Myoclonus epilepsy with ragged-red fibers
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This article includes discussion of hyperornithinemia, atrophia gyrata, and gyrate atrophy of the choroid and retina. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Slowly progressive ophthalmological changes beginning in childhood and leading to blindness in the fifth decade are the characteristics of gyrate atrophy of the choroid and retina. Gyrate atrophy is an inherited metabolic disease that is caused by deficiency of the enzyme ornithine aminotransferase. The biochemical hallmark of the disease is the distinctly increased amino acid ornithine in plasma. In this article, the author provides an in-depth review of the clinical presentation, pathophysiology, diagnosis, and treatment options for gyrate atrophy.
• Hyperornithinemia is a slowly progressive disease, primarily of the eyes, with visual deterioration starting in late childhood and blindness around the fifth decade of life.
• It is an autosomal-recessive inborn error of metabolism due to deficiency of the enzyme ornithine aminotransferase.
• Chorioretinal degeneration and hyperornithinemia are diagnostic for the disease.
• Except for a few cases that respond to vitamin B6, treatment is strict protein restriction and supplementation of arginine-free amino acid mixture.
• Successful reduction of ornithine halts the progression of the disease.
The report of a case of "atypical retinitis pigmentosa" by Jacobsohn in 1888 represents probably the first description of a patient with gyrate atrophy of the choroid and retina, as defined by the characteristic appearance of the ocular fundus and a typical history of visual deterioration (30). Cutler in 1895 and Fuchs in 1896 were the first ophthalmologists to recognize this condition as a distinct entity (13; 19). Fuchs gave the disorder its euphonious appellation. Usher reviewed 26 cases in 1935, emphasizing the genetic aspects (90). Despite of the observation in 1960 of an abnormally large lysine-ornithine spot in the urine of a patient with gyrate atrophy, hyperornithinemia and ornithinuria were not recognized as the biochemical counterparts of this disorder (41) until the report of Simell and Takki in 1973 (85 years after the initial ophthalmologic description). They postulated that the hyperornithinemia was presumably due to deficiency of ornithine aminotransferase (OAT) in 9 patients with gyrate atrophy of the choroid and retina (80).
Ornithine aminotransferase was first described in animal tissues by Quastel and Witty and Meister (60; 47). The deficiency of the ornithine aminotransferase in a patient with gyrate atrophy was first demonstrated by Valle and colleagues (92). Mitchell and colleagues identified the first mutations in the ornithine aminotransferase gene of patients with gyrate atrophy (50). The quantitative importance of the ornithine aminotransferase transamination reaction in the regulation of ornithine homeostasis was first proven by Seiler and colleagues (76).
To elucidate the pathophysiology of the disease, animal models were implemented by initially using intravitreal injection of L-ornithine (42) and later application of 5FMOrn as selective ornithine aminotransferase inhibitor (14). Since 1995, the transgenic mouse model for ornithine aminotransferase deficiency has provided an opportunity to glean deeper insights (100). The retarded hair growth (rhg) mutant mouse may offer an ideal model for gyrate atrophy of the choroid and retina in humans. This mouse mutant is caused by the same missense mutation that is known in some families (07).
Gyrate atrophy of the choroid and retina is a disease with slowly progressive ophthalmologic changes beginning in the childhood and leading to blindness typically in the fifth decade, with relatively few other organ manifestations.
Night blindness and myopia are usually the first symptoms. Young patients often come to attention of the ophthalmologists in late childhood or around puberty, the time when the retinal degeneration seems to accelerate. Funduscopic appearance of chorioretinal atrophy is pathognomonic for gyrate atrophy.
It is characterized by sharply demarcated, circular areas of chorioretinal degeneration in the midperiphery of the ocular fundus with sometimes increased pigmentation around the margins of these lesions. These lesions start as punctuate yellowish dots that gradually enlarge to circular areas 1 to 2 disc diameters in size (18). Later on, the lesions enlarge, coalesce, and extend towards the posterior pole of the fundus. The few choroidal vessels traversing the atrophic areas are narrowed and in some patients additional foci develop in the peripapillary area.
