Dihydropteridine reductase deficiency localized to the central nervous system

Blau, Nenad; Thöny, Beat; Renneberg, Axel; Arnold, L. A.; Hyland, Keith

doi:10.1023/a:1005327313348

Cited by 20 publications

(6 citation statements)

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“…By this method, we showed that both the classic forms of BH 4 deficiency and DRD can be differentiated in fibroblasts (Bonafé et al 2001). In this study, we investigated fibroblasts from two patients with severe neurotransmitter depletion without hyperphenylalaninemia who were initially diagnosed with a "central" form of DHPR deficiency (MIM 261630) (Blau et al 1998). Pterin metabolites and enzymatic activities revealed SR deficiency, which was confirmed by DNA mutation analysis.…”

Section: Figurementioning

confidence: 77%

“…Patient 360 (BIODEF) is a 14-year-old adolescent male born of consanguineous parents of Turkish origin. He presented with psychomotor retardation, spasticity, dystonia, microcephaly, and growth retardation (Blau et al 1998). Patient 229 (BIODEF) is a 9-year-old boy born of unrelated parents of Turkish origin.…”

Section: Patientsmentioning

confidence: 99%

“…Plasma phenylalanine, urinary and plasma total neopterin and total biopterin, and red blood cell DHPR activity were all normal. After BH 4 Blau et al (1998Blau et al ( , 1999. 5HIAA p 5-hydroxyindoleacetic acid; HVA p homovanillic acid.…”

Section: Patientsmentioning

confidence: 99%

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Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia

Bonafé

Thöny

Penzien

et al. 2001

The American Journal of Human Genetics

196

171

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Classic tetrahydrobiopterin (BH(4)) deficiencies are characterized by hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH(4). Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC-->CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397-1401delAGAAC) resulting in abolished SPR-gene expression and an A-->G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH(4) biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH(4) in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH(4) and to neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.

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Section: Figurementioning

confidence: 77%

Section: Patientsmentioning

confidence: 99%

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Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia

Bonafé

Thöny

Penzien

et al. 2001

The American Journal of Human Genetics

196

171

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“…Diagnosis was established by the measurement of pterins and SR activity in cytokine-stimulated and in nonstimulated cultured skin fibroblasts, respectively, as published previously (5). Initial analysis of CSF revealed high dihydrobiopterin and biopterin concentrations and a severe biogenic amine neurotransmitter deficiency (8). The procedures used were in accordance with the current revision of the Helsinki Declaration of 1975.…”

Section: Methodsmentioning

confidence: 99%

Detection of Sepiapterin in CSF of Patients with Sepiapterin Reductase Deficiency

Zorzi

Redweik

Trippe³

et al. 2002

Molecular Genetics and Metabolism

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“…Patients with DHPRD commonly have an early symptoms onset. The symptoms include hypotonia or trunk hypotonia, movement disorders (mainly dystonia) with distal hypertonia, parkinsonism/hypokinetic rigid syndrome (consisting of bradykinesia or hypokinesia), extrapyramidal rigidity (“cogwheel rigidity”), rest tremor, impaired motor development and cognitive impairment, irritability and mood swings, neonatal dysphagia, lethargy, delayed language acquisition, temperature‐control disorders, and myoclonic seizures 1,5,6 …”

Section: Introductionmentioning

confidence: 99%

Sapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil

Lourenço¹,

Dovidio²,

Lopes³

et al. 2021

JIMD Reports

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Tetrahydrobiopterin (BH4) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l‐tyrosine, l‐3,4‐dihydroxyphenylalanine, 5‐hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH4 regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l‐phenylalanine (l‐Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene—which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report.

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Dihydropteridine reductase deficiency localized to the central nervous system

Cited by 20 publications

References 4 publications

Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia

Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia

Detection of Sepiapterin in CSF of Patients with Sepiapterin Reductase Deficiency

Sapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil

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