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Tetrahydrobiopterin Deficiency

Tetrahydrobiopterin deficiency consists of four different defects: GTPCH deficiency or guanosine triphosphate cyclohydrolase I deficiency- with autosomal dominant (Segawa syndrome) and autosomal recessive forms, dihydropteridine reductase (DHPR) deficiency, PCD deficiency i.e. pterin-4-alpha-carbinolamine dehydratase deficiency and 6-pyruvoyl tetrahydropterin synthase deficiency or PTPS deficiency. All these pathological entities lead to high levels of phenylalanine and impaired production of serotonin, catecholamines and nitric oxide, leading to neurologic, psychiatric and cardiovascular dysfunction, as well as abnormal embryonic development.


Presentation

Tetrahydrobiopterin deficiency may cause a wide variety of symptoms in various individuals, depending on disease severity and transient or permanent character. Disease signs also depend on the type of the defect, with PCD deficiency being less severe and often causing transient motor delay. In general, newborns may appear normal, except for those with severe PTPS deficiency who have low birth weight and are frequently premature. However, all affected newborns may present with microcephaly and unsatisfactory ponderal curve due to inefficient sucking and swallowing. An increased risk for type 2 diabetes during infancy has also been described.

More severe forms are characterized by seizures, trunk hypotonia, and limb hypertonia, both considered to be extrapyramidal neurologic signs [1] or "floppy baby" appearance and difficulty in swallowing. Motion abnormalities consist of opisthotonus, chorea, bradykinesia, and athetosis. These may be accompanied by intellectual and psychomotor retardation, that may improve with treatment [2]. Older children may be red-headed and experience gait abnormalities, dystonia [3], as well as upward, downward or convergent oculogyric crises that can be accompanied by malaise, lacrimation, and excessive blinking.

Associated symptoms include hypersalivation, irritability, and hyperthermia. The general health status may have diurnal fluctuations. Clinical as well as neurological status deteriorate as the child grows older [4] [5]. The physician performing the examination should keep in mind that the central nervous system, pulmonary and cardiac microcirculation are at risk in these conditions, making late detection and delayed treatment result in poor prognosis [6].

Turkish
  • […] study of 626 patients with different genetic causes for their BH 4 deficiency, although the exact genetic mutation and the differing times from diagnosis to treatment make the outcome for BH 4 deficiencies highly variable. [13] Race Children of Chinese, Turkish[thehealthscience.com]
  • […] study of 626 patients with different genetic causes for their BH4 deficiency, although the exact genetic mutation and the differing times from diagnosis to treatment make the outcome for BH4 deficiencies highly variable. [38] Race Children of Chinese, Turkish[emedicine.com]
Lacrimation
  • Older children may be red-headed and experience gait abnormalities, dystonia, as well as upward, downward or convergent oculogyric crises that can be accompanied by malaise, lacrimation, and excessive blinking.[symptoma.com]
  • Severe oculogyric crises can be associated with additional symptoms including the formation of tears (lacrimation), eye blinking, widening (dilation) of the pupils, drooling, backward flexion of the neck, restlessness, or a general feeling of poor health[rarediseases.org]
Impulsivity
  • After a period of good clinical compensation (34 1 months), different impulse control disorders (gambling, compulsive buying, and hypersexuality) were observed in three patients treated with high-dose pramipexole (0.030-0.033 mg/kg/day) beyond adolescence[ncbi.nlm.nih.gov]
  • Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate.[rarediseases.org]
Opisthotonus
  • Motion abnormalities consist of opisthotonus, chorea, bradykinesia, and athetosis. These may be accompanied by intellectual and psychomotor retardation, that may improve with treatment.[symptoma.com]
  • […] movements are common and can include abnormal slowness of movement (bradykinesia), rapid, involuntary, purposeless (chorea), slow, involuntary, writhing movements (athetosis), a type of spasm in which the head and feet bend the backward and the back arches (opisthotonus[rarediseases.org]
Clumsiness
  • In some cases, this clumsiness is due, in part, to involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia).[rarediseases.org]

Workup

Clinical evaluation and patient history raise tetrahydrobiopterin deficiency suspicion, but this must be confirmed using blood workup. However, the diagnosis can be suggested during newborn screening in the presence of elevated phenylalanine levels. In this case, differential diagnosis between tetrahydrobiopterin deficiency and phenylketonuria is needed. Furthermore, phenylalanine can be initially normal and diagnosis may be suggested by progressive and unexplainable neurological impairment. The next step in the workup plans is represented by detection of biopterin and neopterin in the urine and dried blood spots [7]. Several other pterins may also be present in the urine: isoxanthopterin, primapterin, monapterin, and pterin. In GTPCH deficiency, both biopterin and neopterin are low, in PTPS deficiency, neopterin is high and biopterin is low, while in DHPR deficiency both may be elevated or neopterin may be normal. In PCD deficiency, primapterin may also be detected.

Tetrahydrobiopterin loading test [8] can exclude phenylketonuria and consists of the reduction of high phenylalanine levels after tetrahydrobiopterin administration. Other diagnostic tests include DHPR level evaluation using enzyme assay or measurement of folates, pterins or neurotransmitter metabolites like homovanillic acid or 5-hydroxyindoleacetic acid in the cerebrospinal fluid.

In uncertain cases, molecular genetic testing may be necessary, despite being expensive and not widely available.

