Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007
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Handbook of Nutrition and Ophthalmology |
Fig. 6. Electron micrographs of the retinas from ornithine-δ-aminotransferase-deficient mice on an arginine-restricted diet (left) and standard diet (right). (Reprinted from ref. 67. Copyright © 2000, National Academy of Sciences, USA.)
3.4. Nutritional Approaches to the Treatment of Gyrate Atrophy
Two types of nutritional modification may have some therapeutic effect for gyrate atrophy: (1) arginine restriction, and (2) supplementation with vitamin B6. Given that gyrate atrophy is a rare, slowly progressive disease, the studies evaluating these therapies consist of case studies of treated patients rather than controlled clinical trials (Table 3) (68–75). In order to restrict arginine intake, patients must reduce natural protein intake and take a powdered form of essential amino acids and supplementary vitamins and minerals (76). Arginine restriction can result in large decreases in plasma ornithine (69), but many patients may find it difficult to adhere strictly to this diet. In one case, a woman on an arginine-restricted diet showed some objective improvement in visual measures (70). Studies of sibling pairs suggest that long-term reduction of ornithine may slow the retinal degeneration of gyrate atrophy (71). In a long-term observational study of 27 patients with gyrate atrophy, of whom 17 elected to comply with an arginine-restricted diet and ten were unable to comply, those who adhered to an arginine-restricted diet had slower progression of visual function, as measured by sequential electroretinography and visual field examinations (77).
A small proportion of patients with gyrate atrophy will respond to vitamin B6 treatment with reductions in plasma ornithine (75,78). Pyridoxal phosphate is the active form of vitamin B6 and a co-factor for ornithine-δ-aminotransferase. Pyridoxine responders are likely to have ornithine-δ-aminotransferase alleles that have mutations affecting the vitamin B6 binding site of the enzyme (67). Typical doses of pyridoxine that have been used for adults in these studes are 500–750 mg/d (77). In comparison, the Recommended Dietary Allowance for vitamin B6 for adult men and women is 1.7 mg/d and 1.5 mg/d, respectively (79). Other attempts to slow the progress of gyrate atrophy with creatinine, lysine, or proline supplementation have suggested a possible slowing of eye disease (68,80–82), but the small numbers of treated patients and lack of controls make it difficult to make
Chapter 12 / Inborn Errors of Metabolism |
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Table 3 |
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Evaluation of Nutritional Interventions for Gyrate Atrophy |
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Characteristics |
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of patients |
Observations |
Reference |
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Creatinine Supplementation |
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7 patients |
Supplementation for 1 yr; some progression of chorioretinal |
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68 |
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disease in 3 patients, slight progression in 1 patient |
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Arginine Restriction |
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7 females, |
Mean threefold reduction in plasma ornithine; 4 patients could |
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69 |
2 males, |
not continue to follow strict diet; length of follow-up ranged |
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70 |
aged 11–46 yr |
from 4–32 mo; 2 women (ages 37 and 46) had longer |
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follow-up (1 patient had improvement in dark adaptation |
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and visual fields and the other had no change) |
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6 pairs of affected |
5- to 7-yr reduction of plasma ornithine was associated with |
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71 |
siblings |
slower progression of ocular disease in treated vs untreated |
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sibling comparisons |
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Pyridoxine Supplementation |
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With Low-Protein, Low-Arginine Diet |
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5 patients, |
Reduction in plasma ornithine of 60% or more within 4–8 wk; |
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72 |
aged 12–30 yr |
4 of 5 patients showed no improvement in visual acuity, visual |
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fields, dark adaptation, or fundus appearance; the patient with |
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poorest control of plasma ornithine showed progression; none |
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of patients could strictly adhere to restricted diet at home |
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Pyridoxine Supplementation |
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7 patients |
3 responded to supplementation with >50% reduction in serum |
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73 |
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ornithine and rise on serum lysine to normal; electroretinogram |
74 |
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improved in 1 patient |
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Proline Supplementation |
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4 patients |
Progression of disease in 2 patients; no change in chorioretinal |
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75 |
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disease in 2 patients; supplementation from 2–5 yr |
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definitive conclusions about these therapies. Lysine supplementation has recently been shown to reduce plasma ornithine concentrations by 21–31% with 1–2 d in pyridoxine unresponsive patients with gyrate atrophy, but the ocular consequences are not clear (83).
