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

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Fig. 1. Montage of photographs of a right eye (above) and left eye (below) of a patient with abetalipoproteinemia. Note clumping of pigment and bone spicules. (From ref. 7, with permission from Elsevier Science.)

2.2. Clinical Features

Abetalipoproteinemia is characterized early in infancy by fat malabsorption and growth failure. In the second decade, neurological abnormalities begin to appear and include the loss of deep tendon reflexes, loss of vibratory sense in the lower extremities, loss of proprioception, progressive ataxia, and spastic gait. Neuropathological findings include spinocerebellar degeneration. In the first decade, visual acuity and visual fields may be normal, but impaired dark adaptation may be present (6). A pigmentary retinopathy usually appears in the second decade with gradual onset of night blindness, reduced color vision, and blindness occurs by the fifth decade. The fundus appearance is characterized by pigmentary abnormalities and bone spicules (Fig. 1) (7). There have been many case reports in the last four decades (8–17). Angioid streaks have been described in abetalipoproteinemia (18,19). The ocular histopathology of abetalipoproteinemia is consistent with that of advanced retinitis pigmentosa and includes loss of photoreceptors, invasion of

Fig. 2. Blood smear (left) and scanning electron micrograph (right) of red blood cells from a patient with abetalipoproteinemia, demonstrating the typical crenated appearance of acanthocytes. (Reprinted from ref. 22. Copyright © 1993, American Medical Association. All rights reserved.)

Table 1

Clinical and Laboratory Findings in Abetalipoproteinemia

•Fat malabsorption

•Failure to thrive

•Loss of deep tendon reflexes

•Loss of vibratory sense in lower extremities

•Ataxia

•Spastic gait

•Night blindness

•Dyschromatopsia

•Pigmentary retinopathy

•Anemia with acanthocytes

•Abnormal lipid profile

pigmented cells into the neuroretina (20,21). Patients with abetalipoproteinemia usually have a mild to moderate anemia with acanthocytes (Fig. 2) (22). Iron deficiency and/or folate deficiency may also occur due to malabsorption (22), and malabsorption of vitamin K may cause an elevated prothrombin time (23). The clinical and laboratory findings of abetalipoproteinemia are summarized in Table 1.

2.3. Metabolic Aspects

Abetalipoproteinemia, a recessive disorder due to mutations of the microsomal triglyceride transfer protein gene, is characterized by an abnormal lipid profile, with total plasma cholesterol concentrations of 0.50–1.30 mmol/L (20–50 mg/dL) and low triglycerides (22). There may be undetectable levels of very low-density lipoproteins (VLDLs), lowdensity lipoproteins (LDLs), and apolipoprotein B. The fundamental metabolic defect in abetalipoproteinemia is a lack of apolipoprotein B, an essential component of chylomicrons, VLDLs, and LDLs. Although it was originally thought that the defect was in the apolipoprotein B gene itself (22), further studies showed that there was no structural defect in the apoliprotein B gene (24–26) but rather a defect of the gene encoding the microsomal triglyceride transfer protein (27–30). Microsomal triglyceride transfer protein forms a

Fig. 3. Vitamin E metabolism in abetalipoproteinemia, showing sites of defective synthesis of microsomal triglyceride transfer protein. (Illustration by Frank Corl.)

heterodimer with protein disulfide isomerase and functions in the loading of apolipoprotein B with lipid (31). In the absence of sufficient lipid, apolipoprotein B is rapidly degraded before secretion (32,33). The gene for microsomal triglyceride transfer protein has been localized to chromosome 4q22-24 (31). A mutation in the α-tocopherol transfer protein gene also causes a syndrome similar to abetalipoproteinemia with progressive ataxia and retinitis pigmentosa (34,35). To summarize, a defect in the production of microsomal triglyceride transfer protein results in the impaired ability to package fat-soluble vitamins A, E, and K, into chylomicrons for transport from the intestine to the liver (Fig. 3). The incorporation of vitamin E into VLDLs by the liver is impaired by the absence of microsomal triglyceride transfer protein, and the overall consequences are extremely low concentrations of chylomicrons, VLDLs, LDLs, and vitamins E, A and K (Fig. 3). The role of microsomal triglyceride transfer protein in abetalipoproteinemia has been reviewed in detail elsewhere (36).

2.4. Nutritional Approaches to the Treatment of Abetalipoproteinemia

In 1961, Angelo DiGeorge and colleagues demonstrated that provision of intravenous lipids in the form of a cottonseed oil emulsion, a rich source of vitamin E, could reverse the acanthocytosis in a patient with abetalipoproteinemia (32). Subsequent studies showed that the abnormalities of the electroretinogram could be reversed in part by high-dose oral vitamin A supplementation (38,39). An 11-yr-old girl with abetalipoproteinemia was treated for 2.5 yr with parenteral vitamins A and E plus medium chain triglycerides, and improvement in both neurological and visual deficits was noted (40). Oral supplementation with vitamins A and E appeared to halt any deterioration of visual function in eight patients with abetalipoproteinemia (41), improved scotopic electroretinogram findings in one patient (42), and delayed the progression of neurological and retinal lesions in others

