Abstract
BACKGROUND: Dysfunction of δ-aminolevulinic acid dehydratase (ALAD), the second enzyme involved in heme biosynthesis, leads to two pathologies: genetic and acquired. The genetic form is an ultrarare, severe childhood-onset disease inherited in an autosomal recessive manner, whereas the acquired form usually affects adults due to enzyme inhibition by specific chemicals. AIMS AND PATIENT COHORT: This study reports the molecular characterization of three pediatric patients with genetic ALAD deficiency porphyria (ADP), including two siblings, and five adults who exhibited features suggestive of heavy metal poisoning. Furthermore, using an innovative mouse liver model, we performed in vivo functional analysis of the pathogenic variants and lead susceptibility alleles identified in the ALAD gene. RESULTS: Siblings (one female) were found to carry the c440_441delinsTT (p.Arg147Leu) variant in homozygosis. However, the vector expression system confirmed a pathogenic role only for the c.440C > T substitution. The third patient exhibited compound heterozygosity, with a c.839G > A (p.Gly280Glu) dominant variant and a hypomorphic c.724G > A (p.Val242Ile) allele. The rs1805313 and rs8177800 common intron variants were most prevalent in patients with acquired ADP. However, increased ALAD activity for the rs1139488 synonymous variant and a hexameric ALAD conformation for the rs1800435 missense variant have been established. CONCLUSION: These findings underscore the molecular heterogeneity of the ALAD gene and present the first reported case of ADP in a female patient.