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Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations

Isaac Bernhardt1, Emma Glamuzina1, Leah K Dowsett2,3

  • 1National Metabolic Service Auckland City Hospital and Starship Children's Hospital Auckland New Zealand.

JIMD Reports
|July 13, 2022
PubMed

Insights

Carnitine palmitoyltransferase 1A (CPT1A) deficiency diagnosis has increased with expanded metabolic screening. This study identifies two new CPT1A variants in Micronesian and Niuean populations, highlighting genotype-phenotype correlations for improved newborn screening and patient care.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disorders

Background:

  • Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare genetic disorder affecting long-chain fatty acid oxidation.
  • Expanded metabolic screening (EMS) has increased CPT1A deficiency detection rates in newborn populations.
  • Pacific Islander populations, including Micronesians and Niueans, are increasingly recognized in metabolic screening contexts.

Purpose of the Study:

  • To identify and characterize novel CPT1A variants in Micronesian and Niuean populations.
  • To investigate the genotype-phenotype correlations of these variants.
  • To inform newborn screening protocols and clinical management for these populations.

Main Methods:

  • Genetic analysis of individuals with CPT1A deficiency from Micronesian and Niuean ancestries.
  • Enzyme activity assays using cultured skin fibroblasts.
  • Clinical data review for metabolic decompensation and presentation.

Main Results:

  • A novel CPT1A c.100T>C (p.S34P) variant was identified in 22 Micronesian individuals, with residual enzyme activity of 26% and no clinical decompensation.
  • A CPT1A c.2122A>C (p.S708R) variant was found in three Niuean individuals, exhibiting severe enzyme deficiency (4% activity) and classic CPT1A deficiency symptoms.
  • Asymptomatic adults homozygous for the Micronesian variant were identified through family screening.

Conclusions:

  • The study identified two distinct CPT1A variants in Pacific Islander populations, with varying clinical presentations and enzyme activities.
  • Understanding these genotype-phenotype correlations is crucial for accurate diagnosis and management of CPT1A deficiency detected through newborn screening.
  • Increased migration may lead to a higher prevalence of these variants in global metabolic services, necessitating awareness and tailored approaches.

Keywords:
CPT1Acarnitine palmitoyltransferase type 1 deficiencyfatty acid oxidation disordersnewborn screening

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