Neurotrophic keratitis in a patient with dihydroxypyrimidine dehydrogenase deficiency.

We describe a case of neurotrophic keratitis in association with dihydroxypyrimidine dehydrogenase (DHPD) deficiency. Ocular manifestations in patients with DHPD are rare and neurotrophic keratitis has never been reported before. A six-year-old boy who was a known case of DHPD deficiency and born of a consanguineous marriage presented to our clinic with non-healing corneal ulcers in both eyes. Reduced corneal sensations were detected and the patient was started on lubricating eye drops. The patient continues to be on lubricant eye drops and there has been no recurrence of the disease.

Dihydroxypyrimidine dehydrogenase (DHPD) deficiency is a rare metabolic disease. The patient usually presents in early infancy with features of cerebral dysfunction.1 Though other ocular manifestations have been reported, to our knowledge corneal involvement has not been documented in the past.2 This is the first case report of DHPD deficiency with corneal involvement.

Case History

An 18-day-old baby with failure to thrive was referred to our clinic for eye examination. The patient was born of a consanguineous marriage. His parents were first cousins. At birth he was lethargic with poor cry and feeble suck. He had bilateral hydrocele and large anterior fontanelle. He was investigated for possible metabolic diseases. Blood investigations included total and differential blood count, blood sugar, serum electrolytes, serum ammonia, serum lactate, serum pyruvate, liver enzymes, thyroid function tests and arterial blood gases. Urine was tested for pH, ketones, odor and reducing substances. Karyotyping with G-banding studies was also performed. Though all above investigations were within normal range urine gas chromatography showed increased thiamine and uracil levels. Fibroblast cultures indicated deletion of the DHPD gene and diagnosis of DHPD deficiency was made. His elder brother was homozygous for the mutation and excreted increased amount of thiamine and uracil in urine; however, he was clinically asymptomatic. His eldest sister has two normal alleles but his mother was heterozygous for the condition.

Ocular assessment at that time did not detect any pathology. On subsequent follow-up his vision was found to be reduced to 20/100 (Cardiff Acuity Cards). Ophthalmic examination under general anesthesia was essentially normal apart from astigmatism in both eyes. Glasses were prescribed with orthoptic follow-up. At the age of six years his visual acuities deteriorated to 20/200 and 20/120 (Sheridan Gardner) in the right and left eye respectively. Bilateral central corneal opacities were noticed along with peripheral corneal vascularization. He subsequently developed recurrent corneal epithelial defects [Fig. 1]. Schirmer′s Test revealed normal tear secretion. An initial diagnosis of exposure keratopathy was made.

Figure 1

Central epithelial defect

However, on subsequent follow-up, he was found to have markedly reduced corneal sensations and a revised diagnosis of neurotrophic keratitis was made. For the last three years his vision has remained unchanged and his eyes have been managed satisfactorily with ocular lubricants with no further recurrence of the corneal epithelial defects [Fig. 2].

Figure 2

Healed epithelial defect

Discussion

The DHPD enzyme is the rate-limiting step in the metabolism of pyrimidine bases.3 It catalyses the first step in the conversion of thymine and uracil to beta-aminobutyric acid and beta- alanine respectively [Fig. 3]. Partial or total deficiency leads to increased accumulation of thymine and uracil in the serum as well as cerebrospinal fluid. Excess bases are also excreted in the urine. The cause for the neurological deficit is still unclear. It has been postulated that the DHPD enzyme is required for the synthesis of beta alanine, which is a neurotransmitter in the brain. This may explain the reduced corneal sensation and the development of neurotrophic keratitis in this child. Various manifestations associated with DHPD deficiency have been described, but most children present with microcephaly, epilepsy and abnormal EEG profile, however, many may be asymptomatic.4 Ocular manifestations such as microphthalmia, choroidal coloboma and nystagmus have also been reported.2

Figure 3

Biochemical pathway of thymine and uracil catabolism

The condition has attracted interest in the recent years as the DHPD enzyme is also the initial step for the metabolism of widely used anti-neoplastic drug 5 Fluorouracil. Severe toxicity, including death, following administration of 5 Fluorouracil was reported in patients with DHPD.3