Sepiapterin reductase deficiencyis an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known asdystonia.Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures.[2]Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma.[3]
| Sepiapterin reductase deficiency | |
|---|---|
| Other names | SPR deficiency[1] |
Signs and symptoms
editCognitive problems
edit- Intellectual disability: Delay in cognitive development
- Extreme mood swings
- Language delay[4]
Motor problems
edit- Dystonia: involuntary muscle contractions
- Axialhypotonia:low muscle tone and strength[5]
- Dysarthria:impairment in muscles used for speech
- Muscle stiffness and tremors
- Seizures
- Coordination and balance impairment
- Oculogyric crises:abnormal rotation of the eyes
The oculogyric crises usually occur in the later half of the day and during these episodes patients undergo extreme agitation and irritability along with uncontrolled head and neck movements. Apart from the aforementioned symptoms, patients can also displayparkinsonism,sleep disturbances, small head size (microcephaly), behavioral abnormalities, weakness, drooling, and gastrointestinal symptoms.[4]
Causes
editThis disorder occurs through a mutation in the SPR gene, which is responsible for encoding thesepiapterin reductaseenzyme. The enzyme is involved in the last step of producingtetrahydrobiopterin,better known as BH4.BH4is involved in the processing of amino acids and the production of neurotransmitters, specifically that ofdopamineandserotoninwhich are primarily used in transmission of signals between nerve cells in the brain. The mutation in the SPR gene interferes with the production of the enzyme by producing enzymes with little or no function at all. This interference results in a lack of BH4specifically in the brain. The lack of BH4only occurs in the brain because other parts of the body adapt and utilize alternate pathways for the production of BH4.The mutation in the SPR gene leads to nonfunctional sepiapterin reductase enzymes, which results in a lack of BH4and ultimately disrupts the production of dopamine and serotonin in the brain.[6]The disruption of dopamine and serotonin production leads to the visible symptoms present in patients suffering from sepiapterin reductase deficiency. SR deficiency is considered an inheritedautosomal recessivecondition disorder because each parent carries one copy of the mutated gene, but typically do not show any signs or symptoms of the condition.[7]
Diagnosis
editCSF neurotransmitter screening
editThe diagnosis of SR deficiency is based on the analysis of thepterinsandbiogenic aminesfound in thecerebrospinal fluid(CSF) of the brain. The pterin compound functions as a cofactor in enzyme catalysis and biogenic amines which include adrenaline, dopamine, and serotonin have functions that vary from the control of homeostasis to the management of cognitive tasks.[8]This analysis reveals decreased concentrations ofhomovanillic acid(HVA),5-hydroxyindolacetic acid(HIAA), and elevated levels of7,8-dihydrobiopterin,a compound produced in the synthesis of neurotransmitters. Sepiapterin is not detected by the regularly used methods applied in the investigation of biogenic monoamine metabolites in the cerebrospinal fluid. It must be determined by specialized methods that work by indicating a marked and abnormal increase of sepiapterin in cerebrospinal fluid. Confirmation of the diagnosis occurs by demonstrating high levels of CSF sepiapterin and a marked decrease of SR activity of thefibroblastsalong with SPR gene molecular analysis.[2][9]
Treatment
editLevodopa and Carbidopa
editSR deficiency is currently being treated using a combination therapy of levodopa and carbidopa. These treatments are also used for individuals suffering from Parkinson's. The treatment is noninvasive and only requires the patient to take oral tablets 3 or 4 times a day, where the dosage oflevodopaandcarbidopais determined by the severity of the symptoms. Levodopa is in a class of medications called central nervous system agents where its main function is to become dopamine in the brain. Carbidopa is in a class of medications called decarboxylase inhibitors and it works by preventing levodopa from being broken down before it reaches the brain. This treatment is effective in mitigating motor symptoms, but it does not totally eradicate them and it is not as effective on cognitive problems. Patients who have been diagnosed with SR deficiency and have undergone this treatment have shown improvements with most motor impairments including oculogyric crises, dystonia, balance, and coordination.[9][10]
Case Studies
editAutosomal Recessive DOPA-responsive Dystonia
editThe diagnosis of sepiapterin reductase deficiency in a patient at the age of 14 years was delayed by an earlier diagnosis of an initially unclassified form ofmethylmalonic aciduriaat the age of 2. At that time the hypotonia and delayed development were not considered to be suggestive of a neurotransmitter defect. The clinically relevant diagnosis was only made following the onset ofdystoniawith diurnal variation, when the patient was a teenager. Variability in occurrence and severity of other symptoms of the condition, such as hypotonia,ataxia,tremors, spasticity, bulbar involvement, oculogyric crises, and cognitive impairment, is comparable with autosomal dominant GTPCH andtyrosine hydroxylasedeficiency, which are both classified as forms of DOPA-responsive dystonia.[11]
Homozygous Mutation causing Parkinsonism
editHypotonia and Parkinsonism were present in two Turkish siblings, brother and sister. By usingexome sequencing,which sequences a selective coding region of thegenome,researchers have found ahomozygousfive-nucleotidedeletion in the SPR gene which confirmed both siblings were homozygous. It is predicted that this mutation leads to premature translational termination. Translation is the biological process through which proteins are manufactured. The homozygous mutation of the SPR gene in these two siblings exhibiting early-onset Parkinsonism showcases that SPR gene mutations can vary in combinations of clinical symptoms and movement. These differences result in a wider spectrum for the diseasephenotypeand increases the geneticheterogeneitycausing difficulties in diagnosing the disease.[3]
Quantification of Sepiapterin in CSF
editThis study examined the clinical history of the CSF and urine of two Greek siblings who were both diagnosed with SR deficiency. Both siblings displayed delayed psychomotor development and a movement disorder. The diagnosis was confirmed by measuring the SR enzyme activity and mutation analysis. The mutation analysis of the gene was performed using genomic DNA isolated from blood samples. The results concluded that both patients have low concentrations of HVA and HIAA and high concentrations of sepiapterin in the CSF, but neopterin and biopterin were abnormal in only one sibling. The results of this research indicates that when diagnosing the SR deficiency, the quantification of sepiapterin in the CSF is more important and indicative of SR deficiency than usingneopterinandbiopterinalone. The results also show that the urine concentrations of neurotransmitter metabolites are abnormal in patients with this disorder. This finding may provide an initial and easier indication of the deficiency before CSF analysis is performed.[12]
Figures
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See also
editReferences
edit- ^Reference, Genetics Home."Sepiapterin reductase deficiency".Genetics Home Reference.
