Elevated plasma dihydroorotate in Miller syndrome: Biochemical, diagnostic and clinical implications, and treatment with uridine.

Abstract

BACKGROUND:

Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis.

METHODS:

We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60h. The patient received a 3-month trial of oral uridine for behavioural problems.

RESULTS:

The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO.

CONCLUSION:

This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening.

• Authors: John A Duley, Michael G Henman, Kevin H Carpenter, Michael J Bamshad, George A Marshall, Chee Y Ooi, Bridget Wilcken, Jason R Pinner
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 119 Issue 1-2 Pg. 83-90 (09 2016) ISSN: 1096-7206 [Electronic] United States
• PMID: 27370710 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Dihydroorotate Dehydrogenase
• 4,5-dihydroorotic acid
• Orotic Acid
• Oxidoreductases Acting on CH-CH Group Donors
• Uridine

Topics

• Abnormalities, Multiple (blood, genetics, physiopathology, urine)
• Child, Preschool
• Dihydroorotate Dehydrogenase
• Genotype
• Humans
• Limb Deformities, Congenital (blood, genetics, physiopathology, urine)
• Male
• Mandibulofacial Dysostosis (blood, genetics, physiopathology, urine)
• Micrognathism (blood, genetics, physiopathology, urine)
• Mutation
• Orotic Acid (analogs & derivatives, blood, urine)
• Oxidation-Reduction
• Oxidoreductases Acting on CH-CH Group Donors (blood, genetics, urine)
• Uridine (blood, urine)