Standard tests of visual function become abnormal. Periods of rapid progression are interspersed with periods of stable function. Visual acuity (myopia) decreases gradually over decades in some patients and abruptly over a few years in others. The visual field is constricted and progresses by concentric reduction to a “tunnel-vision.” Electrophysiological examination reveals elevated dark-adaptation thresholds and small or nondetectable electroretinographic responses. The ERG may be normal early in the course of the disease when only a few focal lesions are present. It then becomes diminished in amplitude and is usually totally extinguished well before the atrophy becomes complete (62). Caruso and colleagues examined the natural history of visual function variables in 5 patients with gyrate atrophy (09). In the 4 to 6 years during which each patient was followed, median visual field half-lives were 17.0 years (static perimetry) and 11.4 years (kinetic perimetry). Median electroretinogram half-lives were 16.0 years (maximal response) and 10.7 years (flicker response).
Posterior subcapsular cataracts occurring late in the 2nd decade of life combined with restricted visual fields typically result in severe vision impairment in the 3rd decade of life. By this time much of the fundus is involved. Increased pigmentation in the macular area and filamentous vitreous opacities are common findings whereas the optic disc, cornea, and iris remain normal in appearance.
Patients become virtually blind between 40 and 55 years of age. In this stage there is complete chorioretinal degeneration with a few strands of pigmentation traversing the fundus. The appearance in the final stages is similar to that of other forms of chorioretinal degeneration, such as the X-linked disorder choroideremia (OMIM 303100). Though the chorioretinal degeneration in gyrate atrophy is usually slow to progress and symmetrical, in rare cases gyrate atrophy-related single-sided retinal detachment has been observed, eg, causing unilateral blindness at an early age in a 12-year-old girl (03; 06).
In addition to the ocular findings, systemic abnormalities have been reported in some patients. Most patients have normal intelligence. Valtonen and colleagues investigated CNS involvement in gyrate atrophy (96). Brain MRI revealed degenerative lesions in the white matter in 50% of the subjects, and 70% of the patients had premature atrophic changes and a striking increase in the number of Virchow spaces. Of the patients whose EEG was recorded, 58% had abnormally slow background activity, focal lesions, or high-amplitude beta rhythm (96). Three of 39 patients in this series had a history of seizures or epilepsy. Peltola and colleagues investigated peripheral nervous system involvement in 40 patients with gyrate atrophy (56). Neurophysiologic studies revealed abnormalities in 53% of the patients. The abnormalities correlated with the severity of the ophthalmologic changes and the age of the patients. With quantitative sensory threshold testing, abnormal large-fiber function was found in 18% and abnormal small-fiber function was found in 10%. Somatosensory evoked potential and brainstem auditory evoked potential responses were abolished in 12% (56). In a small series of 7 gyrate atrophy patients, neurologic impairment (eg, intellectual disability, school failure, major visuospatial dyspraxia, aggressive behavior, and epilepsy) was found in 5 patients (91). Posterior porencephaly has been observed in a 4-year-old girl with gyrate atrophy presenting with psychomotor delay, low vision, and horizontal nystagmus (69). Muscle pathology includes tubular aggregates and type-2 fiber atrophy (84), but only a small number of patients have clinical evidence of muscle weakness. Abnormal ultrastructure of hepatic mitochondria has been described (02). Peculiar fine, sparse, straight hair with microscopic abnormalities has been found in some patients (35). One report emphasized for the first time that there may be an association between gyrate atrophy and osteoporosis (01).
