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| {{context|date=October 2009}} | | {{Short description|A rare genetic disorder affecting peroxisomal function}} |
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| | name = D-bifunctional protein deficiency
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| | synonyms = 17β-hydroxysteroid dehydrogenase IV deficiency
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| '''D-Bifunctional protein deficiency''' is an [[autosome|autosomal]] [[Dominance (genetics)|recessive]] [[Peroxisome|peroxisomal]] [[Fatty-acid metabolism disorder|fatty acid oxidation disorder]]. [[Peroxisomal disorder]]s are usually caused by a combination of peroxisomal assembly defects or by deficiencies of specific peroxisomal [[enzyme]]s. The [[peroxisome]] is an organelle in the cell similar to the [[lysosome]] that functions to detoxify the cell. Peroxisomes contain many different enzymes, such as [[catalase]], and their main function is to neutralize free radicals and detoxify drugs. For this reason peroxisomes are ubiquitous in the liver and kidney. D-BP deficiency is the most severe peroxisomal disorder,<ref name="ref-5">{{cite journal | vauthors = Möller G, van Grunsven EG, Wanders RJ, Adamski J | title = Molecular basis of D-bifunctional protein deficiency | journal = Mol. Cell. Endocrinol. | volume = 171 | issue = 1-2 | pages = 61–70 | date = January 2001 | pmid = 11165012 | doi = 10.1016/s0303-7207(00)00388-9}}</ref> often resembling [[Zellweger syndrome]].<ref name="ref-2">{{cite journal | vauthors = Itoh M, Suzuki Y, Akaboshi S, Zhang Z, Miyabara S, Takashima S | title = Developmental and pathological expression of peroxisomal enzymes: their relationship of D-bifunctional protein deficiency and Zellweger syndrome | journal = Brain Res. | volume = 858 | issue = 1 | pages = 40–7 | date = March 2000 | pmid = 10700594 | doi = 10.1016/S0006-8993(99)02423-3 }}</ref> | | '''D-bifunctional protein deficiency''' is a rare [[genetic disorder]] that affects the normal functioning of [[peroxisomes]], which are essential cellular organelles involved in various metabolic pathways, including the breakdown of [[very long-chain fatty acids]] (VLCFAs) and the synthesis of [[plasmalogens]]. This condition is characterized by a deficiency in the D-bifunctional protein, which is crucial for the peroxisomal beta-oxidation of VLCFAs. |
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| Characteristics of the disorder include neonatal [[hypotonia]] and seizures, occurring mostly within the first month of life, as well as visual and hearing impairment.<ref name="ref-1">{{cite journal | vauthors = Buoni S, Zannolli R, Waterham H, Wanders R, Fois A | title = D-bifunctional protein deficiency associated with drug resistant infantile spasms | journal = Brain Dev. | volume = 29 | issue = 1 | pages = 51–4 | date = January 2007 | pmid = 16919904 | doi = 10.1016/j.braindev.2006.06.004 }}</ref> Other symptoms include severe craniofacial disfiguration, psychomotor delay, and neuronal migration defects. Most onsets of the disorder begin in the gestational weeks of development and most affected individuals die within the first two years of life.
