Sterol Carrier Protein 2 Deficiency

Mendelian MONDO:0013391 Pathograph 18 Show in embeddings browser Peroxisomal Disease Inborn Error of Metabolism Leukodystrophy

Sterol carrier protein 2 deficiency is an autosomal recessive single-enzyme peroxisomal beta-oxidation defect caused by biallelic SCP2 variants. The SCP2 locus is transcribed from two promoters and yields two distinct proteins - the 58 kDa peroxisomal thiolase SCPx and the small lipid-binding protein SCP2 - and the disease is a loss of the thiolase arm, which is why the older literature calls it SCPx deficiency. SCPx catalyses the final thiolytic step of the peroxisomal beta-oxidation spiral for 2-methyl-branched substrates, so losing it blocks the degradation of pristanic acid and the side-chain shortening of the C27 bile acid intermediates. The biochemical signature that follows is narrow and is what makes the disease findable: a marked rise in plasma pristanic acid with phytanic acid only mildly raised, normal plasma very-long-chain fatty acids, and abnormal bile alcohol glucuronides in urine. It is a beta-oxidation lesion alone, and not the two-sided picture of a peroxisome biogenesis disorder, in which substrate accumulation and ether-lipid deficiency occur together. Clinically the reported picture is a childhood- or adult-onset central nervous system disease with symmetrical thalamic and brainstem lesions on MRI. Beyond that shared imaging finding the three published patients differ from one another considerably - torticollis, head tremor, nystagmus, hyposmia and a motor neuropathy in the first; ataxia, gait disturbance, deafness and brain iron accumulation in the second; episodic infection-triggered psychosis and status epilepticus in the third - and with three patients there is no basis for calling any of these features typical. The evidence base is correspondingly thin and this entry is deliberately short. ClinGen's Peroxisomal Gene Curation Expert Panel scored the SCP2 gene-disease relationship as Moderate on 6 genetic and 4 experimental evidence points, and renamed the entity from the descriptive LKDMN phenotype label to SCP2 deficiency to leave room for the phenotype to expand. The mouse literature predates the human literature and is larger, and the widely used knockout ablates SCP2 and SCPx together, which is not the human lesion.

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3
Mappings
1
Inheritance
5
Pathophys.
18
Phenotypes
4
Gaps
18
Pathograph
1
Genes
3
Variants
3
Medical Actions
3
Models
11
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC ENDOCRINOLOGY METABOLISM
ICIMD (Inherited Metabolic Disorders)
peroxisomal fatty acid oxidation
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Mappings

MONDO
MONDO:0019233 disorder of peroxisomal beta oxidation Not Yet Curated
skos:broadMatch MONDO
One of the two parents MONDO asserts for MONDO:0013391, and the one that names the lesion. Recorded as broadMatch because it is a broader class covering the other single-enzyme beta-oxidation defects as well. ClinGen's Peroxisomal GCEP independently places SCP2 deficiency as a subclass of this same term.
MONDO:0019046 leukodystrophy Not Yet Curated
skos:broadMatch MONDO
The second parent MONDO asserts for MONDO:0013391. Recorded as broadMatch: it reflects the white matter imaging finding that gave the disease its original LKDMN name, and it is a much broader class. This entry builds its causal chain on the peroxisomal parent instead, because that is the parent that names the enzyme defect.
ICD-10-CM
ICD10CM:E71.548 Other peroxisomal disorders
skos:broadMatch dismech curation
ICD-10-CM has no code for SCP2 deficiency. E71.548 is the residual peroxisomal-disorder code and is the closest coded home for this lesion; it is a broader residual category rather than a cross-reference asserted by MONDO or Orphanet.
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic SCP2 variants. Two of the three reported patients were homozygous and one was a compound heterozygote; in the third patient the father and sisters were heterozygous carriers. Penetrance and expressivity are recorded as UNKNOWN: with three patients there is no unaffected biallelic carrier to argue from, and the three phenotypes are too dissimilar to characterise a range.
Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: UNKNOWN
Show evidence (3 references)
PMID:16685654 SUPPORT Human Clinical
"Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7)."
The homozygous biallelic genotype of the first reported patient.
PMID:35996156 SUPPORT BACKGROUND Human Clinical
"Previously, there have been two reports of SCPx deficiency, which resulted from a homozygous or compound heterozygous SCP2 mutation."
States the biallelic requirement across the two then-published patients. Quoted from the introduction of a paper whose own subject is a different, heterozygous case, so this sentence restates prior clinical reports rather than its own result.
PMID:37905191 SUPPORT Human Clinical
"Through whole-exome sequencing, we identified a homozygous splicing mutation in SCP2 (c.674 + 1G > C), and further RNA sequencing revealed exon 8 skipping in the mature transcripts of SCP2."
The homozygous biallelic genotype of the third reported patient.
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Discussions and Knowledge Gaps

4
By what route does the block in peroxisomal branched-chain beta-oxidation produce symmetrical thalamic and brainstem lesions?
KNOWLEDGE GAP OPEN scp2-imaging-lesion-mechanism-unknown
Attached to
pathophysiology#Symmetrical Thalamic, Brainstem and White Matter Lesions
The lesion is the one finding common to all three reported patients and nothing is known about how it arises. None of the published reports carries neuropathology, a measurement of branched-chain fatty acid concentration in brain tissue, spectroscopy, or a correlation between metabolite level and imaging burden - the third patient had the same lesion pattern with a pristanic acid only marginally above the reference range, which is the one observation bearing on the question and it argues against a simple dose-response. The edge this entry draws from the metabolic block to the lesion is therefore a disease-level attribution and not a mechanism. Why the thalamus and pons specifically is also unexplained in any of the reports.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
The dissociation that makes the question live: the same imaging lesion at markedly different metabolite concentrations.
Is the Scp2 knockout mouse a valid model of human SCP2 deficiency, given that it deletes both gene products and accumulates phytanic rather than pristanic acid?
HUMAN MODEL MISMATCH OPEN scp2-mouse-accumulates-the-wrong-metabolite
Attached to
pathophysiology#Pristanic Acid Accumulation animal_models#Mouse
The mouse literature is older and far larger than the human literature, so it is the default source of mechanism for this disease - and it diverges from the human lesion in two ways at once. First, the widely used knockout ablates the whole Scp2 locus, removing both the thiolase and the small lipid-carrier protein, whereas the human disease-causing variants lie in the SCPx-coding region and leave SCP2 transcribed from its own promoter; the SCP-x-null mouse showed directly that the two can be separated. Second, the combined knockout's defining biochemical abnormality is a ten-fold phytanic acid accumulation, while the human disease is defined by a marked pristanic acid rise with phytanic acid only mildly raised - the opposite emphasis. No brain phenotype resembling the human thalamic and pontine lesions is reported in any of the mouse papers cited here. What follows practically: a mouse finding should not be carried into this entry as a human mechanism without saying which model it came from, and the SCP-x-null model is the one that matches the human genotype.
Proposed experiments
Brain phenotyping of the SCP-x-null mouse
scp2-scpx-null-brain-phenotyping
Characterise brain imaging and neuropathology in the SCPx-selective knockout, with and without a phytol load, and measure pristanic and phytanic acid in brain tissue. This is the model whose genotype matches the human disease, and no brain phenotype has been reported for it.
Would support
pathophysiology#Symmetrical Thalamic, Brainstem and White Matter Lesions
Supporting outcome
  • Symmetrical thalamic or brainstem lesions, or regional white matter pathology, appearing in SCPx-null but not wild-type animals and tracking with brain branched-chain fatty acid content.
Refuting outcome
  • No brain lesion and no regional branched-chain fatty acid accumulation in SCPx-null animals even under sustained phytol loading, which would argue the human lesion is not a direct consequence of the thiolase block.
Show evidence (2 references)
PMID:9553048 SUPPORT Model Organism
"The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice."
The model's accumulating species, which is not the human one.
PMID:17068117 SUPPORT Model Organism
"It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x)"
Demonstrates that the two gene products are separable, which is what makes the combined knockout the wrong genotype for this disease.
Does a single heterozygous SCP2 missense variant cause SCPx deficiency, as the fourth reported case claims?
OPEN QUESTION OPEN scp2-heterozygous-case-disputed
Attached to
genetic#SCP2
A fourth patient has been reported, with progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting and azoospermia, carrying a single heterozygous SCP2 missense variant that the report itself classified as of uncertain significance. The paper's supporting evidence is cellular - reduced SCPx protein and transcript in patient fibroblasts, fewer peroxisomes, and altered lipid and transcript profiles - and it makes a real claim, since a dominant-negative or haploinsufficiency mechanism is not excluded a priori. But every other reported patient is biallelic, a subsequent review states that whether this patient has SCPx deficiency remains to be established, and ClinGen's expert panel scored only two individuals when it curated the gene. This entry therefore records the disease as autosomal recessive and does not curate that patient's features as phenotypes of it; the cardiac and muscle findings in particular appear nowhere else in this disease.
Show evidence (3 references)
PMID:35996156 SUPPORT Human Clinical
"We report herein the first patient with a heterozygous SCP2 mutation leading to SCPx deficiency."
The claim itself, in the words of the report making it.
PMID:35996156 SUPPORT Human Clinical
"Clinical presentations of the patient included progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia."
The features attributed to that patient, none of which except azoospermia is reported in a biallelic patient.
PMID:38693715 REFUTE REVIEW SYNTHESIS Human Clinical
"A third patient with presumed SCPx deficiency was recently reported by Galano et al., but it remains to be established whether this patient is truly affected by SCPx deficiency."
A review of the peroxisomal fatty acid disorders declining to accept the case, which is why this entry does not curate it.
What is the phenotype of SCP2 deficiency, given that the three reported patients share almost nothing except an MRI pattern?
KNOWLEDGE GAP OPEN scp2-phenotype-expansion
Attached to
phenotypes#
Torticollis with a motor neuropathy, an adult-onset ataxia with deafness and brain iron accumulation, and infection-triggered episodic psychosis with status epilepticus are three different clinical pictures. Only stutter, tremor and the imaging lesion recur. This entry consequently records no frequency on any phenotype and calls none of them typical, because with an n of three every feature is either universal or unique depending on how it is counted. ClinGen's expert panel renamed the disease from the descriptive LKDMN label to SCP2 deficiency for the same reason - to leave room for the phenotype to expand - and that rename is the clearest statement available that the clinical definition is not settled. A further retinal phenotype has been described in the second patient and is not curated here, because the report has no abstract in the reference cache and nothing quotable could be verified.
Show evidence (2 references)
PMID:37236006 SUPPORT Human Clinical
"For instance, the disorder associated with SCP2 variants was termed SCP2 deficiency to replace the phenotype-based nomenclature, leukoencephalopathy-dystonia-motor neuropathy syndrome."
The expert panel's rename, made explicitly to allow for phenotype expansion.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"An unusual retinal phenotype was later described in the same patient."
Records that a further organ system has been reported in one patient. The primary report is cited in `references` but nothing from it is quoted, for the reason given in the rationale.
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Pathophysiology

