Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

tetracosanoic acid in tissues and body fluids. These fatty acids are normally degraded within peroxisomes, but patients with adrenoleukodystrophy have a defect in β-oxidation of these very long chain fatty acids. Peroxisomes are small intracellular organelles that are found in almost all cells except mature erythrocytes, and their functions include the β-oxi- dation of very long chain fatty acids, biosynthesis of plasmalogens and bile acids, and glyoxylate detoxification (168). The gene predisposing to adrenoleukodystrophy was mapped to Xq28 (175) and isolated (176). The ALD (ABCD1) gene encodes the ALD protein, one of four ATP-binding casette transporters found in the peroxisomal membrane, and over 340 ALD mutations have been reported (167). The diagnosis of adrenoleukodystrophy can be based on increased concentrations of very long chain fatty acids in plasma or culture skin fibroblasts or by mutation analysis (167). Gas chromatography/mass spectrometry (177) and electrospray ionization mass spectrometry (178) methods have been developed for detection of very long-chain fatty acids. Very long-chain fatty acids up to 32 carbons have been described in plasma of patients with X-linked adrenoleukodystrophy (179).

7.3. Nutritional Approaches to the Treatment of Adrenoleukodystrophy

Various dietary interventions have been attempted for the treatment of adrenoleukodystrophy, including restriction of dietary hexacosanoic acid (180), restriction of dietary very long chain fatty acids with administration of glyceryl trioleate oil (169), and restriction of dietary very long chain fatty acids with administration of Lorenzo’s oil, a highly purified oil mixture containing a 4:1 mix of glyceryl trioleate and glyceryl trierucate (181). The early results of these interventions yielded disappointing results in regard to the clinical course of the disease in patients who were already symptomatic (169). Although Lorenzo’s oil has been shown to reduce levels of very long chain fatty acids, functional deterioration continued to occur in treated patients (181). Long-term treatment with Lorenzo’s oil did not modify the course of the disease in adult onset adrenoleukodystrophy (182), but early treatment may have slowed the progression of disease somewhat in children with adrenoleukodystrophy (183). A recent multicenter study involving 104 asymptomatic boys who were less than 6 yr old and had a normal magnetic resonance imaging (MRI) showed that treatment with Lorenzo’s oil reduced the risk of developing neurological abnormalities and changes in MRI (184). Bone marrow transplantation may provide stabilization of disease in boys or adolescents in the early stages of inflammatory brain disease (185).

8. HOMOCYSTINURIA

(CYSTATHIONINE β-SYNTHETASE DEFICIENCY)

8.1. Clinical Features

Patients with elevated homocystine concentrations in urine were described in 1962 (186, 187), and 2 yr later the enzyme defect was identified as a deficiency in cystathionine β-syn- thetase (188). Homocystinuria is an autosomal recessive disorder characterized by ectopia lentis, myopia, osteoporosis, biconcave vertebrae, scoliosis, thinning and lengthening of long bones (dolichostenomelia) and other skeletal abnormalities, variable degrees of mental retardation, psychiatric disturbances, and vascular occlusions (189). Ectopia lentis is found in about 90% of patients and usually presents in untreated individuals at about 2 yr of age (190). Prior to dislocation, the lens may exhibit phacodonesis, and iridodonesis may be a sign that the lens has dislocated. The lens may dislocate into the anterior chamber

cysteine per gram of protein (193). Methionine is transported across the intestinal mucosa by neutral amino acid transport systems and circulates free in the plasma until uptake by tissues such as the liver. Methionine is metabolized to homocysteine via the intermediates S-adenosylmethionine and S-adenosylhomocysteine (Fig. 11). Homocysteine then undergoes transsulfuration to form cysteine or can undergo remethylation to form methionine again. The metabolism of homocyteine to cysteine involves two enzymes, cystathionine β-synthase and cystathionine γ -lyase, both which require pyridoxal 5'-phosphate (vitamin B6) as cofactors (Fig. 11). The most common cause of homocystinuria is cystathionine β-synthase deficiency, but there are also other genetic defects in the conversion of homocysteine to methionine that may lead to elevated plasma homocysteine concentrations (189). Human cystathionine β-synthase cDNA has been cloned (194), and many cystathionine β-synthase mutations have been described (189). The gene for cystathionine β-synthase has been mapped to chromosone 21q22.3 (195). The zonular fibers contain fibrillin, a 350-kDa glycoprotein that is rich in cysteine residues, suggesting a possible pathogenic mechanism for cystathionine β-synthase deficiency and ectopia lentis (196).