The prognosis in gyrate atrophy is poor if patients are untreated. As described above in the “Clinical manifestations” section, the natural course ends regularly in blindness in the fifth decade. Patients responsive to vitamin B6 supplementation have a good prognosis, but they may have minor ocular symptoms. The prognosis in treated patients who are not responsive to vitamin B6 supplementation depends on whether plasma ornithine can be chronically reduced with treatment. Permanent reduction of plasma ornithine to values below 200 µmol/L slows or stops the chorioretinal degeneration.
Vitreous hemorrhage causing sudden loss of vision (87) and neonatal hyperammonemia observed in 2 patients (12) are rare complications of the disease.
A healthy 30-year-old woman was admitted to the hospital because of an accident. In broad daylight she had fallen in an excavation on the sidewalk. Further elucidation revealed a restriction of her visual field that led to tunnel vision. The ophthalmological findings were typical for gyrate atrophy. The electroretinogram was almost completely diminished. The diagnosis was confirmed by an investigation of plasma amino acids that revealed a markedly increased plasma ornithine concentration of 650 µmol/L (normal is below 90 µmol/L). Treatment with vitamin B6 failed to reduce plasma ornithine, as did an arginine-restricted diet (because of nonadherence) and a trial of high-dose lysine.
An 11-year-old girl started experiencing vision loss in the form of myopia at the age of 3. She started wearing glasses at that age after her annual eye exam with her optometrist. She changed her glasses prescription every 2 years for progressive vision loss. At 11 years of age, she was seen by a different optometrist that suggested the presence of retinitis pigmentosa on her eye exam and, therefore, she was referred to a vision electrophysiology unit. In the last 2 years, she also started complaining of issues with night vision, especially when it gets dusky after sunset. She would have to grab her mom's hand for guidance whenever it was dark. She also started complaining of peripheral vision loss and tunnel vision in the last year. She denied having any color vision changes. She denied having muscle weaknesses, numbness, or tingling sensations. She seemed to be physically active. She was doing well intellectually and cognitively. Further investigation revealed typical peripheral chorioretinal atrophic lesions of gyrate atrophy and hyperornithinemia.
Gyrate atrophy is an autosomal recessive disease due to deficiency of the mitochondrial matrix enzyme ornithine aminotransferase (L-ornithine:2-oxoacid aminotransferase, EC 188.8.131.52).
Biochemical abnormalities. Most of the biochemical abnormalities in gyrate atrophy are explained by deficiency of the ornithine aminotransferase enzyme. Ornithine aminotransferase is a pyridoxal phosphate-requiring omega-transaminase. Investigation of the quaternary structure of the human enzyme provided strong evidence that the mature enzyme is a 256-kDa homohexamer (44). One molecule of the cofactor pyridoxal phosphate binds to each subunit (37; 81). Ornithine aminotransferase catalyzes the reversible conversion of ornithine and alpha-ketoglutarate to P5C and glutamate. In the mature organism, the equilibrium of the reaction rests quantitatively on the side of ornithine elimination and P5C formation.
Blockage of ornithine aminotransferase results in hyperornithinemia. The massive (10- to 20-fold) increase of tissue ornithine concentrations due to selective inhibition of ornithine aminotransferase in mice was the first direct demonstration of the quantitative importance of ornithine transamination in the regulation of ornithine homeostasis in practically all tissues (76; 14) and indicates that the vertebrate organism has no alternative method for the efficient elimination of ornithine other than transamination by the ornithine aminotransferase. Interestingly, during the neonatal period the metabolic flux (P5C --> ornithine --> arginine) is the opposite of that in older individuals (arginine --> ornithine --> P5C). Wang and colleagues found that ornithine aminotransferase-deficient mice produced by gene targeting exhibit neonatal hypo-ornithinemia and lethality and this phenotype was rescued by short-term arginine supplementation (100). Post-weaning, these mice developed hyperornithinemia similar to human gyrate atrophy patients. A neonate with ornithine aminotransferase deficiency presented with hyperammonemia and subnormal plasma ornithine levels (25). Both resolved immediately when supplemented with arginine, but relapsed when the child was taken off arginine. It took until 1 year of age until persistent hyperornithinemia occurred and hyperammonemia was resolved.
