Somatic mosaicism in the δ-aminolevulinate dehydratase gene causing late-onset porphyria with erythroid-driven pathogenesis.

δ-Aminolevulinate dehydratase deficiency porphyria (ADP) is an extremely rare autosomal recessive disorder, with only 12 previously reported cases. It is characterized by the accumulation of delta-aminolevulinic acid (ALA), which is associated with neurovisceral symptoms. We report the first case of ADP in Russia with late-onset symptoms and unique genetic findings. A 47-year-old Russian woman experienced recurrent abdominal pain, tachycardia, hypertension, and neuropathy onset at age 38. Biochemical tests revealed a marked and persistent elevation of urinary ALA, whereas PBG levels showed only moderate and episodic increases. Whole-exome sequencing (WES) revealed two variants in the ALAD gene: a novel heterozygous variant c.299dup, p.(Ala101SerfsTer3) and a mosaic (19% of reads) c.415G>A, p.(Gly139Arg). The c.299dup variant was detected in blood and fibroblasts, while the c.415G>A variant was found only in blood, confirming its mosaic state. The c.415G>A variant was recently reported in a neonatal ADP case as a paternally inherited allele, in contrast with its de novo mosaic origin in our patient. Somatic mosaicism has not been previously described for this disease. Accumulating evidence, including the findings from our case, points to a significant contribution of the erythroid lineage to the disease pathogenesis, suggesting that ADP involves both hepatic and erythroid components, whose relative contributions depend on the tissue-specific genotype and other precipitating factors.