| | ==Pathophysiology== |
| | D-bifunctional protein deficiency is caused by mutations in the [[HSD17B4]] gene, which encodes the D-bifunctional protein. This protein has two enzymatic activities: enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase, both of which are necessary for the beta-oxidation of VLCFAs within peroxisomes. The deficiency leads to the accumulation of VLCFAs and other toxic metabolites, resulting in cellular damage and the clinical manifestations of the disease. |
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| ==Classification== | | ==Clinical Features== |
| DBP deficiency can be divided into three types:<ref name="ref-6">{{cite journal | vauthors = Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T | title = Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis | journal = Am. J. Hum. Genet. | volume = 78 | issue = 1 | pages = 112–24 | date = January 2006 | pmid = 16385454 | pmc = 1380208 | doi = 10.1086/498880 }}</ref>
| | The clinical presentation of D-bifunctional protein deficiency is variable but often includes severe [[neurological symptoms]], such as [[hypotonia]], [[seizures]], and developmental delay. Other features may include [[hearing loss]], [[vision problems]], and [[liver dysfunction]]. The severity of symptoms can range from mild to severe, with some patients experiencing life-threatening complications in infancy. |
| * type I, characterized by a deficiency in both the hydratase and dehydrogenase units of D-BP
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| * type II, in which only the hydratase unit is non-functional
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| * type III, with only a deficiency in the dehydrogenase unit
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| Type I deficient patients showed a large structural modification to the D-BP as a whole. Most of these individuals showed either a deletion or an insertion resulting in a [[frameshift mutation]]. Type II and III patients showed small scale changes in the overall structure of D-BP[6]. Amino acid changes in the catalytic domains or those in contact with substrate or cofactors were the main cause of these variations of D-BP deficiency. Other amino acid changes were seen to alter the dimerization of the protein, leading to improper folding. Many mutations have been found in the gene coding for D-BP (''[[HSD17B4]]'') on the q arm two of [[Chromosome 5 (human)|chromosome five]] (5q23.1) in ''Homo sapiens'', most notably individuals homozygous for a [[missense mutation]] (616S).<ref name="ref-6" />
| | ==Diagnosis== |
| | Diagnosis of D-bifunctional protein deficiency typically involves a combination of clinical evaluation, biochemical testing, and genetic analysis. Biochemical tests may reveal elevated levels of VLCFAs in the blood, while genetic testing can identify mutations in the HSD17B4 gene. Additional tests, such as [[magnetic resonance imaging]] (MRI) of the brain, may be used to assess neurological involvement. |
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| == D-BP Protein == | | ==Management== |
| | There is currently no cure for D-bifunctional protein deficiency, and treatment is primarily supportive and symptomatic. Management strategies may include dietary modifications to reduce VLCFA intake, physical therapy to address motor deficits, and medications to control seizures. Early intervention and a multidisciplinary approach are essential to optimize patient outcomes. |
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| The D-bifunctional protein is composed of three enzymatic domains: the [[N-terminal]] short chain alcohol dehydrogenase reductase (SDR), central hydratase domain, and the [[C-terminal]] sterol carrier protein 2 (SDR).<ref name="ref-5" /> | | ==Prognosis== |
| | The prognosis for individuals with D-bifunctional protein deficiency varies depending on the severity of the condition. Severe forms of the disorder are often associated with significant neurological impairment and reduced life expectancy. However, milder forms may allow for a longer lifespan with appropriate management. |
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| The DBP protein (79[[kDa]]) also known as "multifunctional protein 2", "multifunctional enzyme 2", or "D-peroxisomal bifunctional"enzyme", catalyzes the second and third steps of peroxisomal β-oxidation of [[fatty acid]]s and their derivatives .
| | ==Related pages== |
| | * [[Peroxisomal disorders]] |
| | * [[Very long-chain fatty acids]] |
| | * [[HSD17B4 gene]] |
| | * [[Neurological disorders]] |
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| A non-functional D-BP protein results in the abnormal accumulation of long chain fatty acids and [[bile acid]] intermediates. The D-BP protein contains a peroxisomal targeting signal 1 (PTS1) unit at the C-terminus allowing for its transport into peroxisomes by the PTS1 receptor. Inside the peroxisomes, the D-BP protein is partially cleaved exclusively between the SDR and hydratase"domains.<ref name="ref-5" />
| | [[Category:Genetic disorders]] |
| | | [[Category:Metabolic disorders]] |
| DBP is a stereospecific enzyme; hydratase domain forms only (R)-hydroxy-acyl-CoA intermediates from trans-2-enoyl-CoAs.<ref name="ref-6" /> D-BP is expressed throughout the entire human body, with the highest [[mRNA]] levels in the liver and brain. The hydrogenase and hydratase units of DBP exist as [[Protein dimer|dimers]], necessary for correct folding and therefore function of the enzyme.