Ornithine metabolism is closely linked to the urea cycle and the synthesis of creatine, polyamines, and proline. Furthermore ornithine might influence NO metabolism by the close chemical and metabolic relationships of ornithine and arginine, the precursor of NO. Ornithine is formed from arginine by arginase and, to a lesser extent, by arginine:glycine amidinotransferase. The fate of the ornithine carbon atoms is either the incorporation into protein as arginine, proline, glutamate, or any of the a-ketoglutarate-derived nonessential amino acids, the conversion to polyamines and GABA, or oxidation in the urea cycle.
If ornithine accumulates, ornithine excretion increases accordingly, particularly at plasma concentrations more than 600 µM (94). Ornithine and other dibasic amino acids (lysine, arginine, and cystine) in normal plasma concentration are completely reabsorbed by the tubular dibasic amino acid transporter. In ornithine excess, the high renal filtered load of ornithine also results in increased renal clearance of lysine, arginine, and cystine (95). Thereby, hyperornithinemia may account for some of the abnormal concentrations of other plasma metabolites, such as hypolysinemia (95).
As another consequence of ornithine accumulation, the synthesis of creatine is disturbed by inhibition of the first step in creatine synthesis, the arginine:glycine amidinotransferase reaction. Ornithine acts as competitive inhibitor of the amidinotransferase; thus, hyperornithinemia results in decreased formation of guanidinoacetate, the precursor of creatine.
With the elevation of ornithine concentrations it is likely shifted into the remaining 2 pathways: carbamoylation and decarboxylation. The former results in increased urea formation. But in fact urea production is appropriate to protein intake in these patients (95). The limited urea production might be caused either by availability of urea precursors (glutamate, glutamine, ammonia) (05) or by the inhibition of arginase by ornithine. In addition to carbamoylation when elevated, ornithine may be decarboxylated by L-ornithine decarboxylase, leading to enhanced polyamine synthesis. Fragmentary data in patients with gyrate atrophy suggest that serum spermine, spermidine, and putrescine concentrations are in the normal range (40); however, increased urinary levels of polyamines and decreased cadaverine were found in all of 7 patients (86). Furthermore, consistent with the expected enhancement of polyamine formation were findings of increased tissue levels and excretion of polyamines in ornithine aminotransferase-deficient animal model studies (76).
Pathophysiology of chorioretinal degeneration. The pathophysiologic mechanism of the chorioretinal degeneration is unclear. It is not known which of the many specialized types of cells found in the retina are the first to be affected. Clarification is complicated by the fact that because of their interdependence, damage to any of the cellular components of the retina may adversely affect others. Attention has focused on the pigment epithelium and the photoreceptors, the 2 outermost cell layers of the retina. Most observations in humans, especially fluorescein angiography, indicate that around the completely atrophic areas the granular retinal pigment epithelium overlies a normal-appearing choroid (97). The observation of diffuse depigmentation of the pigment epithelium in a few young patients (36), studies in animal models (42; 101), and retinal pigment epithelial cells (89) suggest that the pigment layer is the site of initial insult in gyrate atrophy.
Accumulation of ornithine has been elucidated as a necessary factor in the pathophysiology of the chorioretinal degeneration in gyrate atrophy. Local, intravitreal injection of L-ornithine hydrochloride in physiologic saline solution caused marked edema in the pigment epithelium of rats and monkeys. Swelling of the pigment epithelial cells disappeared by 24 hours. However, many pigment epithelial cells gradually degenerated, and this resulted in patches of denuded areas. The photoreceptor cells overlying the damaged pigment epithelium degenerated secondarily (42). The evidence for ornithine accumulation causing the pathophysiology is corroborated by improved or stable visual function in those patients whose plasma ornithine has been reduced by means of arginine-restricted diet (34; 31; 72). Further, in a transgenic mouse model for ornithine aminotransferase deficiency, dietary arginine restriction prevented the appearance of retinopathy at the age when untreated mice developed gyrate atrophy (100). Interestingly and controversially, long-term supplementation of very high doses of L-ornithine, 100 times higher than the recommended dose for healthy humans, did not induce retinal damage in rats (71).
