Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency

Dudešek, Aleš; Röschinger, Wulf; Muntau, Ania C.; Seidel, Jörg; Leupold, D.; Thöny, Beat; Blau, Nenad

doi:10.1007/s004310000722

Cited by 48 publications

(28 citation statements)

References 31 publications

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“…The c.200C4T mutation has been reported in Albania and Italy, 32,33 whereas the c.317C4T has been previously observed in the Caucasus region and Turkey. 17 No association of c.200C4T with any D11S1347 alleles was found, indicating that several independent mutations had occurred at this mutation hot spot (Table 3b).…”

Section: Selection Of a Marker For Linkage Analysismentioning

confidence: 89%

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

Chiu

Chang²,

et al. 2012

J Hum Genet

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The enzyme 6-pyruvoyl-tetrahydropterin synthase (PTPS, gene symbol: PTS) is involved in the second step of the de novo biosynthesis of tetrahydrobiopterin (BH4), which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases; the latter are important enzymes in the production of neurotransmitters. We conducted a study of PTS mutations in East Asia, including Taiwan, Mainland China, Japan, South Korea, the Philippines, Thailand and Malaysia. A total of 43 mutations were identified, comprising 22 previously reported mutations and 21 new discovered mutations. Among these, the c.155A4G, c.259C4T, c. 272A4G, c.286G4A and c.84-291A4G mutations were the most common PTS mutations in East Asia, while the c.58T4C and c.243G4A mutations were, respectively, specific to Filipinos and Japanese originating from Okinawa. Further studies demonstrated that each of the mutations listed above was in linkage disequilibrium to a specific allele of polymorphic microsatellite marker, D11S1347. These results suggest the presence of founder effects that have affected these frequent mutations in East Asia populations. In this context, D11S1347 should become one of the most reliable polymorphic markers for use in prenatal diagnosis among PTPS deficient families, especially where mutations are yet to be identified.

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Section: Selection Of a Marker For Linkage Analysismentioning

confidence: 89%

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

Chiu

Chang²,

et al. 2012

J Hum Genet

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“…Our case and others indicate that a negative newborn screen for HPA can occur in severe PTPS deficiency. 1,9 Furthermore, subsequent measurements in childhood may also be less than the cutoff values routinely used in newborn population screening (typically 120 -180mol/L). This was seen in our case; however, the values were clearly greater than the age-related (Ϯ2 standard deviations) reference range established for the use of quantitative amino acid analysis in metabolic patient investigations.…”

Section: Discussionmentioning

confidence: 99%

“…When reevaluated at 8 years old, she had already been labeled as having cerebral palsy with no obvious 3 ), PTPS deficiency typically is associated with plasma phenylalanine levels of 240 to 2,500mol/L; thus, the HPA usually can be detected through neonatal PKU screening programs. 7 A review of the BIODEF database 1 for registered severe PTPS patients (N ϭ 223), as well as review of published literature, 9 shows that there are two patients (BIODEF no. 4 and no.…”

Section: Discussionmentioning

confidence: 99%

6‐Pyruvoyl‐tetrahydropterin synthase deficiency with mild hyperphenylalaninemia

Demos¹,

Waters²,

Vallance³

et al. 2005

Annals of Neurology

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Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for hyperphenylalaninemia.

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“…Many patients have residual neurological symptoms that usually have diurnal variation, being worst when the patients get tired or when the dosage or interval for medications is not respected. There is correlation between severity of the mutation, age at which therapy is initiated, type of disease, degree of correction of CSF neurotransmitters, and residual functional deficits (Dudešek et al 2001;Echenne et al 2006;Jaggi et al 2008;Liu et al 2008).…”

Section: Outcomementioning

confidence: 95%

Disorders of biopterin metabolism

Longo

2009

J of Inher Metab Disea

133

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Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4alpha-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of L-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.

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Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency

Cited by 48 publications

References 31 publications

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

6‐Pyruvoyl‐tetrahydropterin synthase deficiency with mild hyperphenylalaninemia

Disorders of biopterin metabolism

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