorly perfused, and is responsive only to pain. You receive the following laboratory values:
Blood gas: pH 7.20 (7.33-7.46), pCO2 20 (40-50 mmHg), HCO3 9 (22-27 mmol/L)
Na 136 (135-145 mmol/L)
K 4.7 (3.5-5.0 mmol/L)
Cl 99 (95-107 mmol/L)
Glucose 1.4 (3.5-7.7 mmol/L)
Ammonia 600 (10-55 umol/L)
Lactate 3.6 (0.5-2.5 mmol/L)

a) List 4 additional tests you want to help you make the diagnosis.
b) Acylcarnitine profile shows an elevated C3 carnitine level. List 3 conditions on your differential diagnosis for this case.

Answer 2

a)
Plasma amino acids
Urine organic acids
Acylcarnitine profile
Total and free carnitine
Urine for ketones
Urine for orotic acid

b)
Methylmalonic acidemia (most likely in this case)
Propionic acidemia
Cobalamin C deficiency
Cobalamin A/B deficiency
Biotinidase deficiency/holocarboxylase synthetase deficiency
SUCLA2/SUCLG1-related mitochondrial disorders