Closing the loop: biochemical analysis and the VUS dilemma
Clinical Genetics and Therapeutics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism characterized by the elevated 3-methylcrotonylglycine and 3-OH-isovaleric acid observed in urine. Symptoms and onset of 3-MCC vary greatly from each person and even among family members. Symptoms include poor appetite, tiredness, hypotonia, spasticity and developmental delays.
Case Presentation
We present a 2-month-old baby who presented on newborn screen with elevated C5OH at 5.62umol/L (reference range <0.8umol/L).
Diagnostic Workup
Following the call out, he had an acylcarnitine profile that was flagged for elevated C5OH at 2.5umol/L (reference range <0.08umol/L) and a urine organic acid profile with large peaks of 3-methylcrotonylglycine and 3-OH isovaleric acid observed consistent with 3-MCC. Following biochemical analysis, molecular analysis of the newborn screening confirmation panel was performed revealing heterozygous mutations in the MCCC2 gene. One mutation, c.242dup, was classified as pathogenic while the other, c.1567A>G, was classified as a Variant of Uncertain Significance.
Treatment and Management
Since the initial findings, our patient has had decreased plasma carnitine levels requiring carnitine supplementation.
Discussion
This case is of great significance as it highlights the limitations of molecular analysis and the need for biochemical labs and gives clinical evidence to argue for reclassifying the VUS as Likely Pathogenic.
3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism characterized by the elevated 3-methylcrotonylglycine and 3-OH-isovaleric acid observed in urine. Symptoms and onset of 3-MCC vary greatly from each person and even among family members. Symptoms include poor appetite, tiredness, hypotonia, spasticity and developmental delays.
Case Presentation
We present a 2-month-old baby who presented on newborn screen with elevated C5OH at 5.62umol/L (reference range <0.8umol/L).
Diagnostic Workup
Following the call out, he had an acylcarnitine profile that was flagged for elevated C5OH at 2.5umol/L (reference range <0.08umol/L) and a urine organic acid profile with large peaks of 3-methylcrotonylglycine and 3-OH isovaleric acid observed consistent with 3-MCC. Following biochemical analysis, molecular analysis of the newborn screening confirmation panel was performed revealing heterozygous mutations in the MCCC2 gene. One mutation, c.242dup, was classified as pathogenic while the other, c.1567A>G, was classified as a Variant of Uncertain Significance.
Treatment and Management
Since the initial findings, our patient has had decreased plasma carnitine levels requiring carnitine supplementation.
Discussion
This case is of great significance as it highlights the limitations of molecular analysis and the need for biochemical labs and gives clinical evidence to argue for reclassifying the VUS as Likely Pathogenic.