Other lines of evidence suggest additional factors for chorioretinal degeneration in addition to elevated ornithine levels. For example, hyperornithinemia without accumulation of ornithine in the mitochondria is found in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome, OMIM 238970). In this condition, ornithine transport is diminished, owing to a defective mitochondrial ornithine transporter. Patients with HHH syndrome do not express visual problems or fundus changes like those with hyperornithinemia due to gyrate atrophy. In mice receiving the selective ornithine aminotransferase inhibitor 5FMOrn, no impairment of the visual system despite distinct ornithine accumulation was observed, though this is most probably due to 10% to 20% residual activity of ornithine aminotransferase in this mouse model (14). These findings suggest that an elevated level of ornithine must be combined with an increased sensitivity to ornithine as a result of complete or near absence ornithine aminotransferase activity to lead to the specific retinal pigment epithelial degeneration seen in gyrate atrophy.
In rat liver and kidney, ornithine aminotransferase activity is barely detectable prenatally or during the first 2 postnatal weeks, but by 30 days it has increased approximately 15-fold to adult levels (26; 61). Ornithine aminotransferase is most abundant in liver, followed by kidney, retina, and intestine. Ornithine aminotransferase activity has been measured in the ocular tissues of a variety of species, including humans. Studies in mammals revealed high levels of ornithine aminotransferase activity in retinal pigment epithelia, neural retina, ciliary body, and the iris (65). The activity in retinal pigment epithelia was 3 to 10 times higher than in neural retina or liver (68). The fact that ornithine aminotransferase is present in these tissues suggests that the enzyme function may be important there.
The mechanism of the chorioretinal degeneration in gyrate atrophy is either a toxic effect of the accumulated precursor (ornithine or of one of its metabolites) or a deficiency of the reaction product (P5C or one of its metabolites). Two nonexclusive hypotheses have been proposed. In one, high ornithine concentration inhibits arginine:glycine amidinotransferase, resulting in reduced synthesis of creatine. In the other, the combination of the deficiency of ornithine aminotransferase and the inhibitory effect of ornithine on P5C synthase (43) results in decreased formation of P5C and proline.
Sipila and colleagues (84; 82) proposed that a deficiency of creatine and phosphocreatine may account for both the histological abnormalities in muscle (84) and the chorioretinal degeneration. The sensitivity of the amidinotransferase to ornithine inhibition is well documented in vitro (66; 67; 82). In gyrate atrophy, observations of reduced guanidinoacetate, creatine, and creatinine in body fluids (82) and reduction of phosphocreatine in skeletal muscle and brain (23; 51) indicate that the amidinotransferase is inhibited and that the total body creatine-phosphocreatine pool is significantly reduced. However, it is unlikely that creatine deficiency is the primary cause for the chorioretinal degeneration. The arginine:glycine amidinotransferase is not expressed in photoreceptor cells (65). Also, in individuals with hereditary defects of creatine metabolism and transport (guanidinoacetate methyltransferase deficiency, OMIM 601240; arginine:glycine amidinotransferase deficiency, OMIM 602360; and creatine transporter defect, OMIM 300352), an impairment of the visual system, especially chorioretinal degeneration, has never been observed (74; 74).
