A

Immunoisolatory

membrane

Oxygen and nutrients

Immune system components

Therapeutic

factors

B

Figure 28.2  Depiction of encapsulated cell technology showing the structure of the intravitreal implant (A) containing the cells secreting a known concentration of ciliary neurotrophic factor (CNTF). The implant is also shown in cross-section (B).

egress of CNTF into the vitreous cavity, allows influx of various nutrients and oxygen, but prevents the entry of immune antibodies (Figure 28.2B). This device allows for long-term sustained delivery of constant levels of CNTF in the vitreous cavity close to the retina (Figure 28.3). Another advantage of this technology is that it can be retrieved, if needed. It was implanted in dog and rabbit models of RP with no deleterious effects on ERG. Based on several prior animal studies, a phase I human clinical trial was completed in 10 patients with RP, which showed that the implant was relatively safe for a period of at

REFSUM’S DISEASE

Refsum’s disease is a rare autosomal-recessive disorder caused by defective alpha-oxidation of phytanic acid (3,7,11,15 tetramethylhexadecanoic acid), a branched-chain fatty acid. The source of phytanic acid is all exogenous and comes from a wide range of food products, including dairy products, some meats, and fish.15 The physiological role of phytanic acid in the body is unknown and is normally metabolized by an enzyme phytanoyl-CoA hydroxylase, which converts it to pristanic acid.16 Deficiency of this enzyme results in accumulation of phytanic acid, with elevated levels in blood, cerebrospinal fluid, and other tissues, including fat and neurons.17,18 In the eye, accumulation of phytanic acid in the RPE is postulated to interfere with vitamin A esterification and progressive visual function loss.

Clinically, there is RP-like retinal degeneration associated with cerebellar ataxia, polyneuropathy, elevated levels of proteins in cerebrospinal fluid with normal cell count, nerve deafness, and ichthyosis. Plasma phytanic acid concentration of more than 200 mol/l is diagnostic for Refsum’s disease. It is now considered to be a peroxisomal disorder with mutations having been identified in two genes: PHYH, the gene encoding phytanoyl-CoAhydroxylase and PEX7, the gene that encodes the type 2 peroxisome-targeting signal receptor.

Treatment

Dietary restriction

Since the source of phytanic acid is almost exclusively dietary, the key factor in the treatment of Refsum’s disease is dietary restriction.19 An average diet consists of 50–100 mg/day of phytanic acid. Fish, lamb, beef, and dairy products are rich sources of phytanic acid.20 Restriction of dietary consumption to 10–20 mg/day is required to decrease serum levels. Obviously, the sooner the restriction starts in life, the less the pathological damage. Improvement in ataxia, polyneuropathy, motor nerve conduction velocity, and cerebrospinal fluid protein levels after initiation of treatment has been reported. However, the factors that negatively affect patient compliance are that the effect of diet restriction is not seen immediately as phytanic acid has to be mobilized from the body lipids,18,19 and diets low in phytanic acid are extremely unpalatable.