Journal of Pediatric Ophthalmology and Strabismus

Megalocornea in Nonketotic Hyperglycinemia

Creig S Hoyt, MD; Richard A Brown, MD

Abstract

Buphthalmia is a general descriptive term connoting an eye so enlarged as to be bovine in appearance.1 It is often implied erroneously that elevation in intraocular pressure is the sole mechanism by which an infant eye may enlarge. However, developmental, nonprogressive anomalies of the cornea may present with enlargement of the cornea in the absence of clinical signs of glaucoma.2 Furthermore, the buphthalmos associated with neurofibromatosis is not always the direct result of elevated intraocular pressure.3-5 In this paper we report the association of megalocornea without elevated intraocular pressure in a patient with a primary defect in glycine metabolism. The enlargement of the eyes of this patient may have been due to a coincidental developmental anomaly of the cornea. However, in light of what is known about the overgrowth of connective tissue of the vitreous of chicks fed an excess of glycine,6 we suggest that the enlargement of the eyes in this patient may have been the consequence of a similar process.

CASE REPORT

C.S. is a nine-month-old girl, the second child of nonconsanguineous emigrants from Lebanon. The first child, a boy, is normal. Pregnancy and birth were uncomplicated. Birth weight was 3142 g, and body length was 54 cm. The Apgar score was 6, and it was noted immediately that she was hypotonic with a very weak cry. She fed poorly due to very poor sucking power. Her hypotonia was so severe that a diagnosis of neonatal myasthenia was entertained, butthis was not supported on the basis of either a neostigmine test or electromyography. Although she remained extremely hypotonic her parents took her home against medical advice at 15 days of age.

She did not do well at home during the next 10 weeks. She continued to feed poorly and did not seem to respond to either visual or auditory stimuli. At three months of age she developed generalized seizures increasing in frequency and intensity despite the administration of adequate doses of various anticonvulsants. At six months of age she remained profoundly hypotonic, unable to sit up, turn over, or hold her head off the bed. At eight months of age she was admitted to the hospital with the diagnosis of "failure to thrive."

On examination the patient was a poorly developed white female who weighed 28.4 kg. She was unable to raise her head, sit, or roll over. She did not appear to react to any auditory or visual stimuli. She had generalized seizures as frequently as one every hour. Between seizures she lay quietly in bed without crying. She was extremely hypotonic and moro and tendon reflexes were absent. Breathing was shallow and irregular with periods of müd cyanosis. Because of her apparent "blindness" an ophthalmologic consultation was requested.

On ophthalmologic examination no apparent visual response to any test object, including large colorful toys, could be demonstrated. However, the brightest intensity of the indirect ophthalmoscope caused the child to cry and when the child was rotated, refixation saccades were noted. The pupils were both 5 mm and reacted equally and briskly to direct and consensual light. Both corneas were enlarged but lusterousand clear without any breaks in Descemet's membrane. The horizontal corneal diameter measured 13.5 mm and the left, 1 2.5 mm. Intraocular pressure measured without sedation and with a Schiotz tonometer was 10 and 12 mm Hg in the right and left eye respectively. Both anterior chambers were deep. The lenses were clear. The fundi appeared normal and the cup/disk ratio was 0.1 in each eye. Placido disk examination with a plus 1 0.00 lens did not show any distortion of the mires. Gonioscopy was performed…

Buphthalmia is a general descriptive term connoting an eye so enlarged as to be bovine in appearance.1 It is often implied erroneously that elevation in intraocular pressure is the sole mechanism by which an infant eye may enlarge. However, developmental, nonprogressive anomalies of the cornea may present with enlargement of the cornea in the absence of clinical signs of glaucoma.2 Furthermore, the buphthalmos associated with neurofibromatosis is not always the direct result of elevated intraocular pressure.3-5 In this paper we report the association of megalocornea without elevated intraocular pressure in a patient with a primary defect in glycine metabolism. The enlargement of the eyes of this patient may have been due to a coincidental developmental anomaly of the cornea. However, in light of what is known about the overgrowth of connective tissue of the vitreous of chicks fed an excess of glycine,6 we suggest that the enlargement of the eyes in this patient may have been the consequence of a similar process.

