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Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias Clinical Presentation

  • Author: Norman C Reynolds, Jr, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
Updated: Aug 20, 2014


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.


See the list below:

  • 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.


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.
Contributor Information and Disclosures

Norman C Reynolds, Jr, MD Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin

Norman C Reynolds, Jr, MD is a member of the following medical societies: American Academy of Neurology, Association of Military Surgeons of the US, International Parkinson and Movement Disorder Society, Sigma Xi, Society for Neuroscience

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kenneth J Mack, MD, PhD Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, Society for Neuroscience

Disclosure: Nothing to disclose.

Chief Editor

Stephen A Berman, MD, PhD, MBA Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Ann M Neumeyer, MD Medical Director, Lurie Center for Autism; Assistant Professor of Neurology, Harvard Medical School; Child Neurologist, Massachusetts General Hospital

Ann M Neumeyer, MD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Massachusetts Medical Society

Disclosure: Nothing to disclose.

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Tetrapyrrole molecules are large-ringed structures developed from 4 pyrrole groups and used in energy metabolism in both plants and animals.
Three characteristic substrate molecules of the heme porphyrin pathway.
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