Alternative titles; symbols
SNOMEDCT: 1187545003; ORPHA: 70594; DO: 0111168;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.2 | Dystonia, dopa-responsive, due to sepiapterin reductase deficiency | 612716 | ?Autosomal dominant; Autosomal recessive | 3 | SPR | 182125 |
A number sign (#) is used with this entry because dopa-responsive dystonia due to sepiapterin reductase deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding sepiapterin reductase (SPR; 182125), a component of the tetrahydrobiopterin (BH4) synthetic pathway, on chromosome 2p. One patient with a heterozygous mutation has been reported (Steinberger et al., 2004).
SPR deficiency results in neurologic deterioration due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Clinically, affected individuals show an L-DOPA-responsive, diurnally fluctuating movement disorder usually associated with cognitive delay and severe neurologic dysfunction. BH4 is a required cofactor for the synthesis of the neurotransmitters dopamine and serotonin. BH4 is also a required cofactor for phenylalanine hydroxylase (PAH; 612349), but patients with SPR deficiency do not exhibit overt hyperphenylalaninemia. The lack of hyperphenylalaninemia distinguishes SPR deficiency from other disorders of BH4 synthesis (see, e.g., HPABH4A, 261640). However, the neurologic phenotype of SPR deficiency resembles the other BH4-deficient disorders (summary by Bonafe et al., 2001 and Friedman et al., 2012).
Another form of dopa-responsive dystonia (DTY5; 128230) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225), which is also a component of the biopterin synthetic pathway.
Bonafe et al. (2001) reported 2 patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. The patients had normal urinary pterins and did not have hyperphenylalaninemia. Studies of skin fibroblasts revealed inactive sepiapterin reductase, the enzyme that catalyzes the final 2-step reaction in the biosynthesis of BH4. The patients had previously been reported by Blau et al. (1998, 1999). Blau et al. (1999) had shown that the patients developed hyperphenylalaninemia on oral challenge with phenylalanine, indicating impaired hepatic hydroxylation.
Steinberger et al. (2004) reported a 26-year-old woman with a mild form of dopa-responsive dystonia. The patient had walked on tiptoes as a child, suggesting fixed pes equinovarus. At age 15 years, she noticed abnormal movements of the fourth and fifth digits of the left hand; at age 19 years, she developed gait abnormalities with internal rotation, adduction, and extension of the left leg; and at age 23 years, she had dystonic movements and tremor. Sepiapterin reductase activity was significantly reduced compared to controls (approximately 50%) and western blot analysis showed reduced protein quantities (approximately 39% of normal). Biopterin concentration was also reduced. Genetic analysis showed a heterozygous mutation in the 5-prime untranslated region of the SPR gene (182125.0004). The biologic parents were unknown. The findings suggested that even haploinsufficiency of SPR can result in clinical symptoms in some cases.
Friedman et al. (2006) reported a 27-year-old woman with SPR deficiency. She had delayed childhood development, low IQ, abnormal gait, oculomotor apraxia, dysarthria, weakness, generalized dystonia, myoclonus, choreoathetosis, and hypersomnolence, requiring 13 hours of sleep per day. Cerebrospinal fluid (CSF) analysis showed markedly decreased 5-HIAA and HVA, and increased 7,8-dihydropterin, consistent with SPR deficiency. Initial treatment with L-DOPA resulted in marked clinical improvement but also intolerable dyskinesias. Maximal clinical benefit was found with selegiline and melatonin. Maternal relatives of the patient reportedly had abnormal limb posturing. Genetic analysis identified a homozygous mutation in the SPR gene (182125.0003).
Verbeek et al. (2008) reported 2 Greek sibs with SPR deficiency. Both showed delayed psychomotor development in infancy. At age 17 months, the girl had mild pyramidal tract signs with hyperreflexia, clonus, and extensor plantar responses. She also had drooling and horizontal nystagmus, which was occasionally cyclic. By age 9 years, she had ataxia, dystonia, and mild athetoid movements, and developed episodic stiffening of the body and independent oculogyric crises. Her younger brother developed stiffening episodes at age 7 years. Between these episodes, he had mild truncal ataxia with diurnal variation of athetosis and dystonia. Both children had sleep disturbances and temperature dysregulation. Treatment with L-DOPA resulted in marked clinical improvement and both children attended normal schools with average performance. Laboratory analysis of CSF before treatment showed decreased HVA, 5-HIAA, and norepinephrine (3-methoxy-4-hydroxyphenylethyleneglycol; MHPG), and increased sepiapterin. Decreased levels of neurotransmitter metabolites were also detected in the urine. Verbeek et al. (2008) noted that fewer than 25 patients with SPR deficiency had been reported.
