6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects

Abstract

a b s t r a c tBackground: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. Method: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. Results: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). Conclusion: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.

Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan

“…These findings align with previous reports from other countries in the region. A high incidence of BH 4 deficiency (~12%) was reported for the Kingdom of Saudi Arabia 22 and Iran 23 …”

Spotlight on Oculogyric Crisis: A Review

“… 17 6-pyruvoyl-tetrahydropterin synthase deficiency, which results in hyperphenylalaninemia along with dopamine and serotonin depletion in the central nervous system, usually presents with hypotonia, seizures, OGC, and developmental delay. 18 , 19 PLA2G6 associated neurodegeneration (PLAN), which occurs due to a homozygous mutation of PLA2G6, is a rare cause of OGC. 20 …”

“…17 6-pyruvoyl-tetrahydropterin synthase deficiency, which results in hyperphenylalaninemia along with dopamine and serotonin depletion in the central nervous system, usually presents with hypotonia, seizures, OGC, and developmental delay. 18,19 PLA2G6 associated neurodegeneration (PLAN), which occurs due to a homozygous mutation of PLA2G6, is a rare cause of OGC. 20 Some neurodegenerative disorders are also found to be associated with the occurrence of OGC, such as mutations in the GRIN1 gene, which affects the function of both N-methyl-D-aspartate and dopamine D1 receptors, leading to oculomotor dystonic reactions; 21,22 Neuronal intranuclear hyaline inclusion disease, a multisystem degenerative disorder that involves both central and peripheral nervous systems, causing diffuse muscle spasms, dysarthria, dysphagia, tremors, ataxia, OGC, progressive muscle weakness, and atrophy 23 ; Rett syndrome, progressive neurodegenerative disorder in females, leads to gait disturbance, bruxism, OGC, parkinsonism, and dystonia 24 and tyrosine hydroxylase (TOH) deficiency, an inborn error of catecholamine biosynthesis causing dystonia along with tremor, hypersensitivity to levodopa therapy, OGC, akinesia, and rigidity.…”

Treatment of Dystonia: Medications, Neurotoxins, Neuromodulation, and Rehabilitation

“…A marked and sustained positive response to levodopa without levodopa-induced dyskinesia is described in PTP synthase deficiency, though its use is frequently in combination with BH4 and 5-HT. These patients also tend to display other neurological symptoms including early childhood seizures, spasticity, and cognitive deficits [15,24,26]. Motor outcomes for those with TH, PTP synthase, DHPR, and autosomal recessive GTP-CH-I deficiencies are less favorable compared to those with sepiapterin or autosomal dominant GTP-CH-I deficiencies [26].…”