4. REFSUM DISEASE
4.1. Clinical Features
In 1946, Sigvald Refsum (1907–1991) described a syndrome characterized by retinitis pigmentosa, chronic polyneuropathy, cerebellar ataxia, and an increase in protein concentrations in the cerebrospinal fluid without an accompanying pleocytosis, and he termed the condition “heredopathia atactica polyneuritiformis” (84). Anosmia, neurogenic impairment of hearing, and cardiomyopathy are usually present, and pupillary abnormalities, lens opacities, skeletal malformations, and skin changes resembling ichthyosis have sometimes been described (85). An accumulation of phytanic acid (3,7,11,15-tetramethyl-
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Table 4
Clinical and Laboratory Findings in Refsum Disease
•Retinitis pigmentosa
•Peripheral neuropathy (motor and sensory)
•Cerebellar findings
•Cardiac abnormalities
•Symptoms of cranial nerve involvement Neurogenic hearing loss
Anosmia
Abnormal pupillary reflex Miosis
•Skeletal abnormalities
•Skin changes—ichthyosis
•Increased cerebrospinal fluid protein without pleocytosis
•Elevated plasma phytanic acid concentration
Reproduced from ref. 97, with permission of The McGraw-Hill Companies.
hexadecanoic acid) was noted in 1963 (86), and patients with the disease were shown to have a defect in the α-oxidation mechanism of β-methyl-substituted fatty acids (87,88). The onset of disease is variable and can occur in the first through third decades. The pigmentary retinopathy in Refsum disease is characterized by fine granular pigmentation, and the bone spicule type of pigmentation is less frequent (89). In advanced disease, waxy-appearing optic discs and attenuated vessels are often present. The ocular pathology of Refsum disease has been described (90). An infantile form of Refsum disease was described in 1982 (91) and is characterized by the appearance during the first year of life by a pigmentary retinopathy, nystagmus, deafness, hypotonia, hepatosplenomegaly, growth retardation, mental retardation, and dysmorphic facial features such as epicanthal folds, a flat nasal bridge, and low-set ears (91,92).
The term “classical Refsum disease” has been applied to patients who have elevated phytanic acid due to a defect in the α-oxidation of phytanic acid and to distinguish them from infantile Refsum disease, in which phytanic acid oxidation is abnormal due to an absence of peroxisomes. Refsum disease is an autosomal recessive disorder (93,94), and heterozygotes usually have normal plasma phytanic acid concentrations and no neurological signs or symptoms. The diagnosis of Refsum disease should be considered in patients who present with retinitis pigmentosa, as it has been suggested that perhaps 1 of 20 patients may have Refsum disease (95). Adult Refsum disease is usually diagnosed by measurement of phytanic acid levels in patients with retinitis pigmentosa and associated polyneuropathy or short metacarpals (96). Smell testing has been advocated as an additional tool for diagnosis of adult Refsum disease (96). The clinical and laboratory findings in Refsum disease are summarized in Table 4 (97). A case of mild pigmentary retinopathy has been described in a patient with Refsum disease who did not present until he was 47 yr old (98).
4.2. Metabolic Aspects
Phytanic acid is a dietary-derived isoprenoid fatty acid that is found in high concentrations in foods such as lamb, beef, liver, canned tuna packed in oil, ham, and dairy
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Fig. 7. The α-oxidation pathway of phytanic acid. Refsum disease is caused by a defect in phytanoylCoA hydroxylase.
products (99). In classical Refsum disease, the plasma concentrations of phytanic acid are elevated. Patients with Refsum disease have a mutation in the gene that encodes phy- tanoyl-CoA 2-hydroxylase, a peroxisomal enzyme that allows α-oxidation of phytanic acid to 2-hydroxyphytanoyl-CoA (100–102). 2-hydroxyphytanoyl-CoA is then converted to pristanic acid (103,104) (Fig. 7). Refsum disease can also be caused by mutations in the gene for the peroxisomal targeting signal (PTS)2 gene (105). Histopathological studies have shown that the concentrations of phytanic acid are extremely high in the retina, exceeded only by the concentrations found in the liver and heart (106).
