Dihydropyridine Reductase Deficiency: Acute Encephalopathy Related to Folinic Acid Treatment Interruption in a Girl

Abstract

We reported the case of acute encephalopathy related to colonic acid treatment interruption in a 12-year-old female child presenting to our unit with episodes of vomiting, headache, irritability, acute confusional state, seizures, and left lower limb hypotonia. Brain magnetic resonance imaging (MRI) showed signs of vasogenic and cytotoxic edema at the cerebellar level bilaterally, and lesions at the temporo-occipito-parietal right level, temporomandibular left, and right thalamic with swelling of the convolutions and reduced differentiation between white and gray matter. The patient had suspended the folinic acid treatment at least 6 months before the present admission. The relation between the clinical signs presented by the girl and folic acid deficiency was confirmed by the result of laboratory assessment and by the answer to the notable clinical improvement with the renewal of folinic acid treatment. Dihydropteridine reductase (DHPR) deficiency is a rare autosomal recessive genetic disorder caused by the quinoid dihydropteridine reductase (QDPR) gene mutations. DHPR deficiency impairs the synthesis of the tetrahydrobiopterin (BH4), an essential cofactor for the hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. When not precociously treated, the disorder may present whit severe neurologic impairment including developmental delay/intellective disability (DD/ID), microcephaly, seizures, movement disorders, cerebral palsy, and other neurological impairments. The clinical and neuroradiologic anomalies observed in our case were unusual, with signs previously unreported in patients with folic acid deficiency. The present case shows that the clinical presentation and MRI anomalies of the cerebral folic acid deficiency may be various and unusual compared with those reported in the literature, and it confirms the usefulness of the continuation of folinic acid treatment during the course of the disorder in patients with DHPR deficiency.

Keywords

encephalopathy / metabolic disease / genetic disorder

References

[1] Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev 2004; 24(02): 127-150

[2] Li N, Yu P, Rao B.et al.Molecular genetics of tetrahydrobiopterin deficiency in Chinese patients. J Pediatr Endocrinol Metab 2018; 31(08): 911-916

[3] Dahl HH, Hutchison W, McAdam W, Wake S, Morgan FJ, Cotton RG. Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. Nucleic Acids Res 1987; 15(05): 1921-1932

[4] Blau N, Bonafé L, Thöny B.Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001; 74(1-2): 172-185

[5] Dianzani I, de Sanctis L, Smooker PM.et al. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. Hum Mutat 1998; 12(04): 267-273

[6] Howells DW, Forrest SM, Dahl HH, Cotton RG.Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. Am J Hum Genet 1990; 47(02): 279-285

[7] Souza CAA, Alves MRA, Soares RDL.et al.BH₄ deficiency identified in a neonatal screening program for hyperphenylalaninemia. J Pediatr (Rio J) 2018; 94(02): 170-176

[8] Furujo M, Kinoshita M, Ichiba Y, Romstad A, Shintaku H, Kubo T.Clinical characteristics of epileptic seizures in a case of dihydropteridine reductase deficiency. Epilepsy Behav Case Rep 2014; 2: 37-39

[9] Opladen T, Hoffmann GF, Blau N.An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 2012; 35(06): 963-973

[10] van Spronsen FJ, Huijbregts SC, Bosch AM, Leuzzi V. Cognitive, neurophysiological, neurological and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development. Mol Genet Metab 2011; 104(Suppl): S45-S51

[11] Coughlin II CR, Hyland K, Randall R, Ficicioglu C.Dihydropteridine reductase deficiency and treatment with tetrahydrobiopterin: a case report. JIMD Rep 2013; 10: 53-56

[12] Bozaci AE, Er E, Yazici H.et al.Tetrahydrobiopterin deficiencies: lesson from clinical experience. JIMD Rep 2021; 59(01): 42-51

[13] van Spronsen FJ, van Wegberg AM, Ahring K.et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 2017; 5(09): 743-756

[14] Porta F, Ponzone A, Spada M.Long-term safety and effectiveness of pramipexole in tetrahydrobiopterin deficiency. Eur J Paediatr Neurol 2016; 20(06): 839-842

[15] Shintaku H.Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab 2002; 3(02): 123-131

[16] Miladi N, Larnaout A, Dhondt JL, Vincent MF, Kaabachi N, Hentati F.Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings. J Child Neurol 1998; 13(10): 475-480

[17] Molero-Luis M, Serrano M, O'Callaghan MM. et al. Clinical, etiological and therapeutic aspects of cerebral folate deficiency. Expert Rev Neurother 2015; 15(07): 793-802

[18] Pope S, Artuch R, Heales S, Rahman S.Cerebral folate deficiency: analytical tests and differential diagnosis. J Inherit Metab Dis 2019; 42(04): 655-672

[19] Gordon N.Cerebral folate deficiency. Dev Med Child Neurol 2009; 51(03): 180-182

[20] Opladen T, López-Laso E, Cortès-Saladelafont E.et al; International Working Group on Neurotransmitter related Disorders (iNTD). Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH₄) deficiencies. Orphanet J Rare Dis 2020; 15(01): 126

[21] Woody RC, Brewster MA, Glasier C.Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic acid therapy. Neurology 1989; 39(05): 673-675

[22] Sugita R, Takahashi S, Ishii K.et al.Brain CT and MR findings in hyperphenylalaninemia due to dihydropteridine reductase deficiency (variant of phenylketonuria). J Comput Assist Tomogr 1990; 14(05): 699-703

[23] Takahashi Y, Manabe Y, Nakano Y.et al.Parkinsonism in Association with Dihydropteridine Reductase Deficiency. Case Rep Neurol 2017; 9(01): 17-21

RIGHTS & PERMISSIONS

2022 Global Medical Genetics