Sepiapterin reductase deficiency

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Sepiapterin reductase deficiency
Other namesSPR deficiency [1]

Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. 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]

Contents

Signs and symptoms

Cognitive problems

Motor problems

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 display parkinsonism, sleep disturbances, small head size (microcephaly), behavioral abnormalities, weakness, drooling, and gastrointestinal symptoms. [4]

Causes

This disorder occurs through a mutation in the SPR gene, which is responsible for encoding the sepiapterin reductase enzyme. The enzyme is involved in the last step of producing tetrahydrobiopterin, better known as BH4. BH4 is involved in the processing of amino acids and the production of neurotransmitters, specifically that of dopamine and serotonin which 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 BH4 specifically in the brain. The lack of BH4 only 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 BH4 and 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 inherited autosomal recessive condition 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

CSF neurotransmitter screening

The diagnosis of SR deficiency is based on the analysis of the pterins and biogenic amines found in the cerebrospinal 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 of homovanillic acid (HVA), 5-hydroxyindolacetic acid (HIAA), and elevated levels of 7,8-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 the fibroblasts along with SPR gene molecular analysis. [2] [9]

Treatment

Levodopa and Carbidopa

SR 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 of levodopa and carbidopa is 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

Autosomal Recessive DOPA-responsive Dystonia

The 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 of methylmalonic aciduria at 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 of dystonia with 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 and tyrosine hydroxylase deficiency, which are both classified as forms of DOPA-responsive dystonia. [11]

Homozygous Mutation causing Parkinsonism

Hypotonia and Parkinsonism were present in two Turkish siblings, brother and sister. By using exome sequencing, which sequences a selective coding region of the genome, researchers have found a homozygous five-nucleotide deletion 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 disease phenotype and increases the genetic heterogeneity causing difficulties in diagnosing the disease. [3]

Quantification of Sepiapterin in CSF

This 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 using neopterin and biopterin alone. 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]

See also

Related Research Articles

Dystonia Neurological movement disorder

Dystonia is a neurological hyperkinetic movement disorder syndrome in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often intensified or exacerbated by physical activity, and symptoms may progress into adjacent muscles.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders that are distinguished by their underlying cause.

Tetrahydrobiopterin Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide syntheses. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (Quinonoid dihydrobiopterin).

Lesch–Nyhan syndrome Rare genetic syndrome

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

Tetrahydrobiopterin deficiency Medical condition

Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.

6-Pyruvoyltetrahydropterin synthase deficiency Medical condition

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors, monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

GTP cyclohydrolase I

GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).

Tyrosine hydroxylase Mammalian protein found in Homo sapiens

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

Succinic semialdehyde dehydrogenase deficiency Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

Biopterin Chemical compound

Biopterins are pterin derivatives which function as endogenous enzyme cofactors in many species of animals and in some bacteria and fungi. Biopterins act as cofactors for aromatic amino acid hydroxylases (AAAH), which are involved in the synthesis of a number of neurotransmitters including dopamine, norepinephrine, epinepherine, and serotonin, along with several trace amines. Nitric oxide synthesis also uses biopterin derivatives as cofactors. In humans, tetrahydrobiopterin is the endogenous cofactor for AAAH enzymes.

Sepiapterin reductase

Sepiapterin reductase is an enzyme that in humans is encoded by the SPR gene.

Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.

Parkinsons disease Long-term degenerative neurological disorder

Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms become more common. The most obvious early symptoms are tremor, rigidity, slowness of movement, and difficulty with walking. Cognitive and behavioral problems may also occur with depression, anxiety, and apathy occurring in many people with PD. Parkinson's disease dementia becomes common in the advanced stages of the disease. Those with Parkinson's can also have problems with their sleep and sensory systems. The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain, leading to a dopamine deficit. The cause of this cell death is poorly understood, but involves the build-up of misfolded proteins into Lewy bodies in the neurons. Collectively, the main motor symptoms are also known as parkinsonism or a parkinsonian syndrome.

Kufor–Rakeb syndrome Medical condition

Kufor–Rakeb syndrome (KRS) is an autosomal recessive disorder of juvenile onset also known as Parkinson disease-9 (PARK9). It is named after Kufr Rakeb in Irbid, Jordan. Kufor–Rakeb syndrome was first identified in this region in Jordan with a Jordanian couple's 5 children who had rigidity, mask-like face, and bradykinesia. The disease was first described in 1994 by Najim Al-Din et al. The OMIM number is 606693.

Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.

Dopamine transporter deficiency syndrome (DTDS), also known as infantile parkinsonism-dystonia, is a rare movement disorder that causes progressively worsening dystonia and parkinsonism. It is the first known inherited dopamine 'transportophathy.'

Aromatic L-amino acid decarboxylase deficiency is a rare genetic disorder caused by mutations in the DDC gene, which encodes an enzyme called aromatic L-amino acid decarboxylase.

References

  1. ↑ Reference, Genetics Home. "Sepiapterin reductase deficiency". Genetics Home Reference.
  2. 1 2 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. doi: 10.1007/s10048-011-0279-4.
  3. 1 2 Lohmann, 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
  4. 1 2 Friedman, 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. The Biogenic Amines. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11035/.
  9. 1 2 Echenne, 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.


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