The first case of a newborn with co-occurring long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, a long chain fatty acid oxidation disorder (LCFAOD), and Crigler-Najjar syndrome type 1 (CN1) was recently reported in the American Journal of Medical Genetics.

The newborn (male) was born at 36 weeks of gestation with appropriate weight and in good condition (Apgar scale 9/10). Pregnancy was also uneventful, with no evidence of congenital malformations or family history of hereditary diseases. Four days after being discharged from the hospital, the newborn was readmitted due to progressive nonhemolytic jaundice, and the medical team started phototherapy.

Extended metabolic neonatal screening tests revealed an abnormal acylcarnitine profile, and additional molecular analysis confirmed the diagnosis of LCHAD and identified homozygous pathogenic variant in the HADHA gene (chromosome 2p23). The diagnosis prompted the medical team to initiate a high carbohydrate, low-fat content diet supplemented with medium-chain triglycerides.


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Despite the daily phototherapy, the levels of unconjugated bilirubin remained constantly elevated (250-310 μmol/L). “The observed non-hemolytic unconjugated hyperbilirubinemia with normal liver function, which did not respond to continued phototherapy, suggested a loss or reduced activity of [uridine 5′-diphospho]-glucuronyl transferase, typical for [Crigler-Najjar syndromes],” the authors said.

The team conducted additional genetic studies which identified a pathogenic variant in the UGT1A1 gene (chromosome 2q37) consistent with CN1, another autosomal recessive pathology. The 2 point mutations identified on chromosome 2 were homozygous and localized on separate arms., and microarray analysis of the family genetic material confirmed paternal isodisomy of chromosome 2.

“A better understanding of the combined effect of the two diagnosed metabolic abnormalities could help plan the best possible treatment and care to ensure a good quality of life for this very young patient,” the authors concluded.

Reference

Knapp A, Jagła M, Madetko‐Talowska A, et al. Paternal uniparental disomy of chromosome 2 resulting in a concurrent presentation of Crigler–Najjar syndrome type I and long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency. Am J Med Genet Part A. Published online February 24, 2022. doi:10.1002/ajmg.a.62696