Birincil BH4 eksikliği olan hastaların takip ve sonuçları.

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BH4 deficiencies may occur with or without hyperphenylalaninemia (HPA). If identified early through neonatal screening for PKU, the clinical follow-up aims to prevent the onset of typical disease symptoms. In contrast, for the conditions not associated with HPA, diagnosis usually occurs once symptoms manifest, and follow-up focuses on monitoring the treatment's effectiveness in restoring normal neurological function. Except for pterin-4-alpha-carbinolamine dehydratase defect (PCCDd), the core symptoms and natural course of these diseases involve neurodevelopmental impairment and movement disorders. Current information on clinical follow-up and outcome comes from retrospective observational studies, with standardized measures used in only a few of them. Serial clinical observations focusing on the two most consistent areas of neurological impairment are the best predictors of outcome and the main follow-up targets. Available clinical data, often aggregating early- and late-treated patients, show that the best clinical outcome occurs in autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (AD-GTPCHd). In contrast, for recessive conditions, prognosis is variably associated with both the timing of treatment (autosomal recessive [AR]-GTPCHd, 6-pyruvoyltetrahydropterin synthase [PTPS]d, sepiapterin [SR]d, q-dihydropyridine reductase [DHPR]d) and the severity of metabolic derangement (AR-GTPCHd, PTPSd). Neurocognitive, psychiatric, and sleep disorders are currently underestimated and can occur in children and adults, affecting social adaptation and quality of life. Among metabolic alterations, blood Phe levels, when altered, warrant regular monitoring. CSF evaluation can be considered in subjects unresponsive to treatment or with an unexpected clinical course. CSF 5-MTHF monitoring should be reserved for patients with DHPRd experiencing neurological deterioration and seizures. Monitoring prolactin levels, when altered, may assist in personalizing pharmacological treatment. Serum magnesium and glucose are metabolic markers that should be assessed in PDCCd. Brain MRI monitoring is recommended for patients experiencing unusual courses, epilepsy, and neurological deterioration (particularly in PTPSd and DHPRd). A DAT scan is advised for those with AD-GTPCH who present or develop Parkinsonism, and EEG monitoring should be conducted for every patient with epilepsy or suspected seizures. For future clinical studies, it is mandatory that the clinical assessment adopt standardized tools that score impairment across neurological and behavioral domains, taking the patient's age into account.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=1144143, identifier (CRD420251144143).

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