Reductase Deficiency Research Articles

Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling

ContextInactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism.ObjectiveTo describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases.DesignClinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics.ResultsCase 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management.ConclusionsSteroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS).

Analysis of bioactive oxysterols in newborn mouse brain by LC/MS

Unesterified cholesterol is a major component of plasma membranes. In the brain of the adult, it is mostly found in myelin sheaths, where it plays a major architectural role. In the newborn mouse, little myelination of neurons has occurred, and much of this sterol comprises a metabolically active pool. In the current study, we have accessed this metabolically active pool and, using LC/MS, have identified cholesterol precursors and metabolites. Although desmosterol and 24S-hydroxycholesterol represent the major precursor and metabolite, respectively, other steroids, including the oxysterols 22-oxocholesterol, 22R-hydroxycholesterol, 20R,22R-dihydroxycholesterol, and the C(21)-neurosteroid progesterone, were identified. 24S,25-epoxycholesterol formed in parallel to cholesterol was also found to be a major sterol in newborn brain. Like 24S- and 22R-hydroxycholesterols, and also desmosterol, 24S,25-epoxycholesterol is a ligand to the liver X receptors, which are expressed in brain. The desmosterol metabolites (24Z),26-, (24E),26-, and 7α-hydroxydesmosterol were identified in brain for the first time.

Low dietary folate and methylenetetrahydrofolate reductase deficiency may lead to pregnancy complications through modulation of ApoAI and IFN‐γ in spleen and placenta, and through reduction of methylation potential

Genetic or nutritional disturbances in folate metabolism lead to hyperhomocysteinemia and adverse reproductive outcomes. Folate-dependent homocysteine remethylation is required for methylation reactions and may influence choline/betaine metabolism. Hyperhomocysteinemia has been suggested to play a role in inflammation. The goal of this study was to determine whether folate-related pregnancy complications could be due to altered expression of some inflammatory mediators or due to disturbances in methylation intermediates. Pregnant mice with or without a deficiency of methylenetetrahydrofolate reductase (MTHFR) were fed control diets or folate-deficient (FD) diets; tissues were collected at embryonic day 14.5. FD decreased plasma phosphocholine and increased plasma glycerophosphocholine and lysophosphatidylcholine. Liver betaine, phosphocholine, and S-adenosylmethionine:S-adenosylhomocysteine ratios were reduced in FD. In liver, spleen, and placenta, the lowest levels of apolipoprotein AI (ApoAI) were observed in Mthfr(+/-) mice fed FD. Increased interferon-gamma (IFN-γ) was observed in spleen and placentae due to FD or Mthfr genotype. Plasma homocysteine correlated negatively with liver and spleen ApoAI, and positively with IFN-γ. Low dietary folate or Mthfr deficiency during pregnancy may result in adverse pregnancy outcomes by altering expression of the inflammatory mediators ApoAI and IFN-γ in spleen and placenta. Disturbances in choline metabolism or methylation reactions may also play a role.

1034 A Hypotonic Infant with Methylene Tetrahydrofolate Reductase (MTHFR) Deficiency; Homozygous Mutation of C.1015T>G in Mtfhr Gene

BackgroundMethylene tetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder, caused by mutated alleles of the MTHFR gene. Since this enzyme catalyzes the conversion of 5.10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, its...

Aldose Reductase Deficiency Reduced Vascular Changes in Neonatal Mouse Retina in Oxygen-Induced Retinopathy

Retinal neovascularization is the major pathologic process in many ocular diseases and is associated with oxidative stress. Deficiency of aldose reductase (AR), the first enzyme in the polyol pathway for glucose metabolism, has been shown to reduce oxidative stress and blood vessel leakage. The present study aimed to investigate the effect of AR deficiency on retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model. Seven-day-old wild-type (WT) and AR-deficient (AR(-/-)) mice were exposed to 75% oxygen for 5 days and then returned to room air. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. Immunohistochemistry for AR, nitrotyrosine (NT), poly(ADP-ribose) (PAR), glial fibrillary acidic protein (GFAP), and Iba-1, as well as Western blots for vascular endothelial growth factor (VEGF), phospho-Erk (p-Erk), phospho-Akt (p-Akt), and phospho-IκB (p-IκB) were performed. Compared with WT OIR retinae, AR(-/-) OIR retinae displayed significantly smaller central retinal vaso-obliterated area, less neovascularization, and reduced blood vessel leakage. Significantly reduced oxidative stress and glial responses were also observed in AR(-/-) OIR retinae. Moreover, reduced microglial response in the avascular area but increased microglial responses in the neovascular area were found with AR deficiency. Furthermore, expression levels of VEGF, p-Erk, p-Akt, and p-IκB were significantly reduced in AR(-/-) OIR retinae. Our observations indicated that AR deficiency reduced retinal vascular changes in the mouse model of OIR, indicating that AR can be a potential therapeutic target in ischemia-induced retinopathy.