(43,44). Long-term supplementation with massive oral doses of vitamin E for 12–18 yr with dietary modification appeared to prevent retinopathy in six patients with abetalipoproteinemia (45). Patients with abetalipoproteinemia should avoid dietary fat, especially long-chain saturated fatty acids, in order to reduce steatorrhea, and should take fatsoluble vitamins. Oral supplementation with vitamin E, 150–200 mg/kg per day and vitamin A, 25,000 IU per day or every other day, are recommended for patients (22). Monitoring of vitamin E status is difficult because plasma vitamin E concentrations cannot be used to monitor therapy, and alternatively, the measurement of vitamin E in adipose tissue has been employed (46). Long-term follow-up of 10 patients with abetalipoproteinemia and three patients with homozygous hypobetaliproteinemia showed that despite vitamin A and E treatment, fundus changes and functional retinal changes can occur (47). Patients with abetalipoproteinemia who receive long-term supplementation with vitamins A and E do not seem to have enhanced oxidative stress (48).

2.5. Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia, a related defect in the assembly and secretion of apo B-containing lipoproteins in the liver and/or intestine, is a mildly symptomatic genetically heterogeneous autosomal trait characterized by plasma total cholesterol, LDL-cholesterol, and apolipoprotein B levels below the fifth percentile (49). Most people with familial hypobetalipoproteinemia are simple heterozygotes who are asymptomatic, and a large proportion of patients may develop nonalcoholic fatty livers. Malabsorption and mild diarrhea may occur in some patients (49). Familial hypobetalipoproteinemia is due to a truncationspecifying mutation of the APOB gene on chromosome 2, or linkage to chromosome 3 (3p21), or absent linkage to both APOB and to 3p21 (49). “De novo” mutations of apolipoprotein B (50) and mutations in the microsomal triglyceride transfer protein have also been described in familial hypobetalipoproteinemia (51). Progressive retinal degeneration can occur in homozygous familial hypobetalipoproteinemia as with abetalipoproteinemia (47). A 51-yr-old white woman with familial heterozygous hypobetalipoproteinemia presented with night blindness and bilateral symmetric depigmentation of the posterior pole (52). Pigment clumping and pavingstone degeneration were present in the retinal periphery. By 75 yr of age, at which time the patient died, the vision had declined to hand motions. Ocular pathology revealed loss of photoreceptors and massive deposition of a basal linear deposit contaning macrophages and processes of glial cells, with calcification in some segments (52). Familial hypobetalipoproteinemia is also treated with oral supplementation of vitamin A and vitamin E (47).

3. GYRATE ATROPHY

3.1. Clinical Features

Gyrate atrophy is a progressive chorioretinal dystrophy that is inherited as an autosomal recessive trait. The disease is chararacterized by an underlying defect in a pyridoxal phosphate (PLP)- or vitamin B6-dependent mitochondrial matrix enzyme, ornithine-δ-amino- transferase. Gyrate atrophy presents in childhood with myopia, and by age 10 yr, there is usually impaired peripheral vision and night blindness. Subcapsular cataracts occur in the second decade, and patients often require cataract extraction. The degree of myopia

Fig. 5. Pathways of ornithine metabolism.

to 15-fold increase in ornithine in body fluids. Small reductions in plasma glutamate, glutamine, lysine, and creatinine also occur in gyrate atrophy. Ornithine is formed in the body from arginine in the urea cycle. Patients with gyrate atrophy have a great variability in the severity of the disease and their therapeutic response to pyridoxine (vitamin B6), and this variability is likely related to the amount of residual ornithine-δ-aminotransferase that may be present. Elevated plasma ornithine concentrations were noted in gyrate atrophy patients in 1973 (57) and associated with a defect in ornithine-δ-aminotransferase in 1988 (58). The ornithine-δ-aminotransferase has been cloned and is located on chromosome 10q26. More than 60 different mutations have been identified at the ornithine-δ-amino- transferase locus. Gyrate atrophy has been described worldwide, and some ornithine-δ- aminotransferase gene mutations appear to be unique to certain racial or ethnic groups (59). The V332M mutation (60,61), A226V mutation (62), and E318K mutation (63) have been identified as pyridoxine-responsive. Patients who are responsive to pyridoxine generally have a more slowly progressive disease.

3.3. Experimental Animal Studies

In experimental animal studies, intravitreal injections of L-ornithine in the eyes of rats, rhesus monkeys, and cynomolgus monkeys resulted in degeneration of retinal pigment epithelium and secondary degeneration of adjacent photoreceptor cells (64). No changes were noted after similar intravitreal injections of arginine. An ornithine-δ-aminotransfer- ase-deficient mouse model has been developed by gene targeting (65). Mice in this model develop hyperornithinaemia and a slowly progressive retinal degeneration, with the primary insult appearing the retinal pigment epithelium (66). Restriction of dietary arginine has been shown to reduce ornithine accumulation and completely prevent the retinal degeneration in this mouse model (67). Electron micrographs of the retina from ornithine-δ- aminotransferase-deficient mice on an arginine-restricted diet and standard diet are shown in Fig. 6 (67).