The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index; none of the 5 sources its claims cite is checked for support yet.
Peroxisomal D-bifunctional protein deficiency
Open accessAbstract
OBJECTIVE: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic. METHODS: The patients' initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively. RESULTS: Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP's enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced. CONCLUSION: Exome sequencing provides a powerful and elegant tool in the specific diagnosis of "mild" or "atypical" neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.
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Written from the paper’s full text.
TL;DR
Whole-exome sequencing in 3 adult siblings with juvenile-onset cerebellar atrophy, ataxia, cognitive decline, hearing loss, hypogonadism, and demyelinating neuropathy identified compound heterozygous *HSD17B4* mutations causing peroxisomal D-bifunctional protein (DBP) deficiency. Routine peroxisomal blood tests were normal, but DBP enoyl-CoA hydratase activity was markedly reduced, supporting *HSD17B4* molecular testing as a first-line investigation in compatible patients.
Key findings
- WES identified compound heterozygous *HSD17B4* mutations in all 3 affected siblings (2 women, 1 man); both mutations alter a conserved residue within the active site of DBP’s enoyl-CoA hydratase domain.
- Routine peroxisomal screening was normal: phytanic acid was 1.6, 2.3, and 0.8 mmol/L (reference 0–10.0), and very long-chain fatty acids were normal; however, DBP enoyl-CoA hydratase activity was markedly reduced at 33, 32, and 32 pmol/min/mg protein (reference 115–600).
- The phenotype included sensorineural hearing loss in middle childhood, ataxia and progressive cognitive decline from adolescence, marked cerebellar atrophy, demyelinating sensorimotor neuropathy, hypogonadism, and variable white matter lesions; the authors state this increases reported juvenile-onset DBP deficiency to 7 individuals and these are the oldest reported patients to date.
- Patient 2 had left-sided weakness, abnormal eye movements, gadolinium-enhancing infra- and supratentorial white-matter lesions including Dawson fingers, CSF oligoclonal bands, and response to pulse steroids/immunosuppression.
Methods
- Clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies in 3 adult siblings of nonconsanguineous Italian background.
- Whole-exome sequencing of all 3 probands used Agilent SureSelect Human All Exon 50 Mb capture and Illumina Hi-Seq 2000 100-bp paired-end sequencing; variants were annotated and filtered against dbSNP, 1000 Genomes, the NHLBI Exome Variant Server, and 130 local control exomes, then confirmed by Sanger sequencing.
- Peroxisomal investigations in blood and cultured fibroblasts included very long-chain fatty acids, phytanic acid, bile acids, peroxisomal substrate oxidation, and DBP enoyl-CoA hydratase activity, with DBP stability and activity assessed by immunoblot and enzymologic methods per the abstract.
Limitations
- Stated: no proven treatment exists for the underlying biochemical defect; reported patients are too few to permit clinical trials; phytanic acid concentrations in CSF and brain tissue are unknown; whether CSF oligoclonal bands represent coincidence or an autoimmune component is unclear.
- Evident from the text: findings rest on only 3 affected siblings from a single family, limiting generalizability; the study reports clinical and biochemical characterization plus mutation identification, but no functional rescue or treatment trial.
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12 Own result · 4 Sources not found · 2 Own interpretation · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Oligoclonal bands were present in CSF”
- Also stated in: § Mutation identification. · plain
“The presence of CSF oligoclonal bands in patient 2 is interesting”
§ Three adults diagnosed by whole-exome sequencing > Clinical description.
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Mutation identification. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Peroxisome morphology (anti-catalase immunofluorescence) | Normal | Normal | Normal | Normal”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal.”
- Also stated in: § Mutation identification. · plain
“Although our probands do not demonstrate phytanic acid accumulation in peripheral blood, concentrations in other tissues (e.g., CSF and brain tissue) are unknown.”
§ Three adults diagnosed by whole-exome sequencing > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Mutation identification. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both identified mutations alter a conserved residue within the active site of DBP's enoyl-CoA hydratase domain.”
- Also stated in: § Mutation identification. · plain
“Both of these mutations alter a highly conserved residue within the active site of DBP's enoyl-CoA hydratase domain (figure e-1 on the Neurology ® Web site at Neurology.org).”
