Four Years of Diagnostic Challenges with Tetrahydrobiopterin Deficiencies in Iranian Patients

Khatami, Shohreh; Dehnabeh, Soghra Rouhi; Zeinali, Sirous; Thöny, Beat; Alaei, Mohammadreza; Salehpour, Saghar; Setoodeh, Aria; Rohani, Farzaneh; Hajivalizadeh, Fatemeh; Samavat, Ashraf

doi:10.1007/8904_2016_572

Cited by 16 publications

(13 citation statements)

References 8 publications

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“…However, this patient had a low biopterin and neopterin levels in both plasma and CSF known as typical pattern. The homozygous mutations c.200C > T (p.Thr67Met) and c.84‐3C > G previously reported as severe form mutations from Albania, Italy, and Iran were detected in our PTPS deficiency patients who had normal neopterin and low biopterin levels in plasma 21,22,23,24 …”

Section: Discussionmentioning

confidence: 48%

Tetrahydrobiopterin deficiencies: Lesson from clinical experience

Bozacı

Yazici

et al. 2021

JIMD Reports

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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.

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Section: Discussionmentioning

confidence: 48%

Tetrahydrobiopterin deficiencies: Lesson from clinical experience

Bozacı

Yazici

et al. 2021

JIMD Reports

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“…These findings align with previous reports from other countries in the region. A high incidence of BH 4 deficiency (~12%) was reported for the Kingdom of Saudi Arabia 22 and Iran 23 …”

Section: Discussionmentioning

confidence: 99%

Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan

et al. 2020

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Background Information regarding the prevalence of PKU in the Middle East in comparison to other world regions is scarce, which might be explained by difficulties in the implementation of national newborn screening programs. Objective This study seeks for the first time to genotype and biochemically characterize patients diagnosed with hyperphenylalaninemia (HPA) at the Pediatric Metabolic Genetics Clinic at the King Hussein Medical Center, Amman, Jordan. Methods A total of 33 patients with HPA and 55 family members were investigated for pterins (neopterin and biopterin) and dihydropteridine reductase (DHPR) activity in dried blood spots. Patients with HPA were genotyped for phenylketonuria (PKU) and the genes involved in tetrahydrobiopterin (BH4) metabolism. Results In total 20 patients were diagnosed with PKU due to phenylalanine hydroxylase (PAH) deficiency, 2 with GTP cyclohydrolase I (GTPCH) deficiency, 6 with DHPR deficiency, and 3 with the 6‐pyruvoyl‐tetrahydropterin synthase (PTPS) deficiency. Diagnosis was not possible in 2 patients. This study documents a high percentage of BH4 deficiencies within HPA patients. With one exception, all patients were homozygous for particular gene variants. Conclusions This approach enables differentiation between PKU and BH4 deficiencies and, thus, allows for critical selection of a specific treatment strategies.

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“…In spite of the treatment, the blood l ‐Phe levels remained persistently increased and the patient continued to suffer seizures and neurodevelopmental delay. In fact, it has been reported that patients with DHPR may develop neurological symptoms even with blood l ‐Phe levels within the normal range 6 …”

Section: Discussionmentioning

confidence: 99%

“…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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Four Years of Diagnostic Challenges with Tetrahydrobiopterin Deficiencies in Iranian Patients

Cited by 16 publications

References 8 publications

Tetrahydrobiopterin deficiencies: Lesson from clinical experience

Tetrahydrobiopterin deficiencies: Lesson from clinical experience

Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan

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

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