Refsum Syndrome

A rare disorder of lipid metabolism characterized by peripheral neuropathy, ataxia, retinitis pigmentosa, and bone and skin changes. Other features include cutaneous ichthyosis and cardiac failure.

Phytanic Acid Oxidase Deficiency; Heredopathia Atactica Polyneuritiformis; Hereditary Motor and Sensory Neuropathy IV.

Autosomal recessive. This slowly progressive disorder is most common in children and young adults of Scandinavian heritage.

Phytanic acid is derived from the metabolism of chlorophyll. Refsum disease is caused by mutations in the gene encoding phytanoyl-CoA hydroxylase (PAHX or PHYH) or the gene encoding peroxin-7 (PEX7), resulting in accumulation of exogenous phytanic acid (milk, fat of cows and sheep) in blood plasma and tissues. It belongs to the pathological group of leukodystrophy that affects growth of the myelin. Genes are located on 6q22-q24 and 10pter-p11.2.

Usually evocated and diagnosed during childhood or young adulthood on the association of retinitis pigmentosa, chronic polyneuropathy, and cerebellar signs. It can be confirmed by laboratory investigations: phytanic acid oxidase deficiency and 3,7,11,15-tetramethyl-hexadecanic acid in serum and tissue deposits. Histological analysis shows interstitial hypertrophic polyneuritis and degeneration of nuclei and fiber tracts in brainstem.

Congenital skeletal abnormalities can occur: multiple epiphyseal dysplasia, and bilateral fourth metatarsal shortening. Progressive problems appear secondarily: ocular (retinitis pigmentosa, myosis, ptosis, cataract, nystagmus), neurological (chronic polyneuritis, cerebellar signs, ataxia, anosmia, nerve deafness, hypotonia, hemiparesis), cardiac (electrocardiographic changes, congestive heart failure), and cutaneous (ichthyosis). Other features include renal failure, amyotrophy, and respiratory distress.

A complete evaluation of the cardiac function (echography, ECG, radionuclide imaging if necessary); renal function (kalemia, urea, creatinine); respiratory function (chest radiograph, arterial blood gas analysis, pulmonary function test) must be obtained. A review of the neuropathy evolution and muscular weakness is essential.

Exacerbation of this disease has been observed with surgery and pregnancy. Perioperative fluid management should be realized in case of renal dysfunction. Careful perioperative positioning is necessary to avoid nerve compression in these patients with neuropathy. Cardiac perioperative monitoring is necessary because of the risk of ECG change.

Avoid cardiodepressive, ototoxic, and nephrotoxic drugs. Aminoglycosides can be used, but real interest has to be evaluated in the presence of incomplete deafness or renal dysfunction. Avoid succinylcholine in patients with neuropathy (risk of hyperkalemia). Local anesthetics are not contraindicated; however, the interest should be evaluated in consideration for an evolutive neuropathic disease. Clear information has to be given and understood by the patient.

Refsum Infantile Form (Infantile Phytanic Acid Storage Disease): Autosomal recessive. Caused by mutations in peroxisomal membrane protein-3 (35 kDa); gene located on 8q21.1, 7q21-q22. Clinical features include early onset, mental retardation, minor facial dysmorphism, retinitis pigmentosa, sensorineural hearing deficit, hepatomegaly, osteoporosis, failure to thrive, and hypocholesterolemia.

Refsum Disease with Increased Pipecolic Acidemia (RDPA): Autosomal recessive. Gene located on 10pter-p11.2. Characterized by accumulation of l-pipecolic acid and clinically by rapidly progressing neurological deteriorations.

Note: Refsum Disease can be confused with other similar disorders, including Bassen-Kornzweig Disease and Kearns-Sayre Syndrome. (See each description in the book)