A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.

Overview of Genetic Defects in Endocrinopathies in the Island of Cyprus; Evidence of a Founder Effect

Hereditary endocrinopathies in Cyprus exhibit evidence of a founder effect and display the influence of past migration patterns. The genetic frequency and mutation pattern of a specific disorder of sex development (DSD), which is classified as 46,XX DSD or 46,XY DSD, and the non-classic form of congenital adrenal hyperplasia (NC-CAH) outline a type of genetic drift. Not only the high prevalence of the NC-CAH p.V281L mutation but also the rarity of CAH large lesions present a genetic diversity similar to that observed in the Middle Eastern countries. In addition, both the high frequency of the 5-alpha steroid reductase deficiency (5αSRD) IVS1-2A>G mutation and the carrier frequency of the 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD-3) p.R80Q mutation are good examples of a founder effect. p.R80Q can be considered a founder mutation, even though it has been identified in patients of Dutch, Brazilian, and Portuguese origin. This has led to the speculation that it has a Phoenician origin. Phoenicians as ancient traders migrated around 750 BC from present day Syria, Lebanon, and Israel toward Portugal, Spain, and also to nearby Cyprus. While the 5αSRD IVS1-2A>G mutation has already been extensively reported in Turkish patients, it is very common in the Eastern Mediterranean region. This short article portrays clearly, through specific endocrine genetic disorders, the past migration trends in Cyprus that shaped the present-day gene pool of the Greek-Cypriot population.

Methemoglobin Reductase Deficiency

Cytochrome b5 reductase (CB5R) deficiency is a recessively inherited autosomal disorder that is either benign (type I) or associated with severe neurological problems (type II). Specific mutations in the CYB5R gene are not exclusive to each type. Two cyanotic children with developmental delay but with slow progression were investigated for CB5R deficiency. A novel mutation, p.Arg58Pro, was independently detected in both cases. The clinical variability and severity of the disease reflect the combined effects of impaired function of the 2 mutant enzymes. As illustrated by these 2 cases, inheritance of p.Arg58Pro with either p.Gly76Ser or pLeu188del causes a clinical condition more severe than type I and less severe than the type II cases reported to date.

Methylenetetrahydrofolate reductase (MTHFR) deficiency presenting as a rash

We report on the case of a 2-year-old girl recently diagnosed with Methylenetetrahydrofolate reductase (MTHFR) deficiency who originally presented in the neonatal period with a distinctive rash. At 11 weeks of age she developed seizures, she had acquired microcephaly and developmental delay. The rash deteriorated dramatically following commencement of phenobarbitone; both rash and seizures abated following empiric introduction of pyridoxine and folinic acid as treatment of possible vitamin responsive seizures. We postulate that phenobarbitone in combination with MTHFR deficiency may have caused her rash to deteriorate and subsequent folinic acid was helpful in treating the rash and preventing further acute neurological decline as commonly associated with this condition.

Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan

Tetrahydrobiopterin (BH4) deficiency is a rare, congenital and lethal condition resulting in phenylalanine build-up that can lead to mental retardation and developmental defects, unless properly treated. About 1 million newborn infants in Japan undergo neonatal PKU screening every year, of which about 1 in 2 million are diagnosed with the condition. In this post-marketing surveillance study, 19 patients with BH4 deficiency in whom BH4 supplementation with sapropterin dihydrochloride (Biopten®) (hereafter referred to as ‘BH4 therapy’) was initiated before the age of 4years, were followed up for ⩽28years. Patients who screened positive for BH4 deficiency were treated with supplemental BH4 plus L-dopa and 5-hydroxytryptophan. Data on the patients’ clinical courses were collected once yearly at 10 medical centers in Japan. Seventeen patients were diagnosed with 6-pyruvoyl tetrahydropterin synthase deficiency and two with dihydropteridine reductase deficiency at an average age of 3.6months; the mean age at end of follow-up was 14.6years. Average duration of BH4 therapy (mean dose, 5mg/kg per day) was 13.2years. Serum phenylalanine was reduced from more than 10mg/dL at the start of drug administration to less than 2mg/dL at end of follow-up. No abnormalities in height or weight were observed in any patients, except for one female patient with familial obesity. No unwarranted side effects were reported throughout the long-term course of treatment, even during pregnancy. BH4 therapy can effectively maintain serum phenylalanine levels within the normal range in patients with BH4 deficiency, and demonstrated excellent long-term safety, with no side effects.

