Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias

The neurotoxin in Refsum disease is phytanic acid, which in affected individuals is stored in neural and visceral parenchyma because of a deficiency in phytanic acid alpha-hydroxylase. The source of phytanic acid is either direct absorption or conversion of absorbed phytol from ruminant fat in meat or milk (only ruminants can release phytol from chlorophyll during digestion). Homozygosity is required for significant phytanic acid build-up.

The hepatic porphyrias also are associated with neurologic problems. The neurotoxins in these conditions are porphyrin precursors (delta-aminolevulinic acid [ALA], porphobilinogen [PBG]) and porphyrinogen substrates in heme synthesis, whose levels are elevated (see the image below). The actual porphyrins are oxidized products of the substrates, which are excreted in the feces and urine (the latter characterized by its reddish-brown, fluorescent color.)

Three characteristic substrate molecules of the heme porphyrin pathway.

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Whereas the enzyme deficiency in Refsum disease is inherited in an autosomal-recessive pattern, the enzyme deficiencies involved in the hepatic porphyrias typically are inherited in an autosomal-dominant mode. The hepatic porphyrias account for a varying spectrum of upstream accumulations of porphyrins and porphyrin precursors specific to each type of porphyria. ^[2] The following are common hepatic porphyrias:

• Acute intermittent porphyria (AIP) - Uroporphyrinogen synthase (or "porphobilinogen deaminase") deficiency with high ALA or PBG in urine and serum

• Variegate porphyria (VP) - Protoporphyrinogen oxidase deficiency ^[3] with high fecal levels of protoporphyrin and coproporphyrin ^[4]

• Hereditary coproporphyria - Coproporphyrinogen oxidase deficiency with high urinary and/or fecal levels of coproporphyrins

• Porphyria cutanea tarda (PCT) - Uroporphyrinogen decarboxylase deficiency with high urinary and red cell levels of uroporphyrin

• ALA dehydratase deficient porphyria (rare)

• Erythropoietic protoporphyria (EPP), "protoporphyria", or "erythrohepatic protoporphyria" (not a hepatic porphyria) ^{[5, 6]} 5 ​: ferrochelatase deficiency, whereby fecal and erythrocyte levels of protoporphyrins are increased without any urinary porphyrins; abnormal porphyrin metabolism originates in erythrocytes, not the liver, yet ironically, patients with EPP may develop chronic liver failure; EPP is not characterized by neurologic symptoms and does not respond to sugar or hemin (ie, hematin) treatment

Refsum disease is rare, but heterozygote carriers may be at risk if they have diets highly selective for beef and dairy products.

The incidence of acute intermittent porphyria is 5-10 per 100,000 (underestimated because of positive cases not being induced and long periods of latency). AIP is widely believed to be latent in 90% of cases. Porphyria cutanea tarda is believed to be the most common type, but because of poor recording, no data have been published. Erythropoietic protoporphyria is also believed to be common but not clearly documented. Other forms of true hepatic porphyrias are rare except variegate porphyria in individuals with ancestry of Afrikaner lineage. Variegate porphyria is common in South Africa (about 3 cases per 1000 population).

Mortality/Morbidity

Both Refsum disease and hepatic porphyrias are characterized by remissions and exacerbations of neurologic dysfunction, which can resolve completely or manifest stepwise deterioration. Permanent residual deficits are not uncommon; residual defects during latent periods include polyneuropathy in both conditions, ataxia and retinitis pigmentosa with night blindness in Refsum disease, ^[7] and photosensitive dermatitis in porphyrias (rare in acute intermittent porphyria). Death in either disease is commonly caused by cardiac arrhythmias during exacerbations. Cardiomyopathy can occur in Refsum disease owing to phytanic acid storage and in acute porphyric crises owing to electrolyte disturbance (in as many as 25% of acute intermittent porphyria cases).

Race

Both Refsum disease and the porphyrias tend to occur more often in individuals of white hereditary lineage. The exception is porphyria cutanea tarda, which is noted among blacks of Bantu lineage (as well as whites).

Acute intermittent porphyria is most common among whites of English or Scandinavian heritage. Variegate porphyria is most common among Afrikaners, selectively concentrated in royal European lineage (eg, as documented in the popular film "The Madness Of King George"), and also present in certain large families of Great Britain, Holland, Sweden, and the United States.

Sex

Prevalence is expected to be equal between the sexes because of autosomal inheritance; however, clinical attacks may be more common in females with acute intermittent porphyria and in males with porphyria cutanea tarda. Consanguinity, causing the homozygous recessive condition, is not an uncommon cause of Refsum disease.

Age

Initial attacks in both disease categories can occur in early childhood, but in the hepatic porphyrias, the onset is usually postpubertal. ^[8] Erythropoietic protoporphyria is characterized by childhood onset of acute cutaneous photosensitivity to direct sunlight.

Childhood epilepsy is an exception to the postpuberty onset rule for initial porphyric attacks in the hepatic forms. Long-term drug use in idiopathic epilepsy with inactive or latent hepatic porphyria, even in prepubertal children, is a potent activator of cytochrome P450. Liver synthesis of heme groups is accelerated, leading to high levels of porphyrins and premature porphyric crises.

Earlier-onset Refsum disease is due to a pervasive dietary risk from consuming large quantities of beef and, to a greater degree, milk. For this same reason, persisting residual deficits are typical by age 20 years. Sporadic intake of provocative drugs in latent porphyria can induce exacerbations and eventually lead to persisting residual deficits.

Prognosis in Refsum disease and the hepatic porphyrias depends entirely on the proper dietary and drug restrictions.

The patient's ability to survive an acute exacerbation depends on the adequacy of acute care (especially the care available in an intensive care unit).

Survival in an acute porphyric attack depends on monitoring levels of porphyrins and the proper use of D10W and hemin infusions. Despite appropriate treatment measures, mortality rate in acute attacks of acute intermittent porphyria may be as high as 25%.

Both patients with Refsum disease and those with porphyria must become experts in understanding their disease. Both the Hereditary Disease Foundation and the American Porphyria Foundation can be a source of peer support and information for patients and physicians.

Monitoring of phytanic acid and ALA/PBG levels is a key element in providing outpatient treatment.

For patients with Refsum disease, specific review of safe dietary patterns must be a regular part of outpatient care.

Safety of specific drugs must be emphasized to the patient with porphyria (ie, avoiding drugs that induce cytochrome P450 activity). Encourage patients to seek advice by telephone if they have questions or concerns.

Genetic inheritance patterns must be understood, so that the patient can exercise responsibility in sexual relations or family planning.

Patients with porphyria have a 50% risk of passing along an autosomal-dominant trait with high expressivity.

Patients with Refsum disease should avoid marriage or sexual involvement with blood relatives (consanguinity), especially if distant relatives have diagnoses of neurodegenerative disease with childhood onset. Planning offspring is especially difficult, since no simple method is available to detect heterozygotes in this autosomal-recessive disease.