Homocystinuria occurs in 1 of 52,544 births in Ireland (197) and 1 of 60,000 births in New South Wales, Australia (198), but the worldwide frequency may be somewhat lower, between 1:200,000 and 1:335,000 (189). A national newborn screening program in Ireland used a bacterial inhibition assay for initial screening at 3–5 d of life to detect high blood methionine concentrations, and for infants with high blood methionine, further diagnostic studies included analysis for blood concentrations of methionine, free homocystine, and cystine (199). Screening programs have used different criteria for detection of homocystinuria, and early screening may miss many cases of patients who are responsive to vitamin B6 therapy (189). Overall, about 44% of patients with homocystinuria appear to be responsive to vitamin B6 therapy, but proportion of patients that are responsive to vitamin B6 therapy as detected in newborn screening programs is about 14% (189). Thus, most patients who are responsive to vitamin B6 therapy are detected after the newborn period.

8.3. Nutritional Approaches to the Treatment of Homocystinuria

In 1967, G. Winston Barber and George Spaeth reported that three patients with homocystinuria responded to high doses of pyridoxine (vitamin B6) of 250 to 500 mg/d with a dramatic decrease in plasma and urine homocysteine and decreases of plasma methionine concentrations to the normal range (200). Cystathionine β-synthase requires pyridoxal-5- phosphate, formed from vitamin B6, as a cofactor (Fig. 11), and the provision of vitamin B6 may increase the residual enzyme activity in some patients. As mentioned previously, an estimated 44% of patients are responsive to vitamin B6 therapy. The daily doses of vitamin B6 used by different groups have ranged from 100–800 mg/d for adults and 150–500 mg/d for infants and children (201). In addition to vitamin B6 supplementation, current strategies include dietary methionine restriction, supplementing with cystine, giving folate and vitamin B12 in addition to vitamin B6 and betaine supplementation (201,202). The safety issues of high doses of vitamin B6 have been reviewed by Adrianne Bendich and Marvin Cohen (203). For adults, doses of 500 mg/d for up to 2 yr appears to be safe (203), but doses of 500 mg/d for infants have been associated with respiratory failure (189).

Detailed guidelines for therapy and monitoring of homocystinuria are presented in detail elsewhere (189). Although most infants detected by newborn screening are not responsive to vitamin B6, the first step is to determine whether the infant will respond to

Fig. 11. The metabolism of methionine to homocysteine to cysteine. Homocysteine can also be remethylated back to methionine. The main cause of homocystinuria is β-cystathionine synthase deficiency (*). Both β-cystathionine synthase and cystathionine γ-lyase require pyridoxal 5'-phosphate as cofactors.

vitamin B6 therapy at an initial dose of 250 mg/d for 4–6 d. Plasma methionine, homocystine, and/or total homocysteine are monitored daily. Most infants who are responsive to vitamin B6 will show at least a partial biochemical response to this initial treatment (189). If a response is observed, then the dose of vitamin B6 is reduced in 50 mg/d decrements to determine the lowest dose that achieves a response. Dietary methionine restriction can be used for infants that are not responsive to vitamin B6, and methionine-free, cystinesupplemented synthetic mixtures are available (189). In individuals who are diagnosed as having homocystinuria that is not responsive to vitamin B6 after the newborn period, dietary methionine restriction and/or betaine supplementation can be used, but adherence is often difficult (202). The rationale for betaine supplementation is to utilize an alternative pathway involving the remethylation of homocysteine to methionine by betaine-homo- cysteine methyltransferase (204).

Early detection and treatment of homocystinuria appears to reduce the risk of lens dislocation and progressive myopia (205,206). In a study of 19 patients with homocystinuria in Ireland, of 14 who had early dietary intervention in the newborn period, none developed ectopia lentis after mean follow-up of 8.2 yr. Of five patients who did not receive treatment until childhood, three had prexisting ectopia lentis, and two without ectopia lentis subsequently developed the condition (197). Patients with late diagnosis of homocystinuria or poor control appear to have worse myopia and problems with ectopia lentis (207). Treatment to lower plasma homocysteine significantly reduces the risk of vascular complications (208) and mental retardation (202,208). Betaine treatment has been shown to reduce the risk of vascular events (209).