5
SCPx Loss of Function
Biallelic SCP2 variants remove the peroxisomal 3-ketoacyl-CoA thiolase SCPx. The organelle itself is not the lesion: this entry enters the peroxisomal module by its single-enzyme arm, with one matrix enzyme lost rather than a failure of assembly or import. In the first reported patient the loss was demonstrated at both levels - no SCPx protein on western blot and no thiolytic activity in cultured fibroblasts - and in the second it was the immunoblot that converted two variants of unknown significance into a diagnosis.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous in two of the three reported patients and compound heterozygous in the third; the zygosity recorded here is that of the better-characterised genotypes rather than a property of the disease.
peroxisomal 3-ketoacyl-CoA thiolase (SCPx) activity GO:0003988 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves peroxisomal 3-ketoacyl-CoA thiolase (SCPx) activity, annotated with acetyl-CoA C-acyltransferase activity (GO:0003988), qualified as loss of function. GO:0003988 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
peroxisome GO:0005777 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisome (GO:0005777). GO:0005777 is a cellular component from the Gene Ontology.
Downstream
Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA Losing the thiolase removes the enzyme that performs the last step of the beta-oxidation cycle for these substrates.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
Demonstrates the lesion at the protein and activity level in patient cells, which is what makes this a proven enzyme deficiency rather than a variant association.
Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA
The thiolytic cleavage that completes each round of peroxisomal beta-oxidation for 2-methyl-branched acyl-CoA esters no longer occurs. The direct evidence that this is the reaction lost comes from the mouse: gene disruption impaired thiolytic cleavage of 3-ketopristanoyl-CoA specifically. In humans the step is inferred from the absent fibroblast thiolase activity plus the substrate pattern that accumulates.
peroxisomal beta-oxidation of 2-methyl-branched acyl-CoA esters GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peroxisomal beta-oxidation of 2-methyl-branched acyl-CoA esters, annotated with fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED
peroxisome GO:0005777 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisome (GO:0005777). GO:0005777 is a cellular component from the Gene Ontology.
Animal models
Scp2 knockout mouse Mouse recapitulates The model demonstrates the specific enzymatic lesion: defective thiolytic cleavage of 3-ketopristanoyl-CoA.
SCP-x-null mouse Mouse recapitulates Establishes at whole-animal level that losing SCPx alone impairs branched-chain lipid metabolism, which is the claim the human disease rests on.
Downstream
Pristanic Acid Accumulation With the cycle unable to complete, its branched-chain substrate accumulates upstream of the block.
Incomplete Side-Chain Shortening of C27 Bile Acid Intermediates The same thiolytic step shortens the C27 bile acid side chain, so that conversion is also left incomplete.
Show evidence (2 references)
PMID:9553048 SUPPORT INDIRECT Model Organism
"Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA."
Identifies the blocked reaction directly, in mice lacking both SCP2 and SCPx. Marked INDIRECT because the mouse lesion removes both gene products while the human disease removes only the thiolase.
PMID:16685654 SUPPORT Human Clinical
"In this report, we describe the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids."
Assigns branched-chain fatty acid breakdown to this enzyme in the report that established the human deficiency.
Pristanic Acid Accumulation
Plasma pristanic acid rises markedly while phytanic acid rises only mildly and very-long-chain fatty acids stay normal. That combination is the diagnostic fingerprint and it distinguishes this disease from adult Refsum disease, the disorder of peroxisomal alpha-oxidation in which the block sits one step earlier, at the conversion of phytanic acid into pristanic acid; and from D-bifunctional protein deficiency, in which very-long-chain fatty acids, bile acid intermediates and pristanic acid accumulate together. The third reported patient is the exception that bounds the rule: his pristanic acid was only marginally above the control range, consistent with a partially functional enzyme.
Animal models
Scp2 knockout mouse Mouse partially recapitulates Branched-chain fatty acid accumulation occurs, but the species that accumulates is phytanic acid.
Downstream
Elevated circulating pristanic acid concentration The accumulation is what the diagnostic plasma assay measures.
Symmetrical Thalamic, Brainstem and White Matter Lesions Asserted as the route from the metabolic block to the imaging lesion because every patient with proven SCPx deficiency has both, and because that is the inference the founding report and the expert-panel curation rest on. No intermediate step has been demonstrated in humans - there is no neuropathology, no measurement of branched-chain fatty acid in brain tissue, and no imaging-metabolite correlation - so this edge is a disease-level attribution rather than a mechanism. See the open discussion attached to the downstream node.
Show evidence (2 references)
PMID:16685654 SUPPORT Human Clinical
"Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
The accumulation in the first reported patient, alongside the bile-acid finding.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
The same pattern in the second patient, as summarised by a review of the peroxisomal fatty acid disorders. It is the sentence that fixes the discriminating profile.
Incomplete Side-Chain Shortening of C27 Bile Acid Intermediates
The peroxisomal thiolytic step that SCPx performs is also the one that shortens the C27 bile acid side chain. In the first reported patient the consequence seen was the urinary excretion of abnormal bile alcohol glucuronides. What route produces those glucuronides in this disease has not been investigated, so the node stops at the blocked step and the abnormal excretion that follows it. None of the published reports describes liver disease in any patient, so unlike the other peroxisomal bile-acid defects this arm has so far been biochemical only.
peroxisomal side-chain shortening of C27 bile acid intermediates GO:0006699 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peroxisomal side-chain shortening of C27 bile acid intermediates, annotated with bile acid biosynthetic process (GO:0006699). GO:0006699 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Elevated urinary bile alcohol level Bile alcohols accumulate and are excreted as glucuronides when the peroxisomal route cannot complete the side-chain shortening.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
The abnormal bile alcohol excretion that is the only reported readout of this arm of the block.
Symmetrical Thalamic, Brainstem and White Matter Lesions
The one finding shared by all three reported patients: bilateral T2-hyperintense thalamic signal and pontine lesions, without gadolinium enhancement, with cerebral white matter involvement in the first patient. It is defined entirely by imaging. None of the published reports describes a biopsy or autopsy, so whether this represents demyelination, oedema, gliosis or neuronal loss is unknown, and the node is named for what was observed rather than for a pathological process.
Downstream
Focal T2 hyperintense thalamic lesion The thalamic component of the shared imaging finding.
Focal T2 hyperintense brainstem lesion The pontine and mesencephalic component of the shared imaging finding.
Leukoencephalopathy The cerebral white matter component, reported in the first patient and the feature the disease was originally named for.
Show evidence (2 references)
PMID:37905191 SUPPORT Human Clinical
"MRI findings were consistent among all three patients, revealing symmetrical thalamus and brainstem lesions without gadolinium enhancement."
States the shared imaging finding across the three reported patients, which is the claim this node makes.
PMID:16685654 SUPPORT Human Clinical
"Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons."
The imaging description in the first reported patient, including white matter.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sterol Carrier Protein 2 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Ear 1
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"The other patient developed hand clumsiness in his 30s, followed by gait disturbance and deafness"
The hearing loss of the second reported patient.
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The eye movement finding in the first reported patient.
Genitourinary 2
Elevated urinary bile alcohol level HP:6001007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urinary bile alcohol level (HP:6001007). HP:6001007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
The urinary finding in the first reported patient.
Azoospermia HP:0000027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Azoospermia (HP:0000027). HP:0000027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The reproductive finding in the first reported patient.
Head and Neck 2
Torticollis HP:0000473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Torticollis (HP:0000473). HP:0000473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The presenting sign of the first reported patient.
Hyposmia HP:0004409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyposmia (HP:0004409). HP:0004409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The olfactory finding in the first reported patient.
Metabolism 1
Elevated circulating pristanic acid concentration HP:0034721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating pristanic acid concentration (HP:0034721). HP:0034721 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
Contrasts the marked elevation of the two earlier patients with the mild elevation of the third, which is the range this phenotype covers.
Nervous System 11
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons."
The imaging finding in the first reported patient.
Focal T2 hyperintense thalamic lesion HP:0012692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal T2 hyperintense thalamic lesion (HP:0012692). HP:0012692 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"| Cranial MRI results | bilateral hyperintense T2 signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, without gadolinium enhancement | abnormal T2 signal, in the pons and thalamus | bilateral hyperintense T2 signals in the thalamus, and..."
The imaging row of the three-patient comparison table, recording thalamic T2 hyperintensity in each.
Focal T2 hyperintense brainstem lesion HP:0012748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal T2 hyperintense brainstem lesion (HP:0012748). HP:0012748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"| Cranial MRI results | bilateral hyperintense T2 signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, without gadolinium enhancement | abnormal T2 signal, in the pons and thalamus | bilateral hyperintense T2 signals in the thalamus, and..."
The imaging row of the three-patient comparison table, recording pontine lesions in each.
Head tremor HP:0002346 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Head tremor (HP:0002346). HP:0002346 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The head tremor of the first reported patient.
PMID:37905191 SUPPORT Human Clinical
"As summarized in Table 1, these shared clinical features in SCPx deficiency include stutter, tremors, and symmetrical lesions in the thalamus and brainstem without gadolinium enhancement"
Names tremor as one of only three features the author considers shared across the three reported patients.
Intention tremor HP:0002080 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intention tremor (HP:0002080). HP:0002080 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
The cerebellar signs of the first reported patient.
Motor polyneuropathy HP:0007178 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor polyneuropathy (HP:0007178). HP:0007178 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"| Electrophysiology | a predominantly motor and slight sensory neuropathy, with conduction blocks in the tibial nerves, reduced motor action potentials in the left peroneal nerve, and reduced amplitude of the left sural nerve | No evidence of polyneuropathy | No evidence of polyneuropathy |"
The nerve conduction row of the three-patient table: neuropathy in the first patient and explicitly absent in the other two.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37905191 SUPPORT Human Clinical
"The other patient developed hand clumsiness in his 30s, followed by gait disturbance and deafness"
The presenting course of the second reported patient.
PMID:35996156 SUPPORT BACKGROUND Human Clinical
"with spinocerebellar ataxia and brain iron accumulation"
The same patient characterised as a spinocerebellar ataxia in a later paper's introduction, which is where that label for the second patient comes from.
Iron accumulation in brain HP:0012675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iron accumulation in brain (HP:0012675). HP:0012675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35996156 SUPPORT BACKGROUND Human Clinical
"with spinocerebellar ataxia and brain iron accumulation"
The second patient's imaging phenotype as restated in a later report's introduction.
Psychosis HP:0000709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychosis (HP:0000709). HP:0000709 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37905191 SUPPORT Human Clinical
"During each attack, he experienced delusions, irritability, aggressive behavior, bursts of uncontrollable laughter, crying, and talking to himself."
The content of the psychotic episodes in the third reported patient.
PMID:37905191 SUPPORT Human Clinical
"Each episode was triggered by an acute upper respiratory tract infection."
The episodic, infection-triggered pattern.
Bilateral tonic-clonic seizure HP:0002069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral tonic-clonic seizure (HP:0002069). HP:0002069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"In January 2018, the patient was readmitted to the hospital for continuous generalized tonic-clonic seizures (GTCS) that lasted 18 h without recovery between seizures."
The seizure presentation of the third reported patient.
Stuttering HP:0025268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stuttering (HP:0025268). HP:0025268 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"As summarized in Table 1, these shared clinical features in SCPx deficiency include stutter, tremors, and symmetrical lesions in the thalamus and brainstem without gadolinium enhancement"
Names stutter as a feature shared across the three reported patients.
🧬

Genetic Associations

1
SCP2
Gene: SCP2 hgnc:10606 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCP2 (hgnc:10606). hgnc:10606 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:37236006 SUPPORT Human Clinical
"Loss of function variants in another tier 2 gene, SCP2, have been reported in two individuals"
ClinGen's Peroxisomal Gene Curation Expert Panel states the human genetic evidence it scored - two individuals with loss-of-function variants.
PMID:37236006 SUPPORT Human Clinical
"With an overall score of 10 points, this gene-disease relationship earned a Moderate classification."
The expert-panel verdict on the strength of the SCP2 gene-disease relationship. It is Moderate, not Definitive, and this entry is written to that standard.
Variants (3)
c.545_546insA (p.I184fsX7)
Homozygous in the first reported patient, producing a frameshift and premature stop codon. SCPx protein was undetectable by western blot in that patient's fibroblasts.
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7)."
The variant and its predicted consequence as reported.
c.674+1G>C
Homozygous in the third reported patient. RNA sequencing and cDNA analysis showed skipping of exon 8 in the mature transcript, deleting a block of residues that overlaps the thiolase N-terminal domain; the authors argue the enzyme may therefore retain partial function, which would fit that patient's only marginally raised pristanic acid.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"Through whole-exome sequencing, we identified a homozygous splicing mutation in SCP2 (c.674 + 1G > C), and further RNA sequencing revealed exon 8 skipping in the mature transcripts of SCP2."
The variant and the transcript consequence demonstrated for it.
c.121G>T and c.349C>T
The compound heterozygous pair reported in the second patient, tabulated as c.121G>T and c.349C>T. Both were initially classified as variants of unknown significance; immunoblotting showing near-absent SCPx protein is what established the diagnosis rather than the variant classification.
Show evidence (2 references)
PMID:37905191 SUPPORT Human Clinical
"| Genetics | c.545_546insA(hom); | c.121G>T &c.349C>T(comhet); | c.674 + 1g>c(hom); |"
The genotype row of the three-patient comparison table, giving the second patient's compound heterozygous pair.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"This prompted molecular analysis, which revealed two variants of unknown significance in the SCP2 gene."
A review's account of how the second patient's variants were classified when found, which is why protein-level confirmation was needed.
💊

Medical Actions

3
Phytanic Acid-Restricted Diet
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
The only disease-directed treatment reported. The third patient was discharged on a phytanic-acid-restricted diet. It is mechanistically reasonable, because dietary phytol and phytanic acid are the source, through alpha-oxidation, of the pristanic acid that accumulates. No outcome of the diet has been reported in this disease, in this patient or any other, so this record establishes that it has been tried and nothing more.
Mechanism Target:
Pristanic Acid Accumulation — Restricting dietary phytol and phytanic acid limits the supply of the precursor from which pristanic acid is made. Whether this lowers plasma pristanic acid in SCP2 deficiency has not been reported.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"Subsequently, the patient was discharged while being placed on a phytanic acid-restricted diet."
The single reported use of dietary restriction in this disease. No follow-up result is given.
Symptomatic Management of Episodic Psychosis and Seizures
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: olanzapine CHEBI:7735 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses olanzapine (CHEBI:7735). CHEBI:7735 is a therapeutic agent from Chemical Entities of Biological Interest. quetiapine CHEBI:8707 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses quetiapine (CHEBI:8707). CHEBI:8707 is a therapeutic agent from Chemical Entities of Biological Interest. diazepam CHEBI:49575 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diazepam (CHEBI:49575). CHEBI:49575 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
In the third patient the psychiatric episodes improved over three to six months on olanzapine or quetiapine and the status epilepticus was terminated with diazepam. That is symptomatic treatment of the presentation, with no effect on the metabolic lesion, and it is a single patient's experience.
Show evidence (2 references)
PMID:37905191 SUPPORT Human Clinical
"Psychiatric symptoms gradually improved after 3-6 months of treatment with antipsychotic drugs such as olanzapine or quetiapine."
The symptomatic response reported in the third patient.
PMID:37905191 SUPPORT Human Clinical
"The patient's seizures were effectively halted with diazepam, and the psychiatric symptoms gradually improved."
The anticonvulsant arm of the same patient's symptomatic management, and the reason diazepam is listed as a third agent.
Pharmacological Upregulation of SCPx (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fenofibrate CHEBI:5001 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fenofibrate (CHEBI:5001). CHEBI:5001 is a therapeutic agent from Chemical Entities of Biological Interest. 4-hydroxytamoxifen CHEBI:231618 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 4-hydroxytamoxifen (CHEBI:231618). CHEBI:231618 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Not a treatment anyone has received. In fibroblasts from the fourth, disputed patient, fenofibrate or 4-hydroxytamoxifen raised SCPx protein levels and shifted some fatty acid levels, and the authors propose raising SCPx pharmacologically as a strategy. Two caveats have to travel with it and neither is small. The cells came from the one reported patient whose diagnosis this entry declines to accept, so it is not established that the experiment was performed in SCPx deficiency at all. And the strategy is logically restricted to alleles that still make protein: that patient was heterozygous and still expressed SCPx, at reduced level, whereas the first reported patient had no detectable SCPx on western blot, and there is nothing to upregulate from a null allele. Recorded as a lead so it is discoverable, not as a therapy.
Mechanism Target:
SCPx Loss of Function — Acts on the lesion itself by raising residual SCPx protein, which is why it is restricted to alleles that still produce some.
Show evidence (2 references)
PMID:35996156 SUPPORT In Vitro
"Treatment with fenofibrate or 4-hydroxytamoxifen increased SCPx levels, and certain fatty acid levels in patient fibroblasts."
The cell-culture result itself: both compounds raised SCPx levels in the patient's fibroblasts.
PMID:35996156 SUPPORT INDIRECT In Vitro
"Increasing SCPx levels through pharmacological interventions may reverse some effects of SCPx deficiency."
The authors' own therapeutic inference from that result. Marked INDIRECT because it is a proposal extrapolated from fibroblast protein levels, with no measured clinical or organism-level outcome behind it.
🔬

Biochemical Markers

5
Plasma pristanic acid (INCREASED)
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
The range of elevation across the three reported patients.
Plasma phytanic acid (INCREASED)
Show evidence (1 reference)
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
States the relative behaviour of the two branched-chain acids, and in the same sentence the normal very-long-chain fatty acids that complete the profile.
Plasma very-long-chain fatty acids (NORMAL)
Show evidence (1 reference)
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
Records the normal very-long-chain fatty acids in the second reported patient.
Urinary bile alcohol glucuronides (INCREASED)
Show evidence (1 reference)
PMID:16685654 SUPPORT Human Clinical
"Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
The urinary bile alcohol finding in the first reported patient.
SCPx thiolytic activity and protein in cultured skin fibroblasts (DECREASED)
Show evidence (2 references)
PMID:16685654 SUPPORT Human Clinical
"In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
Both readouts in the first reported patient.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"This prompted molecular analysis, which revealed two variants of unknown significance in the SCP2 gene."
Why protein-level confirmation mattered in the second patient: the variants alone did not carry the diagnosis.
🔬

Diagnosis

3
Plasma branched-chain fatty acid profiling
The step that makes the diagnosis reachable, and the step that is skipped when the workup stops at a very-long-chain fatty acid screen. What identifies this disease is a raised pristanic acid with a disproportionately low phytanic acid and normal very-long-chain fatty acids. Pristanic acid accumulation is not specific to this enzyme, because the same 2-methyl-branched beta-oxidation stream runs through ACOX2, D-bifunctional protein and alpha-methylacyl-CoA racemase as well, so the profile localises the pathway rather than the gene.
plasma branched-chain fatty acid profiling NCIT:C25294 NCI Thesaurus (NCIT)
Markers: Plasma pristanic acid; plasma phytanic acid; plasma very-long-chain fatty acids.
Show evidence (2 references)
PMID:31822849 SUPPORT Other
"The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells."
The professional-society statement of what the first-line biochemical workup for a peroxisomal disorder consists of.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
The discriminating profile itself, as it presented in the second patient.
Fibroblast SCPx protein and thiolase activity assay
What converts a sequencing result into a diagnosis. In the second patient the two SCP2 variants were of unknown significance and it was the near-absence of SCPx protein on immunoblot that established the deficiency. Where sequencing is the first-tier test, biochemical confirmation is the general expectation in peroxisomal disease and not a peculiarity of this gene.
peroxisomal enzyme studies in cultured fibroblasts NCIT:C25294 NCI Thesaurus (NCIT)
Markers: SCPx immunoblot in cultured skin fibroblasts; SCPx thiolytic activity.
Show evidence (2 references)
PMID:16685654 SUPPORT Human Clinical
"In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
The two fibroblast readouts as performed in the first patient.
PMID:31822849 SUPPORT Other
"When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction."
States the general requirement that makes the fibroblast assay necessary after a sequencing-first workup, which is exactly what happened in the second patient.
Brain magnetic resonance imaging
Not diagnostic on its own, but the finding that should raise the question. All three reported patients had symmetrical, non-enhancing thalamic and brainstem lesions, and in the third patient that pattern was repeatedly misread before the metabolic diagnosis was made.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Markers: Symmetrical T2 hyperintensity in the thalamus and pons, without gadolinium enhancement.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"MRI findings were consistent among all three patients, revealing symmetrical thalamus and brainstem lesions without gadolinium enhancement."
The consistency of the imaging pattern across the reported patients.
📈

