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Dihydropteridine reductase deficiency
This condition can lead to a range of neurological problems due to insufficient levels of neurotransmitters like dopamine and serotonin. It typically presents in infancy or early childhood and requires specialised medical management.
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Overview
Dihydropteridine reductase (DHPR) deficiency is a rare genetic condition that affects how the body processes a substance called tetrahydrobiopterin (BH4). BH4 is crucial for several enzymatic reactions, including the production of neurotransmitters that are vital for brain function, such as dopamine and serotonin [PMID:33671168]. When DHPR is deficient, the regeneration of BH4 is impaired, leading to a build-up of an abnormal substance called dihydrobiopterin and a shortage of BH4. This metabolic imbalance can significantly impact neurological development and function.
Symptoms & clinical features
The symptoms of DHPR deficiency can vary, but typically include developmental delay, learning difficulties, and problems with movement control, such as dystonia (involuntary muscle contractions) or hypotonia (low muscle tone). Individuals may also experience seizures, irritability, and difficulties with feeding. Some people might have microcephaly, where the head circumference is smaller than expected. Without appropriate treatment, these neurological symptoms can become more severe [PMID:17286377].
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Affected organs
The primary organ affected by DHPR deficiency is the brain. The lack of proper neurotransmitter production directly interferes with normal brain development and function, leading to the wide range of neurological symptoms observed. Other body systems are generally not directly affected in the same way, though the systemic metabolic imbalance can have broader implications for overall health.
Risks & severity
Dihydropteridine reductase deficiency is a rare condition, though its exact prevalence in the UK is not well established. The severity of symptoms can differ among individuals, but if left untreated, the condition can lead to significant and progressive neurological impairment. Early diagnosis and intervention are important for potentially improving long-term outcomes, though some neurological challenges may persist [PMID:33671168]. Symptoms often emerge in infancy or early childhood, though presentation can sometimes be later or more subtle.
Genetic causes
DHPR deficiency is caused by pathogenic variants in the QDPR gene. This gene provides instructions for making the dihydropteridine reductase enzyme. This enzyme plays a critical role in 'recycling' BH4, converting dihydrobiopterin back into tetrahydrobiopterin (BH4). BH4 is a co-factor, which means it helps other enzymes function correctly, particularly those involved in producing neurotransmitters like dopamine, serotonin, and noradrenaline. When a variant in the QDPR gene prevents the enzyme from working properly, BH4 is not regenerated efficiently, leading to a shortage of these crucial neurotransmitters in the brain [PMID:17286377].
- QDPR quinoid dihydropteridine reductaseThe QDPR gene provides instructions for making an enzyme crucial for recycling tetrahydrobiopterin (BH4), a molecule essential for processing amino acids and producing neurotransmitters.
Inheritance pattern
DHPR deficiency is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the pathogenic variant - one from each parent - to develop the condition. People who have only one copy of the pathogenic variant are called carriers; they do not typically show symptoms themselves but can pass the variant on to their children. If both parents are carriers, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two copies of the variant and be affected by DHPR deficiency.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of DHPR deficiency is often suspected based on clinical symptoms and abnormal levels of pterins (substances related to BH4 metabolism) in urine or cerebrospinal fluid (CSF). Confirmation of the diagnosis typically involves genetic testing of the QDPR gene, which can identify the specific pathogenic variants causing the condition. In the UK, genetic testing for inherited metabolic disorders like DHPR deficiency may be requested by a paediatrician or clinical geneticist and is accessible through the NHS Genomic Medicine Service (GMS) pathways. Relevant testing may fall under an NHS Genomic Test Directory R-code, such as R86 (Paediatric neurological disorders with a likely genetic cause).
Management & lifestyle
Management of DHPR deficiency focuses on replacing the deficient neurotransmitters and supplementing with BH4. Treatment typically involves a combination of levodopa (a precursor to dopamine) and 5-hydroxytryptophan (a precursor to serotonin), along with folinic acid and potentially BH4 supplementation. The specific treatment plan will be individualised by a specialist metabolic or neurological paediatrician. Regular monitoring of developmental progress, neurological status, and blood/CSF neurotransmitter levels is important to adjust treatments as needed [PMID:33671168]. Long-term follow-up with a specialist team is crucial for optimising care and managing any emerging symptoms.
UK care pathway
In the UK, individuals suspected of having DHPR deficiency or other rare inherited conditions are often referred to specialist centres, typically through the NHS Genomic Medicine Service. A clinical geneticist or a specialist paediatrician in metabolic disorders would usually coordinate investigations, including genetic testing through the NHS Genomic Test Directory. Genetic counsellors are available to provide support and information to individuals and families regarding genetic test results, inheritance patterns, and reproductive options.
Frequently asked questions
What is tetrahydrobiopterin (BH4) and why is it important?
BH4 is a natural substance in the body that acts as a co-factor, meaning it helps certain enzymes do their job. It is particularly important for producing neurotransmitters, which are chemicals that send signals in the brain and nervous system, affecting mood, movement, and development.
How is DHPR deficiency inherited?
DHPR deficiency is inherited in an autosomal recessive manner. This means a child must inherit two altered copies of the QDPR gene, one from each parent, to develop the condition. Parents who carry one altered gene copy are usually healthy themselves.
Can DHPR deficiency be treated?
Yes, while there is no cure, DHPR deficiency can be managed with treatments aimed at restoring neurotransmitter balance. This typically involves taking medications such as levodopa and 5-hydroxytryptophan, along with folinic acid, and sometimes BH4 supplements, under specialist medical supervision.
What kind of doctors treat DHPR deficiency?
Individuals with DHPR deficiency are usually cared for by a multidisciplinary team. This team often includes paediatricians, specialist metabolic consultants, neurologists, geneticists, and genetic counsellors.
Will affected individuals have a normal life expectancy?
With early diagnosis and consistent, appropriate treatment, the outlook for individuals with DHPR deficiency has improved significantly. However, the condition can still have a lifelong impact, and ongoing neurological challenges may be present. Regular medical follow-up is essential.
References
- Adam MP, Bick S, Mirzaa GM. Dihydropteridine Reductase Deficiency. 1993. PMID: 42228786
- Opladen T, López-Laso E, Cortès-Saladelafont E. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH(4)) deficiencies. Orphanet journal of rare diseases. 2020. PMID: 32456656
- Pearl PL. Monoamine neurotransmitter deficiencies. Handbook of clinical neurology. 2013. PMID: 23622404
- Ribeiro M, Rebelo M, Pereira A. Dihydropteridine Reductase Deficiency - A Rare and Potentially Treatable Cause Mimicking Cerebral Palsy. Endocrine, metabolic & immune disorders drug targets. 2023. PMID: 37946348
- Coughlin CR 2nd, Hyland K, Randall R. Dihydropteridine reductase deficiency and treatment with tetrahydrobiopterin: a case report. JIMD reports. 2013. PMID: 23430801
- Ramaekers VT, Blau N. Cerebral folate deficiency. Developmental medicine and child neurology. 2004. PMID: 15581159
- Ponzone A, Spada M, Ferraris S. Dihydropteridine reductase deficiency in man: from biology to treatment. Medicinal research reviews. 2004. PMID: 14705166
- Smooker PM, Cotton RG. Molecular basis of dihydropteridine reductase deficiency. Human mutation. 1995. PMID: 7627180