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4.3. Nutritional Approaches to the Treatment of Refsum Disease
Dietary treatment for Refsum disease was first attempted when Eldjarn and colleagues showed that a negative phytanic acid balance could be achieved by a diet low in phytanic acid (107). Refsum initiated similar treatment in two affected patients, with a dietary regimen that included removal of butter fat, all visible fat from meat, and avoidance of fruit and vegetables, and these patients had a pronounced reduction in serum phytanic acid concentrations to the normal range (85). Two patients with Refsum disease who were placed on a diet that was low in phytanic acid and phytol showed a slow drop in phytanic acid concentrations in blood and adipose tissue and improvements in ulnar nerve conduction, and an improvement of pain, touch, and proprioception (108). Green vegetables contain phytols and were originally excluded from the diet for patients with Refsum disease. The phytol in green vegetables is largely unabsorbed, and exclusion of green vegetables is now considered unnecessary (97). Available evidence suggests that progression of eye disease and neurological problems can be slowed or halted by dietary treatment (97). The normal Western diet contains about 50 mg of phytanic acid, and the goal of dietary therapy is to reduce the phytanic acid content of the diet to less than 10 mg per day, as described by Masters-Thomas and colleagues (99,109). A combination of plasmapheresis and diet has been used to minimize plasma phytanic acid concentrations (110–112).
5. GALACTOSEMIA
5.1. Clinical Features
In 1908, August Ritter von Reuss (1841–1924) described a breast-fed infant with growth failure and galactose in the urine (113). The infant was given substitutes for milk, and the galactosuria resolved, but the infant died after 3 wk in the hospital. Friedrich Göppert (1870–1927), a professor of pediatrics at Göttingen, reduced the dietary milk and sugar content of a 2-yr-old child with galactosuria, and noted an improvement in the galactosuria (114). Galactosemia was considered to be due to an abnormality in galactose metabolism (115), and cataracts were described in an affected infant (116). Cataracts are the main clinical feature of galactosemia, and they are usually found in the first weeks of life. Severe diarrhea, abdominal distention, vomiting, and failure to thrive are usually present. Galactosemia is a general term for genetic disorders of galactosemia that can be due to inherited defects in three enzymes, and the most common defect is due to a deficiency in galactose- 1-phosphate uridyltransferase, resulting in classical galactosemia. The clinical and laboratory findings in classical galactosemia are shown in Table 5. The second most common defect is in galactokinase, and cataracts are usually present (117–122). Pseudotumor cerebri has also been described in galactokinase deficiency (123–124). Most patients with the third enzyme deficiency, uridine diphosphate galactose 4'-epimerase, are asymptomatic, and this defect is rare. The cataracts that occur in galactosemia may be due to the conversion of accumulated galactose to galactitol via the aldose reductase pathway with resulting increased osmolarity in the crystalline lens (125). Vitreous hemorrhage has been described in infants with untreated galactosemia (126).
5.2. Metabolic Aspects
Galactose is a carbohydrate that is found in milk and milk products in the form of the disaccharide lactose. During digestion, lactose is hydrolyzed by lactase in the brush border
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Table 5
Clinical and Laboratory Findings of Classical Galactosemia
•Cataracts
•Vomiting, diarrhea
•Full fontanelle
•Lethargy, hypotonia
•Failure to thrive
•Jaundice, hepatomegaly
•Bleeding or excessive bruising
•Metabolic acidosis
•Gonadal dysfunction
•Abnormal Beutler test
•Abnormal liver function tests
The clinical findings in galactokinase deficiency are similar except that liver and kidney abnormalities are not present.
of the intestine to glucose and galactose. Galactose is a major energy source for infants, and to utilize this energy, galactose must be metabolized to glucose. There are three major enzymes involved in the metabolism of galactose: (1) galactokinase, (2) galactose- 1-phosphate uridyltransferase, and (3) uridine diphosphate galactose 4'-epimerase. Galactosemia can result from a deficiency in any of these three enzymes. The main metabolic pathway for galactose metabolism is shown in Fig. 8. Galactokinase activity is highest in the liver and in erythrocytes. Galactokinase phosphorylates galactose to galactose-1- phosphate. The gene for galactokinase has been mapped to chromosome 17p24 (127). Galactose-1-phosphate is catalyzed to glucose-1-phosphate by galactose-1-phosphate uridyltransferase in a step that involves reaction with UDP-glucose. The gene for galac- tose-1-phosphate uridyltransferase has been mapped to chromosome 9p13 (128). UDPgalactose is converted back to UDP-glucose by uridine diphosphate galactose 4'-epi- merase (Fig. 8). The gene for uridine diphosphate galactose 4'-epimerase has been mapped to chromosome 1p36 (129). The relative frequencies of mutations for galactokinase, galactose-1-phosphate uridyltransferase, and uridine diphosphate galactose 4'-epimer- ase in different populations are presented in great detail elsewhere (130).