Progression

1
Age at onset
Onset spans childhood to adulthood across the three patients: seven years in the first, thirty years in the second, and not clearly datable in the third, whose stutter and tremor predated the first documented episode. No natural history has been described.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"| Age at disease onset | 7 years | 30 years | Young, not clear |"
The onset row of the three-patient comparison table.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Three published patients, reported singly in three separate reports, plus one further patient with a heterozygous variant of uncertain significance whose status is disputed. All three are male. That is recorded as an observation and nothing is inferred from it: SCP2 is autosomal and the inheritance is recessive with carrier parents documented, so with an n of three the sex distribution is what three consecutive single-patient reports happened to contain. No prevalence or incidence estimate has been published and no numeric rate is recorded here, because none has been measured.
Show evidence (3 references)
PMID:37905191 SUPPORT Human Clinical
"SCPx deficiency is a rare disorder of peroxisomal beta-oxidation dysfunction, and it has only been documented in two patients thus far."
The patient count before the third report, which is that report's own patient.
PMID:38693715 SUPPORT REVIEW SYNTHESIS Human Clinical
"A third patient with presumed SCPx deficiency was recently reported by Galano et al., but it remains to be established whether this patient is truly affected by SCPx deficiency."
The disputed fourth case, and the reason it is counted separately here rather than folded into the total.
PMID:37905191 SUPPORT Human Clinical
"| Gender | Male | Male | Male |"
The sex row of the three-patient comparison table.
⚖️

Clinical Burden

Moderate
Recorded as MODERATE and with low confidence. Every reported patient has a chronic neurological disorder with a structural brain lesion, and two of the three have a disabling motor or psychiatric syndrome; the third patient was repeatedly hospitalised and misdiagnosed across three admissions before the cause was found, which is a burden in itself. Against that, none of the published reports describes liver involvement, and the second patient's illness began in his thirties. With three patients there is no natural history, no disability measure and no survival data, so this level is an impression from three case reports rather than an assessment.
Show evidence (1 reference)
PMID:37905191 SUPPORT Human Clinical
"The patient was previously diagnosed with viral encephalitis, cerebral infarction, or mitochondrial encephalopathy."
The diagnostic odyssey in the third patient - three separate wrong diagnoses across repeated admissions before the metabolic cause was identified.
🐁

Animal Models

3
Scp2 knockout mouse
The original and most-used model, and the one that identified the blocked reaction. It ablates the whole locus, so both gene products are lost, which is not the human lesion - the reported patients lose the thiolase while the small SCP2 protein is made from its own promoter. The phenotype is dominated by phytanic acid accumulation, where the human disease accumulates pristanic acid.
Species
Mouse
Genotype
Scp2-/- (combined SCP2 and SCPx deficiency)
Publication
PMID:9553048
Pathograph links
Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA recapitulates fidelity: moderate observes: molecular The model demonstrates the specific enzymatic lesion: defective thiolytic cleavage of 3-ketopristanoyl-CoA.
Limitations: The knockout removes SCP2 as well as SCPx, so an observed phenotype cannot be assigned to the thiolase alone, and the model also shows impaired peroxisomal import of phytanoyl-CoA, which is a function of the lipid-carrier product rather than of the thiolase.
Show evidence (1 reference)
PMID:9553048 SUPPORT Model Organism
"Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA."
The blocked reaction, demonstrated in the model.
Pristanic Acid Accumulation partially recapitulates fidelity: low observes: organism Branched-chain fatty acid accumulation occurs, but the species that accumulates is phytanic acid.
Limitations: The mouse accumulates phytanic acid up to ten-fold, whereas the human disease is defined by a marked pristanic acid rise with phytanic acid only mildly elevated. The direction of the branched-chain lesion is reproduced; its composition is not.
Divergences from the human mechanism
species mismatch qualifying
Mouse and human differ in which branched-chain species dominates the accumulation. The model's readout is phytanic acid; the human diagnostic analyte is pristanic acid.
proxy quantity qualifying
The quantity measured in the model is tissue and plasma phytanic acid. The quantity this node asserts is plasma pristanic acid. They are adjacent metabolites in one pathway, not the same measurement.
Show evidence (1 reference)
PMID:9553048 SUPPORT Model Organism
"The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice."
The accumulating species and its magnitude in the model.
Show evidence (1 reference)
PMID:9553048 SUPPORT Model Organism
"Complete deficiency of SCP2 and SCPx was associated with marked alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired body weight control, and neuropathy."
The whole-animal phenotype, including the neuropathy that is the model's closest approach to the human neurological disease. It is cited to bound what the model represents: hypolipidemia and impaired body weight control have no counterpart in any reported patient.
SCP-x-null mouse
The model that matches the human lesion, because it removes the thiolase while leaving SCP2 expression intact. That separation is itself one of its findings. It was characterised under a phytol-enriched diet, which is a substrate challenge rather than the steady state a patient lives in.
Species
Mouse
Genotype
SCP-x-null (SCPx ablated, SCP2 expression preserved)
Publication
PMID:17068117
Pathograph links
Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA recapitulates fidelity: moderate observes: organism Establishes at whole-animal level that losing SCPx alone impairs branched-chain lipid metabolism, which is the claim the human disease rests on.
Limitations: The branched-chain phenotype was elicited by a phytol-enriched diet, so it measures reserve capacity under load rather than the unchallenged state, and the reported consequences are hepatic and nutritional rather than neurological. No brain phenotype is reported for this model.
Show evidence (1 reference)
PMID:17068117 SUPPORT Model Organism
"In summary, the present work with SCP-x gene-ablated mice demonstrates, for the first time, a direct physiological relationship between lack of SCP-x and decreased ability to metabolize branched-chain lipids."
The model's own summary of what it established: SCPx loss alone impairs branched-chain lipid metabolism.
Show evidence (1 reference)
PMID:17068117 SUPPORT Model Organism
"It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x)"
Why this model is the better analogue of the human genotype: ablating SCPx does not take SCP2 with it, so the two gene products can be separated.
Scp2-null mouse on a phytol-enriched diet, cardiac phenotype
A cardiac electrophysiology study of the combined knockout under phytol loading. It is recorded here because one of the four reported human cases - the disputed heterozygous patient - had a cardiac dysrhythmia, and because this is the only model result that would predict one. Nothing connects them yet: none of the reports of the three patients with a confirmed biallelic SCP2 genotype describes an arrhythmia or a cardiac assessment.
Species
Mouse
Genotype
Scp2-/- (combined SCP2 and SCPx deficiency), phytol-enriched diet
Publication
PMID:15574183
Show evidence (1 reference)
PMID:15574183 SUPPORT Model Organism
"Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model."
The cardiac phenotype of the combined knockout under phytol loading, and the mechanism the authors propose for it. Recorded without a modeled_mechanisms link because no node in this entry corresponds to it.
{ }

Source YAML

click to show 
name: Sterol Carrier Protein 2 Deficiency
category: Mendelian
creation_date: '2026-09-19T05:40:32Z'
synonyms:
- SCP2 deficiency
- SCPx deficiency
- sterol carrier protein X deficiency
- leukoencephalopathy with dystonia and motor neuropathy
- leukoencephalopathy-dystonia-motor neuropathy syndrome
- LKDMN
description: >-
  Sterol carrier protein 2 deficiency is an autosomal recessive single-enzyme peroxisomal
  beta-oxidation defect caused by biallelic SCP2 variants. The SCP2 locus is transcribed
  from two promoters and yields two distinct proteins - the 58 kDa peroxisomal thiolase
  SCPx and the small lipid-binding protein SCP2 - and the disease is a loss of the thiolase
  arm, which is why the older literature calls it SCPx deficiency. SCPx catalyses the final
  thiolytic step of the peroxisomal beta-oxidation spiral for 2-methyl-branched substrates,
  so losing it blocks the degradation of pristanic acid and the side-chain shortening of
  the C27 bile acid intermediates.

  The biochemical signature that follows is narrow and is what makes the disease findable:
  a marked rise in plasma pristanic acid with phytanic acid only mildly raised, normal
  plasma very-long-chain fatty acids, and abnormal bile alcohol glucuronides in urine. It
  is a beta-oxidation lesion alone, and not the two-sided picture of a peroxisome
  biogenesis disorder, in which substrate accumulation and ether-lipid deficiency occur
  together.

  Clinically the reported picture is a childhood- or adult-onset central nervous
  system disease with symmetrical thalamic and brainstem lesions on MRI. Beyond that shared
  imaging finding the three published patients differ from one another considerably -
  torticollis, head tremor, nystagmus, hyposmia and a motor neuropathy in the first;
  ataxia, gait disturbance, deafness and brain iron accumulation in the second; episodic
  infection-triggered psychosis and status epilepticus in the third - and with three
  patients there is no basis for calling any of these features typical.

