Tetrahydrobiopterin deficiencies: Lesson from clinical experience

Abstract

Objectives The present study describes clinical, biochemical, molecular genetic data, current treatment strategies and follow‐up in nine patients with tetrahydrobiopterin (BH4) deficiency due to various inherited genetic defects. Methods We analyzed clinical, biochemical, and molecular data of nine patients with suspected BH4 deficiency. All patients were diagnosed at Ege University Faculty of Medicine in Izmir, Turkey and comprised data collected from 2006 to 2019. The diagnostic laboratory examinations included blood phenylalanine and urinary or plasma pterins, dihydropteridine reductase (DHPR) enzyme activity measurement in dried blood spots, folic acid and monoamine neurotransmitter metabolites in cerebrospinal fluid, as well as DNA sequencing. Results Among the nine patients, we identified one with autosomal recessive GTP cyclohydrolase I (ar GTPCH) deficiency, two with 6‐pyruvoyl‐tetrahydropterin synthase (PTPS) deficiency, three with sepiapterin reductase (SR) deficiency, and three with DHPR deficiency. Similar to previous observations, the most common clinical symptoms are developmental delay, intellectual disability, and movement disorders. All patients received treatment with l‐dopa and 5‐hydroxytryptophan, while only the ar GTPCH, the PTPS, and one DHPR deficient patients were supplemented in addition with BH4. The recommended dose range varies among patients and depends on the type of disease. The consequences of BH4 deficiencies are quite variable; however, early diagnosis and treatment will improve outcomes. Conclusions As BH4 deficiencies are rare group of treatable neurometabolic disorders, it is essential to diagnose the underlying (genetic) defect in newborns with hyperphenylalaninemia. Irreversible brain damage and progressive neurological deterioration may occur in untreated or late diagnosed patients. Prognosis could be satisfying in the cases with early diagnose and treatment.

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

“…The frequency of PCD deficiency in the present study was 7.1%, exceeding the 2.6% reported in BIODEFdb (BIODEFdb), which could suggest that the frequency of the different BH4 disorders varies among populations ( Souza et al, 2018 ; Carducci et al, 2020 ; Bozaci et al, 2021 ; Gundorova et al, 2021 ; Ray et al, 2022 ). We only found one homozygous c.289G > A or p.(Glu97Lys) male patient.…”

In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing Approaches towards the Discovery of Effective BH4 Therapeutics

“…Hyperkinesia and locomotor disorders have been reported with the prolonged use of the parent drug phenytoin, and further investigations are warranted to determine whether such effects may be due to the impairment of GTPCH1 activity by its metabolite phenytoin catechol. It is well reported that BH 4 deficient conditions, such as BH 4 -dependent congenital hyperphenylalaninemia and dopa-responsive dystonia, express phenotypes of variable severity, ranging from poor motor control, hypo/hypertonia to Parkinsonism [ 9 , 53 ].…”

“…While GTPCH1 plays a well-documented role within the setting of both cardiovascular and neurological diseases [ 3 , 8 , 9 ], it has also garnered significant interest regarding the role that it may have in pain pathways [ 10 ]. In a hallmark study, the enzyme was identified as a key modulator in peripheral neuropathic and inflammatory pain settings [ 11 ].…”

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

“…Early and correct treatment for patients affected by DHPR deficiency is essential, as a delay or an inadequate treatment may result in severe neurologic impairment including developmental delay/intellective disability (DD/ID), microcephaly, seizures, movement disorders, cerebral palsy, and other neurological impairments. Bozaci et al 12 reported on nine patients: three affected by DHPR deficiency and six by BH 4 deficiency. All the three patients affected by DHPR deficiency were females.…”

“…Long-acting dopamine agonists are also utilized in the treatment of this disorder. [11][12][13][14][15] We reported here a 12-year-old girl who was previously hospitalized for a few days to a local pediatric emergency section for two short episodes of seizures. One month after the discharged, she came to Pediatric Department of Catania University (Italy) presenting with episodes of vomiting, headache, irritability, acute confusional state, seizures, and left lower limb hypotonia; she was known to be affected by DHPR deficiency and in treatment since infancy.…”