CASE REPORT

C.S. is a nine-month-old girl, the second child of nonconsanguineous emigrants from Lebanon. The first child, a boy, is normal. Pregnancy and birth were uncomplicated. Birth weight was 3142 g, and body length was 54 cm. The Apgar score was 6, and it was noted immediately that she was hypotonic with a very weak cry. She fed poorly due to very poor sucking power. Her hypotonia was so severe that a diagnosis of neonatal myasthenia was entertained, butthis was not supported on the basis of either a neostigmine test or electromyography. Although she remained extremely hypotonic her parents took her home against medical advice at 15 days of age.

She did not do well at home during the next 10 weeks. She continued to feed poorly and did not seem to respond to either visual or auditory stimuli. At three months of age she developed generalized seizures increasing in frequency and intensity despite the administration of adequate doses of various anticonvulsants. At six months of age she remained profoundly hypotonic, unable to sit up, turn over, or hold her head off the bed. At eight months of age she was admitted to the hospital with the diagnosis of "failure to thrive."

On examination the patient was a poorly developed white female who weighed 28.4 kg. She was unable to raise her head, sit, or roll over. She did not appear to react to any auditory or visual stimuli. She had generalized seizures as frequently as one every hour. Between seizures she lay quietly in bed without crying. She was extremely hypotonic and moro and tendon reflexes were absent. Breathing was shallow and irregular with periods of müd cyanosis. Because of her apparent "blindness" an ophthalmologic consultation was requested.

On ophthalmologic examination no apparent visual response to any test object, including large colorful toys, could be demonstrated. However, the brightest intensity of the indirect ophthalmoscope caused the child to cry and when the child was rotated, refixation saccades were noted. The pupils were both 5 mm and reacted equally and briskly to direct and consensual light. Both corneas were enlarged but lusterousand clear without any breaks in Descemet's membrane. The horizontal corneal diameter measured 13.5 mm and the left, 1 2.5 mm. Intraocular pressure measured without sedation and with a Schiotz tonometer was 10 and 12 mm Hg in the right and left eye respectively. Both anterior chambers were deep. The lenses were clear. The fundi appeared normal and the cup/disk ratio was 0.1 in each eye. Placido disk examination with a plus 1 0.00 lens did not show any distortion of the mires. Gonioscopy was performed with considerable difficulty due to the patient's frequent myoclonic jerks, but the angles appeared open with normal nonpigmented trabecular meshwork and no abnormal iris processes. An examination under anesthesia was recommended, but the patient's general status was such that her pediatricians felt this was not warranted.

High-voltage electrophoresis of the urine revealed a large spot for glycine. A diagnosis of hyperglycinemia was established by column chromatography. The patient was placed on a diet with an amino acid mixture developed for patients with hyperglycinemia. She appeared to become slightly more alert but continued to have frequent seizures. At the time of this report, she continues to have severe psychomotor retardation, She does not respond to her surroundings, does not fix or follow objects, and shows only infrequent limb movements. Generalized seizures have continued to occur frequently. The EEG continues to demonstrate a mixture of diffuse highvoltage delta waves, multifocal spikes, and sharp waves, similar to hypsarrhythmia. Her ocular findings have been unchanged on two subsequent examinations with no evidence of elevated intraocular pressure.

DISCUSSION

The average horizontal diameter of the newborn cornea is 10 mm and by two years of age the average adult measurement of 11.8 mm is attained.7 A measured diameter of over 12 mm in a patient under one year is highly suspicious, and is diagnostic of infantile glaucoma if coupled with tears in Descemet's membrane.' However, an enlarged cornea may occur as a developmental anomaly without any signs of glaucoma.

Megalocornea is an important cause of corneal enlargement without elevation in intraocular pressure. Itismostcommonlyseenasan x-chromosome linked recessive trait in which there is marked corneal enlargement and a deep anterior chamber, but no tears in Descemet's membrane and normal intraocular pressure and optic discs.2'7 Megalocornea usually occurs as an isolated anomaly, but has been reported in association with Marian's syndrome,8 osteogenesis imperfecta,9 progressive facial hemiatrophy,10 Thomson's congenital poililoderma," craniostenosis,12 oxycephaly,13 dwarfism,14 and Down's syndrome.15 Although our patient is a girl, it is conceivable that megalocornea accounts for her enlarged corneas since we have not demonstrated progressive enlargement and her intraocular pressure remains normal. However, there is no family history of similar ocular condition and we have examined her parents and brother and have found normal corneal diameters in these family members.