§ Three adults diagnosed by whole-exome sequencing > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Mutation identification. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cranial MRI revealed marked cerebellar atrophy (figure 1)”
§ Three adults diagnosed by whole-exome sequencing > Clinical description.
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“Before this study, the patients underwent a panoply of diagnostic and laboratory investigations, none of which revealed a specific diagnosis.”
§ Three adults diagnosed by whole-exome sequencing > Clinical description.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“White matter lesions, a variable feature in our patients, are a known sequela of classic DBP deficiency”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
boostedn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our study participants are the oldest reported patients to date.”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DBP enzymatic activity was markedly reduced.”
§ Three adults diagnosed by whole-exome sequencing > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands.”
- Also stated in: § Mutation identification. · plain
“revealing the presence of 2 rare, nonsynonymous coding variants in HSD17B4 in all 3 affected individuals.”
§ Three adults diagnosed by whole-exome sequencing > Abstract
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Mutation identification. · plain
- It may state two separate claims as one. 3
- Probably not a substantial claim. 3
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this was accompanied by a progressive peripheral neuropathy, with diminished deep tendon reflexes, reduced vibration sensation, and a demyelinating motor polyneuropathy on nerve conduction testing.”
§ Three adults diagnosed by whole-exome sequencing > Clinical description.
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes”
§ Three adults diagnosed by whole-exome sequencing > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“periventricular cerebral demyelination and callosal thinning reported to occur in 17% and 55% of cases, respectively.2”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
What the sources say
- Not matchedcites [2]
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plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“the recognized prevalence of this disorder is likely to increase as exome sequencing enters the clinical mainstream.”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the recent report of severe, chronic cerebral inflammation in knockout mice lacking DBP. 10”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
What the sources say
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The difficulty in clinically recognizing this condition stems from (1) its extreme rarity, (2) its poor resemblance to the classic neonatal form, and (3) the presence of many of its key findings in other, relatively common, conditions.”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
All reported diagnoses of juvenile DBP deficiency to date have been accomplished by whole-exome sequencing, rather than by conventional clinical means.
“All reported diagnoses of juvenile DBP deficiency to date have been accomplished by whole-exome sequencing, rather than by conventional clinical means.”
The paper relies on this without support.
The pretest probability for each of the disorders in the differential diagnosis is low.
“Given the low pretest probability for each of these disorders”
The paper relies on this without support.
White matter disease has not previously been reported in later (juvenile)-onset DBP deficiency patients.
“As far as we are aware, white matter disease has not previously been reported in later (juvenile)-onset patients.”
The paper relies on this without support.
No proven treatments exist to address the underlying biochemical defect in DBP deficiency.
“No proven treatments exist to address the underlying biochemical defect in this disorder”
Claims other papers make about this one
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In some cases, other peroxisomal disorders, such as Zellweger spectrum disorder [31], acyl-CoA oxidase deficiency [32], and D-bifunctional protein deficiencies [33], have been reported to present with abnormalities that show in an MRI and that resemble X-linked ALD, particularly in patients with late-onset symptoms [34].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [33]
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Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Three adults diagnosed by whole-exome sequencing > Abstract
“the absence of detectable biochemical abnormalities in blood”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
“| | | Total bile acids (mmol/L) | | | [15.5 | [12.1 | [11.7 | ,6.7 | |”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Three adults diagnosed by whole-exome sequencing > Abstract
“a demyelinating sensorimotor neuropathy”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
“| Neuropathy, type | Demyelinating, | Demyelinating, | Demyelinating, | Demyelinating, | Axonal, | Demyelinating, | Demyelinating, | | | motor | motor | motor | sensorimotor | sensorimotor | sensorimotor | sensorimotor |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Three adults diagnosed by whole-exome sequencing > Clinical description.
“this was accompanied by a progressive peripheral neuropathy, with diminished deep tendon reflexes, reduced vibration sensation, and a demyelinating motor polyneuropathy on nerve conduction testing.”
§ Three adults diagnosed by whole-exome sequencing > Mutation identification.
“| Deep tendon | Absent LE; reduced | Increased LE; | Reduced LE; absent/ | Present | Present | Absent | NR | | reflexes | UE | normal UE | reduced UE | | | | |”
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“The retinopathy hallmarks consist of abnormal retinal pigmentation upon fundoscopic evaluation, with or without decreased ERG responses and visual acuity, and can also occur in milder cases (Ferdinandusse et al., 2006; McMillan et al., 2012; Lines et al., 2014; Amor et al., 2016).”
