Late-onset porphyrias: what are they?

Area of Science:

• Biochemistry
• Genetics
• Hematology

Background:

• Porphyrias are inherited metabolic disorders affecting heme biosynthesis.
• Autosomal recessive porphyrias, such as ALA dehydratase porphyria (ADP) and congenital erythropoietic porphyria (CEP), typically manifest in childhood.
• Late-onset presentations of these porphyrias are rare but documented.

Observation:

• A 63-year-old patient with late-onset ADP presented with acute porphyria symptoms.
• This patient also had polycythemia vera, a clonal hematopoietic stem cell disorder.
• Literature review revealed late-onset CEP cases associated with myelodysplastic syndrome (MDS), another clonal disorder.

Findings:

• The late-onset ADP was attributed to the clonal expansion of an abnormal ALAD allele by polycythemia vera.
• The association of late-onset CEP with MDS suggests a common underlying mechanism involving clonal hematologic abnormalities.
• These cases indicate that late-onset recessive porphyrias may occur in heterozygotes when a loss of heterozygosity event impacts the porphyria-related gene.

Implications:

• Late-onset recessive porphyrias might be unmasked by acquired clonal events in hematopoietic cells.
• Loss of heterozygosity, through allelic expansion or secondary mutation, can precipitate clinical symptoms in predisposed individuals.
• Understanding these mechanisms is crucial for diagnosing and managing late-onset porphyrias, particularly when co-occurring with hematologic malignancies.