Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients
Oya Kuseyri HübschmannAlexander MohrJennifer FriedmanFilippo MantiGabriella HorváthElisenda Cortès‐SaladelafontSaadet Mercimek‐AndrewsYılmaz YıldızRoser PonsJan KulhánekMari OppebøenJeanette KohtInés Podzamczer‐VallsRosario Domingo‐JiménezSalvador IbáñezO Alcoverro FortunyTeresa Gómez‐AlemanyPedro de CastroChiara AlfonsiDimitrios I. ZafeiriouEduardo López‐LasoPhilipp GuderRené SanterTomáš HonzíkGeorg F. HoffmannSven F. GarbadeSerap SivriVincenzo LeuzziKathrin JeltschÁngeles García‐CazorlaThomas OpladenInga Harting
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Abstract Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non‐specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re‐evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1‐52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto‐occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic‐ischemic injury and a combination of deep gray matter and watershed injury (aromatic l ‐amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post‐infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2‐hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.Keywords:
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Abstract We investigated CSF concentrations of nitrite and nitrate as indicators of nitric oxide (NO) production in patients with tetrahydrobiopterin (BH 4 ) deficiencies. Patients with 6‐pyruvoyl‐tetra‐hydropterin synthase, sepiapterin reductase and dihydropteridine reductase deficiencies exhibited decreased CSF nitrite + nitrate levels compared with healthy control subjects. Reduced levels of nitrite + nitrate were not influenced by oral administration of 2.5–5.0 mg/kg tetrahydrobiopterin. Our data indicate impaired NO synthase function in patients with BH 4 deficiency and suggest possible involvement in the neuronal cell dysfunction.
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Summary Cellular uptake of sepiapterin and tetrahydrobiopterin was compared quantitatively with RBL2H3 cells in culture. RBL2H3 is a mast cell line and has the ability to synthesize serotonin. Sepiapterin was incorporated and converted into tetrahydrobiopterin in the cell. The incorporation of sepiapterin was about 10 times faster than tetrahydrobiopterin. A low concentration of tetrahydrobiopterin was incorporated in a saturable manner up to about 10 μM, and it was superimposed upon a linearly concentration- dependent process. Overnight treatment with DAHP depleted endogenous tetrahydrobiopterin. The DAHP treated cells took up tetrahydrobiopterin faster than untreated cells.
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Qualitative analysis of 100 consecutive computed tomographic (CT) studies of the brain in children with symptomatic but untreated acquired immunodeficiency syndrome was performed. After excluding children with associated medical illnesses that might confound the diagnosis of encephalopathy or alter brain structure, an abnormality of at least one of the measures of ventricular size, cortical atrophy, white matter attenuation (leukoaraiosis), or cerebral calcification was found in 86% of the patients studied. Ventricular enlargement was the most common abnormality, followed by cortical atrophy, leukoaraiosis, and cerebral calcification. Cerebellar atrophy was an unexpected but relatively common finding in 12% of the children. Sixty-five percent of the children were encephalopathic at the time of evaluation. All 16 children with cerebral calcification were encephalopathic and had acquired human immunodeficiency virus (HIV) through vertical transmission. Encephalopathic children were significantly younger and had significantly greater abnormality ratings on each CT measure when compared with the nonencephalopathic children. Discriminant analysis using age and the qualitative CT measures was applied as a method to identify the presence of encephalopathy. CT measures proved to have a specificity and a sensitivity of only 76%. We conclude that abnormalities of cerebral structure are seen in a high percentage of children symptomatic with HIV. Although most of the children are encephalopathic, CT abnormalities are seen in children without encephalopathy, suggesting presymptomatic brain disease. The presence of cerebral calcification on CT suggests in utero infection with HIV and the presence of encephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
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Tetrahydrobiopterin is an essential cofactor for the aromatic amino acid monooxygenase group of enzymes. Inborn errors of tetrahydrobiopterin metabolism result in hyperphenylalaninaemia and impaired catecholamine and serotonin turnover.
Tetrahydrobiopterin is also a cofactor for all known isoforms of nitric oxide synthase (NOS). The effect of tetrahydrobiopterin deficiency on brain nitric oxide metabolism has to date been given little consideration. In this thesis the effect of tetrahydrobiopterin deficiency on brain nitric oxide metabolism has been studied using a mouse model of tetrahydrobiopterin deficiency, the hph-1 mouse.
Tetrahydrobiopterin was measured in 10 and 30 day old mice in whole brain and cerebellum. At both age points there was a significant -50% reduction in tetrahydrobiopterin content for whole brain and cerebellum in the hph-1 mouse compared to corresponding control mice. NOS activity was measured in whole brain from 10 and 30 day old hph-1 and control mice. No difference was observed in enzyme activity when tetrahydrobiopterin was included in the incubation medium. However, omission of tetrahydrobiopterin from the reaction buffer resulted in significantly lower NOS activity in the hph-1 mouse group compared to controls.
Tetrahy-drobiopterin was also shown to have a potent effect on the affinity of brain NOS for arginine. The Km for arginine was virtually identical for the control and hph-1 mouse when tetrahydrobiopterin was included in the reaction buffer. In the absence of cofactor, the for arginine was three fold greater for control and five fold higher for hph-1 preparations. The accumulation of cGMP from slices prepared from the cerebellum was measured in both groups of mice at both 10 and 30 days using the glutamate analogue, kainate. In the 10 day old hph-1 mouse there was a significant 50% reduction in cGMP levels under basal and stimulated conditions. In the 30 day old hph-1 mouse there was a significant 30% reduction in cGMP accumulation in both basal and activated states. Whole brain amino acid levels were measured. In the 10 day old hph-1 mouse confounding hyperphenylalaninaemia may affect the availability of the NOS substrate, arginine. In the 30 day old hph-1 mouse, which has normal phenylalanine levels, reduced citrulline levels may indicate reduced NOS activity. Reduced levels of tetrahydrobiopterin and also arginine, have been shown to lead to superoxide formation by nitric oxide synthase. Superoxide can react with nitric oxide to form the oxidising species, peroxynitrite, which has been shown to damage of the mitochondrial electron transport chain. Mitochondrial function together with the antioxidant, glutathione, were analysed in both hph-1 and control mice at 10 and 30 days to measure oxidative stress. However, no differences were observed between the two groups. In summary, partial deficiency of tetrahydrobiopterin appears to lead to impaired brain NOS function leading to an impairment of the nitric oxide/cGMP pathway.
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The present study was designed to investigate the interaction between 5-methyltetrahydrofolate and tetrahydrobiopterin in modulating endothelial function. Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide- versus superoxide-producing enzyme. The structure of 5-methyltetrahydrofolate is similar to tetrahydrobiopterin and both agents have been shown to improve endothelium-dependent vasodilatation. We hypothesized that 5-methyltetrahydrofolate interacts with nitric oxide synthase in a fashion analogous, yet independent, of tetrahydrobiopterin to improve endothelial function. We demonstrate that 5-methyltetrahydrofolate binds the active site of nitric oxide synthase and mimics the orientation of tetrahydrobiopterin. Furthermore, 5-methyltetrahydrofolate attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis) and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function. 5-Methyltetrahydrofolate may represent an important strategy for intervention aimed at improving tetrahydrobiopterin bioavailability.
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Endothelial function disorder exists in many cardiovascular diseases,which may come from the decrement of nitric oxide.Tetrahydrobiopterin is a kind of essential cofactor of nitric oxide synthase,which can regulate nitric oxide synthase function and activity of nitric oxide.This article reviews the usefulness of tetrahydrobiopterin in cardiovascular diseases.
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