Spastic Paraparesis-Cataracts-Speech Delay Syndrome

Mendelian MONDO:0036212 Pathograph 11 Show in embeddings browser hereditary disease inborn error of metabolism peroxisomal disease

Spastic paraparesis-cataracts-speech delay syndrome is the dominant, gain-of-function arm of FAR1 disease. It is caused by de novo heterozygous variants at a single codon - Arg480 - of fatty acyl-CoA reductase 1, the rate-limiting enzyme of ether lipid synthesis, and it is the mechanistic inverse of the recessive FAR1 deficiency (RCDP4) that this knowledge base curates elsewhere. Read that inversion carefully, because the two FAR1 diseases are easy to conflate and most of the literature on the gene is about the other one. In RCDP4, biallelic loss of FAR1 abolishes fatty-alcohol production and patients are plasmalogen-*deficient*. Here, FAR1 works perfectly well: its catalytic function is preserved and it is correctly targeted to the peroxisome. What the Arg480 variants destroy is the brake. FAR1 protein is normally degraded in response to rising plasmalogen levels, a negative feedback loop that holds ether lipid output at a set point. The variants abolish that response, so FAR1 accumulates, and ether lipid synthesis runs without a governor. Patients' fibroblasts have plasmalogen levels about twice control, FAR1 enzyme activity roughly three to four times control, and a fourfold increase in flux into ether lipids measured directly with a labelled fatty acid. The clinical consequence is the part that resists a simple story. Despite biochemical phenotypes that are, in the authors' words, diametrically opposed, the two FAR1 diseases share their cardinal features: spastic paraparesis, bilateral cataracts, seizures. What separates them clinically is severity and what is *absent* here - normal growth, no microcephaly, no dysmorphism, and normal brain MRI in ten of twelve patients. The observation that too much and too little of the same lipid class produce the same neurological and ocular picture is the central unexplained fact of this entity, and it is shared with a small group of other ether-lipid-excess disorders. It is curated below as an open question rather than smoothed over.

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Mappings
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Inheritance
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Pathophys.
10
Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0036212 spastic paraparesis-cataracts-speech delay syndrome
skos:exactMatch MONDO
Primary MONDO identifier for the disease; carries the OMIM (619338) and Orphanet (615938) cross-references.
MONDO:0100230 fatty acyl-CoA reductase 1 upregulation
skos:exactMatch MONDO
MONDO appears to hold two live terms for this one disease. MONDO:0100230 is defined as "A disorder of plasmalogens biosynthesis, that is an autosomal dominant neurological disorder that results in uncontrolled synthesis of ether lipids", which is the defining paper's title restated, and it carries only a GARD cross-reference. MONDO:0036212 carries the OMIM, Orphanet, MedGen and UMLS cross-references and has "Fatty acyl-CoA reductase 1 superactivity" as a synonym. They name the same entity. This entry anchors on MONDO:0036212 as the better-referenced of the two and maps the other as an exact match; the duplication is a MONDO issue rather than a curation choice, and is noted here so a later merge does not look like a change of scope. Note that Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect refers to this disease by the MONDO:0100230 identifier in its differential.
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Monoallelic and, in every reported case, de novo. Twelve patients in the defining cohort each carry one variant Arg480 allele with two unaffected parents; subsequent single cases are likewise de novo. No transmission from an affected parent to a child has been described, so the 50 percent recurrence risk usually quoted for a dominant disorder is a theoretical figure here rather than an observed one, and reproductive outcomes for affected individuals are unknown. The contrast with the other FAR1 disease is the point. RCDP4 is autosomal recessive: two loss-of-function alleles, unaffected heterozygous parents. This disease needs one gain-of-function allele. A single heterozygous FAR1 variant found in a patient is therefore not automatically a carrier finding - which allele class it is decides everything.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:33239752 SUPPORT Human Clinical
"We identified 12 individuals from around the world with heterozygous de novo missense variants in FAR1 (NM_032228.6): 4 patients with variant c.1439G>A (p.Arg480His), 7 patients with variant c.1438C>T (p.Arg480Cys), and 1 patient with variant c.1439G>T (p. Arg480Leu) (Table 1)."
Establishes heterozygous de novo inheritance in all twelve defining patients, with the allele counts.
PMID:33239752 SUPPORT Human Clinical
"Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype."
The authors' own statement that this is a distinct dominant entity from recessive FAR1 deficiency, which is the scope decision this entry rests on.
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Discussions and Knowledge Gaps