| | [[Category:Rare diseases]] |
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| == Genetic ==
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| The D-BP gene (''HSD17B4''), found on the long arm of chromosome 5, consists of 24 [[exons]] and 23 [[introns]] and is over 100kb in size. Exons 1-12 code for the SDR domain, 12-21 for the hydratase domain, and 21-24 for the SCP2 domain. [[Transcription (genetics)|Transcription]] is regulated at 400 basepairs upstream of the transcription start site.<ref name="ref-5" />
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| The missense mutation G16S is the most common mutation that leads to D-BP deficiency. In a 2006 study in which 110 patients were tested, 28 suffered from this frameshift mutation. The second most frequent mutation was the missense mutation N457Y which was seen in 13 of the 110 patients. Type I patients showed only deletions, insertions, and nonsense mutations were identified, most leading to shortened polypeptides. Most type II patients show missense mutations in D-BP hydratase unit as well as some in-frame deletions. Type III"individuals commonly show missense mutations in the coding region of the dehydrogenase domain.<ref name="ref-6" />
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| == Chemistry ==
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| Enzymatic activity of D-BP fails if the protein cannot effectively bind the cofactor [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], as shown in the G16S mutation. Glycine 16 forms a short loop and creates a hole for the adenine ring of NAD<sup>+</sup> to enter. Other amino acid side chains alter the shape of this loop due to steric hindrance, and prevent proper NAD<sup>+</sup> binding. Other mutations that exist are due to incorrect polypeptide folding. L405 (leucine located at residue 405) located in the substrate binding domain of the hydratase 2 unit, plays an important role in binding CoA ester moiety. One mutation seen in D-BP deficiency patients is caused by a leucine to proline substitution. This breaks the hydrophobic interactions necessary for proper substrate binding with CoA esters.<ref name="ref-6" />
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| == Diagnosis ==
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| The most common clinical observations of patients suffering from D-bifunctional protein deficiency include hypotonia, facial and skull [[dysmorphism]], neonatal seizures, and neuronal [[demyelination]].<ref name="ref-3">{{cite journal | vauthors = van Grunsven EG, Mooijer PA, Aubourg P, Wanders RJ | title = Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency | journal = Hum. Mol. Genet. | volume = 8 | issue = 8 | pages = 1509–16 | date = August 1999 | pmid = 10400999 | doi = 10.1093/hmg/8.8.1509 | doi-access = free }}</ref> High levels of branched fatty acids, such as pristinic acid, bile acid intermediates, and other D-BP substrates are seen to exist. Reduced pristinic acid β-oxidation is a common indicator of D-BP deficiency.<ref name="ref-5" /> D-BP can be distinguished from Zellweger Syndrome by normal [[plasmalogen]] synthesis. Recent studies in D-BP knockout mice show compensatory upregulation of other peroxisomal enzymes in absence of D-BP such as palmitoyl-CoA oxidase, peroxisomal thiolase, and branched chain acyl-CoA oxidase.<ref name="ref-5" />
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| == References ==
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| == External links ==
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| {{Medical resources
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| | DiseasesDB = 33358
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| | ICD10 = {{ICD10|E|80|3|e|80}}
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| | OMIM = 261515
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| {{Peroxisomal disorders}}
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| [[Category:Peroxisomal disorders]] | |
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A rare genetic disorder affecting peroxisomal function
D-bifunctional protein deficiency is a rare genetic disorder that affects the normal functioning of peroxisomes, which are essential cellular organelles involved in various metabolic pathways, including the breakdown of very long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens. This condition is characterized by a deficiency in the D-bifunctional protein, which is crucial for the peroxisomal beta-oxidation of VLCFAs.
Pathophysiology
D-bifunctional protein deficiency is caused by mutations in the HSD17B4 gene, which encodes the D-bifunctional protein. This protein has two enzymatic activities: enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase, both of which are necessary for the beta-oxidation of VLCFAs within peroxisomes. The deficiency leads to the accumulation of VLCFAs and other toxic metabolites, resulting in cellular damage and the clinical manifestations of the disease.
Clinical Features
The clinical presentation of D-bifunctional protein deficiency is variable but often includes severe neurological symptoms, such as hypotonia, seizures, and developmental delay. Other features may include hearing loss, vision problems, and liver dysfunction. The severity of symptoms can range from mild to severe, with some patients experiencing life-threatening complications in infancy.
Diagnosis
Diagnosis of D-bifunctional protein deficiency typically involves a combination of clinical evaluation, biochemical testing, and genetic analysis. Biochemical tests may reveal elevated levels of VLCFAs in the blood, while genetic testing can identify mutations in the HSD17B4 gene. Additional tests, such as magnetic resonance imaging (MRI) of the brain, may be used to assess neurological involvement.
Management
There is currently no cure for D-bifunctional protein deficiency, and treatment is primarily supportive and symptomatic. Management strategies may include dietary modifications to reduce VLCFA intake, physical therapy to address motor deficits, and medications to control seizures. Early intervention and a multidisciplinary approach are essential to optimize patient outcomes.
Prognosis
The prognosis for individuals with D-bifunctional protein deficiency varies depending on the severity of the condition. Severe forms of the disorder are often associated with significant neurological impairment and reduced life expectancy. However, milder forms may allow for a longer lifespan with appropriate management.
Related pages