Recessive congenital methemoglobinemia due to NADH-cytochrome b5 reductase deficiency associated with recurrent early pregnancy loss (REPL) in an Indian family

Recessive congenital methemoglobinemia due to NADH-cytochrome b5 reductase deficiency associated with recurrent early pregnancy loss (REPL) in an Indian family

An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia

The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.

Genetics of adrenocortical disease

Disease states characterized by abnormal cellular function or proliferation frequently reflect aberrant genetic information. By revealing disease-specific DNA mutations, we gain insight into normal physiology, pathophysiology, potential therapeutic targets and are better equipped to evaluate an individual's disease risks. This review examines recent advances in our understanding of the genetic basis of adrenal cortical disease. Important advances made in the past year have included identification of KCNJ5 potassium channel mutations in the pathogenesis of both aldosterone-producing adenomas and familial hyperaldosteronism type III; characterization of phosphodiesterase 11A as a modifier of phenotype in Carney complex caused by protein kinase, cAMP-dependent, regulatory subunit, type-I mutations; the finding of 11β-hydroxysteroid dehydrogenase type I mutations as a novel mechanism for cortisone reductase deficiency; and demonstration of potential mortality benefit in pursuing comprehensive presymptomatic screening for patients with Li-Fraumeni syndrome, including possible reduction in risks associated with adrenocortical carcinoma. This research review provides a framework for the endocrinologist to maintain an up-to-date understanding of adrenal cortical disease genetics.

Sepiapterin Reductase Deficiency: Mimic of Cerebral Palsy

Researchers at University of California at San Diego, and 22 other US national and international centers studied the clinical, biochemical, and molecular findings in a cohort of 38 patients with sepiapterin reductase deficiency (SRD).

Recessive congenital methemoglobinemia caused by a rare mechanism: Maternal uniparental heterodisomy with segmental isodisomy of a chromosome 22

Recessive congenital methemoglobinemia (RCM) is a very rare disorder caused by NADH-cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, caused by cb5r deficiency have been recognized. In type I, the enzyme deficiency is restricted only to erythrocytes with cyanosis being the only major symptom. In contrast, in type II, the enzyme deficiency is generalized to all tissues and associated with neurological impairment, mental and growth retardation and reduced life expectancy, in addition to cyanosis. Recently, we conducted a study on an 11-year-old boy with cb5r deficiency type I. The mutational analysis of the CYB5R3 gene revealed that the boy is homozygous for L72P mutation. Surprisingly, his mother is heterozygous for this L72P mutant, but not his father. Thirteen microsatellite markers of chromosome 22 were selected to analyze the origins of the patient's chromosome 22. The result showed that both of the chromosome 22(s) of this patient came from the maternal side (uniparental heterodisomy of chromosome 22 with segmental isodisomy). This is the first case report of a patient with cb5r deficiency type I resulting from uniparental disomy and also discloses an alternate mechanism whereby this enzymatic disorder can be derived from a single parent.

Detection of Anti-Folate Receptor Antibodies in the Serum and CSF of Cerebral Folate Deficiency Patients (P02.171)

Objective: To develop an assay to quantify and determine the isotype of autoantibodies recognizing the folate receptor protein (FOLR1) in order to aid in the diagnosis of patients suffering from cerebral folate deficiency (CFD). Background CFD is a neurological syndrome in which a low concentration of 5-methyltetrahydrofolate (5MTHF) is present in the cerebrospinal fluid (CSF) of afflicted patients, while peripheral levels are normal. Symptoms of CFD can range from irritability and learning difficulties to seizures, psychomotor retardation, and brain damage. A variety of inherited disorders can lead to CFD, including dyhydropteridine reductase deficiency, 3-phosphoglycerate dehydrogenase deficiency, Kearns-Sayre syndrome, and mutations in the folate receptor gene (FOLR1). In addition to these inherited causes, CFD has also been attributed to autoantibodies directed against the FOLR1 protein. Design/Methods: An ELISA was developed to detect and quantify anti-FOLR1 antibodies of different isotypes. Serum from over 150 patients was analyzed with this assay in order to determine the prevalence of these autoantibodies in this population. Additionally, CSF from over 50 patients with low CSF 5MTHF levels was analyzed in order to determine if anti-FOLR1 antibodies could be detected. Results: The prevalence, quantity, and isotypes of anti-FOLR1 autoantibodies in the serum of patients in our cohort were determined. We were also able to detect anti-FOLR1 antibodies in the CSF of some of the patients with low CSF 5MTHF levels. To our knowledge, this is the first time that anti-FOLR1 antibodies have been reported in CSF samples from patients suffering from CFD. Conclusions: In patients with CFD where inherited disorders do not appear to be causative, the ability to detect autoantibodies may allow for improved diagnosis and treatment options. Our findings of autoantibodies in the CSF of some patients with suspected CFD give further insight into the etiology of the disease in these patients. Supported by: Medical Neurogenetics, LLC. Disclosure: Dr. Langley has received personal compensation for activities with Medical Neurogenetics, LLC as an employee. Dr. Hyland has received personal compensation for activities with Medical Neurogenetics as co-owner.Dr. Hyland has received compensation for serving as the vice president of Medical Neurogenetics.Dr. Hyland has received research support from National Institute of Health and Neurotransmitter Disease Foundation. Dr. Mylacraine has received personal compensation for activities with Medical Neurogenetics, LLC as an employee. Dr. Shoffner has received personal compensation for activities with Medical Neurogenetics, LLC. Dr. Shoffner holds stock and/or stock options in Medical Neurogenetics, LLC.

Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus

The brain is particularly sensitive to folate metabolic disturbances, since methyl groups are critical for its functions. Methylenetetrahydrofolate reductase (MTHFR) generates the primary circulatory form of folate required for homocysteine remethylation to methionine. Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency. The goal of this study was to determine if behavioral anomalies are present in severe Mthfr-deficient (Mthfr−/−) mice and to identify neurobiological changes that could contribute to these anomalies. Adult male mice of 3 Mthfr genotypes (+/+, +/−, −/−) were tested on motor, anxiety, exploratory and cognitive tasks. Volumes (whole brain and hippocampus) and morphology, global DNA methylation, apoptosis, expression of choline acetyltransferase (ChAT) and glucocorticoid receptor (GR), and concentrations of choline metabolites were assessed in hippocampus. Mthfr−/− mice had impairments in motor function and in short- and long-term memory, increased exploratory behavior and decreased anxiety. They showed decreased whole brain and hippocampal volumes, reduced thickness of the pyramidal cell layer of CA1 and CA3, and increased apoptosis in hippocampus. There was a disturbance in choline metabolism as manifested by differences in acetylcholine, betaine or glycerophosphocholine concentrations, and by increased ChAT levels. Mthfr−/− mice also had increased GR mRNA and protein. Our study has revealed significant anomalies in affective behavior and impairments in memory of Mthfr−/− mice. We identified structural changes, increased apoptosis, altered choline metabolism and GR dysregulation in hippocampus. These findings, as well as some similar observations in cerebellum, could contribute to the behavioral changes and suggest that choline is a critical metabolite in homocystinuria.

Sepiapterin reductase deficiency: A Treatable Mimic of Cerebral Palsy

Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Sepiapterin reductase deficiency (SRD) is a dopa-sensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12.1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org). While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafe et al.2 With the following case report and review of 21 published cases,2,–,10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach. We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished. At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the …

Dopamine agonists in dihydropteridine reductase deficiency

The traditional treatment of severe disorders of tetrahydrobiopterin (BH4) metabolism is based on the replacement therapy with BH4, 5-hydroxytryptophan, and l-dopa. Major problems are encountered with l-dopa therapy, especially with increasing age when higher doses are necessary, because of its short half-life and adverse effects. Consequently, different l-dopa-sparing strategies have been successively introduced, with partial reduction of l-dopa dosage and amelioration of the clinical outcome. Recently, we demonstrated that the dopamine agonist pramipexole improves the therapeutic effect of l-dopa in 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, the most common disorder of BH4 metabolism. Here we report its effectiveness in two patients (males, 7 and 22years) with dihydropteridine reductase (DHPR) deficiency, the second most frequent cause of BH4 deficiency. Both patients experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of l-dopa therapy, associated with fluctuating hyperprolactinemia. They had full clinical and biochemical assessment, by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of diurnal plasma prolactin (PRL) profile before and after a trial with pramipexole. Besides allowing the reduction of l-dopa daily dosage (−58%) and administrations (from three to two) in one patient and to stop l-dopa therapy in the other, the introduction of pramipexole markedly improved and stabilized clinical and biochemical picture in both patients, as revealed by reduction of UPDRS scores and normalization of diurnal plasma prolactin profiles. Dopamine agonists can improve or even replace l-dopa therapy in disorders of synthesis and regeneration of BH4.