- ^abArrabal, L., Teresa, L., Sanchez-Alcudia, R., Castro, M., Medrano, C., Gutierrez-Solana, L.,... Desviat, L. R. (2011). Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics, 12(3), 183-191. doi: 10.1007/s10048-011-0279-4.
- ^abLohmann, E., Koroglu, C., Hanagasi, H. A., Dursun, B., Tasan, E., & Tolun, A. (2012). A homozygous frameshift mutation of sepiapterin reductase gene causing parkinsonism with onset in childhood. Parkinsonism & Related Disorders, 18(2), 191-193.doi:10.1016/j.parkreldis.2011.10.001
- ^abFriedman, J., Roze, E., Abdenur, J. E., Chang, R., Gasperini, S., Saletti, V.,... Blau, N. (2012). Sepiapterin reductase deficiency: A Treatable Mimic of Cerebral Palsy. Annals of Neurology, 71(4), 520-530. doi: 10.1002/ana.22685.
- ^Dill, P., Wagner, M., Somerville, A., Thony, B., Blau, N., & Weber, P. (2012). Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia Hallmarks of sepiapterin reductase deficiency. Neurology, 78(5), E29-E32. doi: 10.1212/WNL.0b013e3182452849.
- ^Clot, F., Grabli, D., Cazeneuve, C., Roze, E., Castelnau, P., Chabrol, B.,... French Dystonia, N. (2009). Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain, 132, 1753-1763.
- ^Pearl, P. L., Taylor, J. L., Trzcinski, S., & Sokohl, A. (2007). The pediatric neurotransmitter disorders. Journal of Child Neurology, 22(5), 606-616. doi: 10.1177/0883073807302619.
- ^Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. The Biogenic Amines. Available from:https:// ncbi.nlm.nih.gov/books/NBK11035/.
- ^abEchenne, B., Roubertie, A., Assmann, B., Lutz, T., Penzien, J. M., Thony, B.,... Hoffmann, G. F. (2006). Sepiapterin reductase deficiency: Clinical presentation and evaluation of long-term therapy. Pediatric Neurology, 35(5), 308-313. doi: 10.1016/j.pediatrneurol.2006.05.006 Friedman, J., Hyland, K., Blau, N., & MacCollin, M. (2006). Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology, 67(11), 2032-2035. doi: 10.1212/01.wnl.0000247274.21261.b4.
- ^Neville, B. G. R., Parascandalo, R., Farrugia, R., & Felice, A. (2005). Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain, 128, 2291-2296. doi: 10.1093/brain/awh603.
- ^Abeling, N. G., Duran, M., Bakker, H. D., Stroomer, L., Thony, B., Blau, N.,... Poll-The, B. T. (2006). Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Molecular Genetics and Metabolism, 89(1-2), 116-120. Arrabal, L., Teresa, L., Sanchez-Alcudia, R., Castro, M., Medrano, C., Gutierrez-Solana, L.,... Desviat, L. R. (2011). Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics, 12(3), 183-191.
- ^Verbeekac, M. M., Willemsen, M., Wevers, R. A., Lagerwerf, A. J., Abeling, N., Blau, N.,... Zafeiriou, D. I. (2008). Two Greek siblings with sepiapterin reductase deficiency. Molecular Genetics and Metabolism, 94(4), 403-409. doi: 10.1016/j.ymgme.2008.04.003.
- ^Wu Y, Chen P, Sun L, Yuan S, Cheng Z, Lu L, Du H, Zhan M (September 2020)."Sepiapterin reductase: Characteristics and role in diseases".Journal of Cellular and Molecular Medicine.24(17): 9495–9506.doi:10.1111/jcmm.15608.PMC7520308.PMID32734666.
External links
edit- SR deficiencyGenetics Home Reference
- SR deficiencyNational Institute of Health