RARE DISEASE
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Synonyms: Autosomal recessive sepiapterin reductase-deficient DRD, DRD due to SRD, SPR deficiency, Sepiapterin reductase deficiency
Synonyms: Autosomal recessive sepiapterin reductase-deficient DRD, DRD due to SRD, SPR deficiency, Sepiapterin reductase deficiency
Synonyms: Autosomal recessive sepiapterin reductase-deficient DRD, DRD due to SRD, SPR deficiency, Sepiapterin reductase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Dopa-responsive dystonia due to sepiapterin reductase deficiency (SRD) is a rare autosomal recessive neurometabolic disorder characterized by infantile-onset dystonia, axial hypotonia, oculogyric crises, motor/cognitive delays, and diurnal symptom fluctuations [4][7][16]. Diagnosis involves elevated cerebrospinal fluid biopterins and SPR gene mutations [4][16]. Patients exhibit dramatic, sustained responsiveness to low-dose levodopa combined with carbidopa, though residual deficits may occur if treatment is delayed [4][16].
Burden
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
53 drug discovery papers about Dopa-responsive dystonia due to sepiapterin reductase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
53 drug discovery papers about Dopa-responsive dystonia due to sepiapterin reductase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-14 | Prenatal Diagnosis of Sepiapterin Reductase Deficiency: Lighting and Shadows of Early Treatment With L-DOPA/Carbidopa.
Sepiapterin reductase deficiency (SPD) is an extremely rare autosomal recessive neurotransmitter disorder caused by mutations in the sepiapterin reductase gene. Clinical features include motor and cognitive manifestations, and L-DOPA/Carbidopa is the main therapy available. To date, it is not known if prenatal diagnosis of SPD may improve the motor and cognitive outcomes by prompt correction of dopamine and serotonin deficiency after birth. We describe the motor and cognitive profiles of 2 siblings with SPD with a follow-up of 9 and 6 years, respectively. The diagnosis of the second patient was prenatally performed and the patient was treated by the neonatal age. Conversely, the first patient was treated by 10 months of age. Early treatment with L-DOPA/Carbidopa seems to be effective in improving motor outcomes but had no impact on cognitive impairment. Protocols for further treatment attempts, potentially also started before birth, are needed to provide conclusive results.
2026-05-02 | AKR1C3-driven restoration of tetrahydrobiopterin synthesis in cellular sepiapterin reductase deficiency.
Sepiapterin reductase (SPR) catalyzes several key steps in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases, and therefore for neurotransmitter production. Although several reductases-including carbonyl reductase 1 (CBR1), aldose reductase (AKR1B1), and AKR1C3-can substitute for SPR activity in vitro, their physiological significance remains unresolved. This study examines AKR1C3 as a component of an alternative BH4-generating pathway and evaluates its capacity to compensate for BH4 loss under diminished SPR activity. In vitro assays identified 2'-OXPH4 as the primary product of AKR1C3, redirecting pathway flux away from the canonical 1'-OXPH4 intermediate and the sepiapterin-salvage pathway. To assess the occurrence and efficiency of this route in cells, we generated SPR-knockout (SPR-KO) cell and evaluated pathway products in SPR-KO and wild-type (WT) backgrounds. In WT cells neither AKR1C3 nor SPR overexpression altered BH4 synthesis, indicating that neither enzyme is rate-limiting. In contrast, AKR1C3 increased BH4 levels in SPR-KO cells, while inhibiting sepiapterin production, revealing that AKR1C3 becomes functionally engaged only when SPR activity is decreased. Based on relative enzyme abundance, AKR1C3 and SPR exhibited comparable catalytic efficiency in this context. Importantly, AKR1C3-mediated BH4 production was sufficient to sustain tyrosine hydroxylase (TH) activity in SPR-KO cells, as demonstrated by L-DOPA formation. These findings establish AKR1C3-driven 2'-OXPH4 synthesis as a bona fide, inducible pathway capable of maintaining BH4 levels when SPR activity is limiting. This alternative path provides a compelling therapeutic target and introduces a new diagnostic consideration for patients with diminished SPR activity.
2025-02-04 | Unclear symptoms, early diagnosis and perfect outcome: a case diagnosed as sepiapterin reductase deficiency hidden behind vitamin B12 deficiency.
Sepiapterin reductase deficiency (SRD) is a rare dopa-sensitive neurotransmitter disorder caused by autosomal recessive mutations in the sepiapterin reductase gene. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia are highly suggestive in some patients. However, in other patients, the clinical picture may be nonspecific and remain under-recognized and misdiagnosed as cerebral palsy. We present a nine-month-old boy who initially presented with hypotonia and developmental delay, diagnosed as vitamin B12 deficiency. Upon he did not respond to vitamin replacement treatment, he was diagnosed with SRD by whole-exome sequencing (WES). The boy improved dramatically under treatment with L-dopa, 5-hydroxytryptophan and BH4. We aim to emphasize that SRD can present with nonspecific symptoms, leading to a diagnostic delay for this rare but treatable disease. Moreover, our case is the first to demonstrate the clinical benefit of BH4 add-on treatment. Early intervention is crucial for good outcome and neurodevelopment.