9. WILSON DISEASE (HEPATOLENTICULAR DEGENERATION)

9.1. Clinical Features

In 1912, Samuel Alexander Kinnier Wilson (1878–1937) described a disorder characterized by progressive degeneration of the lenticular nuclei associated with hepatic cirrhosis (210). This disorder was also described earlier in the nineteenth century by Friedrich Theodor Frerichs (1819–1885) (211). Wilson disease is an inborn error of copper metabolism that is transmitted as an autosomal recessive trait. The main ophthalmological finding is the Kayser-Fleischer ring, which consists of fine granular deposition of copper in the periphery of Descemet’s membrane (212). This characteristic ring was described by Bernhard Kayser (1869–1954) and Bruno Fleischer (1874–1965) (213–215). The KayserFleischer ring may be visible only by slit lamp microscopy and appear as a brownish haze in the cornea periphery (Fig. 12). The Kayser-Fleischer ring is usually a golden-brown color but other color variations include green, yellow, blue, ruby red, or a mixture of these colors (212). The ring usually begins in the superior and inferior cornea at the limbus and spreads circumferentially until a complete ring is formed. Unilateral Kayser-Fleischer ring has been described (216). Electron dense deposits consisting of copper are found in Descement’s membrane and the adjacent corneal stroma (Fig. 13) (217). Although the Kayser-Fleischer ring may disappear with penicillamine therapy and low copper diets (218), there is not a close correlation between the Kayser-Fleischer ring and neurological findings (219). Kayser-Fleischer rings are not pathognomonic for Wilson disease and can also occur in other conditions associated with abnormal copper metabolism such as primary biliary cirrhosis, chronic active hepatitis, and other diseases (212,220,221). About 15–20% of

Fig. 12. Kayser-Fleischer ring. (Courtesy of W. Richard Green.)

patients may have a so-called “sunflower” cataract (218,223). The cataract consists of a central disk-shaped opacity of iridescent powdery deposits under the anterior and posterior capsule with spoke-like radiations. Loss of accommodation has been described in two patients with Wilson disease (223).

Patients with Wilson disease typically present with hepatic or neuropsychiatric disease. In children, the most common initial finding is liver dysfunction (224). Liver disease can range from a mild elevation in liver enzymes to chronic active hepatitis to massive liver failure. Liver biopsy may show micronodular cirrhosis with copper deposition. Patients who present with neuropsychiatric disease may present later in life, in the third or fourth decade, and presentation can be highly variable. Neurological signs and symptoms may resemble those found in Parkinson’s disease, with reduced facial expression and dyarthria, and there may be tremor, personality changes, depression, and schizophrenia.

The clinical and laboratory findings of Wilson disease are shown in Table 9.

9.2. Metabolic Aspects

Copper is an essential nutrient that plays a role in copper-containing enzymes involved in a wide variety of processes, including respiration, protection against oxidative stress, hormone metabolism, iron metabolism, and hematopoiesis. Copper is a transition metal that has properties of redox chemistry that lend well to the transfer of electrons, thus, many biological reactions are catalyzed by copper-containing enzymes. Among the coppercontaining enzymes important in humans are cytochrome c oxidase, copper/zinc superoxide dismutase, ferroxidase II, monoamine oxidase, tyrosinase, and dopamine β-hydroxyl- ase. The average human adult contains a total of about 110 mg of copper (225). The average dietary copper intake is about 2 mg per day (226), and about 30–75% of dietary copper is usually absorbed, primarily in the duodenum. Foods that are rich in copper include oysters and shellfish, chocolate, nuts, and legumes, and the bran and germ of cereal grains are rich in copper.

Fig. 13. Electron dense deposits consisting of copper are found in Descemet’s membrane and adjacent corneal stroma in Wilson disease. (Reproduced from ref. 217, with permission from BMJ Publishing Group.)

Copper is transported in the circulation bound primarily to albumin, and much of the copper is taken up by the liver, where it is incorporated into ceruloplasmin, a glycoprotein that contains six to seven copper atoms. The liver releases ceruloplasmin, and plasma ceruloplasmin accounts for about 60–65% of plasma copper (227). Copper is taken up by cells that have specific ceruloplasmin receptors on their surface. The main route of copper excretion is through biliary excretion into the gastrointestinal tract and feces, with only minor amounts lost through urine, sweat, hair, and skin.