Arrabal et al. (2011) reported 4 patients from Spain with genetically confirmed SPR deficiency. One had the classic phenotype, with onset in infancy of psychomotor retardation, hypotonia, hypersalivation, hypersomnolence, ataxia, and extrapyramidal signs. The diagnosis was made after neurotransmitter analysis and genetic testing. Treatment with L-DOPA and 5-hydroxytryptophan resulted in neurologic improvement, although he still had slight psychomotor delay 3 years later. The 3 additional patients were sisters, all of whom demonstrated a milder phenotype. The proband in that family presented at age 7 years with gait difficulties and left foot equinovarus. She also had weakness and weariness with diurnal variation. Other findings included intermittent postural tremor, abnormal ocular movements, oral dyskinesia when stressed, bradykinesia, mask-like facial expression, asymmetric postural dystonia, axial hypotonia, and rigidity. She also had hyperreflexia and myoclonic movements; cognition was normal. Treatment with L-DOPA was highly effective. Her sisters had similar, but milder symptoms.
Friedman et al. (2012) retrospectively reviewed the features of 43 individuals with genetically confirmed SPR deficiency identified from 23 international medical centers. Thirty of the patients had previously been reported. Detailed features were available for 38 patients. Most patients showed onset of neurologic symptoms in infancy or childhood. The average age at onset was 7 months, with a delay in diagnosis up to 9 years. The most common features included motor and language delay, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit. Common, but variable, features included dysarthria, parkinsonism, hyperreflexia, autonomic signs, sleep disturbances, and psychiatric/behavioral abnormalities. There was variability in the presentation and severity of symptoms. Many of the earlier features were nonspecific, such as hypotonia and developmental delay, and dystonia was often absent in young children. Eight percent of patients had normal cognition. Many patients were misdiagnosed as having cerebral palsy. Almost all showed a dramatic improvement with levodopa/carbidopa treatment with further improvement with the addition of 5-hydroxytryptophan. CSF of all patients examined showed low 5-HIAA and HVA and increased total biopterin, dihydrobiopterin, and sepiapterin.
Friedman et al. (2012) presented a diagnostic algorithm for patients with a possible disorder of neurotransmitter metabolism. They emphasized the importance of correct and early diagnosis of SPR deficiency since treatment with L-DOPA can offer substantial clinical improvement. Biochemical evaluation of cerebrospinal fluid is the preferred method of initial investigation.
Carducci et al. (2015) developed an analytic method based on HPLC that allowed quantification of sepiapterin in urine. Urine from 4 SRD patients showed accumulation of sepiapterin several times greater than that found in healthy controls or carriers, regardless of age or treatment.
Most patients with SPR deficiency show dramatic improvement with L-DOPA treatment. Improvement is most apparent for motor disturbances, but other symptoms may also respond. Many patients also show improvement with 5-hydroxytryptophan (Friedman et al., 2012).
Most cases of SPR deficiency are transmitted in an autosomal recessive pattern resulting from homozygous or compound heterozygous mutations in the SPR gene (Bonafe et al., 2001). However, 1 patient with a milder disorder and a heterozygous mutation has been reported (Steinberger et al., 2004).
In 2 patients with SPR deficiency and neurologic features, Bonafe et al. (2001) identified homozygous (182125.0001) and compound heterozygous (182125.0002; 182125.0003) mutations in the SPR gene. The authors suggested that autosomal recessive deficiency of sepiapterin reductase leads to BH4 and neurotransmitter deficiencies without hyperphenylalaninemia.
In 2 Greek sibs with SPR deficiency, Verbeek et al. (2008) identified a homozygous truncating mutation in the SPR gene (K251X; 182125.0006).
Friedman et al. (2012) reported 16 different SPR mutations, including 5 novel mutations, among 42 patients with SPR deficiency; many of the patients had previously been reported. The most common mutations were a splice site mutation (182125.0008), common in the Maltese population, and R150G (182125.0003), both occurring at a frequency of 20%. K251X (182125.0006) occurred at a frequency of 17%.
In a Spanish boy with the classic infantile onset of neurologic symptoms due to SPR deficiency, Arrabal et al. (2011) identified a homozygous truncating mutation in the SPR gene (K251X; 182125.0006). Three sisters from a different Spanish family with a much milder form of the disorder were compound heterozygous for 2 missense mutations in the SPR gene: R150G (182125.0003) and G102C (182125.0007). In vitro functional expression studies in E. coli showed that the G102C mutant protein had 15% residual enzyme activity. Minigene analysis showed that the G102C mutation also resulted in some splicing abnormalities, although some normal splicing still occurred, resulting in a mutant protein with the missense change. Arrabal et al. (2011) concluded that the milder phenotype in the 3 sisters resulted from residual enzyme activity conferred by the G102C mutation, since R150G had been shown to be functionally null.
Bonafe et al. (2001) and Verbeek et al. (2008) noted that, in the absence of SPR, there are alternative pathways for the final 2-step reaction for BH4 biosynthesis in peripheral tissues by use of aldose reductase (AR; 103880), carbonyl reductase (CBR1; 114830), and dihydrofolate reductase (DHFR; 126060). The brain expresses AR and CBR1, but has low levels of DHFR, which results in decreased central production of BH4. Thus, patients with SPR deficiency have central nervous system manifestations, but do not have hyperphenylalaninemia, since peripheral production of BH4 can be compensated by alternative enzymes in the final 2-step reaction.