2024-09-12 | Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency.
sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child's needs, as the splitting of the tablet into smaller portions or its dilution in water. It's essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients. we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD. we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance. in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.
2024-03-27 | Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142 : A Case Report and Review of the UPD2 Literature.
We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR , and a variant of uncertain significance in ZNF142 . Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.
small molecules
2026-05-14 | Prenatal Diagnosis of Sepiapterin Reductase Deficiency: Lighting and Shadows of Early Treatment With L-DOPA/Carbidopa.
Sepiapterin reductase deficiency (SPD) is an extremely rare autosomal recessive neurotransmitter disorder caused by mutations in the sepiapterin reductase gene. Clinical features include motor and cognitive manifestations, and L-DOPA/Carbidopa is the main therapy available. To date, it is not known if prenatal diagnosis of SPD may improve the motor and cognitive outcomes by prompt correction of dopamine and serotonin deficiency after birth. We describe the motor and cognitive profiles of 2 siblings with SPD with a follow-up of 9 and 6 years, respectively. The diagnosis of the second patient was prenatally performed and the patient was treated by the neonatal age. Conversely, the first patient was treated by 10 months of age. Early treatment with L-DOPA/Carbidopa seems to be effective in improving motor outcomes but had no impact on cognitive impairment. Protocols for further treatment attempts, potentially also started before birth, are needed to provide conclusive results.
2026-05-02 | AKR1C3-driven restoration of tetrahydrobiopterin synthesis in cellular sepiapterin reductase deficiency.
Sepiapterin reductase (SPR) catalyzes several key steps in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases, and therefore for neurotransmitter production. Although several reductases-including carbonyl reductase 1 (CBR1), aldose reductase (AKR1B1), and AKR1C3-can substitute for SPR activity in vitro, their physiological significance remains unresolved. This study examines AKR1C3 as a component of an alternative BH4-generating pathway and evaluates its capacity to compensate for BH4 loss under diminished SPR activity. In vitro assays identified 2'-OXPH4 as the primary product of AKR1C3, redirecting pathway flux away from the canonical 1'-OXPH4 intermediate and the sepiapterin-salvage pathway. To assess the occurrence and efficiency of this route in cells, we generated SPR-knockout (SPR-KO) cell and evaluated pathway products in SPR-KO and wild-type (WT) backgrounds. In WT cells neither AKR1C3 nor SPR overexpression altered BH4 synthesis, indicating that neither enzyme is rate-limiting. In contrast, AKR1C3 increased BH4 levels in SPR-KO cells, while inhibiting sepiapterin production, revealing that AKR1C3 becomes functionally engaged only when SPR activity is decreased. Based on relative enzyme abundance, AKR1C3 and SPR exhibited comparable catalytic efficiency in this context. Importantly, AKR1C3-mediated BH4 production was sufficient to sustain tyrosine hydroxylase (TH) activity in SPR-KO cells, as demonstrated by L-DOPA formation. These findings establish AKR1C3-driven 2'-OXPH4 synthesis as a bona fide, inducible pathway capable of maintaining BH4 levels when SPR activity is limiting. This alternative path provides a compelling therapeutic target and introduces a new diagnostic consideration for patients with diminished SPR activity.
2025-02-04 | Unclear symptoms, early diagnosis and perfect outcome: a case diagnosed as sepiapterin reductase deficiency hidden behind vitamin B12 deficiency.
Sepiapterin reductase deficiency (SRD) is a rare dopa-sensitive neurotransmitter disorder caused by autosomal recessive mutations in the sepiapterin reductase gene. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia are highly suggestive in some patients. However, in other patients, the clinical picture may be nonspecific and remain under-recognized and misdiagnosed as cerebral palsy. We present a nine-month-old boy who initially presented with hypotonia and developmental delay, diagnosed as vitamin B12 deficiency. Upon he did not respond to vitamin replacement treatment, he was diagnosed with SRD by whole-exome sequencing (WES). The boy improved dramatically under treatment with L-dopa, 5-hydroxytryptophan and BH4. We aim to emphasize that SRD can present with nonspecific symptoms, leading to a diagnostic delay for this rare but treatable disease. Moreover, our case is the first to demonstrate the clinical benefit of BH4 add-on treatment. Early intervention is crucial for good outcome and neurodevelopment.
2024-09-12 | Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency.
sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child's needs, as the splitting of the tablet into smaller portions or its dilution in water. It's essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients. we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD. we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance. in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.
2024-03-27 | Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142 : A Case Report and Review of the UPD2 Literature.
We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR , and a variant of uncertain significance in ZNF142 . Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.
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