  The evidence base is correspondingly thin and this entry is deliberately short. ClinGen's
  Peroxisomal Gene Curation Expert Panel scored the SCP2 gene-disease relationship as
  Moderate on 6 genetic and 4 experimental evidence points, and renamed the entity from the
  descriptive LKDMN phenotype label to SCP2 deficiency to leave room for the phenotype to
  expand. The mouse literature predates the human literature and is larger, and the widely used
  knockout ablates SCP2 and SCPx together, which is not the human lesion.
disease_term:
  preferred_term: Sterol carrier protein 2 deficiency
  term:
    id: MONDO:0013391
    label: sterol carrier protein 2 deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019233
      label: disorder of peroxisomal beta oxidation
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      One of the two parents MONDO asserts for MONDO:0013391, and the one that names the
      lesion. Recorded as broadMatch because it is a broader class covering the other
      single-enzyme beta-oxidation defects as well. ClinGen's Peroxisomal GCEP independently
      places SCP2 deficiency as a subclass of this same term.
  - term:
      id: MONDO:0019046
      label: leukodystrophy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      The second parent MONDO asserts for MONDO:0013391. Recorded as broadMatch: it reflects
      the white matter imaging finding that gave the disease its original LKDMN name, and it
      is a much broader class. This entry builds its causal chain on the peroxisomal parent
      instead, because that is the parent that names the enzyme defect.
  icd10cm_mappings:
  - term:
      id: ICD10CM:E71.548
      label: Other peroxisomal disorders
    mapping_predicate: skos:broadMatch
    mapping_source: dismech curation
    mapping_justification: >-
      ICD-10-CM has no code for SCP2 deficiency. E71.548 is the residual peroxisomal-disorder
      code and is the closest coded home for this lesion; it is a broader residual category
      rather than a cross-reference asserted by MONDO or Orphanet.
parents:
- Peroxisomal Disease
- Inborn Error of Metabolism
- Leukodystrophy
references:
- reference: PMID:16685654
  title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
- reference: PMID:26497993
  title: SCP2 mutations and neurodegeneration with brain iron accumulation.
- reference: PMID:28033445
  title: An Unusual Retinal Phenotype Associated With a Mutation in Sterol Carrier Protein SCP2.
- reference: PMID:35996156
  title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
- reference: PMID:37905191
  title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
- reference: PMID:37236006
  title: Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
- reference: PMID:38693715
  title: Disorders of fatty acid homeostasis.
- reference: PMID:31822849
  title: "Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)."
- reference: PMID:9553048
  title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
- reference: PMID:17068117
  title: Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
- reference: PMID:15574183
  title: Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Every reported patient presented neurologically, and the shared finding across all
      three is a central nervous system imaging abnormality.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      An inborn error of peroxisomal fatty acid metabolism, diagnosed on a plasma
      branched-chain fatty acid profile.
  icimd_category:
  - classification_value: peroxisomal_fatty_acid_oxidation
    notes: >-
      SCPx catalyses the final thiolytic step of peroxisomal beta-oxidation for
      2-methyl-branched substrates, so the lesion sits squarely in this ICIMD group rather
      than in peroxisomal biogenesis.
    evidence:
    - reference: PMID:37905191
      reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: "SCPx functions as a peroxisomal enzyme with thiolase activity involved in peroxisomal beta-oxidation."
      explanation: >-
        Places the enzyme in the peroxisomal beta-oxidation pathway, which is what the
        category asserts. Quoted from the case report's introduction, where it restates
        established enzymology rather than reporting the study's own result.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic SCP2 variants. Two of the three reported patients were homozygous and one was
    a compound heterozygote; in the third patient the father and sisters were heterozygous
    carriers. Penetrance and expressivity are recorded as UNKNOWN: with three
    patients there is no unaffected biallelic carrier to argue from, and the three
    phenotypes are too dissimilar to characterise a range.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: UNKNOWN
  expressivity: UNKNOWN
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7)."
    explanation: The homozygous biallelic genotype of the first reported patient.
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, there have been two reports of SCPx deficiency, which resulted from a homozygous or compound heterozygous SCP2 mutation."
    explanation: >-
      States the biallelic requirement across the two then-published patients. Quoted from
      the introduction of a paper whose own subject is a different, heterozygous case, so
      this sentence restates prior clinical reports rather than its own result.
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through whole-exome sequencing, we identified a homozygous splicing mutation in SCP2 (c.674 + 1G > C), and further RNA sequencing revealed exon 8 skipping in the mature transcripts of SCP2."
    explanation: The homozygous biallelic genotype of the third reported patient.
genetic:
- name: SCP2
  relationship_type: CAUSATIVE
  notes: >-
    The locus is transcribed from two promoters and encodes two proteins, so "SCP2
    deficiency" and "SCPx deficiency" name the same disease from different ends of the same
    gene. All three reported disease-causing genotypes lie in the SCPx-coding region.
    Searching by symbol is a Named Entity Confusion hazard in two directions: SCP2D1
    (hgnc:16211) is a different gene, and much of the SCP2 literature is mouse lipid
    physiology rather than human disease.
  gene_term:
    preferred_term: SCP2
    term:
      id: hgnc:10606
      label: SCP2
  evidence:
  - reference: PMID:37236006
    reference_title: Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of function variants in another tier 2 gene, SCP2, have been reported in two individuals"
    explanation: >-
      ClinGen's Peroxisomal Gene Curation Expert Panel states the human genetic evidence it
      scored - two individuals with loss-of-function variants.
  - reference: PMID:37236006
    reference_title: Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With an overall score of 10 points, this gene-disease relationship earned a Moderate classification."
    explanation: >-
      The expert-panel verdict on the strength of the SCP2 gene-disease relationship. It is
      Moderate, not Definitive, and this entry is written to that standard.
  variants:
  - name: c.545_546insA (p.I184fsX7)
    description: >-
      Homozygous in the first reported patient, producing a frameshift and premature stop
      codon. SCPx protein was undetectable by western blot in that patient's fibroblasts.
    evidence:
    - reference: PMID:16685654
      reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7)."
      explanation: The variant and its predicted consequence as reported.
  - name: c.674+1G>C
    description: >-
      Homozygous in the third reported patient. RNA sequencing and cDNA analysis showed
      skipping of exon 8 in the mature transcript, deleting a block of residues that
      overlaps the thiolase N-terminal domain; the authors argue the enzyme may therefore
      retain partial function, which would fit that patient's only marginally raised
      pristanic acid.
    evidence:
    - reference: PMID:37905191
      reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Through whole-exome sequencing, we identified a homozygous splicing mutation in SCP2 (c.674 + 1G > C), and further RNA sequencing revealed exon 8 skipping in the mature transcripts of SCP2."
      explanation: The variant and the transcript consequence demonstrated for it.
  - name: c.121G>T and c.349C>T
    description: >-
      The compound heterozygous pair reported in the second patient, tabulated as
      c.121G>T and c.349C>T. Both were initially classified as variants of unknown
      significance; immunoblotting showing near-absent SCPx protein is what established the
      diagnosis rather than the variant classification.
    evidence:
    - reference: PMID:37905191
      reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "| Genetics | c.545_546insA(hom); | c.121G>T &c.349C>T(comhet); | c.674 + 1g>c(hom); |"
      explanation: >-
        The genotype row of the three-patient comparison table, giving the second patient's
        compound heterozygous pair.
    - reference: PMID:38693715
      reference_title: Disorders of fatty acid homeostasis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "This prompted molecular analysis, which revealed two variants of unknown significance in the SCP2 gene."
      explanation: >-
        A review's account of how the second patient's variants were classified when found,
        which is why protein-level confirmation was needed.
pathophysiology:
- name: SCPx Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
  description: >-
    Biallelic SCP2 variants remove the peroxisomal 3-ketoacyl-CoA thiolase SCPx. The
    organelle itself is not the lesion: this entry enters the peroxisomal module by its
    single-enzyme arm, with one matrix enzyme lost rather than a failure of assembly or
    import. In the first reported patient the loss was demonstrated at both levels - no
    SCPx protein on western blot and no thiolytic activity in cultured fibroblasts - and in
    the second it was the immunoblot that converted two variants of unknown significance
    into a diagnosis.
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous in two of the three reported patients and compound heterozygous in the
      third; the zygosity recorded here is that of the better-characterised genotypes rather
      than a property of the disease.
  molecular_functions:
  - preferred_term: peroxisomal 3-ketoacyl-CoA thiolase (SCPx) activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003988
      label: acetyl-CoA C-acyltransferase activity
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
    explanation: >-
      Demonstrates the lesion at the protein and activity level in patient cells, which is
      what makes this a proven enzyme deficiency rather than a variant association.
  downstream:
  - target: Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA
    description: >-
      Losing the thiolase removes the enzyme that performs the last step of the
      beta-oxidation cycle for these substrates.
    evidence:
    - reference: PMID:37905191
      reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: "SCPx functions as a peroxisomal enzyme with thiolase activity involved in peroxisomal beta-oxidation."
      explanation: >-
        Names the reaction the enzyme performs, which is the step this edge says is lost.
- name: Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    The thiolytic cleavage that completes each round of peroxisomal beta-oxidation for
    2-methyl-branched acyl-CoA esters no longer occurs. The direct evidence that this is the
    reaction lost comes from the mouse: gene disruption impaired thiolytic cleavage of
    3-ketopristanoyl-CoA specifically. In humans the step is inferred from the absent
    fibroblast thiolase activity plus the substrate pattern that accumulates.
  biological_processes:
  - preferred_term: peroxisomal beta-oxidation of 2-methyl-branched acyl-CoA esters
    modifier: DECREASED
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  evidence:
  - reference: PMID:9553048
    reference_title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA."
    explanation: >-
      Identifies the blocked reaction directly, in mice lacking both SCP2 and SCPx. Marked
      INDIRECT because the mouse lesion removes both gene products while the human disease
      removes only the thiolase.
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this report, we describe the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids."
    explanation: >-
      Assigns branched-chain fatty acid breakdown to this enzyme in the report that
      established the human deficiency.
  downstream:
  - target: Pristanic Acid Accumulation
    description: >-
      With the cycle unable to complete, its branched-chain substrate accumulates upstream
      of the block.
  - target: Incomplete Side-Chain Shortening of C27 Bile Acid Intermediates
    description: >-
      The same thiolytic step shortens the C27 bile acid side chain, so that conversion is
      also left incomplete.
- name: Pristanic Acid Accumulation
  role: amplifier
  biological_scale: ORGANISM
  description: >-
    Plasma pristanic acid rises markedly while phytanic acid rises only mildly and
    very-long-chain fatty acids stay normal. That combination is the diagnostic fingerprint
    and it distinguishes this disease from adult Refsum disease, the disorder of peroxisomal
    alpha-oxidation in which the block sits one step earlier, at the conversion of phytanic
    acid into pristanic acid; and from D-bifunctional protein deficiency, in which
    very-long-chain fatty acids, bile acid intermediates and pristanic acid accumulate
    together. The third reported patient is the exception that bounds the rule:
    his pristanic acid was only marginally above the control range, consistent with a
    partially functional enzyme.
  chemical_entities:
  - preferred_term: pristanic acid
    modifier: INCREASED
    term:
      id: CHEBI:51340
      label: pristanic acid
  - preferred_term: phytanic acid
    modifier: INCREASED
    term:
      id: CHEBI:16285
      label: phytanic acid
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
    explanation: The accumulation in the first reported patient, alongside the bile-acid finding.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
    explanation: >-
      The same pattern in the second patient, as summarised by a review of the peroxisomal
      fatty acid disorders. It is the sentence that fixes the discriminating profile.
  downstream:
  - target: Elevated circulating pristanic acid concentration
    description: >-
      The accumulation is what the diagnostic plasma assay measures.
  - target: Symmetrical Thalamic, Brainstem and White Matter Lesions
    description: >-
      Asserted as the route from the metabolic block to the imaging lesion because every
      patient with proven SCPx deficiency has both, and because that is the inference the
      founding report and the expert-panel curation rest on. No intermediate step has been
      demonstrated in humans - there is no neuropathology, no measurement of branched-chain
      fatty acid in brain tissue, and no imaging-metabolite correlation - so this edge is a
      disease-level attribution rather than a mechanism. See the open discussion attached to
      the downstream node.
    evidence:
    - reference: PMID:37236006
      reference_title: Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "With an overall score of 10 points, this gene-disease relationship earned a Moderate classification."
      explanation: >-
        The expert-panel judgement that SCP2 loss of function causes this phenotype at all.
        Marked INDIRECT because it grades the gene-disease relationship as a whole and says
        nothing about the steps between the metabolic block and the lesion.
- name: Incomplete Side-Chain Shortening of C27 Bile Acid Intermediates
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    The peroxisomal thiolytic step that SCPx performs is also the one that shortens the C27
    bile acid side chain. In the first reported patient
    the consequence seen was the urinary excretion of abnormal bile alcohol glucuronides.
    What route produces those glucuronides in this disease has not been investigated, so
    the node stops at the blocked step and the abnormal excretion that follows it. None of
    the published reports describes liver disease in any patient, so unlike the other
    peroxisomal bile-acid defects this arm has so far been biochemical only.
  biological_processes:
  - preferred_term: peroxisomal side-chain shortening of C27 bile acid intermediates
    modifier: DECREASED
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
    explanation: >-
      The abnormal bile alcohol excretion that is the only reported readout of this arm of
      the block.
  downstream:
  - target: Elevated urinary bile alcohol level
    description: >-
      Bile alcohols accumulate and are excreted as glucuronides when the peroxisomal route
      cannot complete the side-chain shortening.
- name: Symmetrical Thalamic, Brainstem and White Matter Lesions
  role: effector
  biological_scale: TISSUE
  description: >-
    The one finding shared by all three reported patients: bilateral T2-hyperintense
    thalamic signal and pontine lesions, without gadolinium enhancement, with cerebral
    white matter involvement in the first patient. It is defined entirely by imaging. None
    of the published reports describes a biopsy or autopsy, so whether this represents
    demyelination, oedema, gliosis or neuronal loss is unknown, and the node is named for
    what was observed rather than for a pathological process.
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI findings were consistent among all three patients, revealing symmetrical thalamus and brainstem lesions without gadolinium enhancement."
    explanation: >-
      States the shared imaging finding across the three reported patients, which is the
      claim this node makes.
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons."
    explanation: The imaging description in the first reported patient, including white matter.
  downstream:
  - target: Focal T2 hyperintense thalamic lesion
    description: The thalamic component of the shared imaging finding.
  - target: Focal T2 hyperintense brainstem lesion
    description: The pontine and mesencephalic component of the shared imaging finding.
  - target: Leukoencephalopathy
    description: >-
      The cerebral white matter component, reported in the first patient and the feature the
      disease was originally named for.
phenotypes:
- category: Neurologic
  name: Leukoencephalopathy
  description: >-
    Reported in the first patient and the feature behind the original LKDMN name. It is not
    a constant finding: the three-patient comparison table records thalamic and pontine
    lesions in all three but white matter involvement is described only for the first.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons."
    explanation: The imaging finding in the first reported patient.
- category: Neurologic
  name: Focal T2 hyperintense thalamic lesion
  description: >-
    Bilateral, symmetrical and present in all three reported patients, without gadolinium
    enhancement.
  phenotype_term:
    preferred_term: Focal T2 hyperintense thalamic lesion
    term:
      id: HP:0012692
      label: Focal T2 hyperintense thalamic lesion
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Cranial MRI results | bilateral hyperintense T2 signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, without gadolinium enhancement | abnormal T2 signal, in the pons and thalamus | bilateral hyperintense T2 signals in the thalamus, and butterfly-like lesions in the pons |"
    explanation: >-
      The imaging row of the three-patient comparison table, recording thalamic T2
      hyperintensity in each.
- category: Neurologic
  name: Focal T2 hyperintense brainstem lesion
  description: >-
    Pontine lesions, described as butterfly-like in two patients, with mesencephalic
    involvement in the third. Present in all three reported patients.
  phenotype_term:
    preferred_term: Focal T2 hyperintense brainstem lesion
    term:
      id: HP:0012748
      label: Focal T2 hyperintense brainstem lesion
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Cranial MRI results | bilateral hyperintense T2 signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, without gadolinium enhancement | abnormal T2 signal, in the pons and thalamus | bilateral hyperintense T2 signals in the thalamus, and butterfly-like lesions in the pons |"
    explanation: >-
      The imaging row of the three-patient comparison table, recording pontine lesions in
      each.
- category: Laboratory
  name: Elevated circulating pristanic acid concentration
  description: >-
    The diagnostic analyte. Markedly raised in the two patients with a complete enzyme
    deficiency and only mildly raised in the third, whose splice variant is argued to leave
    partial thiolase function.
  phenotype_term:
    preferred_term: Elevated circulating pristanic acid concentration
    term:
      id: HP:0034721
      label: Elevated circulating pristanic acid concentration
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
    explanation: >-
      Contrasts the marked elevation of the two earlier patients with the mild elevation of
      the third, which is the range this phenotype covers.
- category: Laboratory
  name: Elevated urinary bile alcohol level
  description: >-
    Abnormal bile alcohol glucuronides in urine, reported in the first patient. It has not
    been reported for the other two, and none of the published reports describes liver disease.
  phenotype_term:
    preferred_term: Elevated urinary bile alcohol level
    term:
      id: HP:6001007
      label: Elevated urinary bile alcohol level
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
    explanation: The urinary finding in the first reported patient.
- category: Neurologic
  name: Torticollis
  description: >-
    Spasmodic torticollis was the presenting sign in the first patient. Deliberately not
    wired into the pathograph: no reported work connects the metabolic block to a specific
    motor pathway, and inventing an edge from the imaging lesion to a dystonic sign would
    assert an anatomical attribution nobody has made.
  phenotype_term:
    preferred_term: Torticollis
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The presenting sign of the first reported patient.
- category: Neurologic
  name: Head tremor
  description: >-
    Dystonic head tremor in the first patient; tremor is one of the three features the
    later comparison describes as shared across all three patients, alongside stutter and
    the imaging lesions. Left unwired for the same reason as the other motor signs.
  phenotype_term:
    preferred_term: Head tremor
    term:
      id: HP:0002346
      label: Head tremor
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The head tremor of the first reported patient.
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As summarized in Table 1, these shared clinical features in SCPx deficiency include stutter, tremors, and symmetrical lesions in the thalamus and brainstem without gadolinium enhancement"
    explanation: >-
      Names tremor as one of only three features the author considers shared across the
      three reported patients.
- category: Neurologic
  name: Intention tremor
  description: >-
    Part of the mild cerebellar picture in the first patient. Unwired.
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The cerebellar signs of the first reported patient.
- category: Ophthalmologic
  name: Nystagmus
  description: >-
    Reported in the first patient. Unwired.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The eye movement finding in the first reported patient.
- category: Neurologic
  name: Hyposmia
  description: >-
    Reported in the first patient. Unwired: nothing has been reported about olfactory
    pathways in this disease.
  phenotype_term:
    preferred_term: Hyposmia
    term:
      id: HP:0004409
      label: Hyposmia
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The olfactory finding in the first reported patient.
- category: Neurologic
  name: Motor polyneuropathy
  description: >-
    Present in the first patient only, as a predominantly motor neuropathy with conduction
    block. The comparison table records no evidence of polyneuropathy in either of the
    other two patients, so despite the disease's original name a neuropathy is not a
    constant feature. Unwired: the mouse with combined SCP2 and SCPx loss does develop
    neuropathy, but that is a different lesion and cannot carry a human causal edge on its
    own.
  phenotype_term:
    preferred_term: Motor polyneuropathy
    term:
      id: HP:0007178
      label: Motor polyneuropathy
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Electrophysiology | a predominantly motor and slight sensory neuropathy, with conduction blocks in the tibial nerves, reduced motor action potentials in the left peroneal nerve, and reduced amplitude of the left sural nerve | No evidence of polyneuropathy | No evidence of polyneuropathy |"
    explanation: >-
      The nerve conduction row of the three-patient table: neuropathy in the first patient
      and explicitly absent in the other two.
- category: Neurologic
  name: Ataxia
  description: >-
    The second patient presented in his thirties with hand clumsiness followed by gait
    disturbance, and is described in review as an adult-onset spinocerebellar ataxia; the
    first had mild cerebellar signs only. Unwired.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other patient developed hand clumsiness in his 30s, followed by gait disturbance and deafness"
    explanation: The presenting course of the second reported patient.
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "with spinocerebellar ataxia and brain iron accumulation"
    explanation: >-
      The same patient characterised as a spinocerebellar ataxia in a later paper's
      introduction, which is where that label for the second patient comes from.
- category: Neurologic
  name: Iron accumulation in brain
  description: >-
    Reported in the second patient, whose brain MRI was read as showing the changes
    characteristic of neurodegeneration with brain iron accumulation. It is a single-patient
    finding and has not been described in the other two. Unwired: no mechanism linking
    peroxisomal branched-chain fatty acid handling to brain iron deposition has been
    proposed or tested.
  phenotype_term:
    preferred_term: Iron accumulation in brain
    term:
      id: HP:0012675
      label: Iron accumulation in brain
  evidence:
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "with spinocerebellar ataxia and brain iron accumulation"
    explanation: >-
      The second patient's imaging phenotype as restated in a later report's introduction.
- category: Hearing
  name: Hearing impairment
  description: >-
    Deafness in the second patient. Single-patient finding; unwired.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other patient developed hand clumsiness in his 30s, followed by gait disturbance and deafness"
    explanation: The hearing loss of the second reported patient.
- category: Neurologic
  name: Psychosis
  description: >-
    The presenting and dominant feature of the third patient, as recurrent episodes of
    delusions, agitation and disorganised behaviour that each followed an acute upper
    respiratory tract infection and remitted over months on antipsychotics. It had not been
    reported in this disease before. Unwired: infection-triggered episodic encephalopathy is
    a recognised pattern in other metabolic disorders, but nothing has been measured in this
    patient or this disease to support a decompensation mechanism.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During each attack, he experienced delusions, irritability, aggressive behavior, bursts of uncontrollable laughter, crying, and talking to himself."
    explanation: The content of the psychotic episodes in the third reported patient.
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each episode was triggered by an acute upper respiratory tract infection."
    explanation: The episodic, infection-triggered pattern.
- category: Neurologic
  name: Bilateral tonic-clonic seizure
  description: >-
    The third patient was admitted in convulsive status epilepticus lasting eighteen hours.
    Single-patient finding; unwired.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In January 2018, the patient was readmitted to the hospital for continuous generalized tonic-clonic seizures (GTCS) that lasted 18 h without recovery between seizures."
    explanation: The seizure presentation of the third reported patient.
- category: Voice
  name: Stuttering
  description: >-
    One of only three features the three-patient comparison identifies as shared, alongside
    tremor and the imaging lesions. Unwired.
  phenotype_term:
    preferred_term: Stuttering
    term:
      id: HP:0025268
      label: Stuttering
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As summarized in Table 1, these shared clinical features in SCPx deficiency include stutter, tremors, and symmetrical lesions in the thalamus and brainstem without gadolinium enhancement"
    explanation: Names stutter as a feature shared across the three reported patients.
- category: Genitourinary
  name: Azoospermia
  description: >-
    Reported in the first patient. SCPx and SCP2 are most highly expressed in tissues that
    traffic and oxidise cholesterol, the testis among them, which makes a testicular
    phenotype biologically plausible - but plausibility is all there is here, and the
