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J Neurol Neurosurg Psychiatry. 2007 June; 78(6): 656–657.
Published online 2006 November 6. doi:  10.1136/jnnp.2006.101386
PMCID: PMC2077941

Myopathy with tubular aggregates and gyrate atrophy of the choroid and retina due to hyperornithinaemia

Gyrate atrophy (GA) of the choroid and retina with hyperornithinaemia is a rare inherited autosomal recessive metabolic disease. It is due to a mitochondrial enzymatic deficiency in ornithine‐amino‐transferase (OAT), leading to hyperornithinaemia. Most frequently, ocular findings are clinically isolated and spread to blindness. Associated muscular weakness is rare.

Case report

The present case is that of a patient, from a consanguineous Turkish marriage and the third of seven brothers and sisters, who developed, at age 15 years, loss of night vision with bilateral retinopathy, myopia and cataract. Ophthalmological symptoms progressively worsened. At the age of 18 years, mild proximal weakness appeared in the right arm and slowly spread to the four limbs. At the age of 33 years, he had proximal muscular atrophy of the lower limbs without pain. Clinical examination showed marked bilateral atrophy and mild weakness of the gluteus maximus, and detachment of the shoulder blades. There was no sensitive symptom, reflexes were normal, and there was no sign of central nervous system involvement.

Visual acuity was estimated to be 6/30 (right eye) and 6/15 (left eye). Fundoscopy revealed major chorioretinal atrophy with a typical pattern of gyrate atrophy: garland‐shaped, sharply defined, zones of atrophy in the midperiphery of the fundus, and large atrophic areas with festooned edges (fig 11).

figure jn101386.f1
Figure 1 Fundoscopy of gyrate atrophy.

Standard biological investigations were normal; creative phosphokinase serum level was 189 U/l (N: 40–250).

Electromyography showed a myopathic pattern in the proximal muscles.

Histological analysis (no 2349–95 IPS) of the deltoideus muscle revealed subsarcolemmal and intermyofibrillary slits or lakes affecting numerous muscle fibres. These areas were pink on H&E and red on Gomori's trichrome stain. They were strongly stained with nicotinamide dinucleotide tetrazolium reductase and were unstained with succinic acid dehydrogenase. They were exclusively found in type II fibres. On semi‐thin toluidine blue‐stained resin sections, these masses appeared pale blue, subdivided by thin septae. Electron microscopy showed that these areas consisted of densely packed tubules with a diameter of about 50 nm. Some of these tubules were dilated. This pattern corresponded to tubular aggregates.

Enzymatic activities of the mitochondrial chain and mitochondrial DNA were normal.

Serum and urinary levels of ornithine were very high, respectively, 1300 μmol/l (N: 111±64) and 633 μmol/mmol creatine (N<5).

Cerebral MRI was normal.

The diagnosis of myopathy with tubular aggregates and GA of the choroid and retina due to hyperornithinaemia was made, and treatment with daily oral pyridoxine was started and a low arginin diet ensured.

Discussion

Two genetic autosomal recessive disorders result from hyperornithinaemia: hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome, and GA of the choroid and retina with hyperornithinaemia. GA of the choroid and retina is a rare disease, first reported in the Finnish population, but now described all over the world.1

The main clinical feature of hyperornithinaemia is its ocular abnormalities. First symptoms are non‐specific and appear during the second or third decade, consisting of hesperanopia, myopia and constricted visual field. Fundoscopy generally reveals a bilateral typical pattern of festooned chorioretinal atrophy, initially occurring in the midperiphery, and posterior subcapsular cataract.2 If not treated, this condition can lead to blindness between the ages of 40–55 years.

Plasma and urinary ornithine levels, mesured by chromatography, are constantly raised (5–20 N).

Ornithine is an amino acid that plays a role in the metabolism of urea, creatine and polyamines and that can be consumed during a reaction catalysed by the OAT in the mitochondria.

Hyperornithinaemia is caused by OAT deficiency secondary to OAT gene mutation. More than 50 pathogenic mutations of the OAT gene, mapped in 10q26, have already been detected.3 Eighty‐five per cent of patients with gyrate atrophy have a normal amount of normal‐sized OAT mRNA, but only 10% have normal amounts of normal‐sized OAT protein. This finding suggests a normal transcription but abnormal transduction.

Systemic involvement, such as thin and rare hairs, mental retardation with diffuse brain atrophy, slow background electro‐encephalographic abnormalities and muscular weakness, has been described previously in association with GA.4 Muscular histological examination, even in patients without weakness, can show muscular abnormalities such as type II fibre atrophy and sarcoplasmic tubular aggregates. The pathogenic role of tubular aggregates is unknown and uncertain. These distinctive inclusions are not specific and have been described in normal subjects, in some other muscular diseases, such as acromegaly, and in porphyria cutanea tarda.

An arginine‐restricted diet can reduce plasma ornithine levels and completely prevent retinal degeneration, over a 12‐month period, in a mouse model of OAT deficiency.5 Long‐term reduction of ornithine levels by the arginine‐restricted diet has been proposed in patients with GA; progression of chorioretinal lesions can be slowed if the diet is started at an early age.6

Administration of pyridoxine stimulates residual OAT activity and is associated with a significant reduction in ornithine plasma levels in some genetically determined responsive patients. The daily dose of pyridoxine is still under discussion (between 20 and 600 mg). However, the pyridoxine therapy does not stop the progression of chorioretinal degeneration.

Conclusion

GA with hyperornithinaemia is a metabolically inherited disease and is one of the rare causes of both ocular and muscular involvement. Lack of specificity of initial ophthalmological symptoms can be responsible for a misdiagnosis. When muscular symptoms are associated with these ophthalmological signs, the diagnosis of GA of the choroid and retina due to hyperornithinaemia has to be considered and ornithine plasma levels have to be assayed.

Footnotes

Competing interests: None declared.

References

1. Cutler C W. Drei ungewönlische Fälle von retino‐choroidal Degeneration. Arch Augenheilk 1895. 30117–122.122
2. Wilson D J, Weleber R G, Green W R. Ocular clinicopathologic study of gyrate atrophy. Am J Ophthalmol 1991. 11124–33.33 [PubMed]
3. Brody L C, Mitchell G A, Obie C. et al Ornithine delta‐amino‐transferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem 1992. 2673302–3307.3307 [PubMed]
4. Kaiser‐Kupfer M I, Kuwabara T, Askanas V. et al Systemic manifestations of gyrate atrophy of the choroid and retina. Ophthalmology 1981. 88302–306.306 [PubMed]
5. Wang T, Steel G, Milam A H. et al Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci USA 2000. 971224–1229.1229 [PubMed]
6. Kaiser‐Kupfer M I, Caruso R C, Valle D. Gyrate atrophy of the choroid and retina: further experience with long‐term reduction of ornithine levels in children. Arch Ophthalmol 2002. 120146–153.153 [PubMed]

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