Inherited Disorders of Haem Synthesis:

Abstract

The porphyrias are inherited metabolic disorders resulting from partial deficiency of enzymes of the haem biosynthetic pathway. Each particular enzyme deficiency gives rise to increased levels of metabolites prior to the pathway blockage, which result in characteristic clinical features, and allow the individual conditions to be diagnosed. The acute neurovisceral attacks, which are common to ALA dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria are the result of neuronal damage by a mechanism which involves accumulation of ALA. Cutaneous manifestations comprise either bullous lesions (fragile skin, blisters), which are common to congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), VP and HCP, or acute photosensitivity which is associated with erythropoietic protoporphyria (EPP). Skin lesions result from photoactivation of circulating porphyrins by light (400–410 nm) resulting in the generation of free oxygen radicals with the different presentations explained by the physicochemical properties of the individual porphyrins. All the porphyrias, apart from the sporadic form of PCT, are inherited either as autosomal dominant (AIP, HCP, PCT, VP, EPP) or autosomal recessive (ADP, CEP) disorders. The molecular genetics of each disorder has been fully characterised and investigation at the DNA level is now indispensable in management of families as it allows accurate presymptomatic testing, and genetic counselling. The mainstay of management remains prevention, either by avoiding sunlight in the case of the cutaneous porphyrias or, in the acute porphyrias, factors such as prescribed drugs which are known to precipitate acute attacks. For severely affected patients newly developed treatments include liver transplantation (in AIP) and bone marrow transplantation in CEP Active research is underway to develop enzyme replacement for AIP and gene therapy for the erythropoietic porphyrias.