Wilson disease is due to a defect in copper-transporting adenosine triphosphates (ATPase) in the trans-Golgi network of cells (228–230). The Wilson disease gene was localized to chromosome 13 (231), specifically to 13q14.3 (232). The absence or dysfunction of the Wilson ATPase interferes with copper transport and biliary copper secretion. More than 100 different mutations have been identified in patients with Wilson disease worldwide (233). The secretion of ceruloplasmin by the liver is impaired in Wilson disease, and often plasma ceruloplasmin concentrations are below normal values. If fever or inflam-

Table 9

Clinical and Laboratory Findings in Wilson Disease

•Kayser-Fleischer rings

•“Sunflower” cataract

•Azure lunulae in the fingernails

•Hepatic disease Chronic active hepatitis Fatty liver

Cirrhosis

•Neuropsychiatric disease Tremor

Dysarthria

Diminished facial expression Personality changes Depression

Schizophrenia

•Elevated urinary copper concentrations

•Reduced serum ceruloplasmin

•Elevated hepatic copper in liver biopsy

mation is present, ceruloplasmin concentrations may be elevated by ceruloplasmin is a positive acute phase reactant. Urinary copper concentrations are often elevated (233). The diagnosis of Wilson disease is made on the basis of physical examination, slit lamp examination, and laboratory analyses (233).

9.3. Nutritional Approaches to the Treatment of Wilson Disease

The treatment of Wilson disease consists of chelation therapy with D-penicillamine, combined with other strategies to lower dietary copper or reduce copper absorption. Foods rich in copper, such as shellfish, chocolate, nuts, legumes, and wheat germ must be avoided. Zinc interferes with copper absorption, thus, administration of zinc supplements may help reduce dietary copper absorption. Zinc supplementation has been advocated for asymptomatic patients who had been diagnosed with Wilson disease in childhood but have elevated serum transaminases (234).

10. MENKES DISEASE

Menkes disease is an X-linked disorder characterized by growth failure and unusual kinky hair. The disease was reported by John Menkes in 1962 (235) and was associated with a defect in copper absorption by David Danks and colleagues in 1973 (236). The Menkes gene is located on the long arm of the X chromosome (237). Transport of dietary copper across the gut results in low serum copper concentrations, but copper accumulates in the duodenum, kidney, and pancreas. Copper is required for cytochrome C oxidase, superoxide dismutase, tyrosinase, lysyl oxidase, and other enzymes. Loss of tyrosinase activity results in lack of hair pigmentation. Abnormalities in elastin and collagen production result in weakening of connective tissue, and diverticuli of the bladder, uterus, and other organs. Infants with the classic form of Menkes disease usually present by 2–3 mo of age with growth failure and seizures, an abnormal facies with sagging jowls, and white or grey hair with fine curling like steel wool (pili torti). Skeletal defects such as osteoporosis, rib frac-

tures, and metaphyseal dysplasia occur. Ophthalmic findings may include optic atrophy, ptosis, and iris hypoplasia and hypopigmentation (238). Laboratory studies show serum copper concentrations <0.75 μg/mL (<11.8 μmol/L) and low serum ceruloplasmin concentrations. Parenteral administration of copper may correct copper deficiency but does not usually stop the progressive neurological degeneration in infants with Menkes disease (239). Most children with the classic form of Menkes disease die by age three, but those with milder clinical variants may survive for many years.

11. SORSBY FUNDUS DYSTROPHY

11.1. Clinical Features

In the 1940s, Arnold Sorsby (1900–1980) and colleagues described an unusual fundus dystrophy characterized by choroidal neovascularization, bilateral central visual loss, and progressive atrophy of the peripheral choroid and retina (240,241). The disorder has an autosomal dominant mode of inheritance, and the condition has also been termed Sorsby pseudoinflammatory macular dystrophy, pseudoinflammatory chorioretinal degeneration of the posterior pole, and hereditary hemorrhagic macular dystrophy. Patients usually present with a central scotoma in one or both eyes in the fifth decade of life with exudation and retinoschisis in the macula with accompanying subretinal hemorrhages and choroidal neovascularization (242–244). The acute lesion heals and is followed by atrophic degeneration of the retina and choroid in the macular region and severe central visual loss (242). Prior to the loss of vision, fundus changes may include pigment epithelial atrophy, small drusen-like lesions or “colloid bodies” in the macula, angioid streaks, and plaque-like subretinal deposits of yellowish material in the macula (245,246). Night blindness may be the earliest symptom of Sorsby fundus dystrophy (247). Onset of visual disturbances may occur as early as the second decade (248). Ocular histopathology shows outer photoreceptor atrophy in the macula, and atrophy of the choriocapillaris, large choroidal vessels, and pigment epithelium in the posterior pole (249). Lipid-rich extracellular deposits accumulate in Bruch’s membrane, and it has been suggested that these deposits interfere with the normal transport of nutrients, such as vitamin A, from the choriocapillaris to the retinal pigment epithelium (250). Sorsby fundus dystrophy can resemble punctate inner choroidopathy (251).

