SPR gene

Also known as: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency; Dopa-Responsive Hypersomnia, DYT-SPR, SPR deficiency

– OMIM#612716 https://omim.org/entry/612716

1. The Disease:

The phenotypic spectrum of sepiapterin reductase deficiency (SRD), which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely understood.

2. The symptoms:

Clinical features in many affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit. Lack of early signs or symptoms does not exclude the diagnosis.

Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioural abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, and drowsiness).

Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia; other features develop over time.

3. Actions to take in case of early diagnosis:  

Babies with a positive genetic test (having biallelic pathogenic variants in the SPR gene) should be referred immediately to a paediatric neurologist for clinical evaluation.

Biochemical correlation is recommended with CSF dosage of neurotransmitters and pterins. It is expected to see low levels of 5-hydroxyindoleacetic (5-HIAA) and homovanillic acid (HVA), and elevated total biopterin and dihydrobiopterin (BH2).

SRD is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.

L-dopa in combination with carbidopa (or another peripheral decarboxylase inhibitor) is the main therapy used to correct CNS dopamine deficiency.

Treatment should be initiated as early as possible to avoid irreversible neurological damage.

The dosage of L-dopa can range from 0.1 to 16 mg/kg/day. Transient dyskinesias frequently occur initially because of treatment but are usually resolved by decreasing the dosage. In patients with insufficient improvement of symptoms under L-dopa therapy, 5-hydroxytrytophan (5-HTP) at a dosage of 0.14 to 6 mg/kg/day should be given with carbidopa (to reduce side effects), since combination therapy may result in further improvements of motor and sleep symptoms.

These medications most consistently correct motor abnormalities; however, in some individuals cognitive manifestations remain more refractory.

Agents to avoid: although adverse events with specific agents have not been reported in patients with SRD, the following should be avoided on a theoretic basis: sulfa drugs, methotrexate, nitrous oxide, neuroleptics, and other dopamine antagonists (e.g., metoclopramide).

Genetic counselling should be offered to at-risk family members.

4. For more information:

Orphanet: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=10965&Disease_Disease_Search_diseaseGroup=SEPIAPTERIN-REDUCTASE-DEFICIENCY&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Dopa-responsive-dystonia-due-to-sepiapterin-reductase-deficiency&title=Dopa-responsive%20dystonia%20due%20to%20sepiapterin%20reductase%20deficiency&search=Disease_Search_Simple

Biblio: https://www.ncbi.nlm.nih.gov/books/NBK304122/