Oral phenylalanine loading in dopa‐responsive dystonia

Abstract

To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg). Seven adults with DRD, two severely affected children with DRD, and nine adult controls were studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the adult patients, phenylalanine levels were higher than in controls at 2, 4, and 6 hours post-load (p < 0.0005); tyrosine concentrations were lower than control levels at 1, 2, and 4 hours post-load (p < 0.05). Phenylalanine to tyrosine ratios were elevated in patients at all times post-load (p < 0.0005). Biopterin levels in the patients were decreased at baseline and 1, 2, and 4 hours post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized phenylalanine and tyrosine profiles in two adult patients. In the children with DRD, phenylalanine to tyrosine ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients but there was no elevation in plasma tyrosine. Baseline biopterin levels were lower in the children with DRD than in the adult patients or the controls and there was no increase in biopterin post-load. In both the children and adults with DRD, neopterin concentrations did not differ from control values at baseline or after phenylalanine load. The results are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a phenylalanine load may be useful in the diagnosis of this disorder.

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

“…Although individuals with DRD never develop hyperphenylalaninemia, a subclinical defect in phenylalanine metabolism caused by partial BH4 defi ciency in the liver can often be detected by the phenylalanine loading test, which analyzes plasma phenylalanineto-tyrosine ratios following an oral phenylalanine load 6 .…”

“…Diagnosis can be based on clinical fi ndings (including dramatic and sustained response to low doses of L-dopa), plasma levels of phenylalanine/tyrosine after an oral phenylalanine load and molecular analysis of GCH1 gene [1][2][3][4][5][6] .…”

Urinary Neopterin and Phenylalanine Loading Test as Tools for the Biochemical Diagnosis of Segawa Disease

“…Based on this, a Phe loading procedure has been proposed (Hyland et al 1997) and different values of Phe/Tyr 4 hours after the loading have been suggested as a critical threshold for the diagnosis: 4.5 (Saunders-Pullman et al 2000), 7.5 (Bandmann et al 2003), 5.25 (Saunders-Pullman et al 2004. In spite of high sensitivity and specificity of the test, false negatives (Saunders-Pullman et al 2004) and positives (Bandmann et al 2003) were reported.…”

“…Neopterin and biopterin were determined in the first morning urine sample and CSF according to the method published elsewhere (Antonozzi et al 1988). Phe and Tyr were measured by ESI-MS/MS (Chace et al 1993) in dried blood spots at baseline and 1, 2, 3, 4, 5 and 6 h after oral Phe loading (100 mg/kg body weight) (Hyland et al 1997) .…”

Screening for dopa-responsive dystonia in patients with scans without evidence of dopaminergic deficiency (SWEDD)

“…A low-protein breakfast was allowed before and no further food was permitted during the test. Phe, tyrosine (Tyr) and Phe/Tyr ratio from capillary blood samples were measured at baseline, and 1, 2, 3, 4, 5, 6 h after Phe loading, as previously described [20]. Phe and Tyr were measured using standard sensitive quantification method based on a liquid chromatographyelectrospray ionization-tandem mass spectrometry [21].…”