Retinal Degeneration

      Dear Editor:
      We report on severe ophthalmological manifestations in a patient with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome. This is a rare mitochondrial neurometabolic disease caused by mutations in SLC25A15, resulting in the defective activity of a mitochondrial carrier that transports ornithine across the inner mitochondrial membrane.
      • Camacho J.A.
      • Obie C.
      • Biery B.
      • et al.
      Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.
      The characteristic metabolic triad results in a hepatocerebral clinical syndrome, and include episodes of hyperammonemia with lethargy/coma, liver dysfunction, coagulation abnormalities, pyramidal tract signs, seizures, and developmental delay/mental retardation.
      A 25-year-old woman was born to healthy consanguineous Italian parents and presented at the age of 5 years a hepatitis-like attack with moderate hyperammonemia. HHH syndrome was suspected based on the presence of the characteristic metabolic triad and was further confirmed by the identification of the homozygous p.R275Q mutation in SLC25A15.
      • Salvi S.
      • Santorelli F.M.
      • Bertini E.
      • et al.
      Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
      At age 23 years, the patient was referred to our hospital because of recurrent episodes of confusion with hyperammonemia while on a protein-restricted diet alone. Clinically, mild intellectual delay and brisk tendon reflexes were noticed. Brain magnetic resonance imaging (MRI) showed mild cortical atrophy, thin corpus callosum, and cerebellar vermis hypoplasia. MRI spectroscopy did not show abnormal peaks (i.e., creatine, choline, N-acetylaspartate [NAA], lactate). By adding arginine (250 mg/kg/day) and benzoate (150 mg/kg/day) to protein-restricted diet, we observed the complete normalization of blood ammonia. Additional investigations revealed low plasma creatine levels (13.6 μmol/L, normal 23–94) with normal guanidinoacetic acid (0.88, normal 0.3–3.0). Creatine (2 g/day) was then supplemented with normalization of circulating levels (range, 28.0–56.0 μmol/L).
      The patient was referred to ophthalmological evaluation because of photophobia and hemeralopia. Visual acuity was 0.5 in the right eye (RE) and 0.4 in the left eye (LE). Anterior segment was normal, while a small posterior subcapsular cataract was present in both eyes. Fundoscopy showed tapetoretinal degeneration (Fig 1A–D; available at http://aaojournal.org). Electroretinogram (ERG) showed a marked reduction of b wave amplitude, especially of the rod response (26 μV in both eyes, normal >300 μV) and a less severe reduction of the combined rod-cone (RE: 125 μV; LE: 159 μV, normal >380 μV) and the cone (RE: 47.5 μV; LE: 39.5 μV, normal >90 μV) responses. Humphrey Visual Field 30.2 showed peripheral constriction at the borders of the central 30° (RE: mean deviation [MD] = –7.80 decibels [dB]; pattern standard deviation [PSD] = 5.20 dB; LE: MD = –5.97 dB; PSD = 3.49 dB). One year after the first evaluation, fundoscopy showed worsening and enlargement of atrophic areas.
      Figure thumbnail gr1
      Figure 1Retinography of right and left eye. Arrows point some of punched-out lesions of chorioretinal atrophy spread over the posterior pole (A) and midperiphery (B) of the right eye, as well as over the posterior pole (C) and midperiphery (D) of left eye.
      Family history was unremarkable for hemeralopia and fundoscopy of parents and sister was normal.
      Although about 80 cases have been collected, the presence of ophthalmological signs in HHH syndrome is rare, being recorded only in one subject showing retinal depigmentation, chorioretinal thinning, with normal ERG.
      • Lemay J.F.
      • Lambert M.A.
      • Mitchell G.A.
      • et al.
      Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.
      The clinical case described in this work presented with severe progressive retinal degeneration, decreased photoreceptor function, bilateral cataract, and concentrically reduced visual field. These findings are very similar to those observed in the early phase of gyrate atrophy of the choroid and retina due to ornithine aminotransferase (OAT) deficiency, the only other known disease causing hyperornithinemia. OAT patients usually develop by puberty typical punched-out lesions of chorioretinal atrophy and cataract and most of them are blind in their 50s. The pathophysiological mechanism of retinal degeneration in OAT is still unclear but the associated secondary creatine deficiency–resulting from the excess of intracellular ornithine that inhibit glycine transamidinase, 1 of the 2 enzymes of creatine biosynthesis–impairing energy transduction of vision or interfering with the phagocytic activity of retinal epithelial cells has been hypothesized. Alternatively, it has been speculated on the possible toxicity of other compounds related to ornithine metabolism (e.g., pyrroline 5-carboxylate, lysine, polyamines, nitric oxide). It is possible that retinal degeneration shares similar mechanisms also in HHH syndrome given the impaired creatine metabolism.
      • Dionisi Vici C.
      • Bachmann C.
      • Gambarara M.
      • et al.
      Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.
      Nonetheless, in OAT deficiency gyrate atrophy seems to progress despite prolonged creatine treatment.
      • Vannas-Sulonen K.
      • Sipilä I.
      • Vannas A.
      • et al.
      Gyrate atrophy of the choroid and retina A five-year follow-up of creatine supplementation.
      Similarly, our patient's vision did not improve upon creatine supplementation. Although a better understanding of the pathophysiology of ocular damage is still lacking, it appears important to include a careful ophthalmological evaluation with electrophysiological testing in the general assessment of HHH syndrome.

      References

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        • Obie C.
        • Biery B.
        • et al.
        Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.
        Nat Genet. 1999; 22: 151-158
        • Salvi S.
        • Santorelli F.M.
        • Bertini E.
        • et al.
        Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
        Neurology. 2001; 57: 911-914
        • Lemay J.F.
        • Lambert M.A.
        • Mitchell G.A.
        • et al.
        Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.
        J Pediatr. 1992; 121: 725-730
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        • Bachmann C.
        • Gambarara M.
        • et al.
        Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.
        Pediatr Res. 1987; 22: 364-367
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        • Sipilä I.
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        • et al.
        Gyrate atrophy of the choroid and retina.
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