Neuropsychiatric Manifestations in Late-Onset Urea Cycle Disorder Patients

Abstract

Inherited urea cycle disorders represent one of the most common groups of inborn errors of metabolism. Late-onset urea cycle disorders caused by partial enzyme deficiencies may present with unexpected clinical phenotypes. We report 9 patients followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity disorder [ADHD], language disorder, and delirium). Generally, these clinical pictures did not benefit from pharmacological treatment. Conversely, dietary treatment improved the symptoms. Regarding biochemical data, 2 patients showed normal ammonium but high glutamine levels. This study highlights the fact that neuropsychiatric/neurodevelopmental findings are common among the initial symptomatology of late-onset urea cycle disorders. The authors recommend that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.

Keywords

attention-deficit hyperactivity disorder autism inborn errors of metabolism mental retardation

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References

Gropman AL , Summar M. , Leonard JV Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007;30(6): 865-869.

Gyato K. , Wray J. , Huang ZJ , Yudkoff M. , Batshaw ML Metabolic and neuropsychological phenotype in women heterozygous for-ornithine transcarbamylase deficiency. Ann Neurol. 2004 ;55(1): 80-86.

Ahrens MJ , Berry SA , Whitley CB , Markowitz DJ , Plante RJ , Tuchman M. Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation. Am J Med Genet. 1996;66(3):311-315.

Bélanger-Quintana A. , Martínez-Pardo M. , García MJ , et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr. 2003;162(11):773-775.

Görker I. , Tüzün U. Autistic-like finding associated with a urea cycle disorder in a 4-year-old girl. J Psychiatry Neurosci. 2005;30(2):133-135.

Pineda M. , Vilaseca MA , Mas A. , Fábrega C. , Fernández Alvarez E. Diagnóstico de la deficiencia de ornitina carbamil transferasa y detección de heterocigotas mediante la prueba de sobrecarga de alopurinol [in Spanish]. Med Clin. 1993; 101(10):383-386.

Nuzum CT , Snodgrass PJ Multiple assays of the five urea-cycle enzymes in human liver homogenates . In: Grisolía Baguena R , Mayor F , eds. The Urea Cycle. New York, NY: John Wiley & Sons Inc; 1976:325-349.

Arranz JA , Riudor E. , Marco-Marín C. , Rubio V. Estimation of the total number of disease-causing mutations in ornithine transcarbamilase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. J Inherit Metab Dis. 2007 ;30(2):217-226.

Häberle J. , Pauli S. , Linnebank M. , et al. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002;110(4):327-333.

10.

Linnebank M. , Tschiedel E. , Häberle J. , et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002;111(4-5):350-359.

11.

Häberle J. , Schmidt E. , Pauli S. , et al. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Hum Mutat. 2003;21(4):444.

12.

American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Washington, DC: American Psychiatric Association; 1994.

13.

Estrov Y. , Scaglia F. , Bodamer OA Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis. 2000;23(1):2-6.

14.

Sedel F. , Baumann N. , Turpin JC , Lyon-Caen O. , Saudubray JM , Cohen D. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis. 2007;30(5):631-641.

15.

Nicolaides P. , Liebsch D. , Dale N. , Leonard J. , Surtees R. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002;86(1):54-56.

16.

Cooper AJ Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity . Ment Retard Dev Disabil Res Rev. 2001;7(4):280-286.

17.

Lichter-Konecki U. Profiling of astrocyte properties in the hyperammonaemic brain: shedding new light on the pathophysiology of the brain damage in hyperammonaemia . J Inherit Metab Dis. 2008;31(4):492-502.

18.

Tuchman M. , Plante RJ , McCann MT , Qureshi AA Seven new mutations in the human ornithine transcarbamylase gene. Hum Mutat. 1994;4(1):57-60.

19.

Tuchman M. , Jaleel N. , Morizono H. , Sheehy L. , Lynch MG Mutations and polymorphisms in the human ornithine transcarbamylase gene. Hum Mutat. 2002;19(2):93-107.

20.

Gao H. , Kobayashi K. , Tabata A. , et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003;22(1):24-34.

21.

Vilaseca MA , Kobayashi K. , Briones P. , et al. Phenotype and genotype heterogeneity in Mediterranean citrullinemia. Mol Genet Metab. 2001;74(3):396-398.