11.2. Genetic and Metabolic Aspects

Sorsby fundus dystrophy was genetically linked with chromosome 22q13-1qter (252). The 22q13-1qter region also contains the gene for tissue inhibitor of metalloproteinases (TIMP)-3. The tissue inhibitors of metalloproteinases are a family of small homologous proteins that function in the inhibition and activation of matrix metalloproteins, promotion of cell growth, matrix binding, inhibition of angiogenesis, and induction of apoptosis (253). Patients with Sorsby fundus dystrophy have mutations in the gene for TIMP-3 (254–261). TIMP-3 is a component of Bruch’s membrane (262) and retinal pigment epithelial cells (263). In Sorsby fundus dystrophy, the thick extracellular deposits found in Bruch’s membrane have high concentrations of TIMP-3 (264,265). TIMP-3 may possibly induce retinal pathology by inducing apoptosis in retinal pigment epithelial cells (266) and promoting choroidal neovascularization (267). Deposition of dimerized TIMP-3 has also been hypothesized to play a role in the pathogenesis of the disease (268).

11.3. Treatment of Sorsby Fundus Dystrophy With Vitamin A

Many patients with Sorsby fundus dystrophy have night blindness, and abnormal dark adaptation and altered rhodopsin kinetics suggested that the metabolism of vitamin A might be adversely affected in the retina (250). Oral vitamin A supplementation, 50,000 IU/d, was reversed night blindness in patients with Sorsby fundus dystrophy (269), adding some weight to the hypothesis that the thickened deposits in Bruch’s membrane act as a barrier for diffusion of vitamin A from the choriocapillaris to the photoreceptors. The similarities of dark adaptation between vitamin A deficiency and Sorsby fundus dystrophy have been examined (270). Vitamin A supplementation at the dose of 50,000 IU/d should be administered under the supervision of a physician, and this dose is contraindicated in women of childbearing age who are not on reliable contraception and pregnant women (271). In one case report, a woman with Sorby fundus dystrophy and choroidal neovascularization responded to steroid treatment (251).

12. RETINITIS PIGMENTOSA

12.1. Clinical Features

Retinitis pigmentosa is a general term used to describe a heterogeneous set of heritable disorders characterized by retinal degeneration. This group of hereditary photoreceptor degenerations has a worldwide prevalence of about 1 in 4000 (272). The typical clinical findings are night blindness with progressive loss of peripheral visual field and then loss of central vision. Ophthalmoscopic features include attenuated retinal blood vessels, a waxy, pale-appearing optic disc, and intraretinal pigment deposits that sometimes resemble “bone spicules.” Cystoid macular edema and cataract are sometimes present. Some forms of retinitis pigmentosa, such as abetalipoproteinemia (Bassen-Korzweig syndrome) and gyrate atrophy, have been presented earlier in this chapter. The ocular histopathology of retinitis pigmentosa has been well characterized. In early disease, there is a loss of the number of rod and cone photoreceptors. The inner nuclear layer undergoes degeneration.

12.2. Metabolic Aspects

Many of the genes for retinitis pigmentosa have not yet been identified. Thaddeus Dryja and colleagues have provided an extensive review of the genes that cause retinitis pigmentosa (273). Some of the genes encode rhodopsin, structural proteins important in the outer segments of photoreceptors, and enzymes involved in the rod phototransduction cascade.

12.3. Nutritional Intervention for Retinitis Pigmentosa

As early as the late 1930s, vitamin A treatment was reported to improve the clinical course of retinitis pigmentosa (274,275). In 1993 it was reported that oral vitamin A supplementation, 15,000 IU/d, slowed the decrease in amplitude of the electroretinogram (ERG) among patients with retinitis pigmentosa (276). These findings showed promise for patients with retinitis pigmentosa (277). Further inquiry showed that vitamin A supplementation was also associated with a slower loss of visual field area among the same patients with retinitis pigmentosa (278), and several studies have shown a correlation between visual field size and ERG amplitude (279). Investigation in two transgenic mouse models for retinitis pigmentosa demonstrate that a high vitamin A diet slowed the course of photoreceptor degeneration in mice with the threonine-17 → methionine (T17M)