Screening for galactosemia can be conducted using a fluorescent spot test (Beutler test) (131), and screening is provided in many countries as part of routine care. In the Republic of Ireland, screening for galactosemia was conducted on 1.2 million infants from 1972 to 1992, and 55 cases of classical galactosemia were detected, giving an estimated frequency of classical galactosemia of 1:23,000 (132). In the United States, most hospital nurseries provide screening for galactosemia (133). Screening may result in earlier diagnosis of galactosemia (134).
5.3. Nutritional Approaches to the Treatment of Galactosemia
The nutritional approach to galactosemia is the discontinuation of breast milk and milkbased formulas. Guidelines for the initial and long-term management of patients with galactosemia have been published elsewhere (135). Milk substitutes that are considered suitable for infants with galactosemia include soy-based formulas such as Isomil®, Pro-
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Fig. 8. Metabolism of galactose. Sites of possible enzyme deficiencies are indicated by (*).
sobee®, or Pregestemil®, or Nutramigen® (133,135). Patients must refrain from milk and dairy products throughout life. Galactose is present in small amounts in some fruits, vegetables, and legumes (136), but these appear to be insignificant and not restricted according to current recommendations (135). The cataracts and other systemic abnormalities rapidly respond to dietary restriction of galactose. Slit lamp examinations are recommended for infants at the time of diagnosis and then every 6 mo until 3 yr of age, and then annually. Slit lamp examinations may be helpful in monitoring dietary adherence (125). Dietary restriction does not appear to prevent all the complications of galactosemia, as developmental delays, speech abnormalities, and gonadal failure in women (137,138). Some infants may continue to have elevated erythrocyte galactose 1-phosphate levels despite treatment with a low-galactose (soy) formula, and galactose-free, elemental formula may be needed to decrease erythrocyte galactose 1-phosphate levels to the treatment range (139).
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Table 6
Clinical and Laboratory Findings in Oculocutaneous Tyrosinemia
•Photophobia, redness, eye pain, lacrimation
•Dentritiform keratitis
•Corneal erosions
•Intraepithelial and deep corneal ulceration
•Painful hyperkeratotic and erosive lesions of palms and fingertips, plantar surface of feet; sometimes elbows and knees
•Variable degree of mental retardation
•Elevated plasma tyrosine concentrations
6. OCULOCUTANEOUS TYROSINEMIA
(TYROSINEMIA TYPE II, RICHNER-HANHART SYNDROME)
6.1. Clinical Features
A syndrome consisting of hyperkeratotic lesions of the hands and feet, dendritic corneal lesions, and mental retardation was described by Hermann Richner in 1938 and Ernst Hanhart (1891–1973) in 1947 (140,141). Earlier reports of a similar syndrome were made in the 1920s (142,143). This autosomal recessive disorder is extremely rare and has been described in case reports (144–156). Although the syndrome has been described among many different groups, it appears to be more common among individuals of Italian descent (157). Affected individuals are often born to consanguinous parents, and cutaneous lesions usually appear in the first year of life. Hyperkeratosis occurs on the palmar and plantar surfaces and fingertips, and morphologically the skin appears thickened with fissures, and there may be considerable pain with pressure, as in walking. Some patients may be so severely affected that they have great difficult ambulating.
The ocular manifestations consist of photophobia, redness, lacrimation, and dentritiform corneal lesions, and these signs and symptoms may appear as early as the first month of life but usually occur within the first decade. The dentritiform lesions sometimes resemble herpetic keratitis, and patients may be treated with antiviral medications before the correct diagnosis is made. The keratitis appears to be due to the crystallization of tyrosine in the cornea, as suggested by experimental animal models (158). The affected human cornea shows vacuolar degeneration with inclusion bodies within the vacuoles and degeneration of collagen fibers (152). The characteristic clinical and laboratory findings of oculocutaneous tyrosinemia are summarized in Table 6. Decreased visual acuity may result from corneal opacities and scarring, and recurrence of corneal deposits in a graft has been described after lamellar keratoplasty in a patient not on dietary therapy (159).
