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D-bifunctional protein deficiency
This severe neurological condition results from the body's inability to properly break down and process certain fats. It typically presents in infancy, causing significant developmental delay and other health problems.
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Overview
D-bifunctional protein deficiency is a very rare inherited metabolic disorder. It is categorised as a peroxisomal disorder, meaning it affects the function of peroxisomes - small compartments within cells crucial for various metabolic processes, particularly the breakdown of very long-chain fatty acids (VLCFAs) [PMID:33678082]. When these processes are disrupted, harmful substances can build up in the body, which can damage cells and tissues, especially in the brain and nervous system.
The condition typically manifests in early infancy or childhood, leading to severe neurological problems and developmental delays. It is distinct from other peroxisomal disorders, such as Zellweger syndrome spectrum, though there can be overlapping features. The severity and specific symptoms can vary, but generally, the prognosis is poor.
Symptoms & clinical features
The symptoms of D-bifunctional protein deficiency are primarily neurological and often severe. Infants may present with hypotonia, which is reduced muscle tone, making them appear 'floppy'. This can affect feeding and movement. Seizures are common and can be difficult to control. Developmental milestones, such as sitting, crawling, or talking, are often significantly delayed or not achieved [PMID:19936859].
Other features can include hearing and vision difficulties, such as sensorineural hearing loss and retinopathy (a problem with the light-sensitive tissue at the back of the eye). Facial features may also be distinctive in some affected individuals, but these are not always present or specific to the condition. Liver dysfunction can also occur in some cases.
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Affected organs
D-bifunctional protein deficiency primarily affects the brain and nervous system. The accumulation of very long-chain fatty acids and other unprocessed substances is particularly damaging to nerve cells, leading to profound neurological impairment and developmental issues. The liver can also be affected, potentially leading to problems with its normal functions.
Other organ systems that may be impacted include the eyes, leading to retinopathy, and the ears, causing hearing loss. Skeletal abnormalities may also be observed in some individuals. The widespread nature of metabolic disruption means that multiple bodily systems can be indirectly affected.
Risks & severity
D-bifunctional protein deficiency is considered a severe disorder, typically associated with significant neurological impairment from early infancy. The condition often progresses, with symptoms worsening over time. Most affected individuals do not survive beyond early childhood due to the severe neurological complications and related health issues.
Exact prevalence figures for D-bifunctional protein deficiency are not well established, but it is considered a very rare condition. The age of onset is typically in the neonatal period or early infancy, and the prognosis is generally poor, with most affected children having a short life expectancy.
Genetic causes
D-bifunctional protein deficiency is caused by pathogenic variants, also known as mutations, in the HSD17B4 gene. This gene provides instructions for making an enzyme called D-bifunctional protein, which plays a critical role in the peroxisomes [PMID:19936859]. Specifically, this enzyme is involved in the beta-oxidation pathway, which is essential for breaking down very long-chain fatty acids into smaller molecules that the body can use or excrete.
When the HSD17B4 gene has pathogenic variants, the D-bifunctional protein either isn't produced correctly or doesn't function as it should. This failure leads to the accumulation of very long-chain fatty acids and their derivatives within cells, particularly in the brain and liver. This build-up is toxic to cells and causes the progressive damage seen in this condition.
- HSD17B4 hydroxysteroid 17-beta dehydrogenase 4The HSD17B4 gene encodes the D-bifunctional protein, a peroxisomal enzyme crucial for the breakdown of certain fatty acids within cells.
Inheritance pattern
D-bifunctional protein deficiency is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the HSD17B4 gene - one from each parent - to develop the condition. If a person inherits only one altered copy and one normal copy, they are considered a 'carrier'. Carriers typically do not show symptoms of the disorder.
When both parents are carriers of a pathogenic variant in the HSD17B4 gene, there is a 25% chance with each pregnancy that their child will inherit two altered copies and be affected by the condition. There is also a 50% chance that the child will be a carrier, like the parents, and a 25% chance that the child will inherit two normal copies of the gene and not be a carrier or affected.
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 D-bifunctional protein deficiency typically begins with careful clinical examination and assessment of symptoms, especially in infants presenting with severe hypotonia, seizures, and developmental delay. Initial biochemical testing often includes measuring levels of very long-chain fatty acids (VLCFAs) in the blood plasma, which are usually elevated in affected individuals [PMID:19936859].
