eMedicine Specialties > Neurology > Introductory Topics

Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias

Author: Norman C Reynolds Jr, MD, Neurologist, Veterans Affairs Medical Center of Milwaukee
Contributor Information and Disclosures

Updated: Mar 23, 2009

Introduction

Background

Refsum disease and the hepatic porphyrias are rare inherited neurodegenerative conditions with exacerbations and remissions due to abnormal metabolism of large tetrapyrrole molecules.

Two common examples of large tetrapyrrole molecules are chlorophyll a, the photosynthetic pigment of green plants, and heme, the prosthetic group of hemoglobin (see Media file 1). Side groups on both species involve relatively small organic groups (methyl, vinyl, and free propionyl); 1 major exception is phytol, a large hydrocarbon alcoholic substituent on chlorophyll. Patients in both disease categories must avoid foods and drugs that lead to high levels of the relevant biological toxin, which can trigger or perpetuate an exacerbation.

Pathophysiology

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 neurological 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 Media file 2). 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.)

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. 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 deficiency¹ with high fecal levels of protoporphyrin and coproporphyrin²
• 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)
  • Ferrochelatase deficiency: 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.

Frequency

United States

• Refsum disease is rare, but heterozygote carriers may be at risk if they eat diets highly selective for beef and dairy products.
• Acute intermittent porphyria incidence ranges from 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.

International

It is the same as in the United States, but 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, 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. 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.

Clinical

History

Family history is critical in diagnosis.

• In Refsum disease, manifest cases are homozygous recessive. If the key symptoms of failing vision and cerebellar ataxia are present, consanguinity should be considered. On the other hand, sporadic cases might occur with heterozygotes who are on selective diets high in beef and dairy products.
• The porphyrias express an autosomal-dominant pattern, and the typical family has a history of combinations of photodermatitis and abdominal crises, concomitant mental and neurological symptoms, and urine of a reddish brown, fluorescent color.
• Patients typically have a history of remissions and exacerbations.
  • Exacerbations - Several days to 2 weeks
  • Remissions - Months to years
• Patients may have a history of drug-induced exacerbations (partial or significant) in the hepatic porphyrias but not in erythropoietic protoporphyria, which has obvious cutaneous photosensitivity and normal urine color during exacerbations without neurological sequelae.

Physical

• Findings in Refsum disease
  • Ocular changes - Retinitis pigmentosa, cataracts
  • Sensorimotor polyneuropathy
  • Nonspecific ECG changes
  • Anosmia
  • CN VIII deafness
  • Ichthyosis (can be widespread or limited to the palms)
  • Signs of epiphyseal dysplasia (eg, syndactyly, pes cavus, hammer toes)
• Findings in hepatic porphyrias
  • During remissions: Signs are limited to residual axonal polyneuropathy and skin sensitivity to mechanical trauma and photodermatitis; these are often disabling in porphyria cutanea tarda but rare in acute intermittent porphyria. In erythropoietic protoporphyria, scarred, thickened skin is due to multiple sun exposure reactions.
  • During acute attacks: Eighty percent of patients initially present with an acute abdomen, 20% ushered in with agitated and hysterical behavior.
    • Other manifestations are autonomic instability (tachycardia, labile blood pressure), generalized pain, segmental sensorimotor polyneuropathy, urinary frequency, and diarrhea.
    • Occasionally, patients present with seizures or coma.
    • Acute attacks in erythropoietic protoporphyria involve rapid-onset burning and edematous, blistering lesions.
  • In erythropoietic protoporphyria, exacerbations are characterized uniquely by acute cutaneous eruptions immediately after ultraviolet light exposure, including that from operating room lights. Ironically, chronic disease may lead to hepatic failure, which can be fatal.
  • In general, the hepatic porphyrias are not associated with hepatic failure but only liver-based aberrant porphyrin metabolism.

Causes

Both Refsum disease and the hepatic porphyrias can be exacerbated by nonspecific causes, particularly environmental stress and prolonged or severe illness.

• Causes unique to Refsum disease
  • Dietary intake of phytol and phytanic acid (from beef and milk)
  • Paradox: Liberal intake of chlorophyll-containing foods is perfectly safe, because hydrolysis to free phytol occurs only in the ruminant gut, not in the human digestive tract.
• Causes unique to hepatic porphyrias
  • Prolonged fasting, hypoglycemia
  • Long-term drug use that leads to increased cytochrome P450 activity: This increases delta-ALA synthase activity, the hepatic, rate-limiting enzyme for the heme/porphyrin pathway. Depending on the inherited enzyme deficiency, specific characteristic porphyrins may build up.
  • Other drugs with acute inducing capability: Experienced patients learn to avoid these.
  • Light (especially UV) can induce skin eruptions in porphyric patients with photocutaneous sensitivity. This sensitivity can be seen in several hepatic porphyrias, particularly porphyria cutanea tarda, but it is the sine qua non of erythropoietic protoporphyria and is the dominant, often sole, clinical problem in this nonhepatic porphyria.
  • Endogenous hormones: Some women have catamenial patterns of exacerbation initiated during the luteal phase of normal menstrual periods or during pregnancy.

• Search for CME/CE on This Topic »