    azoospermia is unwired for that reason.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia."
    explanation: The reproductive finding in the first reported patient.
biochemical:
- name: Plasma pristanic acid
  presence: INCREASED
  notes: >-
    The single most useful analyte. In the two patients with complete enzyme deficiency it
    was far above the upper reference limit; in the third, whose variant is argued to leave
    partial function, it was only marginally raised. The published concentrations and their
    laboratory reference ranges differ between reports and none is quoted here, so no
    numeric value is asserted.
  biomarker_term:
    preferred_term: Elevated circulating pristanic acid concentration
    term:
      id: HP:0034721
      label: Elevated circulating pristanic acid concentration
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
    explanation: The range of elevation across the three reported patients.
- name: Plasma phytanic acid
  presence: INCREASED
  notes: >-
    Raised only mildly, and in the third patient not at all. This is the discriminator
    against adult Refsum disease, where the block is in alpha-oxidation, one step before the
    conversion of phytanic acid into pristanic acid.
  biomarker_term:
    preferred_term: Elevated circulating phytanic acid concentration
    term:
      id: HP:0010571
      label: Elevated circulating phytanic acid concentration
  evidence:
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
    explanation: >-
      States the relative behaviour of the two branched-chain acids, and in the same
      sentence the normal very-long-chain fatty acids that complete the profile.
- name: Plasma very-long-chain fatty acids
  presence: NORMAL
  notes: >-
    Normal, which is a positive diagnostic feature rather than a missing one: it separates
    this disease from X-linked adrenoleukodystrophy and from D-bifunctional protein
    deficiency, in both of which very-long-chain fatty acids accumulate.
    A plasma very-long-chain fatty acid screen alone will therefore miss SCP2 deficiency.
  evidence:
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
    explanation: Records the normal very-long-chain fatty acids in the second reported patient.
- name: Urinary bile alcohol glucuronides
  presence: INCREASED
  notes: >-
    Abnormal bile alcohol glucuronides in urine in the first patient. Whether this is a
    consistent feature is unknown: it is not reported for the other two patients, and
    neither is it reported as having been looked for.
  biomarker_term:
    preferred_term: Elevated urinary bile alcohol level
    term:
      id: HP:6001007
      label: Elevated urinary bile alcohol level
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine."
    explanation: The urinary bile alcohol finding in the first reported patient.
- name: SCPx thiolytic activity and protein in cultured skin fibroblasts
  presence: DECREASED
  notes: >-
    The confirmatory test. Enzyme activity and immunoblot in cultured fibroblasts are what
    established the diagnosis in the first patient and what converted two variants of
    unknown significance into a diagnosis in the second.
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
    explanation: Both readouts in the first reported patient.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This prompted molecular analysis, which revealed two variants of unknown significance in the SCP2 gene."
    explanation: >-
      Why protein-level confirmation mattered in the second patient: the variants alone did
      not carry the diagnosis.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Three published patients, reported singly in three separate reports, plus one
    further patient with a heterozygous variant of uncertain significance whose status is
    disputed. All three are male. That is recorded as an observation and nothing is inferred
    from it: SCP2 is autosomal and the inheritance is recessive with carrier parents
    documented, so with an n of three the sex distribution is what three consecutive
    single-patient reports happened to contain. No prevalence or incidence estimate has been
    published and no numeric rate is recorded here, because none has been measured.
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCPx deficiency is a rare disorder of peroxisomal beta-oxidation dysfunction, and it has only been documented in two patients thus far."
    explanation: >-
      The patient count before the third report, which is that report's own patient.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A third patient with presumed SCPx deficiency was recently reported by Galano et al., but it remains to be established whether this patient is truly affected by SCPx deficiency."
    explanation: >-
      The disputed fourth case, and the reason it is counted separately here rather than
      folded into the total.
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Gender | Male | Male | Male |"
    explanation: The sex row of the three-patient comparison table.
progression:
- phase: Age at onset
  notes: >-
    Onset spans childhood to adulthood across the three patients: seven years in the first,
    thirty years in the second, and not clearly datable in the third, whose stutter and
    tremor predated the first documented episode. No natural history has been described.
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Age at disease onset | 7 years | 30 years | Young, not clear |"
    explanation: The onset row of the three-patient comparison table.
diagnosis:
- name: Plasma branched-chain fatty acid profiling
  description: >-
    The step that makes the diagnosis reachable, and the step that is skipped when the
    workup stops at a very-long-chain fatty acid screen. What identifies this disease is a
    raised pristanic acid with a disproportionately low phytanic acid and normal
    very-long-chain fatty acids. Pristanic acid accumulation is not specific to this
    enzyme, because the same 2-methyl-branched beta-oxidation stream runs through ACOX2,
    D-bifunctional protein and alpha-methylacyl-CoA racemase as well, so the profile
    localises the pathway rather than the gene.
  markers: >-
    Plasma pristanic acid; plasma phytanic acid; plasma very-long-chain fatty acids.
  diagnosis_term:
    preferred_term: plasma branched-chain fatty acid profiling
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:31822849
    reference_title: "Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells."
    explanation: >-
      The professional-society statement of what the first-line biochemical workup for a
      peroxisomal disorder consists of.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal."
    explanation: The discriminating profile itself, as it presented in the second patient.
- name: Fibroblast SCPx protein and thiolase activity assay
  description: >-
    What converts a sequencing result into a diagnosis. In the second patient the two SCP2
    variants were of unknown significance and it was the near-absence of SCPx protein on
    immunoblot that established the deficiency. Where sequencing is the first-tier test,
    biochemical confirmation is the general expectation in peroxisomal disease and not a
    peculiarity of this gene.
  markers: >-
    SCPx immunoblot in cultured skin fibroblasts; SCPx thiolytic activity.
  diagnosis_term:
    preferred_term: peroxisomal enzyme studies in cultured fibroblasts
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:16685654
    reference_title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting."
    explanation: The two fibroblast readouts as performed in the first patient.
  - reference: PMID:31822849
    reference_title: "Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction."
    explanation: >-
      States the general requirement that makes the fibroblast assay necessary after a
      sequencing-first workup, which is exactly what happened in the second patient.
- name: Brain magnetic resonance imaging
  description: >-
    Not diagnostic on its own, but the finding that should raise the question. All three
    reported patients had symmetrical, non-enhancing thalamic and brainstem lesions, and in
    the third patient that pattern was repeatedly misread before the metabolic diagnosis was
    made.
  markers: >-
    Symmetrical T2 hyperintensity in the thalamus and pons, without gadolinium enhancement.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI findings were consistent among all three patients, revealing symmetrical thalamus and brainstem lesions without gadolinium enhancement."
    explanation: The consistency of the imaging pattern across the reported patients.
treatments:
- name: Phytanic Acid-Restricted Diet
  description: >-
    The only disease-directed treatment reported. The third patient was discharged on a
    phytanic-acid-restricted diet. It is mechanistically reasonable, because dietary phytol
    and phytanic acid are the source, through alpha-oxidation, of the pristanic acid that
    accumulates. No outcome of the diet has been reported
    in this disease, in this patient or any other, so this record establishes that it has
    been tried and nothing more.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequently, the patient was discharged while being placed on a phytanic acid-restricted diet."
    explanation: >-
      The single reported use of dietary restriction in this disease. No follow-up result is
      given.
  target_mechanisms:
  - target: Pristanic Acid Accumulation
    description: >-
      Restricting dietary phytol and phytanic acid limits the supply of the precursor from
      which pristanic acid is made. Whether this lowers plasma pristanic acid in SCP2
      deficiency has not been reported.
- name: Symptomatic Management of Episodic Psychosis and Seizures
  description: >-
    In the third patient the psychiatric episodes improved over three to six months on
    olanzapine or quetiapine and the status epilepticus was terminated with diazepam. That
    is symptomatic treatment of the presentation, with no effect on the metabolic lesion,
    and it is a single patient's experience.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: olanzapine
      term:
        id: CHEBI:7735
        label: olanzapine
    - preferred_term: quetiapine
      term:
        id: CHEBI:8707
        label: quetiapine
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Psychiatric symptoms gradually improved after 3-6 months of treatment with antipsychotic drugs such as olanzapine or quetiapine."
    explanation: The symptomatic response reported in the third patient.
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's seizures were effectively halted with diazepam, and the psychiatric symptoms gradually improved."
    explanation: >-
      The anticonvulsant arm of the same patient's symptomatic management, and the reason
      diazepam is listed as a third agent.
- name: Pharmacological Upregulation of SCPx (preclinical)
  description: >-
    Not a treatment anyone has received. In fibroblasts from the fourth, disputed patient,
    fenofibrate or 4-hydroxytamoxifen raised SCPx protein levels and shifted some fatty acid
    levels, and the authors propose raising SCPx pharmacologically as a strategy. Two
    caveats have to travel with it and neither is small. The cells came from the one
    reported patient whose diagnosis this entry declines to accept, so it is not established
    that the experiment was performed in SCPx deficiency at all. And the strategy is
    logically restricted to alleles that still make protein: that patient was heterozygous
    and still expressed SCPx, at reduced level, whereas the first reported patient had no
    detectable SCPx on western blot, and there is nothing to upregulate from a null allele. Recorded as a
    lead so it is discoverable, not as a therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenofibrate
      term:
        id: CHEBI:5001
        label: fenofibrate
    - preferred_term: 4-hydroxytamoxifen
      term:
        id: CHEBI:231618
        label: 4-hydroxytamoxifen
  evidence:
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with fenofibrate or 4-hydroxytamoxifen increased SCPx levels, and certain fatty acid levels in patient fibroblasts."
    explanation: >-
      The cell-culture result itself: both compounds raised SCPx levels in the patient's
      fibroblasts.
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Increasing SCPx levels through pharmacological interventions may reverse some effects of SCPx deficiency."
    explanation: >-
      The authors' own therapeutic inference from that result. Marked INDIRECT because it is
      a proposal extrapolated from fibroblast protein levels, with no measured clinical or
      organism-level outcome behind it.
  target_mechanisms:
  - target: SCPx Loss of Function
    description: >-
      Acts on the lesion itself by raising residual SCPx protein, which is why it is
      restricted to alleles that still produce some.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    Recorded as MODERATE and with low confidence. Every reported patient has a chronic
    neurological disorder with a structural brain lesion, and two of the three have a
    disabling motor or psychiatric syndrome; the third patient was repeatedly hospitalised
    and misdiagnosed across three admissions before the cause was found, which is a burden in
    itself. Against that, none of the published reports describes liver involvement, and the
    second patient's illness began in his thirties. With
    three patients there is no natural history, no disability measure and no survival data,
    so this level is an impression from three case reports rather than an assessment.
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was previously diagnosed with viral encephalitis, cerebral infarction, or mitochondrial encephalopathy."
    explanation: >-
      The diagnostic odyssey in the third patient - three separate wrong diagnoses across
      repeated admissions before the metabolic cause was identified.
animal_models:
- name: Scp2 knockout mouse
  species: Mouse
  genotype: Scp2-/- (combined SCP2 and SCPx deficiency)
  description: >-
    The original and most-used model, and the one that identified the blocked reaction. It
    ablates the whole locus, so both gene products are lost, which is not the human lesion -
    the reported patients lose the thiolase while the small SCP2 protein is made from its
    own promoter. The phenotype is dominated by phytanic acid accumulation, where the human
    disease accumulates pristanic acid.
  publication: PMID:9553048
  modeled_mechanisms:
  - target: Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The model demonstrates the specific enzymatic lesion: defective thiolytic cleavage of
      3-ketopristanoyl-CoA.
    limitations: >-
      The knockout removes SCP2 as well as SCPx, so an observed phenotype cannot be assigned
      to the thiolase alone, and the model also shows impaired peroxisomal import of
      phytanoyl-CoA, which is a function of the lipid-carrier product rather than of the
      thiolase.
    evidence:
    - reference: PMID:9553048
      reference_title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA."
      explanation: The blocked reaction, demonstrated in the model.
  - target: Pristanic Acid Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Branched-chain fatty acid accumulation occurs, but the species that accumulates is
      phytanic acid.
    limitations: >-
      The mouse accumulates phytanic acid up to ten-fold, whereas the human disease is
      defined by a marked pristanic acid rise with phytanic acid only mildly elevated. The
      direction of the branched-chain lesion is reproduced; its composition is not.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse and human differ in which branched-chain species dominates the accumulation.
        The model's readout is phytanic acid; the human diagnostic analyte is pristanic acid.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The quantity measured in the model is tissue and plasma phytanic acid. The quantity
        this node asserts is plasma pristanic acid. They are adjacent metabolites in one
        pathway, not the same measurement.
    evidence:
    - reference: PMID:9553048
      reference_title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice."
      explanation: The accumulating species and its magnitude in the model.
  evidence:
  - reference: PMID:9553048
    reference_title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Complete deficiency of SCP2 and SCPx was associated with marked alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired body weight control, and neuropathy."
    explanation: >-
      The whole-animal phenotype, including the neuropathy that is the model's closest
      approach to the human neurological disease. It is cited to bound what the model
      represents: hypolipidemia and impaired body weight control have no counterpart in any
      reported patient.
- name: SCP-x-null mouse
  species: Mouse
  genotype: SCP-x-null (SCPx ablated, SCP2 expression preserved)
  description: >-
    The model that matches the human lesion, because it removes the thiolase while leaving
    SCP2 expression intact. That separation is itself one of its findings. It was
    characterised under a phytol-enriched diet, which is a substrate challenge rather than
    the steady state a patient lives in.
  publication: PMID:17068117
  modeled_mechanisms:
  - target: Block of Peroxisomal Thiolytic Cleavage of 2-Methyl-Branched 3-Ketoacyl-CoA
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Establishes at whole-animal level that losing SCPx alone impairs branched-chain lipid
      metabolism, which is the claim the human disease rests on.
    limitations: >-
      The branched-chain phenotype was elicited by a phytol-enriched diet, so it measures
      reserve capacity under load rather than the unchallenged state, and the reported
      consequences are hepatic and nutritional rather than neurological. No brain phenotype
      is reported for this model.
    evidence:
    - reference: PMID:17068117
      reference_title: Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In summary, the present work with SCP-x gene-ablated mice demonstrates, for the first time, a direct physiological relationship between lack of SCP-x and decreased ability to metabolize branched-chain lipids."
      explanation: >-
        The model's own summary of what it established: SCPx loss alone impairs
        branched-chain lipid metabolism.
  evidence:
  - reference: PMID:17068117
    reference_title: Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x)"
    explanation: >-
      Why this model is the better analogue of the human genotype: ablating SCPx does not
      take SCP2 with it, so the two gene products can be separated.
- name: Scp2-null mouse on a phytol-enriched diet, cardiac phenotype
  species: Mouse
  genotype: Scp2-/- (combined SCP2 and SCPx deficiency), phytol-enriched diet
  description: >-
    A cardiac electrophysiology study of the combined knockout under phytol loading. It is
    recorded here because one of the four reported human cases - the disputed heterozygous
    patient - had a cardiac dysrhythmia, and because this is the only model result that
    would predict one. Nothing connects them yet: none of the reports of the three patients with a confirmed
    biallelic SCP2 genotype describes an arrhythmia or a cardiac assessment.
  publication: PMID:15574183
  evidence:
  - reference: PMID:15574183
    reference_title: Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model."
    explanation: >-
      The cardiac phenotype of the combined knockout under phytol loading, and the mechanism
      the authors propose for it. Recorded without a modeled_mechanisms link because no node
      in this entry corresponds to it.
discussions:
- discussion_id: scp2-imaging-lesion-mechanism-unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route does the block in peroxisomal branched-chain beta-oxidation produce
    symmetrical thalamic and brainstem lesions?
  attaches_to:
  - pathophysiology#Symmetrical Thalamic, Brainstem and White Matter Lesions
  rationale: >-
    The lesion is the one finding common to all three reported patients and nothing is known
    about how it arises. None of the published reports carries neuropathology, a measurement of
    branched-chain fatty acid concentration in brain tissue, spectroscopy, or a correlation
    between metabolite level and imaging burden - the third patient had the
    same lesion pattern with a pristanic acid only marginally above the reference range,
    which is the one observation bearing on the question and it argues against a simple
    dose-response. The edge this entry draws from the metabolic block to the lesion is
    therefore a disease-level attribution and not a mechanism. Why the thalamus and pons specifically is also
    unexplained in any of the reports.
  evidence:
  - reference: PMID:37905191
    reference_title: "Case report: Episodic psychosis caused by a novel SCP2 splicing mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients in the literature exhibited elevated pristanic acid levels, whereas the index patient showed a mild increase."
    explanation: >-
      The dissociation that makes the question live: the same imaging lesion at markedly
      different metabolite concentrations.
- discussion_id: scp2-mouse-accumulates-the-wrong-metabolite
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is the Scp2 knockout mouse a valid model of human SCP2 deficiency, given that it deletes
    both gene products and accumulates phytanic rather than pristanic acid?
  attaches_to:
  - pathophysiology#Pristanic Acid Accumulation
  - animal_models#Mouse
  rationale: >-
    The mouse literature is older and far larger than the human literature, so it is the
    default source of mechanism for this disease - and it diverges from the human lesion in
    two ways at once. First, the widely used knockout ablates the whole Scp2 locus, removing
    both the thiolase and the small lipid-carrier protein, whereas the human disease-causing
    variants lie in the SCPx-coding region and leave SCP2 transcribed from its own promoter;
    the SCP-x-null mouse showed directly that the two can be separated. Second, the combined
    knockout's defining biochemical abnormality is a ten-fold phytanic acid accumulation,
    while the human disease is defined by a marked pristanic acid rise with phytanic acid
    only mildly raised - the opposite emphasis. No brain phenotype resembling the human
    thalamic and pontine lesions is reported in any of the mouse papers cited here. What follows practically:
    a mouse finding should not be carried into this entry as a human mechanism without
    saying which model it came from, and the SCP-x-null model is the one that matches the
    human genotype.
  evidence:
  - reference: PMID:9553048
    reference_title: Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice."
    explanation: The model's accumulating species, which is not the human one.
  - reference: PMID:17068117
    reference_title: Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x)"
    explanation: >-
      Demonstrates that the two gene products are separable, which is what makes the
      combined knockout the wrong genotype for this disease.
  proposed_experiments:
  - experiment_id: scp2-scpx-null-brain-phenotyping
    name: Brain phenotyping of the SCP-x-null mouse
    description: >-
      Characterise brain imaging and neuropathology in the SCPx-selective knockout, with and
      without a phytol load, and measure pristanic and phytanic acid in brain tissue. This
      is the model whose genotype matches the human disease, and no brain phenotype has been
      reported for it.
    would_support:
    - pathophysiology#Symmetrical Thalamic, Brainstem and White Matter Lesions
    supporting_outcome:
    - >-
      Symmetrical thalamic or brainstem lesions, or regional white matter pathology,
      appearing in SCPx-null but not wild-type animals and tracking with brain branched-chain
      fatty acid content.
    refuting_outcome:
    - >-
      No brain lesion and no regional branched-chain fatty acid accumulation in SCPx-null
      animals even under sustained phytol loading, which would argue the human lesion is not
      a direct consequence of the thiolase block.
- discussion_id: scp2-heterozygous-case-disputed
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does a single heterozygous SCP2 missense variant cause SCPx deficiency, as the fourth
    reported case claims?
  attaches_to:
  - genetic#SCP2
  rationale: >-
    A fourth patient has been reported, with progressive brainstem neurodegeneration,
    cardiac dysrhythmia, muscle wasting and azoospermia, carrying a single heterozygous
    SCP2 missense variant that the report itself classified as of uncertain significance.
    The paper's supporting evidence is cellular - reduced SCPx protein and transcript in
    patient fibroblasts, fewer peroxisomes, and altered lipid and transcript profiles - and
    it makes a real claim, since a dominant-negative or haploinsufficiency mechanism is not
    excluded a priori. But every other reported patient is biallelic, a subsequent review
    states that whether this patient has SCPx deficiency remains to be established, and
    ClinGen's expert panel scored only two individuals when it curated the gene. This entry
    therefore records the disease as autosomal recessive and does not curate that patient's
    features as phenotypes of it; the cardiac and muscle findings in particular appear
    nowhere else in this disease.
  evidence:
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report herein the first patient with a heterozygous SCP2 mutation leading to SCPx deficiency."
    explanation: The claim itself, in the words of the report making it.
  - reference: PMID:35996156
    reference_title: "SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentations of the patient included progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia."
    explanation: >-
      The features attributed to that patient, none of which except azoospermia is reported
      in a biallelic patient.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: REFUTE
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A third patient with presumed SCPx deficiency was recently reported by Galano et al., but it remains to be established whether this patient is truly affected by SCPx deficiency."
    explanation: >-
      A review of the peroxisomal fatty acid disorders declining to accept the case, which is
      why this entry does not curate it.
- discussion_id: scp2-phenotype-expansion
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the phenotype of SCP2 deficiency, given that the three reported patients share
    almost nothing except an MRI pattern?
  attaches_to:
  - phenotypes#
  rationale: >-
    Torticollis with a motor neuropathy, an adult-onset ataxia with deafness and brain iron
    accumulation, and infection-triggered episodic psychosis with status epilepticus are
    three different clinical pictures. Only stutter, tremor and the imaging lesion recur.
    This entry consequently records no frequency on any phenotype and calls none of them
    typical, because with an n of three every feature is either universal or unique
    depending on how it is counted. ClinGen's expert panel renamed the disease from the
    descriptive LKDMN label to SCP2 deficiency for the same reason - to leave room for the
    phenotype to expand - and that rename is the clearest statement available that the
    clinical definition is not settled. A further retinal phenotype has been described in
    the second patient and is not curated here, because the report has no abstract in the
    reference cache and nothing quotable could be verified.
  evidence:
  - reference: PMID:37236006
    reference_title: Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For instance, the disorder associated with SCP2 variants was termed SCP2 deficiency to replace the phenotype-based nomenclature, leukoencephalopathy-dystonia-motor neuropathy syndrome."
    explanation: >-
      The expert panel's rename, made explicitly to allow for phenotype expansion.
  - reference: PMID:38693715
    reference_title: Disorders of fatty acid homeostasis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "An unusual retinal phenotype was later described in the same patient."
    explanation: >-
      Records that a further organ system has been reported in one patient. The primary
      report is cited in `references` but nothing from it is quoted, for the reason given in
      the rationale.
notes: >-
  Lump/split. Curated as a standalone Disease entry. MONDO:0013391 is a leaf with no
  descendants and one causal gene, and the knowledge base already curates each single-enzyme
  peroxisomal beta-oxidation defect separately - ACOX1, HSD17B4, AMACR, ABCD3 - so a
  has_subtypes row on one of those would have been a different lump than the ones already
  made. The peroxisomal entries in kb/disorders/ were checked individually and none is the
  right parent: Congenital_Bile_Acid_Synthesis_Defect_5 is the ABCD3 transporter defect
  (its mention of SCPx is a line in a fibroblast enzyme panel that was normal in that
  patient, not a binding), alpha-Methylacyl-CoA_Racemase_Deficiency and
  D-Bifunctional_Protein_Deficiency are the enzymes immediately upstream of SCPx in the same
  spiral, and the Zellweger and rhizomelic entries are biogenesis and ether-lipid disorders.
  ClinGen's Peroxisomal Gene Curation Expert Panel likewise curates SCP2 as its own
  gene-disease entity and places it as a subclass of peroxisomal beta oxidation.

