-Related Tetrahydrobiopterin Deficiency (PTPSD)

CLINICAL CHARACTERISTICS

-related tetrahydrobiopterin deficiency (PTPSD) results in a lack of tetrahydropterin, an important cofactor for phenylalanine hydroxylase (PAH), tyrosine hydroxylase, and tryptophan hydroxylase. Deficiency can thus lead to neurotransmitter and neuropsychiatric disorders. The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In the severe form, clinical symptoms may become apparent in the neonatal period and can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. Without treatment, developmental delays become more marked. Neurologic symptoms (dysarthria, dystonia, tremors, abnormal gait, parkinsonism, oculogyric crises, motor tics) may be ameliorated by treatment with sapropterin dihydrochloride and neurotransmitter precursors. Other features of the condition can include psychiatric comorbidities (ADHD, anxiety, depression), infant feeding difficulties leading to early growth failure, hyperprolactinemia, growth hormone deficiency, sleep issues, and autonomic dysfunction; many of these features can be ameliorated by appropriate treatment. In treated individuals, development often improves during adolescence, with many adults having a normal IQ level. In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in phenylalanine (Phe) levels. Some remain asymptomatic. However, with time, some have mild developmental delays and can develop deficiency of neurotransmitter production, such that treatment of some asymptomatic individuals may be required.

DIAGNOSIS/TESTING: The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia, elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio in urine or dried blood spots (DBS) and normal dihydropteridine reductase (DHPR) activity in DBS. The molecular diagnosis of PTPSD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in by molecular genetic testing.

MANAGEMENT

Immediate therapy with sapropterin (tetrahydrobiopterin dihydrochloride; BH4), a cofactor/cosubstrate of PAH, is recommended to reduce blood Phe concentrations in individuals with hyperphenylalaninemia. If sapropterin is not available, dietary Phe restriction should be implemented. Because sapropterin has limited access to the central nervous system (CNS), or rather, this access is only achieved at high doses, therapy with sapropterin does not normalize the activity of tyrosine or tryptophan hydroxylase in people with PTPSD. Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors (levodopa plus decarboxylase inhibitor (DCI), i.e., carbidopa or benserazide), 5-hydroxytryptophan, and/or dopamine (rotigotine patch, pramipexole) and/or serotonin agonists, or other medications (MAO inhibitors such as selegiline) to address specific neurotransmitter deficiencies and maintain optimal neurologic function. : Optimization of dosage and intervals of levodopa/DCI in those with abnormal movements/parkinsonism; growth hormone supplementation and/or optimization of neurotransmitter precursor therapy for growth hormone deficiency; optimization of neurotransmitter precursor therapy for recurrent hyperthermia; anticholinergic treatment may be considered for hypersalivation; standard treatment for developmental delay, spasticity, epilepsy, sleep disorders, and decreased bone mineral density. Routine Phe monitoring in infants (age <1 year) weekly until normalized and then every three to six months once levels normalize; every six months in children younger than age 12 years; and every six to 12 months in adolescents and adults; the Phe target ranges correspond to those of PAH deficiency. Prolactin level at each visit. Routine clinical visits with a metabolic specialist (and metabolic dietician if on Phe-restricted diet) every one to three months in infants (age <1 year), every three to six months between ages one and seven years, and every six to 12 months in those age eight years and older. At each visit, measure growth parameters and evaluate nutritional status; asses for new neurologic manifestations (changes in tone, seizures, movement disorders); monitor developmental progress and assess educational needs; monitor for behavioral issues (anxiety, ADHD, emotional dysregulation, depression, aggression); and assess for signs and symptoms of sleep disorders. At ages two, six, 12, and 18 years, consider neuropsychological evaluation. In adulthood, periodic parathormone levels and DXA scan. As needed, consider EEG to differentiate from movement disorder seizures. Persons with PTPSD on Phe-reduced diet should either avoid products containing aspartame or calculate total intake of Phe when using such products and adapt diet components accordingly. If prenatal genetic testing has not been performed, each at-risk newborn sib should be evaluated immediately (at or just after 24 hours) after birth for PTPSD using measurement of blood Phe concentration to allow for earliest possible diagnosis and treatment. If older sibs have not undergone NBS or genetic testing for the known familial pathogenic variants in , measure blood Phe concentrations to clarify their disease status. Women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy may have offspring with normal intellectual and behavioral development, particularly if levels of Phe are kept in the normal range during pregnancy. Intensive clinical and biochemical supervision by a multidisciplinary team before, during, and after pregnancy in a woman with PTPSD is essential to control the symptoms of the disease, adjust the treatment if needed, and monitor the development of the fetus. If the affected woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome (reported specifically in women who have PAH deficiency as the primary cause of their elevated Phe levels), including malformations and intellectual disability, since Phe is a potent teratogen.

GENETIC COUNSELING

PTPSD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Children born of one parent with PTPSD and one parent with two normal alleles are obligate heterozygotes. If the mother is the affected parent, MPKU syndrome is a critical issue. Females with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., MPKU syndrome) when they reach childbearing age. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for PTPSD are possible.