( Diseases Degenerative/Dystrophic and Hereditary• 28Retinalchapter

AMD)-non

Plasmapheresis

Plasma exchange (PE) in Refsum disease can be helpful if the disease is severe or rapidly worsening. Lundberg et al. in 1972 first described the use of PE in two siblings who were resistant to treatment with dietary restriction alone.21 Since then PE has mainly been used in patients with Refsum’s disease whose serum phytanic acid levels are above 900 µmol/l, or patients not complying with the diet, or in cases where diet control is ineffective.22 However, PE can lead to complications including ventricular ectopic beats and urticarial rash.

GYRATE ATROPHY

Gyrate atrophy is a progressive chorioretinal dystrophy, characterized by well-demarcated scalloped areas of RPE and choroidal atrophy. It initially begins in the mid peripheral retina but extends both peripherally and centrally to become more diffuse later on. Inherited as an autosomal-recessive condition, it manifests by late childhood and is associated with hyperornithinemia. High ornithine levels are detectable in urine, plasma, aqueous humor, and cerebrospinal fluid. Ornithine, an intermediate compound in the formation of urea, is reportedly 10–15 times the normal levels in gyrate atrophy. Ornithine is normally converted to glutamic γ-semialdehyde and subsequently to proline by ornithine ketoacid aminotransferase,23 also known as ornithine aminotransferase (OAT). It is the deficiency of this enzyme, OAT, that causes the hyperornithinemia. OAT is a mitochondrial matrix enzyme that utilizes vitamin B6 (pyridoxal phosphate) as a cofactor.

This is a night-blinding disorder: symptoms usually start around the second decade of life. Visual fields show mid peripheral scotomas that coalesce to form a ring scotoma, extending both peripherally and centrally, consistent with the RPE and choroidal atrophy. The ERG is subnormal to nondetectable, depending on the extent of atrophy. Abnormalities in electromyogram have been reported in a majority of patients and muscle biopsy shows atrophic type 2 muscle fibers with tubular aggregates on electron microscopy.

Treatment

Treatment of gyrate atrophy consists of either reducing the substrate arginine, from which ornithine is formed, or increasing the activity of OAT enzyme by providing more cofactor vitamin B6.

Arginine-restricted diet

Since ornithine is produced from arginine, a low-protein diet with arginine restriction is recommended in lowering serum ornithine levels in patients with gyrate atrophy.24 Although there is no short-term advantage, the long-term lowering of serum ornithine level slows the progression of chorioretinal degeneration in these patients. When six pairs of siblings, all 10 years or younger, were placed on an argininerestricted diet and observed over a period of 16–17 years, the younger sibling in two of six pairs, who had received the diet at an earlier age, showed slower progression of the chorioretinal lesions than older siblings.25 In adults, who already have the full-blown manifestation of the disease, as long as the plasma ornithine levels can be maintained below an average of 5.29–6.61 mg/dl (about six times the normal range), it may slow the progression of disease as measured by sequential ERG.26

Vitamin B6 supplementation

Vitamin B6 supplementation has been found to be effective in reducing serum ornithine levels in a subset of patients with gyrate atrophy. There are two categories of patients – responders and nonresponders to B6 supplementation. “Responders” have been shown to manifest a milder form of the disease as compared to “nonresponders.” Dosage of 15– 20 mg/day of vitamin B6 was found to be effective in responders.27 Certain genetic mutations have been identified in vitamin B6 responders and nonresponders that may account for this difference in response to vitamin B6.

ABETALIPOPROTEINEMIA (BASSEN–KORNZWEIG SYNDROME)

Abetalipoproteinemia, an autosomal-recessive disorder, is characterized by retinal degeneration similar to RP associated with spinocerebellar ataxia, peripheral neuropathy, lipid malabsorption, absence or severe reduction of serum cholesterol and acanthocytosis.28,29

The basic defect is the deficiency of microsomal triglyceride transfer protein activity leading to failure of synthesis of beta-apolipoproteins. This then disrupts the transmembrane transport of fat-soluble vitamins in the intestines, leading to deficiency of vitamins A, E, and K. The manifestations of this disease are mainly due to hypovitaminosis. Due to a lack of vitamins A and E, there is photoreceptor degeneration resembling RP.

Treatment

Supplementing vitamin A, E, and K with essential fatty acids for life may help to forestall the progress of neurological and retinal degeneration. The recommended treatment schedule is to administer vitamin A 300 units/kg/day; vitamin E 100 units/kg/day; vitamin K 0.15 mg/ kg/day; and omega-3 fatty acids 0.19 mg/kg/day.30

LEBER CONGENITAL AMAUROSIS

LCA is probably the most severe form of retinal degeneration. Inherited in an autosomal-recessive manner, it consists of a group of retinal diseases characterized by severe and early visual impairment, sensory nystagmus, amaurotic pupils, and nonrecordable electrical signals on ERG.31 Manifesting in early infancy, the symptoms include poor vision, photoaversion, nyctalopia, and the presence of oculodigital phenomenon. LCA has a wide phenotypic variability – features described are normal-appearing retina with attenuated arterioles, macular colobomalike lesions, and pigmentary retinopathy that can vary from bone spicule pattern to salt and pepper pigmentation or preserved paraarteriolar RPE.31,32 Visual acuity in LCA patients ranges widely, usually from 20/200 to light perception or even no light perception.32 High refractive errors, typically hyperopia, keratoconus, and cataracts, are commonly associated with LCA.

LCA is a heterogeneous disease with the underlying disease genes identified in up to an estimated 60–70% of the cases. To date, mutations in 14 different genes have been identified. Mutations in the genes involve phototransduction pathways (AIPL1, GUCY2D), the retinoid cycle (RDH12, LRAT, RPE65), photoreceptor development and structure (CRX, CRB1), transport across photoreceptor connecting cilium (TULP1, RPGRIP1, CEP290, Lebercilin) and some others (IMPDH1, MERTK, RD3).31 Some of these genes have very specific genotype– phenotype correlations.33 RPE65 (RPE-specific 65-kDa) gene is an important component of the retinoid cycle and isomerizes the conversion of all-trans-retinal ester to 11-cis-retinol in the RPE cells. This leads to decreased formation of rhodopsin, thereby causing severe retinal degeneration.

Treatment

RPE65 gene therapy

The main impetus for gene therapy in LCA secondary to RPE65 mutations came after successful treatment in a canine model of human LCA (Briard dogs). These dogs are born blind and have a more severe disease than human LCA. The RPE65 gene was transferred through an adenoassociated virus injected into the subretinal space to provide the gene to the RPE cells. ERG and qualitative improvement were noted in these treated dogs.34 A lentiviral-mediated RPE65 gene therapy in a mouse model also showed substantial improvement.35 Results from both these studies formed the basis of human treatment trials.

The results of recently reported phase I trials have shown that gene therapy is safe, at least in the short term.36–38 Although these studies