  Module conformance. The entry conforms at
  peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect, entering that module
  by its single-enzyme arm. It deliberately does not conform at the module's central effector
  node, "Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency", because that node asserts
  substrate accumulation and ether-lipid deficiency together and this disease has only the
  accumulation half - plasmalogen synthesis is not part of the lesion, and no plasmalogen
  abnormality is reported in any of the published cases. Conformance to cns_myelin_failure and to
  peripheral_axonal_degeneration was considered and rejected: the white matter finding is an
  MRI signal abnormality with no reported neuropathology behind it, and the neuropathy occurs
  in one of three patients, so in both cases conforming would assert a cellular mechanism
  that nothing in the literature establishes.

  Deep research. A deep-research report was run as a post-hoc cross-check and is committed
  under `research/`; see `review_notes` for what it converged on and what was refused from
  it. No content in this entry derives from it.

  What is not here, and why. No prevalence rate, because none has been published. No
  phenotype frequencies, because three patients cannot support a frequency band. No
  histopathology section, because none of the published reports describes a biopsy or
  autopsy. No
  environmental section: dietary phytol is the precursor of the accumulating metabolite and a
  restricted diet was tried in one patient, but no exposure has been reported as triggering
  or modifying the disease, so an environmental entry would be an inference rather than an
  observation. The acute episodes of the third patient followed respiratory infections, which
  the author compares to metabolic decompensation in other disorders; nothing was measured
  during an episode, so that comparison is not curated as a mechanism. Four organ-system
  findings reported only in the disputed heterozygous case - cardiac dysrhythmia, muscle
  wasting, reduced testosterone with raised follicle-stimulating hormone, and the
  fibroblast lipidomic and transcriptomic changes - are described in the relevant discussion
  and are not curated as phenotypes of this disease.
review_notes: >-
  Term provenance. Every CURIE in this entry was looked up at the moment it was written:
  HP, GO and CHEBI terms with `runoak -i sqlite:obo:<onto>`, NCIT terms against
  `cache/ncit/terms.csv`, MONDO and HGNC with `runoak info`. hgnc:10606 was confirmed to be
  SCP2 and distinguished from SCP2D1, which is hgnc:16211.

  One binding chosen against a better-classified alternative. 4-hydroxytamoxifen is bound
  to CHEBI:231618, whose label is exactly that, and not to CHEBI:44616 afimoxifene. Both
  were inspected with `runoak -i sqlite:obo:chebi info ... -O obo` and neither is obsolete.
  CHEBI:44616 is the better-curated entry - real chemical parentage, defined as the active
  metabolite of tamoxifen - but it is specifically the Z-isomer, and the cited paper says
  only "4-hydroxytamoxifen". Binding it would have manufactured a narrower match than the
  source supports. CHEBI:231618 is a thin entry whose only parent is `organic molecular
  entity`, which is a fact about ChEBI's curation of it and not a reason to over-bind.

  Two bindings that are broader than the finding, and why. The pontine lesions are
  bound to HP:0012748 Focal T2 hyperintense brainstem lesion, the most specific available:
  `runoak -i sqlite:obo:hp descendants HP:0012747 -p i` returns only brainstem-level terms
  and no pons-specific T2-hyperintensity term exists, while HP:4000169 Pontine T2
  hypointensity is the wrong direction. The urinary finding is bound to HP:6001007 Elevated
  urinary bile alcohol level; `runoak -i sqlite:obo:hp search "t~bile alcohol"` returns only
  that term and HP:6000821 for the circulating measure, with no glucuronide-specific term.

  Evidence coverage and its limits. Two of the four human reports have no quotable text in
  the reference cache: PMID:26497993, the second patient's Neurology report, cached with
  `content_type: unavailable`, and PMID:28033445, the retinal follow-up on the same patient,
  likewise. Both are listed under `references` with titles copied from the cache frontmatter,
  and every claim about the second patient in this entry is therefore sourced to a third
  party - the 2023 case report's comparison table or the 2025 review - and graded
  accordingly. Nothing in this entry quotes either paper.

  ORPHA:163684 was not cited. MONDO cross-references it and Orphanet is the source of
  MONDO's own definition of this disease, but `just fetch-reference ORPHA:163684` in this
  checkout returns "No source found for reference type", so no cache file could be
  generated and no snippet verified.

  GeneReviews baseline. There is no GeneReviews chapter for this disease, and no StatPearls
  article. That was verified offline with `just check-genereviews` against the committed
  Bookshelf index in `cache/bookshelf/` (snapshot 2026-09-10, 958 GeneReviews and 9646
  StatPearls titles), which reports NO_CHAPTER for both collections. The absence is expected
  for a disease with three published patients and is not a gap in this entry.

  Deep-research cross-check, run after the entry was written. A claude_code deep-research
  report was generated as a post-hoc check on whether this entry is narrow because the
  literature is narrow, or narrow because it was under-consumed:
  `research/Sterol_Carrier_Protein_2_Deficiency-deep-research-claude_code.md`, with its
  `.citations.md` sidecar. It is a cross-check, not a source: nothing in this entry was
  taken from it, and it was produced after every claim here had already been written and
  verified. The result is the reason it is worth recording. It cited 11 PMIDs and they are
  the same 11 this entry cites - zero new references - and it proposed no ontology term this
  entry does not already bind. `just preflight-dr ... MONDO:0013391` returns PASS with
  SCP2 as the canonical gene mentioned 29 times.

  Three things the report offered that were refused. It wrote that patient 1 was "reported
  at 45" and that patient 3 was a "young adult"; neither age is in any cached source, and
  the second contradicts the cited report, which describes a 48-year-old. It wrote that the
  "Orphanet-style class would be <1/1,000,000" while itself noting no figure has been
  published - that class is not recorded here, and `prevalence_class` stays
  `NOT_YET_DOCUMENTED` with `measure_type: CASES_IN_LITERATURE`. The report's own
  reference validation also flags one unsupported quote, attributed to PMID:15574183, the
  mouse cardiac paper; the quote this entry takes from that paper was copied from the cache
  independently and verifies exactly.

  What was searched. PubMed was searched for `"sterol carrier protein X" AND deficiency`,
  `SCPx deficiency human`, `"sterol carrier protein 2" deficiency patient`, `SCP2 AND
  (macula* OR retina* OR fundus)` and the phytol/knockout mouse queries, and the 55 papers
  citing PMID:16685654 were listed and screened by title. That search found four human case
  reports in total - three biallelic and one heterozygous and disputed - plus the retinal
  follow-up on the second patient, and no further patient.