The second and more plausible hypothesis proposes that the pathogenesis is related to deficient synthesis of P5C and proline. This hypothesis is supported by the observation that the toxic effects of ornithine are prevented by the inhibition of P5C dehydrogenase, a P5C-consuming enzyme, and by addition of P5C. Reduced P5C may be detrimental because it decreases proline synthesis, alters the intracellular redox level, and alters the hexose monophosphate shunt activity (58; 20; 21). Retinal pigment epithelial cells lack proline oxidase (46), and the availability of proline in the extracellular fluid of the retina is expected to be low because proline poorly crosses the blood-brain barrier (54) and is virtually absent from the CSF. Other observations support the importance of P5C and proline. Findings of Ueda and colleagues suggest involvement of proline metabolism in the progress of gyrate atrophy. In retinal pigment epithelial cells, administration of proline prevents ornithine toxicity (89). In HHH syndrome the P5C production from ornithine by intact ornithine aminotransferase is normal. Finally, a reduced ornithine level may be beneficial because ornithine inhibition of P5C synthase in decreased.
Additional support for the theory of cytotoxicity of ornithine metabolites comes from observations of retinal pigment epithelial cells. Their viability and proliferative activities are inhibited by spermine, a polyamine derived from ornithine. Furthermore, apoptotic retinal pigment epithelial cell death was induced by spermine in a dose-dependent manner (39).
Additional abnormalities of possible pathologic significance in gyrate atrophy include plasma reductions of glutamate, glutamine, and lysine; abnormalities of polyamines or their metabolites; and a disturbance of NO function or metabolism in the retina.
Genetics. Barrett and colleagues reviewed 80 reported cases of gyrate atrophy and concluded that the pattern of inheritance was always consistent with autosomal recessive inheritance (04). By study of somatic cell hybrids, O'Donnell and colleagues assigned the ornithine aminotransferase locus to human chromosome 10 and mouse chromosome 7 (53). Wu and colleagues presented family linkage data locating ornithine aminotransferase to 10q (102). Barrett and colleagues used a cDNA for ornithine aminotransferase in somatic cell hybrids and in situ hybridization to map the gene to 10q26 (04). Ornithine aminotransferase gene sequences were also found on the X chromosome at Xp11.2 in the same region as a marker that is closely linked to X-linked retinitis pigmentosa (OMIM 312600). Mitchell and colleagues determined that the OAT gene is 21 kb long and contains 11 exons (50). The analysis of the rat gene structure revealed a single expressed gene and 3 pseudogenes (78; 79; 77). Thus, the tissue specific regulation of ornithine aminotransferase gene expression appears to be determined by a single gene. Human and rat ornithine aminotransferase genes are similar in size and organization. The ornithine aminotransferase structure, however, is species and tissue specific. Mitchell and colleagues identified the first mutations in the ornithine aminotransferase gene of patients with gyrate atrophy (50). Brody and colleagues discovered and characterized the molecular defect in 21 newly recognized ornithine aminotransferase alleles (08). The study of 8 kindreds with gyrate atrophy found 4 novel mutations. The functional analysis of a set of missense mutations revealed that mutant proteins were either highly unstable and rapidly degraded, or failed to assemble to form the active OAT hexamer (16). To date, more than 65 mutations have been reported. The allelic heterogeneity is extensive, except for the L402P allele that accounts for about 87% of the mutant ornithine aminotransferase genes in the Finnish population (85). Three alleles, V332M, A226V, and E318K, are known to produce mutant enzymes with in vitro pyridoxine responsiveness (64; 49; 45).
Gyrate atrophy occurs throughout the world and has been described in patients from various ethnic backgrounds. Its prevalence is highest in the Finnish population (88). Quantitative prevalence data do not exist. Valle and Simell reported about 150 biochemically documented patients, half of them Finnish (93).
Prenatal diagnosis is potentially feasible by ornithine aminotransferase measurement in amniotic fluid cells or chorionic villi (52; 24; 70) or by mutation analysis (63) if mutations are known in the index case. Successful prenatal detection of an affected fetus has not been reported to date. Neonatal detection of affected newborns by means of newborn screening for ornithine is not feasible because ornithine is not increased at birth; however, the proline-to-citrulline ratio may be a reliable screening parameter for gyrate atrophy in the newborn (15).