Keratoglobus may also present with enlarged corneal diameters.16 It is characterized by bulging, globular-shaped corneas and attentuation of the stroma. Our patient showed no signs suggestive of these disorders.

It may be that the metabolic abnormalities seen in this patient are related to her ocular findings. The metabolic changes demonstrated in our patient are diagnostic of hyperglycinemia. It has become apparent recently that there are at least three or more distinct causes of hyperglycinemia.17 A ketotic form was first described by Childs et al in 1961.18 Subsequently, Gerritsen and associates reported a child with high levels of glycine in the blood, urine, and cerebrospinal fluid, but without metabolic acidosis.19 This form of hyperglycinemia has been referred to as hypooxaluria or nonketotic. A third disorder is seen in which patients with ketotic hyperglycinemia excrete large quantities of methylmalonic acid in the urine.20

The patient reported in this communication has the nonketotic form of hyperglycinemia. Children with this disorder appear to have a similar course. They may appear normal at birth, but early in the neonatal period they begin showing signs of lethargy, poor feeding, hyptonia, and the eventual onset of generalized seizures.21'22 Most of these children show very little response to visual or auditory stimuli and often are thought to be blind and/or deaf. However, the patient described in this paper is the first case in which an ocular anomaly has been identified.

The effect of dietary glycine on the developing chick eye has been of interest since the report by Groschke and co-authors documented that developing chicks fed a purified diet supplemented with high levels of glycine, gelatine, and nicotinic acid develop enlargement of the eyeballs.23 Subsequently, Naber and co-workers stated that the buphthalmia caused byglycine toxicity in chicks waspartially reversible if folic acid was injected intramuscularily.24 Other investigators have failed to confirm this.25

In a study of the mechanism responsible for buphthalmia in chicks fed an excess of glycine it was suggested that a change in vitreous volume was responsible rather than elevation of intraocular pressure.6 Furthermore, it was demonstrated that the change in vitreous volume was seen in conjunction with an increase in total hydroxyproline and soluble hexuroxic acid. This suggests that the eye abnormality is due primarily to an overgrowth of connective tissue and not an optic fluid imbalance. It is not certain how glycine may bring about these changes. It is noteworthy in speculating how glycine might effect vitreous volume that glycine has been found to be stimulatory for uridine 5'-diphosphoglucose dehydrogenase.26 This enzyme acts as a catalyst in the initial step in the biosynthesis of hyaluronic acid.

In light of the changes noted in chicks fed excessive glycine it is surprising that no investigation of the ocular findings of patients with hyperglycinemia has been reported. Careful clinical study of these patients may not be germane only to the ophthalmologist interested in the mechanisms whereby the neonatal globe enlarges, but also to clinicians and biochemists investigating inborn errors of metabolism. Some authorities have asserted that high plasma glycine levels are harmless, whereas high brain glycine is responsible for the clinical manifestations of patients suffering from hyperglycinemia.2' This theory would have to be revised if buphthalmia were found to be a common anomaly in children with hyperglycinemia.

These children are so severely ill that we suspect that few have been examined carefully by an ophthalmologist. Although the prognosis for these children is poor, careful ophthalmic examination is warranted in light of the possible insights that might be forth coming in regards to the mechanisms by which the neonatal eye may enlarge. It may even be that glycine, which is known to be a neurotransmitter in certain areas of the nervous system27 could be responsible for other causes of buphthalmia, such as the occasional case of buphthalmos without elevated intraocular pressure seen in association with neurofibromatosis.3"5 For these reasons we urge further ophthalmologic study of patients with hyperglycinemia despite their poor general status.

SUMMARY

A nine-month-old girl with nonketotic hyperglycinemia and bilateral enlargement of the corneas is reported. There was no evidence of elevated intraocular pressure or iridocorneal angle anomalies. The corneas have remained clear and lusterous without tears in Descemets membrane. The possibility that the elevated glycine level may play a part in the buphthalmia of this patient is discussed in light of what is known about the effect or excessive dietary glycine on the developing chick eye. Further ophthalmologic study of patients with various forms of glycinemia might provide further understa nding of the ways in which the developing eye may enlarge.

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10.3928/0191-3913-19780301-08

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