  Not searched, and so not asserted. No claim is made anywhere in this entry about carrier
  frequency, population distribution, ancestry, or age or cause of death, because none was
  searched for. No claim is made about the nationality or ancestry of any reported patient.
📚

References & Deep Research

References

11
PMID:16685654
Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
No top-level findings curated for this source.
PMID:26497993
SCP2 mutations and neurodegeneration with brain iron accumulation.
No top-level findings curated for this source.
PMID:28033445
An Unusual Retinal Phenotype Associated With a Mutation in Sterol Carrier Protein SCP2.
No top-level findings curated for this source.
PMID:35996156
SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects.
No top-level findings curated for this source.
PMID:37905191
Case report: Episodic psychosis caused by a novel SCP2 splicing mutation.
No top-level findings curated for this source.
PMID:37236006
Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
No top-level findings curated for this source.
PMID:38693715
Disorders of fatty acid homeostasis.
No top-level findings curated for this source.
PMID:31822849
Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG).
No top-level findings curated for this source.
PMID:9553048
Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
No top-level findings curated for this source.
PMID:17068117
Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
No top-level findings curated for this source.
PMID:15574183
Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record review notes

Term provenance. Every CURIE in this entry was looked up at the moment it was written: HP, GO and CHEBI terms with `runoak -i sqlite:obo:<onto>`, NCIT terms against `cache/ncit/terms.csv`, MONDO and HGNC with `runoak info`. hgnc:10606 was confirmed to be SCP2 and distinguished from SCP2D1, which is hgnc:16211. One binding chosen against a better-classified alternative. 4-hydroxytamoxifen is bound to CHEBI:231618, whose label is exactly that, and not to CHEBI:44616 afimoxifene. Both were inspected with `runoak -i sqlite:obo:chebi info ... -O obo` and neither is obsolete. CHEBI:44616 is the better-curated entry - real chemical parentage, defined as the active metabolite of tamoxifen - but it is specifically the Z-isomer, and the cited paper says only "4-hydroxytamoxifen". Binding it would have manufactured a narrower match than the source supports. CHEBI:231618 is a thin entry whose only parent is `organic molecular entity`, which is a fact about ChEBI's curation of it and not a reason to over-bind. Two bindings that are broader than the finding, and why. The pontine lesions are bound to HP:0012748 Focal T2 hyperintense brainstem lesion, the most specific available: `runoak -i sqlite:obo:hp descendants HP:0012747 -p i` returns only brainstem-level terms and no pons-specific T2-hyperintensity term exists, while HP:4000169 Pontine T2 hypointensity is the wrong direction. The urinary finding is bound to HP:6001007 Elevated urinary bile alcohol level; `runoak -i sqlite:obo:hp search "t~bile alcohol"` returns only that term and HP:6000821 for the circulating measure, with no glucuronide-specific term. Evidence coverage and its limits. Two of the four human reports have no quotable text in the reference cache: PMID:26497993, the second patient's Neurology report, cached with `content_type: unavailable`, and PMID:28033445, the retinal follow-up on the same patient, likewise. Both are listed under `references` with titles copied from the cache frontmatter, and every claim about the second patient in this entry is therefore sourced to a third party - the 2023 case report's comparison table or the 2025 review - and graded accordingly. Nothing in this entry quotes either paper. ORPHA:163684 was not cited. MONDO cross-references it and Orphanet is the source of MONDO's own definition of this disease, but `just fetch-reference ORPHA:163684` in this checkout returns "No source found for reference type", so no cache file could be generated and no snippet verified. GeneReviews baseline. There is no GeneReviews chapter for this disease, and no StatPearls article. That was verified offline with `just check-genereviews` against the committed Bookshelf index in `cache/bookshelf/` (snapshot 2026-09-10, 958 GeneReviews and 9646 StatPearls titles), which reports NO_CHAPTER for both collections. The absence is expected for a disease with three published patients and is not a gap in this entry. Deep-research cross-check, run after the entry was written. A claude_code deep-research report was generated as a post-hoc check on whether this entry is narrow because the literature is narrow, or narrow because it was under-consumed: `research/Sterol_Carrier_Protein_2_Deficiency-deep-research-claude_code.md`, with its `.citations.md` sidecar. It is a cross-check, not a source: nothing in this entry was taken from it, and it was produced after every claim here had already been written and verified. The result is the reason it is worth recording. It cited 11 PMIDs and they are the same 11 this entry cites - zero new references - and it proposed no ontology term this entry does not already bind. `just preflight-dr ... MONDO:0013391` returns PASS with SCP2 as the canonical gene mentioned 29 times. Three things the report offered that were refused. It wrote that patient 1 was "reported at 45" and that patient 3 was a "young adult"; neither age is in any cached source, and the second contradicts the cited report, which describes a 48-year-old. It wrote that the "Orphanet-style class would be <1/1,000,000" while itself noting no figure has been published - that class is not recorded here, and `prevalence_class` stays `NOT_YET_DOCUMENTED` with `measure_type: CASES_IN_LITERATURE`. The report's own reference validation also flags one unsupported quote, attributed to PMID:15574183, the mouse cardiac paper; the quote this entry takes from that paper was copied from the cache independently and verifies exactly. What was searched. PubMed was searched for `"sterol carrier protein X" AND deficiency`, `SCPx deficiency human`, `"sterol carrier protein 2" deficiency patient`, `SCP2 AND (macula* OR retina* OR fundus)` and the phytol/knockout mouse queries, and the 55 papers citing PMID:16685654 were listed and screened by title. That search found four human case reports in total - three biallelic and one heterozygous and disputed - plus the retinal follow-up on the second patient, and no further patient. Not searched, and so not asserted. No claim is made anywhere in this entry about carrier frequency, population distribution, ancestry, or age or cause of death, because none was searched for. No claim is made about the nationality or ancestry of any reported patient.

Record notes

Lump/split. Curated as a standalone Disease entry. MONDO:0013391 is a leaf with no descendants and one causal gene, and the knowledge base already curates each single-enzyme peroxisomal beta-oxidation defect separately - ACOX1, HSD17B4, AMACR, ABCD3 - so a has_subtypes row on one of those would have been a different lump than the ones already made. The peroxisomal entries in kb/disorders/ were checked individually and none is the right parent: Congenital_Bile_Acid_Synthesis_Defect_5 is the ABCD3 transporter defect (its mention of SCPx is a line in a fibroblast enzyme panel that was normal in that patient, not a binding), alpha-Methylacyl-CoA_Racemase_Deficiency and D-Bifunctional_Protein_Deficiency are the enzymes immediately upstream of SCPx in the same spiral, and the Zellweger and rhizomelic entries are biogenesis and ether-lipid disorders. ClinGen's Peroxisomal Gene Curation Expert Panel likewise curates SCP2 as its own gene-disease entity and places it as a subclass of peroxisomal beta oxidation. Module conformance. The entry conforms at peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect, entering that module by its single-enzyme arm. It deliberately does not conform at the module's central effector node, "Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency", because that node asserts substrate accumulation and ether-lipid deficiency together and this disease has only the accumulation half - plasmalogen synthesis is not part of the lesion, and no plasmalogen abnormality is reported in any of the published cases. Conformance to cns_myelin_failure and to peripheral_axonal_degeneration was considered and rejected: the white matter finding is an MRI signal abnormality with no reported neuropathology behind it, and the neuropathy occurs in one of three patients, so in both cases conforming would assert a cellular mechanism that nothing in the literature establishes. Deep research. A deep-research report was run as a post-hoc cross-check and is committed under `research/`; see `review_notes` for what it converged on and what was refused from it. No content in this entry derives from it. What is not here, and why. No prevalence rate, because none has been published. No phenotype frequencies, because three patients cannot support a frequency band. No histopathology section, because none of the published reports describes a biopsy or autopsy. No environmental section: dietary phytol is the precursor of the accumulating metabolite and a restricted diet was tried in one patient, but no exposure has been reported as triggering or modifying the disease, so an environmental entry would be an inference rather than an observation. The acute episodes of the third patient followed respiratory infections, which the author compares to metabolic decompensation in other disorders; nothing was measured during an episode, so that comparison is not curated as a mechanism. Four organ-system findings reported only in the disputed heterozygous case - cardiac dysrhythmia, muscle wasting, reduced testosterone with raised follicle-stimulating hormone, and the fibroblast lipidomic and transcriptomic changes - are described in the relevant discussion and are not curated as phenotypes of this disease.

Review round 1: deep-research artifact, therapeutic_agent bindings, preclinical rescue lead · 2026-09-19T09:32:59Z · View source

Review round 1 on PR #12290. The ai4c-reviewer bot submitted CHANGES_REQUESTED with two blocking items and three suggestions. All five were addressed in a single push; nothing was deferred and nothing was conceded that the entry had got right. Blocking item 1 - no deep-research artifact for a new entry. Accepted and run. `just research-disorder claude_code Sterol_Carrier_Protein_2_Deficiency` produced research/Sterol_Carrier_Protein_2_Deficiency-deep-research-claude_code.md plus its .citations.md sidecar, both committed. No _artifacts/ directory was produced by this provider for this run. The report was generated AFTER the entry was written and verified, and is recorded in notes and review_notes as a post-hoc cross-check rather than a source: no claim in the entry derives from it. Its value is what it converged on. It cites 11 PMIDs and they are the same 11 the entry already cited - zero new references - and it proposed no ontology term the entry did not already bind. just preflight-dr against MONDO:0013391 returns PASS with SCP2 as canonical gene, mentioned 29 times. That is the evidence the reviewer asked for: the entry is narrow because the literature is narrow. Three claims in the report were refused and the refusals recorded in review_notes: patient 1 "reported at 45" and patient 3 as a "young adult" are ages in no cached source, and the second contradicts the cited report, which describes a 48-year-old; and an "Orphanet-style class would be <1/1,000,000", which the report itself notes has never been published. prevalence_class stays NOT_YET_DOCUMENTED with measure_type CASES_IN_LITERATURE. The report's own reference validation flags one unsupported quote attributed to PMID:15574183, an ellipsis-elided paraphrase; the entry's own quote from that paper was copied from the cache independently and verifies exactly. Blocking item 2 - generic Pharmacotherapy binding with no therapeutic_agent. Accepted and fixed. The reviewer's three suggested CHEBI CURIEs were verified independently before use, against cache/chebi/terms.csv and with runoak, rather than pasted: CHEBI:7735 olanzapine, CHEBI:8707 quetiapine, CHEBI:49575 diazepam all resolve with matching labels. A second evidence item was added for the diazepam arm, which the previous single snippet did not cover. Suggestion 3 - uncaptured in-vitro rescue in PMID:35996156. Accepted. Added a treatment "Pharmacological Upregulation of SCPx (preclinical)" following the KB's existing convention for preclinical leads, with two IN_VITRO evidence items and two caveats carried in the description: the fibroblasts came from the one patient whose diagnosis this entry declines to accept, and upregulation is logically restricted to alleles that still make protein, where the first reported patient had no detectable SCPx at all. therapeutic_agent binds CHEBI:5001 fenofibrate and CHEBI:231618 4-hydroxytamoxifen. CHEBI:44616 afimoxifene was inspected and rejected: it is the better-classified entry but is specifically the Z-isomer, and the cited paper says only "4-hydroxytamoxifen", so binding it would have manufactured a narrower match than the source supports. Neither candidate is obsolete. Suggestion 4 - presence: MILDLY INCREASED was a one-off string. Accepted; changed to INCREASED, with the "raised only mildly" nuance already carried in the adjacent notes. Suggestion 5 - causal connectivity 5/18. Noted by the reviewer for the record only, with no change requested; none made. The 13 unwired phenotypes each state their reason. One fact was added from the report's phenotype section after independent verification: all three reported patients are male, quoted from the gender row of the PMID:37905191 comparison table. It is recorded as an observation with an explicit statement that nothing is inferred from it, since SCP2 is autosomal and carrier parents are documented. Validation after the round: just validate and just validate-disorders both pass with 76/76 snippets verified against cached references, up from 72/72. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-case-collisions, check-stubs, check-genereviews and list-gene-term-mismatches (0 findings) all pass. just validate-research-reference on the new report reproduces the single upstream unsupported-quote warning described above.

Claude Code ▸
1. Disease Information
claude-fable-5, claude-haiku-4-5-20251001 9 citations 2026-09-19T02:27:41.493668

1. Disease Information

Overview. Sterol carrier protein 2 deficiency is an autosomal recessive, single-enzyme defect of peroxisomal β-oxidation caused by biallelic loss-of-function variants in SCP2. The SCP2 locus is transcribed from two promoters and produces two proteins: the 58-kDa peroxisomal 3-ketoacyl-CoA thiolase SCPx and the small (13-kDa) non-specific lipid-transfer protein SCP2. The human disease is loss of the thiolase arm (SCPx), which catalyzes the final thiolytic cleavage step of peroxisomal β-oxidation for 2-methyl-branched substrates — pristanic acid degradation and side-chain shortening of C27 bile-acid intermediates. The founding report describes "the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids" (Ferdinandusse et al., Am J Hum Genet 2006; PMID:16685654).

Identifiers.

Resource ID
MONDO MONDO:0013391 (sterol carrier protein 2 deficiency)
OMIM (phenotype) 613724 — Leukoencephalopathy with dystonia and motor neuropathy
OMIM (gene) *184755 — SCP2
Orphanet ORPHA:163684
ICD-10-CM No specific code; closest is E71.548 (Other peroxisomal disorders) — a broad residual category, not an asserted cross-reference
HGNC hgnc:10606 (SCP2), chromosome 1p32.3

Synonyms: SCP2 deficiency; SCPx deficiency; sterol carrier protein X deficiency; leukoencephalopathy with dystonia and motor neuropathy (LKDMN); leukoencephalopathy-dystonia-motor neuropathy syndrome. The ClinGen Peroxisomal GCEP deliberately renamed the entity: "the disorder associated with SCP2 variants was termed SCP2 deficiency to replace the phenotype-based nomenclature, leukoencephalopathy-dystonia-motor neuropathy syndrome" (PMID:37236006) — explicitly to leave room for the phenotype to expand beyond the founding case's features.

Data derivation: All clinical knowledge derives from three individually published case reports (individual-patient level), one expert-panel gene curation, and reviews. No registry, cohort, or EHR-level data exist.

2. Etiology

Causal factor: Biallelic loss-of-function variants in SCP2, specifically abolishing (or in one case reducing) SCPx thiolase. Purely genetic; no environmental, infectious, or somatic etiology is known.

Risk factors: Parental consanguinity/carrier status is the only established risk context (two of three patients were homozygous). No susceptibility loci, modifier genes, or population risk factors are known. No protective genetic or environmental factors have been reported.

Gene–environment interaction (inferred, not demonstrated): The accumulating metabolite, pristanic acid, derives ultimately from dietary phytol/phytanic acid (dairy, ruminant fat, fish), so dietary branched-chain lipid intake is the substrate load on the blocked pathway — the rationale for the phytanic-acid-restricted diet tried in patient 3 (PMID:37905191). Additionally, in patient 3 "each episode was triggered by an acute upper respiratory tract infection" (PMID:37905191), a pattern reminiscent of infection-triggered metabolic decompensation in other IEMs, but nothing was measured during an episode, so this remains an observation, not a mechanism.

3. Phenotypes

With three patients, no frequency bands are meaningful; each feature below is tagged by which patient(s) showed it. The 2023 report's cross-patient comparison identifies only three shared features: "these shared clinical features in SCPx deficiency include stutter, tremors, and symmetrical lesions in the thalamus and brainstem without gadolinium enhancement" (PMID:37905191).

Shared across all 3 patients: - Symmetrical thalamic T2-hyperintense lesions — HP:0012692 (Focal T2 hyperintense thalamic lesion); bilateral, non-enhancing - Brainstem (pontine, "butterfly-like") lesions — HP:0012748 (Focal T2 hyperintense brainstem lesion) - Tremor — HP:0002346 (Head tremor, dystonic in patient 1); HP:0002080 (Intention tremor) - Stuttering — HP:0025268

Patient 1 (male, onset ~age 7, reported at 45; PMID:16685654): "The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia." — Torticollis HP:0000473; Nystagmus HP:0000639; Hyposmia HP:0004409; Azoospermia HP:0000027; Leukoencephalopathy HP:0002352; plus a predominantly motor neuropathy with tibial conduction blocks (HP:0007178, Motor polyneuropathy) — explicitly absent in patients 2 and 3.

Patient 2 (male, onset in his 30s; PMID:26497993): hand clumsiness → gait disturbance (Ataxia HP:0001251), deafness (HP:0000365), and MRI changes of neurodegeneration with brain iron accumulation (HP:0012675); later an unusual retinal phenotype was described in the same patient (PMID:28033445).