Verbeek et al. (2008) further noted that the cerebral neurotransmitter deficiency in patients cannot solely be explained the low-normal BH4 production in the brain. The relative absence of DHFR in the brain results in the accumulation of 7,8-dihydrobiopterin, which is a competitive inhibitor of tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), also adding to the reduction of dopamine and serotonin synthesis, respectively.
In 7 Maltese patients with classic features of SPR deficiency. Neville et al. (2005) identified a homozygous splice site mutation in the SPR gene (182125.0008). The authors postulated a founder effect in this population.
Friedman et al. (2012) identified an R150G mutation in the SPR gene (182125.0003) in 14 patients with SPR deficiency, many of whom were of Mediterranean descent (8 Spanish, 2 Turkish, 1 Italian, and 3 unspecified Caucasian).
A proper level of BH4 is necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH4 deficiency is closely associated with diverse neurologic-psychiatric disorders. Sepiapterin reductase catalyzes the final step of BH4 biosynthesis. Yang et al. (2006) created an Spr knockout mouse (Spr -/-) and found that the deficient mice display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH4 and for the normal functions of BH4-dependent enzymes. The Spr -/- mice exhibited phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH4 and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr -/- mice shared striking similarities with the symptoms observed in SPR-deficient patients.
Arrabal, L., Teresa, L., Sanchez-Alcudia, R., Castro, M., Medrano, C., Gutierrez-Solana, L., Roldan, S., Ormazabal, A., Perez-Cerda, C., Merinero, B., Perez, B., Artuch, R., Ugarte, M., Desviat, L. R. Genotype-phenotype correlations in sepiapterin reductase deficiency: a splicing defect accounts for a new phenotypic variant. Neurogenetics 12: 183-191, 2011. [PubMed: 21431957] [Full Text: https://doi.org/10.1007/s10048-011-0279-4]
Blau, N., Thony, B., Renneberg, A., Arnold, L. A., Hyland, K. Dihydropteridine reductase deficiency localized to the central nervous system. J. Inherit. Metab. Dis. 21: 433-434, 1998. [PubMed: 9700606] [Full Text: https://doi.org/10.1023/a:1005327313348]
Blau, N., Thony, B., Renneberg, A., Penzien, J. M., Hyland, K., Hoffmann, G. Variant of dihydropteridine reductase deficiency without hyperphenylalaninemia: effect of oral phenylalanine loading. J. Inherit. Metab. Dis. 22: 216-220, 1999. [PubMed: 10384371] [Full Text: https://doi.org/10.1023/a:1005584627797]
Bonafe, L., Thony, B., Penzien, J. M., Czarnecki, B., Blau, N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am. J. Hum. Genet. 69: 269-277, 2001. [PubMed: 11443547] [Full Text: https://doi.org/10.1086/321970]
Carducci, C., Santagata, S., Friedman, J., Pasquini, E., Carducci, C., Tolve, M., Angeloni, A., Leuzzi, V. Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency. Molec. Genet. Metab. 115: 157-160, 2015. [PubMed: 26123188] [Full Text: https://doi.org/10.1016/j.ymgme.2015.06.009]
Friedman, J., Hyland, K., Blau, N., MacCollin, M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67: 2032-2035, 2006. [PubMed: 17159114] [Full Text: https://doi.org/10.1212/01.wnl.0000247274.21261.b4]
Friedman, J., Roze, E., Abdenur, J. E., Chang, R., Gasperini, S., Saletti, V., Wali, G. M., Eiroa, H., Neville, B., Felice, A., Parascandalo, R., Zafeiriou, D. I., and 17 others. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann. Neurol. 71: 520-530, 2012. [PubMed: 22522443] [Full Text: https://doi.org/10.1002/ana.22685]
Neville, B. G. R., Parascandalo, R., Farrugia, R., Felice, A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain 128: 2291-2296, 2005. [PubMed: 16049044] [Full Text: https://doi.org/10.1093/brain/awh603]
Steinberger, D., Blau, N., Goriuonov, D., Bitsch, J., Zuker, M., Hummel, S., Muller, U. Heterozygous mutation in 5-prime-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 5: 187-190, 2004. [PubMed: 15241655] [Full Text: https://doi.org/10.1007/s10048-004-0182-3]
Verbeek, M. M., Willemsen, M. A. A. P., Wevers, R. A., Lagerwerf, A. J., Abeling, N. G. G. M., Blau, N., Thony, B., Vargiami, E., Zafeiriou, D. I. Two Greek siblings with sepiapterin reductase deficiency. Molec. Genet. Metab. 94: 403-409, 2008. [PubMed: 18502672] [Full Text: https://doi.org/10.1016/j.ymgme.2008.04.003]
Yang, S., Lee, Y. J., Kim, J.-M., Park, S., Peris, J., Laipis, P., Park, Y. S., Chung, J. H., Oh, S. P. A murine model for human sepiapterin-reductase deficiency. Am. J. Hum. Genet. 78: 575-587, 2006. [PubMed: 16532389] [Full Text: https://doi.org/10.1086/501372]