X-linked sideroblastic anemia (XLSA) and the porphyrias are inherited metabolic disorders resulting from the decreased activities of specific enzymes in the heme biosynthetic pathway. Porphyrias are classified as “hepatic” or “erythroid,” reflecting the predominant accumulation site of metabolic intermediates, and as “acute” or “cutaneous” depending on the major clinical features (Table 124-1). In addition to the underlying enzymatic defect, the clinical severity of the hepatic porphyrias is greatly influenced by environmental and endogenous factors, including drugs, hormones and diet, while disease severity in the erythropoietic disorders depends primarily on the specific mutation(s).

XLSA is an X-linked recessive disorder due to deficient activity of erythroid-specific 5-aminolevulinic acid synthase (ALAS2), the first enzyme in the pathway. Reduced heme synthesis stimulates erythropoiesis, which is ineffective, increasing erythron iron turnover and causing nonferritin iron accumulation in the mitochondria that surround proerythroblast nuclei, giving rise to the characteristic ring sideroblasts. Clinical onset is variable, usually occurring in the second or third decade of life, although later-onset forms can result from milder mutations. The defective enzyme and associated anemia is typically pyridoxine-responsive, but responsiveness can be impaired by significant iron accumulation.

5-Aminolevulinic acid dehydratase porphyria (ADP), an autosomal recessive hepatic disorder, results from the deficient activity of 5-aminolevulinic acid dehydratase (ALAD), the second enzyme in the pathway. In the few reported cases, clinical manifestations were primarily neurologic, without cutaneous photosensitivity.

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal dominant disorder resulting from the half-normal activity of porphobilinogen deaminase [PBGD] (also known as hydroxymethylbilane synthase). Although most carriers (>80 percent) do not develop symptoms, other carriers have neurologic manifestations that are usually intermittent, but no cutaneous photosensitivity. Symptoms usually develop after puberty, are more frequent in women than in men, and are often exacerbated by certain sex steroids, drugs, and diet that induce the housekeeping form of 5-aminolevulinic acid synthase (ALAS1) in the liver, causing increased synthesis of heme pathway intermediates. Neurologic manifestations, which are poorly understood, may result from excess intermediates or from heme deficiency in the nervous system. Glucose and heme administration decreases ALAS1 activity and provides effective therapy.

Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, results from the markedly deficient activity of uroporphyrinogen III synthase [UROS] (also known as uroporphyrinogen III cosynthase). Clinical severity can range from nonimmune hydrops in utero to transfusion-dependent anemia with severe photosensitivity in early childhood and to relatively mild cutaneous photosensitivity in adults. Skin lesions may become infected leading to scarring and deformities. Chronic transfusions for anemia will reduce erythropoiesis and porphyrin accumulation, whereas bone marrow transplantation can be curative.

Porphyria cutanea tarda (PCT), the most common porphyria, results from the decreased activity of uroporphyrinogen decarboxylase (UROD). The clinically indistinguishable subtypes include type 1 (sporadic, most common), type 2 (familial, autosomal dominant), and type 3 (familial, very rare). Only type 2 results from inherited systemic UROD deficiency. In the other types, UROD activity is inhibited or inactivated only in the liver. Factors that can precipitate all subtypes include excess hepatic iron, ethanol use, hepatitis C, HIV infection, estrogen administration, and induction of cytochrome P450 enzymes, as occurs in smokers. Hemochromatosis (HFE) gene mutations also may predispose to PCT. All subtypes respond to repeated phlebotomy or low-dose chloroquine or hydroxychloroquine. Hepatoerythropoietic porphyria (HEP) is an autosomal recessive disease resulting from the marked systemic deficiency of UROD, and clinically resembles CEP with hemolysis, anemia, increased erythrocyte porphyrins, and cutaneous photosensitivity, usually from birth.

Hereditary coproporphyria (HCP) is an autosomal dominant hepatic porphyria resulting from the half-normal activity of coproporphyrinogen oxidase (CPO). The clinical features, precipitating factors, and treatment are essentially identical to those of AIP. Occasional skin photosensitivity occurs.

Variegate porphyria (VP) is an autosomal dominant hepatic porphyria due to the half-normal activity of protoporphyrinogen oxidase (PPO). The clinical features, precipitating factors, and treatment are similar to those of AIP. Photosensitivity is more common than in HCP. The skin lesions are readily confused with PCT and do not respond to phlebotomy or chloroquine. A founder mutation is responsible for its high prevalence in South Africa.

Erythropoietic protoporphyria (EPP) is an autosomal dominant disorder due to the decreased activity of ferrochelatase. EPP is characterized by high levels of protoporphyrin in erythrocytes, bone marrow, and plasma, and mild to moderate cutaneous photosensitivity. Skin redness and swelling commonly occur after sunlight exposure, in contrast to the chronic, blistering lesions that characterize other cutaneous porphyrias. β-Carotene, and especially avoidance of sunlight, are important for prevention of cutaneous symptoms. Hepatic failure, sometimes associated with severe blistering and motor neuropathy, is an uncommon complication and may require liver transplantation.

Genotype/phenotype correlations have been established for certain porphyrias, each having a variety of severe to mild mutations. Rare homozygous autosomal dominant porphyrias have been described. “Dual porphyria” results from simultaneous occurrence of two porphyrias.

Treatment and genetic counseling depend on accurate diagnosis. Initial diagnostic screening for symptomatic acute porphyrias should include urinary porphyrin precursors (5-aminolevulinic acid and porphobilinogen) and plasma total porphyrins for cutaneous porphyrias. Enzyme assays and DNA analyses are useful for diagnostic confirmation, detection of asymptomatic individuals, and genetic counseling.