Guthrie cards can be used to measure DHPR activity in the red blood cells. Other enzymes (PTPS or GTPCH) activities van also be determined in the white blood cells or fibroblasts. Also, the physician should keep in mind that prolactin levels can be high in DHPR deficiency.

Hyperprolactinemia
  • Severe hyperprolactinemia with disruption of the pulsatile and circadian secretion pattern was the prevailing feature. The GH physiologic secretion pattern was not affected, but its stimulation was impaired.[ncbi.nlm.nih.gov]
  • In our patient the prolactin profile showed that hyperprolactinemia was treated insufficiently if the daily amount of L-DOPA/carbidopa was given in three doses.[nature.com]
Gliosis
  • Another possible explanation is that MI concentration in these BH4-deficient patients is higher, which might be consistent with previously reported imaging findings of gliosis.[ajnr.org]

Treatment

  • This study aimed to describe the demographics, geographic distribution, diagnosis, treatment and clinical outcomes of treatment, including intellectual development, in patients with tetrahydrobiopterin (BH4) deficiency in mainland China.[ncbi.nlm.nih.gov]
  • Treatment with an L-DOPA/carbidopa slow release preparation produces virtually normal prolactin levels.[ncbi.nlm.nih.gov]
  • DHPR deficiency seems to be more severe than PTPS deficiency and it is clearly the onset of treatment that determines the outcome.[ncbi.nlm.nih.gov]
  • Three of the children developed normally, two of them under treatment with tetrahydrobiopterin.[ncbi.nlm.nih.gov]
  • They had satisfactory physical and mental development after treatment. One patient with partial PTPS deficiency had normal growth and mental development without treatment.[ncbi.nlm.nih.gov]

Prognosis

  • The physician performing the examination should keep in mind that the central nervous system, pulmonary and cardiac microcirculation are at risk in these conditions, making late detection and delayed treatment result in poor prognosis.[symptoma.com]
  • Prognosis The prognosis for normal intelligence is good with dietary and medical treatment. Nontreatment and treatment failure are associated with neurologic and cognitive dysfunction. Treatment is not always successful.[emedicine.com]
  • […] small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the development and progression of these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis[rarediseases.org]

Etiology

  • Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med. 2008;10(1):4-12. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis.[najms.com]
  • This may suggest an etiological role of a BH4 deficit in these disorders via dysregulation of neurotransmitters.[censapharma.com]

Epidemiology

  • […] deficiencies consists of THB supplementation (2–20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precursors ( L-DOPA and 5-HTP ) and supplements of folinic acid in DHPR deficiency. [2] Epidemiology[ipfs.io]
  • Epidemiology Frequency United StatesThe incidence of classic PKU is approximately 1 case in 15,000 births. The incidence of BH 4 deficiency is approximately 1 case per 1 million births, or 1.5-2% of cases of PKU.[thehealthscience.com]
  • […] identified 42 variants in the PTS gene, 10 variants in the QDPR gene, and 2 in the GCH1 gene. [31] In addition, a novel PTS gene variant was identified in Mexico, [32] and 2 novel compound heterozygous PTS missense mutations were described in Thailand. [33] Epidemiology[emedicine.com]
Sex distribution
Age distribution

Pathophysiology

  • Dihydrofolate reductase shields endothelial nitric oxide synthase involving uncoupling intetrahydrobiopterin deficiency. [3] GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin are important for regulation of beta-adrenergic control of heart rate. [4] Pathophysiology[thehealthscience.com]
  • Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism (about 1:10,000-1:15,000) and was the[mayomedicallaboratories.com]
  • […] tested were found to be tetrahydrobiopterin (BH4) responsive and thus could be potentially treated with BH4 instead of a low-phenylalanine diet. [23] Gramer et al (2007) also found that most of the BH4-responsive patients had mild HPA or mild PKU. [24] Pathophysiology[emedicine.com]

Prevention

  • Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability.[ncbi.nlm.nih.gov]
  • The decrease in serotonin was prevented and prevention of the apparent dysfunction of digestive tract was observed by simultaneous administration of (6R)BH4.[jpet.aspetjournals.org]
  • Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage.[rarediseases.org]
  • One possible explanation is that a higher than average BH4 dosage could stabilize cell membrane damage in the brain and therefore prevent or reduce Cho release.[ajnr.org]
  • BH4 helps regulate eNOS activity and prevents it from dysfunction.[selfhacked.com]

References

Article

  1. Dudesek A, Roschinger W, Muntau A, et al. Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. Europ J Pediat. 2001;160:267-276.
  2. Lee N, Cheng L, Liu T, et al. Long-term follow-up of Chinese patients who received delayed treatment for 6-pyruvoyl-tetrahydropterin synthase deficiency. Molec Genet Metab. 2006;87:128-134.
  3. Opladen T, Hoffmann G, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis. 2012;35:963-973.
  4. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutation in the GTP cyclohydrolase I gene. Nature Genet 1994;8:236–241.
  5. Kure S, Hou DC, Ohura T, et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr. 1999;135(3):375–378.
  6. Thöny B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration, and functions. Biochem J. 2000;347:1–26.
  7. Opladen T, Abu Seda B, Rassi A, et al. Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience. J Inherit Metab Dis. 2011;3:819-826.
  8. Feillet F, Chery C, Namour F, et al. Evaluation of neonatal BH4 loading test in neonates screened for hyperphenylalaninemia. Early Hum Dev. 2008;84(9):561-567.

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Last updated: 2019-07-11 20:11