Confirmation of the diagnosis requires genetic testing to identify pathogenic variants in the HSD17B4 gene. This can involve gene sequencing panels or whole exome sequencing. In the UK, genetic testing for suspected peroxisomal disorders, including D-bifunctional protein deficiency, is available through the NHS Genomic Medicine Service, often initiated following referral from a paediatrician or neurologist to a clinical genetics service. This testing would be guided by relevant R-codes, such as those related to very long-chain fatty acid oxidation disorders.
Management & lifestyle
Currently, there is no cure for D-bifunctional protein deficiency, and management focuses on supportive care to address the symptoms and improve quality of life. This includes managing seizures with anti-epileptic medications, providing nutritional support, and physical and occupational therapy to help with muscle tone and developmental challenges. Regular monitoring by a multidisciplinary team, including neurologists, paediatricians, and dietitians, is essential.
Some dietary interventions, such as restricting very long-chain fatty acids and supplementing with medium-chain triglycerides, have been explored, but their effectiveness in significantly altering the disease course is limited. Families in the UK requiring support and genetic counselling can be referred to their local NHS Clinical Genetics service, who can offer information, recurrence risk discussions, and connect them with relevant support organisations.
UK care pathway
In the UK, suspected cases of D-bifunctional protein deficiency typically enter the NHS Genomic Medicine Service pathway. Referral to a clinical genetics service is common, often following assessment by a paediatrician or neurologist. Genetic counsellors play a key role in explaining the genetic diagnosis, inheritance patterns, and implications for family members. Diagnostic genomic testing, guided by specific R-codes for peroxisomal disorders, is crucial for confirming the diagnosis and informing ongoing care decisions.
Frequently asked questions
What is a peroxisome?
Peroxisomes are tiny compartments found inside nearly all human cells. They play a vital role in several metabolic processes, including breaking down certain types of fats and detoxifying harmful substances, crucial for the normal function of the brain and other organs.
How rare is D-bifunctional protein deficiency?
D-bifunctional protein deficiency is considered a very rare condition. Exact figures aren't widely known, but it's one of the less common genetic disorders affecting metabolic pathways.
Can D-bifunctional protein deficiency be treated?
Currently, there is no cure for D-bifunctional protein deficiency. Treatment focuses on managing the symptoms to improve quality of life, which includes therapies for seizures, nutritional support, and developmental support. Research into new treatments is ongoing.
If I am a carrier, what does that mean for my children?
If you are a carrier of a pathogenic HSD17B4 variant, it means you have one normal and one altered copy of the gene, and you typically won't have symptoms. For your child to be affected, they would need to inherit an altered copy from both parents. If your partner is also a carrier, there is a 25% chance with each pregnancy that your child will have the condition.
How is D-bifunctional protein deficiency diagnosed in the UK?
In the UK, diagnosis typically involves clinical assessment, blood tests to check specific fatty acid levels, and confirmed by genetic testing through the NHS Genomic Medicine Service. A referral from a specialist, such as a paediatrician, to a clinical genetics service is usually the route for this testing.
References
- Engelen M. Peroxisomal leukodystrophy. Handbook of clinical neurology. 2024. PMID: 39322376
- Ognean ML, Mutică IB, Vișa GA. D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature. International journal of molecular sciences. 2024. PMID: 38732138
- Ferdinandusse S, Denis S, Mooyer PA. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Annals of neurology. 2006. PMID: 16278854
- Ferdinandusse S, Ylianttila MS, Gloerich J. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. American journal of human genetics. 2006. PMID: 16385454
- Möller G, van Grunsven EG, Wanders RJ. Molecular basis of D-bifunctional protein deficiency. Molecular and cellular endocrinology. 2001. PMID: 11165012
- Nascimento J, Mota C, Lacerda L. D-bifunctional protein deficiency: a cause of neonatal onset seizures and hypotonia. Pediatric neurology. 2015. PMID: 25882080
- Werner KM, Cox AJ, Qian E. D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia. American journal of medical genetics. Part A. 2022. PMID: 34623748
- Berger J, Dorninger F, Forss-Petter S. Peroxisomes in brain development and function. Biochimica et biophysica acta. 2016. PMID: 26686055