ALAD – Porphyria due to ALA Dehydratase Deficiency

Delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP) is an ultrarare autosomal recessive acute hepatic porphyria caused by deficient porphobilinogen synthase activity leading to episodic neurovisceral attacks. Only eight bona fide cases have been documented, all confirmed by immunological and molecular analyses in unrelated probands (PMID:15303011)(PMID:33199206).

Genetic evidence supports AR inheritance with compound heterozygous ALAD variants identified in six unrelated families. A total of eight probands harbored splice-region (c.165-11C>A and c.165-11C>T) and missense mutations, with parental carriers confirmed by erythrocyte enzyme assays but remaining asymptomatic (PMID:15303011)(PMID:33199206).

The variant spectrum includes two intronic splice-site changes c.165-11C>A and c.165-11C>T disrupting exon 3, and missense alleles such as c.36C>G (p.Phe12Leu) and c.724G>A (p.Val242Ile). Broader screening has revealed at least eight pathogenic missense variants (F12L, E89K, C132R, G133R, V153M, R240W, A274T, V275M) across multiple cohorts (PMID:17236137).

Functional studies demonstrate loss of ALAD activity and altered quaternary assembly. Message amplification phenotyping identified p.Ala274Thr with deficient transcript levels (PMID:2222472), while CHO cell expression of p.Arg240Trp and p.Ala274Thr yielded markedly reduced enzyme activity (PMID:1309003). Conformational analyses confirm a shift to low-activity hexamers in porphyria-associated variants (PMID:17236137).

Clinically, ADP presents with recurrent abdominal colic (HP:0011848) and polyneuropathy, with urinary ALA elevated up to 32-fold and coproporphyrin 76-fold above normal during attacks. Intravenous hemin infusion reduces ALA and porphyrin levels by ~50% during acute episodes and prevents relapses when administered weekly (PMID:15303011)(PMID:33199206).

Integration of genetic, enzymatic, and structural data establishes a definitive AR mechanism via haploinsufficiency and conformational destabilization. Diagnostic evaluation should include genetic sequencing of ALAD and erythrocyte enzyme assays. Hemin therapy remains the cornerstone of management. Key Take-home: Genetic confirmation of compound heterozygous ALAD variants directs diagnosis and guides effective hemin-based therapy in ADP.

References

• Journal of inherited metabolic disease | 2004 | The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. PMID:15303011
• Molecular genetics and metabolism | 2020 | 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin. PMID:33199206
• American journal of human genetics | 2007 | ALAD porphyria is a conformational disease. PMID:17236137
• Biochemical and biophysical research communications | 1990 | Message amplification phenotyping of an inherited delta-aminolevulinate dehydratase deficiency in a family with acute hepatic porphyria. PMID:2222472
• Transactions of the Association of American Physicians | 1992 | Cloning and expression of the defective genes in delta-aminolevulinate dehydratase porphyria: compound heterozygosity in this hereditary liver disease. PMID:1309003

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