Significant hyperornithinemia other than by OAT deficiency can only by caused by HHH-syndrome. However, this condition is not associated with ocular signs and symptoms. Nongenetic causes of modestly increased plasma ornithine include isoniazid therapy (57) and hemolysis. Artificially increased plasma ornithine is found when unspun blood is left at room temperature.
The ocular findings in gyrate atrophy are pathognomonic and typically are not confused with atypical forms of retinitis pigmentosa. Only in the final stages is the appearance less specific, and then OAT deficiency may be easily confused with the end stage of several other forms of chorioretinal degeneration, such as X-linked choroideremia. However, gyrate-like atrophy can be seen in a few other disorders caused be mutations in the following genes: CYP4V2, RPE65, C1QTNF5, and CHM.
The most important laboratory test in OAT deficiency is measurement of the amino acids in plasma. In affected individuals, plasma ornithine values range from 400 to 1400 µmol/L (normal is less than 80 to 90 µmol/L). The combination of elevated plasma ornithine and characteristic ocular findings is highly specific for the diagnosis. Ornithine is also increased in the CSF and urine. Pathologic urinary excretion of ornithine and the other dibasic amino acids (arginine, lysine, cystine) typically occurs at plasma ornithine concentrations greater than 600 µmol/L. In plasma, lysine and creatine may be decreased. In urine, creatine, creatinine, and guanidinoacetate are usually decreased.
Investigation by magnetic resonance spectroscopy reveals a decreased concentration of creatine and phosphocreatine in brain and muscle.
Mutation analysis can be performed to confirm the diagnosis. Enzyme analysis is feasible in stimulated lymphocytes but provides only sparse additional information and is not offered for routine analysis by clinical laboratories. Prenatal diagnosis is potentially possible by ornithine aminotransferase activity measurement in amniotic fluid cells or chorionic villi or by mutation analysis if the mutations are known from the index case.
The main treatment goal is the reduction of ornithine to the lowest level that is possible. Target ranges between 200 and 400 µmol/L are considered successful treatment. Adequacy of treatment is measured by recurrent monitoring of plasma ornithine concentration and funduscopy. In general, combined treatment approaches seem necessary in most patients with gyrate atrophy because no form of therapy is unequivocally effective. A 2006 article by Hoffman and Schulze provides an overview of treatment and follow-up (27).
Vitamin B6. Only about 5% of patients respond to pharmacological doses of the ornithine aminotransferase co-factor pyridoxine (vitamin B6, 40 to 200 mg/day in children, 40 to 500 mg/day in adults) (11). Vitamin B6-responsiveness should be evaluated before attempting other treatment options.
Dietary arginine restriction. For the large majority of cases unresponsive to the co-factor vitamin B6, treatment is based on reducing ornithine plasma levels with an arginine-restricted diet. In some affected individuals, ornithine reduction can be achieved with a semisynthetic diet. The diet consists of restricted intake of natural protein (0.3 to 0.5 g/kg per day in children, 0.25 g/kg per day in adults) and supplementation of an arginine-free essential amino acid mixture (0.3 to 0.5 g/kg per day in children, 0.25 to 0.3 g/kg per day in adults). Sib pair studies with young, well-controlled patients strongly suggest that chronic reduction of plasma ornithine to values below 200 µM with an arginine-restricted diet slows or stops the chorioretinal degeneration (31; 32). Comparison of 17 patients complying with an arginine-restricted diet with 10 patients who were unable to comply revealed that adhering to an arginine-restricted diet that lowered the plasma ornithine level below 400 to 500 µM slowed the loss of function as measured by sequential electroretinography and visual field examinations (33). Conversely, despite excellent biochemical control over a 3 to 4 year period, 4 young patients demonstrated electroretinographic changes that progressed in 2 patients and chorioretinal degeneration that progressed in all (97).