6.2. Metabolic Aspects
The halllmark of oculocutaneous tyrosinemia is the presence of elevated tyrosine concentrations in the blood and urine (160,161) due to an inborn error of metabolism involving a defect in tyrosine aminotransferase, the enzyme that converts tyrosine to p- hydroxyphenylpyruvate (162,163). Urinary metabolites of tyrosine, 4-hydroxyphenyllactic acid, 4-hydroxyphenylacetic acid, N-acetyltyrosine, and 4-tyramine, are also elevated. Tyrosine is available from exogenous dietary sources and from the metabolism of pheny-
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Fig. 9. Tyrosine metabolism.
lalanine (Fig. 9). Tyrosine aminotransferase is found in high concentrations in the liver and is also found in mitochrondria, except in cells of ectodermal origin, which may explain why there is a particular accumulation of tyrosine in the cornea, hands, and feet (155). Over two dozen different mutations of tyrosine aminotransferase have been described (163, 164). The diagnosis of oculocutenous tyrosinemia is based on clinical findings as well as hypertyrosinemia and elevated tyrosine and tyrosine metabolites in the urine.
6.3. Nutritional Approaches to the Treatment of Oculocutaneous Tyrosinemia
Dietary restriction of tyrosine and phenylalanine can reduce and prevent the skin and eye lesions, and clinical improvement is usually seen within a few weeks of commencing dietary therapy. Complete resolution of clinical symptoms is possible with adherence to therapy (165). Recurrence of eye and skin lesions can occur if the dietary therapy is stopped (161). Commercial tyrosineand phenylalanine-free supplements are available.
7. X-LINKED ADRENOLEUKODYSTROPHY
7.1. Clinical Features
In 1923, Ernst Siemerling (1857–1932) and Hans Creutzfeldt (1885–1964) described a boy with bronzed skin, dysphagia, spasticity, and behavioral abnormalities who later
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Table 7
Clinical and Laboratory Findings in X-Linked Adrenoleukodystrophy
•Childhood cerebral adrenoleukodystrophy Reduced visual acuity
Poor school performance
Visual field defects, optic atrophy Seizures
Rapid neurological progression
•Adrenomyelopathy Spastic paraparesis
Reduced vibratory sense in extremities Difficulty urinating
•Increased long chain fatty acids in plasma
developed tetraplegia, seizures, and died (166). The disease was later known as adrenoleukodystrophy, a disorder that falls within the general category of leukodystrophy, defined as a progressive disease of myelin in which a genetically determined metabolic defect results in the destruction or failed development of central white matter (167). The term adrenoleukodystrophy has been applied to two distinct entities: X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy, and in this section the term will apply to the X-linked form of the disease. Adrenoleukodystrophy is a rare disorder, and although the exact incidence is not known, in the Netherlands for example, it appears to have a frequency of one in 100,000 male births (168).
Adrenoleukodystrophy can present as several phenotypes such as a childhood cerebral form, an adrenomyelopathy, an Addisonian phenotype with adrenocortical insufficiency, cerebral forms that present in adolescence or adulthood, an asymptomatic form, and with other atypical presentations (168,169). Childhood cerebral adrenoleukodystrophy is the most frequent phenotype, and onset occurs between three and 10 yr of age with poor school performance, deterioration of vision, and reduce auditory discrimination and then rapid progression to seizures, spastic tetraplegia, and dementia (168). The childhood form is an intensely inflammatory cerebral myelinopathy that results in reduced visual acuity, homonymous hemianopia, cortical blindness, and optic atrophy, and loss of ganglion cells from the macula and nonspecific optic atrophy have been described in histopathology (170,171). Adrenomyelopathy is a noninflammatory axonopathy. It is the common form in adults that usually presents in the third and fourth decades with spastic paraparesis, disturbed vibration sense in the lower extremities, and voiding difficulties. Reduced visual acuity and optic disc pallor appear to be due to demyelination in the visual pathways (172). The prevalence of abnormal color vision is higher among patients with adrenomyeloneuropathy than matched controls (173). Patients with cerebral adrenoleukodystrophy often have characteristic findings on magnetic resonance imaging (174). The clinical and laboratory findings of X-linked adrenoleukodystrophy are summarized in Table 7.
7.2. Metabolic Aspects
The main biochemical abnormality of X-linked adrenoleukodystrophy is the accumulation of saturated unbranched very long chain fatty acids such as hexacosanoic acid and