CPT1A – Carnitine palmitoyltransferase 1A deficiency

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an autosomal recessive disorder of mitochondrial long-chain fatty acid oxidation, characterized by recurrent hypoketotic hypoglycemia, hepatomegaly, and cholestatic features. Early case reports identified an infant with Reye-like episodes and distal renal tubular acidosis (PMID:7877875) and subsequent individual reports described hepatic steatosis, cholestatic jaundice, and encephalopathy in isolated patients (PMID:15669684; PMID:23430491; PMID:27066452; PMID:28748224; PMID:39086449).

Larger multi-patient cohorts have confirmed autosomal recessive inheritance in over 50 affected individuals across diverse populations (PMID:12189492; PMID:11350182; PMID:35822099). Genotype-phenotype correlations include a common 'Arctic' p.Pro479Leu founder allele (c.1436C>T (p.Pro479Leu)) with residual activity and a Micronesian c.100T>C (p.Ser34Pro) variant associated with milder biochemical abnormalities.

The variant spectrum encompasses missense, nonsense, splice site, small insertion/deletion, and large genomic deletions. Representative pathogenic changes include c.1436C>T (p.Pro479Leu) and c.2129G>A (p.Gly710Glu), the latter abolishing activity in yeast and patient fibroblasts (PMID:11350182). Novel splice and frameshift mutations have also been reported from newborn screening populations in China, Finland, and the Hutterite community.

Functional assays demonstrate markedly reduced CPT1A enzymatic activity in patient fibroblasts and heterologous expression systems. The D454G missense change causes protein instability and <2% residual activity in yeast and immunoblot studies (PMID:9691089). Structural modeling categorizes mutations as active-site versus stability determinants, both resulting in impaired β-oxidation and ketogenesis.

No significant conflicting evidence has been reported; all studies uniformly support loss-of-function as the disease mechanism. Variants in CPT1B and secondary regulators do not account for hepatic‐isoform deficiency.

Clinical integration of genetic and functional findings permits definitive molecular diagnosis, guiding dietary management with low-fat, high-carbohydrate regimens and avoidance of fasting. Newborn screening identifies presymptomatic cases, improving outcomes. CPT1A deficiency represents a well-validated autosomal recessive disorder with clear clinical utility for genetic testing and targeted therapy.

Key Take-home: CPT1A deficiency is a strongly supported autosomal recessive fatty acid oxidation disorder; molecular diagnosis and enzymatic confirmation are critical for early intervention.

References

• Pediatric Research • 1994 • Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency PMID:7877875
• Journal of inherited metabolic disease • 2004 • Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation PMID:15669684
• JIMD reports • 2013 • Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency PMID:23430491
• Pediatric gastroenterology, hepatology & nutrition • 2016 • Novel Mutations in the CPT1A Gene Identified in the Patient Presenting Jaundice as the First Manifestation of Carnitine Palmitoyltransferase 1A Deficiency PMID:27066452
• International journal of neonatal screening • 2017 • Utility of Genetic Testing for Confirmation of Abnormal Newborn Screening in Disorders of Long-Chain Fatty Acids: A Missed Case of Carnitine Palmitoyltransferase 1A (CPT1A) Deficiency PMID:28748224
• Journal of pediatric genetics • 2024 • Prolonged Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency PMID:39086449
• Human genetics • 2002 • Organization of the human liver carnitine palmitoyltransferase 1 gene (CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia PMID:12189492
• Molecular genetics and metabolism • 2001 • Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community PMID:11350182
• JIMD reports • 2022 • Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations PMID:35822099
• The Journal of clinical investigation • 1998 • Molecular basis of hepatic carnitine palmitoyltransferase I deficiency PMID:9691089

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