In general, compliance with the semisynthetic diet is crucial in the majority of patients. As shown in one study, the age of the affected individual when the treatment is initiated is the most important prognostic factor for predicting long-term outcome. Out of 12 patients, only 1 patient could be categorized as a good complier according to plasma ornithine levels, 5 were intermediate, and 6 were poor. The study emphasizes the difficulty with dietary treatment and the need for early diagnosis (73). Long-term treatment with a completely natural low-protein diet (0.8 g natural protein per kg per day) might represent a potentially viable alternative in patients refusing the semisynthetic diet (72).
Because of the hypo-ornithinemia at birth (100; 12) and the inverted metabolic flux during the neonatal period, when ornithine serves as the precursor of arginine, the arginine intake in patients less than 3 months of age should not be restricted until plasma ornithine begins to increase.
Other therapeutic trials. Effects on the clinical course from pharmacologic doses of lysine (5 g/m2 per day) (55; 17) or the nonmetabolizable amino acid alpha-aminoisobutyrate (0.1 g/kg per day) (94) that enhance renal clearance of ornithine are either unconvincing or difficult to assess because of the limited number of observations.
Creatine administration has resulted in improvement in the histological abnormalities in muscle, but did not halt the chorioretinal degeneration (99).
An experimental therapy is the administration of proline. The rationale is that the deficient local formation of that nonessential amino acid causes chorioretinal degeneration. In retinal pigment epithelial cells pre-treated with 5-FMO for 30 minutes ornithine administration caused inhibition of DNA synthesis, and this was accompanied by drastic changes in morphologic appearance, disorganization of the cytoskeleton, and cell death. In retinal pigment epithelial cells, proline prevents ornithine toxicity (89). Four patients (5 to 32 years) were treated with oral proline doses ranging from 65 to 488 mg/kg/day. The clinical outcome was mixed, with the youngest subject showing only minimal progression over 5 years, the 8-year-old showing clear progression over 3 years, and the 2 adults showing no progression over 3 years. Plasma proline levels ranged from unchanged to a 3-fold increase (22). However, the hypothesis of local proline deficiency in the retina is based on the lack of entry of proline into retina from blood. If the hypothesis is true that proline does not enter the retina, then it is questionable whether supplemental proline can be expected to be of therapeutic benefit.
Reduction of the carrier-mediated ornithine transport via cationic amino acid transporter-1 (CAT-1) may become another approach for treatment of gyrate atrophy in the future. It has been shown that ornithine transport via CAT-1 may play a crucial role in ornithine cytotoxicity, at least in retinal pigment epithelial cells (38).
Studies using human-induced pluripotent stem cells have commenced (28; 48). Further, Doimo and colleagues found that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator known to increase mitochondrial biogenesis, markedly stimulates OAT expression, thus, representing a possible treatment for a subset of patients with hypomorphic alleles (16). Both may facilitate a customized approach to retinal disease treatment in the future (28; 48).
Symptomatic treatments reportedly efficacious in single cases include intravitreal injections of angiogenesis inhibitors or topical nonsteroidal anti-inflammatory drugs combined with a carbonic anhydrase inhibitor (10; 29; 59).
Patients responsive to vitamin B6 supplementation have a good prognosis, but they may have minor ocular symptoms. The prognosis in treated patients who are not responsive to vitamin B6 supplementation depends on whether plasma ornithine can be chronically reduced with treatment. Permanent reduction of plasma ornithine to values below 200 µmol/L slows or stops the chorioretinal degeneration.
There is no information from the literature that gyrate atrophy in a pregnant woman affects the course of pregnancy and delivery or the fetus; and there is no indication that gyrate atrophy in the fetus affects the pregnant mother.
Andreas Schulze MD PhD
Dr. Schulze of the University of Toronto and Section Head, Metabolic Genetics, and Medical Director, Newborn Screening Program, The Hospital for Sick Children, has no relevant financial relationships to disclose.See Profile
Tyler Reimschisel MD
Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire.See Profile
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