Patient 3 (male, young adult; PMID:37905191): recurrent infection-triggered episodic psychosis (HP:0000709) — "delusions, irritability, aggressive behavior, bursts of uncontrollable laughter, crying, and talking to himself" — and convulsive status epilepticus lasting 18 hours (Bilateral tonic-clonic seizure HP:0002069). Previously misdiagnosed as viral encephalitis, cerebral infarction, and mitochondrial encephalopathy across three admissions.

Laboratory phenotypes (the diagnostic handle): Elevated circulating pristanic acid HP:0034721 (marked in patients 1–2, only mild in patient 3); mildly elevated phytanic acid HP:0010571; normal plasma VLCFA; elevated urinary bile alcohol glucuronides HP:6001007 (patient 1).

Quality of life: No formal QoL instruments have ever been applied. The documented burden is chronic neurological disease in all three, disabling motor/psychiatric syndromes in two, and a multi-year diagnostic odyssey in patient 3.

4. Genetic/Molecular Information

Causal gene: SCP2 (HGNC:10606; OMIM *184755; 1p32.3). Two promoters, two products: full-length 58-kDa SCPx (thiolase domain + SCP2 domain) and 13-kDa SCP2 (lipid transfer). All three disease genotypes fall in the SCPx-coding region; SCP2 remains transcribed from its own promoter — which is why "SCP2 deficiency" and "SCPx deficiency" name the same disease.

Reported pathogenic variants (all germline, loss-of-function):

Variant Patient Zygosity Consequence
c.545_546insA (p.I184fsX7; ClinVar: NM_002979.5 c.550dup) 1 Homozygous Frameshift/PTC; "no SCPx protein could be detected by western blotting" and absent thiolytic activity in fibroblasts (PMID:16685654)
c.121G>T + c.349C>T 2 Compound het Both initially VUS; diagnosis established by near-absent SCPx on immunoblot (PMID:37905191; PMID:38693715)
c.674+1G>C 3 Homozygous Splice-donor; "RNA sequencing revealed exon 8 skipping in the mature transcripts of SCP2" — in-frame deletion overlapping the thiolase N-domain, arguably retaining partial function, consistent with the only marginal pristanic elevation (PMID:37905191)

A fourth, disputed case (Alshehri et al. 2022, PMID:35996156) carried a single heterozygous missense VUS with brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia; a subsequent review states "it remains to be established whether this patient is truly affected by SCPx deficiency" (PMID:38693715), and ClinGen scored only two individuals. Inheritance should be recorded as recessive.

Population allele frequencies: No recurrent variant; no gnomAD carrier-frequency estimate has been published. Modifier genes, epigenetics, chromosomal abnormalities: none reported (one 1p33-p32.2 contiguous deletion including SCP2 has been reported with a complex syndromic phenotype, but that is a multi-gene deletion, not this disease — PMC7647596).

5. Environmental Information

No environmental cause. Dietary phytol/phytanic acid is the substrate source for the accumulating metabolite (relevant to management, not causation). Acute respiratory infections preceded each psychotic episode in patient 3 (trigger association only). No toxin, occupational, or lifestyle factor reported.

6. Mechanism / Pathophysiology

Causal chain:

  1. Biallelic SCP2 loss-of-function variants lead to absent (or reduced) peroxisomal 3-ketoacyl-CoA thiolase SCPx — demonstrated at protein and activity level in patient fibroblasts (PMID:16685654). [GO:0003988 acetyl-CoA C-acyltransferase activity; GO:0005777 peroxisome]
  2. SCPx loss results in a block of the thiolytic cleavage of 2-methyl-branched 3-ketoacyl-CoA — the final step of each peroxisomal β-oxidation cycle for branched substrates. Directly demonstrated in mouse ("defective thiolytic cleavage of 3-ketopristanoyl-CoA," PMID:9553048); inferred in humans from absent fibroblast thiolase activity plus the substrate pattern. [GO:0006635 fatty acid beta-oxidation]
  3. The block causes (branch A) plasma pristanic acid accumulation with only mildly raised phytanic acid and normal VLCFA (PMID:16685654; PMID:38693715) [CHEBI:51340 pristanic acid; CHEBI:16285 phytanic acid], and (branch B) incomplete side-chain shortening of C27 bile-acid intermediates, read out as abnormal urinary bile alcohol glucuronides (PMID:16685654) [GO:0006699 bile acid biosynthetic process]. Branch B has been biochemical only — no liver disease reported in any patient.
  4. The metabolic derangement is attributed to cause the symmetrical thalamic/brainstem/white-matter lesions and the neurological syndrome. This final step is an attribution, not a demonstrated mechanism: no neuropathology, brain metabolite measurement, spectroscopy, or metabolite–imaging correlation exists in any patient; indeed patient 3 had the same lesion pattern with only marginally elevated pristanic acid, arguing against simple dose–response. This is the field's principal knowledge gap.

Differential biochemistry within the pathway: the profile (pristanic ↑↑, phytanic ~normal/mild ↑, VLCFA normal) distinguishes SCPx deficiency from adult Refsum disease (α-oxidation block one step earlier — phytanic accumulates) and from D-bifunctional protein deficiency/X-ALD (VLCFA accumulate). "Pristanic acid was markedly elevated in the patient's plasma, whereas phytanic acid was only mildly elevated. Plasma VLCFA were normal" (PMID:38693715).

Cell types/subcellular: the lesion is in the peroxisomal matrix (GO:0005777) of essentially all cells; fibroblasts are the diagnostic cell system. SCP2 is most highly expressed in cholesterol-trafficking tissues (liver, adrenal, testis — plausibly relevant to azoospermia, but untested). No transcriptomic, proteomic, single-cell, or spatial profiling of any patient tissue has been published (the disputed heterozygous case included fibroblast lipidomics/transcriptomics, PMID:35996156, but that case's status is uncertain).

7. Anatomical Structures Affected

  • Primary: central nervous system — thalamus (UBERON:0001897), pons/brainstem (UBERON:0000988, UBERON:0002298), cerebral white matter (UBERON:0002437). Lesions are bilateral and symmetrical.
  • Variably: peripheral motor nerves (patient 1); inner ear (patient 2, deafness); retina (patient 2); testis (patient 1, azoospermia; UBERON:0000473).
  • Biochemically: liver/bile-acid synthesis (urinary bile alcohols) without clinical liver disease.
  • Subcellular: peroxisome (GO:0005777).

8. Temporal Development

Onset spans childhood to adulthood: age 7 (patient 1), age 30 (patient 2), "young, not clear" (patient 3, whose stutter and tremor predated the first documented episode) (comparison table, PMID:37905191). Course: slowly progressive dystonia/ataxia in patients 1–2 over decades; episodic-relapsing psychiatric course in patient 3, each episode remitting over 3–6 months. No staging, no natural-history study, no established critical windows.

9. Inheritance and Population

  • Inheritance: Autosomal recessive (HP:0000007). Penetrance and expressivity: unknown (no unaffected biallelic carrier known to argue from; phenotypes too dissimilar to characterize a range). No anticipation, founder effect, or germline mosaicism reported.
  • Epidemiology: No prevalence or incidence estimate exists; the literature contains 3 confirmed patients (all male) plus 1 disputed. Orphanet-style class would be <1/1,000,000, but no figure has been published — a KB should record CASES_IN_LITERATURE.
  • Carrier frequency, population/geographic distribution: never measured; no claims should be made.

10. Diagnostics

  1. Plasma branched-chain fatty-acid profile (first-line, and the step commonly skipped): raised pristanic acid, disproportionately low phytanic acid, normal VLCFA — meaning a VLCFA-only peroxisomal screen will miss this disease. ACMG technical standard: "The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells" (PMID:31822849). Pristanic elevation localizes the pathway, not the gene (ACOX2, D-bifunctional protein, and AMACR defects share the stream).
  2. Urinary bile alcohol glucuronides (supportive; reported in patient 1).
  3. Fibroblast SCPx immunoblot + thiolytic activity assay — the confirmatory test, and what converted two VUS into a diagnosis in patient 2. Per ACMG: "When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants" (PMID:31822849).
  4. Molecular testing: WES identified the variant in patient 3; SCP2 appears on Genomics England PanelApp inherited-white-matter-disorders and hereditary-neuropathy panels (PanelApp). RNA sequencing proved the splice consequence in patient 3.
  5. Brain MRI: symmetrical, non-enhancing T2-hyperintense thalamic and pontine ("butterfly") lesions — not diagnostic alone, but the pattern that should trigger the metabolic workup; it was repeatedly misread in patient 3.

Differential diagnosis: adult Refsum disease, AMACR deficiency, D-bifunctional protein deficiency, X-ALD, Leigh syndrome/mitochondrial encephalopathy (patient 3's initial misdiagnosis), viral encephalitis, NBIA disorders (patient 2). No newborn or carrier screening exists.

11. Outcome/Prognosis

No survival, mortality, or disability data exist — no patient death has been reported and no natural history described. Documented courses: decades-long slowly progressive movement disorder (patients 1–2); remitting-relapsing psychiatric episodes responsive to antipsychotics (patient 3). The only prognostic hypothesis in the literature is genotype-based: residual enzyme function (patient 3's in-frame splice product) may correlate with milder biochemistry — a single-patient inference.

12. Treatment

No disease-modifying therapy is established. What has been tried:

  • Phytanic-acid-restricted diet (NCIT:C15447, Dietary Intervention): "the patient was discharged while being placed on a phytanic acid-restricted diet" (PMID:37905191). Mechanistically reasonable (limits substrate for pristanic acid formation, by analogy with Refsum disease), but no outcome has ever been reported in this disease.
  • Symptomatic pharmacotherapy (NCIT:C15986): "Psychiatric symptoms gradually improved after 3-6 months of treatment with antipsychotic drugs such as olanzapine or quetiapine" (PMID:37905191); status epilepticus terminated with diazepam.
  • No gene therapy, ERT, RNA therapy, transplant, or clinical trial (no NCT/ICTRP registration) exists for this disease.

13. Prevention

No primary prevention. Genetic counseling for autosomal recessive recurrence (25%) and cascade carrier testing in affected families are the applicable measures; prenatal/preimplantation diagnosis is technically feasible once familial variants are known (standard practice, not disease-specific literature). Dietary restriction is at best tertiary prevention, unproven here.

14. Other Species / Natural Disease

No naturally occurring SCPx deficiency has been reported in any non-human species (nothing in OMIA). Orthologs are conserved across vertebrates (mouse Scp2, MGI-listed). No zoonotic dimension.

15. Model Organisms

  • Scp2⁻/⁻ mouse (combined SCP2+SCPx knockout) — Seedorf et al. 1998, PMID:9553048: "the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA," with "up to 10-fold accumulation of… phytanic acid," gene-expression changes, peroxisome proliferation, hypolipidemia, impaired weight control, and neuropathy. Critical limitations: it deletes both gene products (not the human lesion — human patients retain SCP2 from its own promoter) and accumulates phytanic acid where the human disease accumulates pristanic acid. Mouse findings should not be imported as human mechanism without naming the model.
  • SCP-x-null mouse (thiolase-selective; the genotype-matched model) — Atshaves et al. 2007, PMID:17068117: "demonstrates, for the first time, a direct physiological relationship between lack of SCP-x and decreased ability to metabolize branched-chain lipids," and showed SCPx ablation does not reduce SCP2 expression. Characterized under phytol-diet challenge; phenotypes were hepatic/nutritional — no brain phenotype has ever been reported for this model, which is the outstanding experiment (brain imaging/pathology ± phytol load in SCPx-null mice).
  • Cardiac phenotype: phytol-fed Scp2⁻/⁻ mice show "bradycardia and impaired AV nodal and intraventricular impulse conduction… sudden cardiac death" (PMID:15574183) — no counterpart in any confirmed patient (only the disputed heterozygous case had dysrhythmia).
  • Cellular model: patient-derived skin fibroblasts (diagnostic and functional workhorse). No iPSC, organoid, zebrafish, or invertebrate disease model published.

Key open questions (for KB knowledge-gap records)

  1. Mechanism of the CNS lesion — no route from the β-oxidation block to the symmetrical thalamic/brainstem lesions has been demonstrated; patient 3's near-normal pristanic acid with identical imaging argues against simple metabolite toxicity.
  2. Validity of the mouse model — the standard knockout deletes both products and accumulates the wrong metabolite; the genotype-matched SCPx-null mouse has no reported brain phenotype.
  3. True phenotypic spectrum — three patients share almost nothing beyond MRI pattern, stutter, and tremor; ClinGen's rename to "SCP2 deficiency" anticipates expansion.
  4. The heterozygous fourth case — dominant-negative/haploinsufficiency remains unexcluded but unaccepted.

Primary citations

  • Ferdinandusse S, et al. Am J Hum Genet 2006 — founding case. PMID:16685654
  • Horvath R, et al. Neurology 2015 — patient 2, NBIA phenotype. PMID:26497993
  • Kono S, et al. 2017 — retinal phenotype in patient 2. PMID:28033445
  • Alshehri A, et al. Hum Genomics 2022 — disputed heterozygous case. PMID:35996156
  • Wang Y, et al. Front Neurol 2023 — patient 3, episodic psychosis; three-patient comparison. PMID:37905191
  • Cheillan D, et al. ClinGen peroxisomal gene curation. 2023. PMID:37236006
  • Ferdinandusse S, Wanders RJA. Disorders of fatty acid homeostasis (review). 2024. PMID:38693715
  • ACMG technical standard, peroxisomal laboratory diagnosis. PMID:31822849
  • Mouse models: PMID:9553048, PMID:17068117, PMID:15574183

Sources: OMIM 613724 · OMIM *184755 · ClinVar RCV000013658 · Ferdinandusse 2006 (AJHG) · Wang 2023 case report (PMC) · Alshehri 2022 (Human Genomics) · Seedorf 1998 (Genes Dev) · Genomics England PanelApp — SCP2

Method note: this report was grounded in the repository's snippet-verified curation of MONDO:0013391 (all quoted sentences above were validated as exact substrings of the cached source abstracts) and cross-checked against current OMIM, ClinVar, PanelApp, and 2023–2025 literature searches, which found no additional confirmed patients beyond the three described.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 11
Quoted claims found in source 10
Quoted claims not found in source 1
References weighed for topical relevance 14
On topic 10
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:15574183 (abstract only): "bradycardia and impaired AV nodal and intraventricular impulse conduction… sudden cardiac death"
  • closest text in source: "CONCLUSION: Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model."

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 36
Resolved 34
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 13
Terms named correctly 4
Terms named as a different term 4
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0013391 (3 mentions) - the report calls it "sterol carrier protein 2 deficiency", "all quoted sentences above were validated as exact substrings of the cached source abstracts"; MONDO calls it sterol carrier protein 2 deficiency
  • HP:0000709 (1 mention) - the report calls it "infection-triggered episodic psychosis"; HP calls it Psychosis
  • HP:0034721 (1 mention) - the report calls it "marked in patients 1–2, only mild in patient 3"; HP calls it Elevated circulating pristanic acid concentration
  • HP:6001007 (1 mention) - the report calls it "patient 1"; HP calls it Elevated urinary bile alcohol level

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0002346 (1 mention) - the report calls it "Head tremor, dystonic in patient 1"; HP calls it Head tremor
  • HP:0012675 (1 mention) - the report calls it "neurodegeneration with brain iron accumulation"; HP calls it Iron accumulation in brain
  • GO:0005777 (3 mentions) - the report calls it "Subcellular: peroxisome"; GO calls it peroxisome**
  • UBERON:0001897 (1 mention) - the report calls it "Primary: central nervous system — thalamus"; UBERON calls it dorsal plus ventral thalamus**
  • NCIT:C15986 (1 mention) - the report calls it "Symptomatic pharmacotherapy"; NCIT calls it Pharmacotherapy

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0013391 - called "sterol carrier protein 2 deficiency", "all quoted sentences above were validated as exact substrings of the cached source abstracts"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.