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“1, encoding an enzyme of 17β-hydroxysteroid dehydrogenase type 4 [10].”
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Movement Disorders Associated with Hypogonadism
González-Latapí, P., Sousa, M., & Lang, A. E. (2021) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.13308 · Cited by 17
“This is important to highlight since these are routinely considered valuable screening tests for types I, II and III DBP.43 The presence of hypogonadotropic hypogonadism and anosmia characterize Kallmann syndrome.44 Kallmann syndrome can also present with central nervous system symptoms including sensorineural deafnes…”
BackgroundSelf-citationDisorders of fatty acid homeostasis
Vaz, F. M., Ferdinandusse, S., Salomons, G. S., & Wanders, R. J. A. (2024) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12734 · Cited by 16
Self-citationClinical and Neuroimaging Spectrum of Peroxisomal Disorders
Tan, A. P., Gonçalves, F. G., Almehdar, A., & Soares, B. P. (2018) · Topics in Magnetic Resonance Imaging · doi:10.1097/rmr.0000000000000172 · Cited by 16
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Application of machine learning algorithms for the differential diagnosis of peroxisomal disorders
Subhashini, P., Krishna, S. J., Rani, G. U., Chander, N. S., Reddy, G. M., & Naushad, S. M. (2018) · The Journal of Biochemistry · doi:10.1093/jb/mvy085 · Cited by 13
Wang, T., Zhang, S., Pei, T., Yu, Z., & Liu, J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00982 · Cited by 14
Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia
Matsuda, Y., Morino, H., Miyamoto, R., et al. (2020) · Neurology Genetics · doi:10.1212/nxg.0000000000000396 · Cited by 12
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Peroxisomal Disorders and Retinal Degeneration
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Unusual Clinical Course and Imaging of D-Bifunctional Protein Deficiency, a Rare Leukodystrophy
Farkas, A. B., Al‐Ramadhani, R., McDonald, K. S., et al. (2018) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2018.09.001 · Cited by 8
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“Experts recommend WES and WGS as standard methods in situations where diagnosing rare diseases is difficult [14,24–26], particularly in areas with fewer specialized centers and specialists.”
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Peroxisomal Disorders in Children
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Nonneoplastic Diseases of the Testis
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Self-citationHSD17B4 mutation: an unusual cause of cerebellar ataxia
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Will New Genetic Techniques Like Exome Sequencing Obviate the Need for Clinical Expertise? No
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Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1
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“In some cases, other peroxisomal disorders, such as Zellweger spectrum disorder [31], acyl-CoA oxidase deficiency [32], and D-bifunctional protein deficiencies [33], have been reported to present with abnormalities that show in an MRI and that resemble X-linked ALD, particularly in patients with late-onset symptoms [3…”
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Peroxisomal disorder characterized with severe cerebral dysgenesis and hypotonia
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Peroxisome Assembly, Degradation, and Disease
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Self-citationPeroxisome Assembly, Degradation, and Disease
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Metadata
- Authors
- Lines, M. A., Jobling, R., Brady, L., Marshall, C. R., Scherer, S. W., Rodriguez, A. R., Lee, L., Lang, A. E., Mestre, T. A., Wanders, R. J. A., Ferdinandusse, S., Tarnopolsky, M. A., & On behalf of the Canadian Pediatric Genetic Disorders Sequencing Consortium (FORGE Canada)
- Affiliations
- Sunnybrook Health Science Centre (CA)
- ORCID
- Venue
- Neurology
- Published
- 2014-03-18
- Volume
- 82
- Issue
- 11
- Pages
- 963-968
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3963001
- OpenAlex
- W2069769433
- Cited by
- 70
- References
- 10
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 3 · 2018: 8 · 2017: 5 · 2016: 11 · 2015: 10
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- HSD17B4, compound heterozygosity, enoyl-CoA hydratase, peroxisomal disorders, cerebellar atrophy, ataxia, intellectual decline, hearing loss, hypogonadism, white matter changes, exome sequencing, genetic diagnosis, neurometabolic disorders
- MeSH terms
- Adult, Cells, Cultured, DNA Mutational Analysis, Fatty Acids, Female, Fibroblasts, Humans, Male, Protein Deficiency, Siblings, Exome, Peroxisomal Multifunctional Protein-2
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