3
Why do ether lipid excess and ether lipid deficiency cause the same cataracts and the same spastic paraparesis?
OPEN QUESTION OPEN far1_gof_excess_and_deficiency_converge
Attached to
pathophysiology#Membrane Lipid Composition Shift pathophysiology#Lens Opacification pathophysiology#Corticospinal Tract Dysfunction
This is the question the entity exists to pose, and no one has answered it. Cataract is caused by ether lipid deficiency: in a Pex7 mouse model of RCDP type 1, supplementing alkylglycerol restored plasmalogens and prevented cataract formation, which is a causal demonstration rather than an association. Cataract is also present in twelve of twelve patients whose ether lipids are elevated. The same holds for spastic paraparesis, which occurs in RCDP4 and in all of these patients, and which is also the shared feature of the three other ether-lipid-*excess* disorders. Too much and too little of the same lipid class damage the same two organs. Three hypotheses are worth keeping distinct, and the sources support none of them over the others. It may be that what matters is the *ratio* of ether to non-ether lipids rather than the absolute level of either, which this entry's lipidomics node is consistent with: total choline- and ethanolamine-lipid content was unchanged while the ether fraction rose, and in RCDP the same ratio is displaced the other way. It may be the fatty alcohols rather than the lipids - the paper notes that fatty alcohols accumulate in Sjogren-Larsson syndrome and in RCDP types 1 to 3, though not in FAR1 deficiency, where they cannot be made. Or the two diseases may reach the same endpoint by genuinely different routes, and the convergence be a coincidence of which organs are most sensitive to any membrane-lipid disturbance. The authors' own verdict is that the mechanism remains enigmatic, and this entry does not improve on it. The practical warning: do not import RCDP mechanism prose into this entry on the strength of the shared phenotype. The biochemistry is inverted and the shared endpoint is the thing to be explained, not the explanation.
Proposed experiments
Dissociate ether/non-ether ratio from absolute ether lipid level
exp_far1gof_ratio_versus_level
In a single cell system, titrate ether lipid content upward (by expressing an Arg480 FAR1 allele) and downward (by FAR1 knockdown) while separately manipulating non-ether phospholipid synthesis, and measure a common cell-biological endpoint such as membrane order, organelle contact-site formation or lipid-raft-dependent signalling. If the endpoint tracks the ratio rather than the absolute level, that would explain the convergence.
A lens model of ether lipid excess
exp_far1gof_lens_model
Generate an Arg480 knock-in mouse and ask whether it develops cataracts, and if so whether they are prevented by limiting ether lipid synthesis - the mirror image of the alkylglycerol rescue experiment that established deficiency as a cause of cataract in the Pex7 model.
What happens to a neuron or a lens fibre cell carrying an Arg480 FAR1 allele?
KNOWLEDGE GAP OPEN far1_gof_no_model_beyond_fibroblasts
Attached to
experimental_models#Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys pathophysiology#Corticospinal Tract Dysfunction
Curated as a genuine absence of evidence, with one qualification. There is no animal model of this disease, no engineered cell line carrying an Arg480 allele, and no patient-derived neuron or lens cell. Every functional statement curated in this entry comes from three patients' skin fibroblasts. Patient tissue beyond fibroblasts is not quite untouched, though: a 2024 neuropathology report (Della Marina et al., J Neuropathol Exp Neurol, PMID:39074165) describes lipid and protein imbalances in muscle from a patient with a heterozygous de novo FAR1 variant - this arm of the disease, in a tissue nobody else has examined. It is named here rather than cited because PubMed carries no abstract for it, so nothing from it can be verified as a snippet; that is the same disposition given to PMID:36781603. A curator with journal access should promote it. What remains true, and is the point of this gap, is that neither of the two tissues that actually fail - the corticospinal tract and the lens - has been examined in any patient. The asymmetry with the recessive arm is what makes this worth flagging rather than merely noting. A Far1 knockout mouse was published in 2023 and is explicitly presented as a model of ether lipid deficiency: subviable, growth-retarded, infertile, with spermatogenesis arrested at the round spermatid stage. So the deficiency arm has an animal model and the excess arm does not - which is the wrong way round for answering the question this entity poses, and which means the genetic background and assay platform for the comparison already exist. The gap is specific rather than generic. The fibroblast carries the full biochemical lesion - elevated plasmalogens, elevated FAR1, fourfold ether lipid flux, a remodelled lipidome - and is entirely well. So the biochemistry alone does not cause cell dysfunction; something about the corticospinal tract and the lens makes them vulnerable, and no model in existence can address what. Two of the four disease alleles, p.Arg480Leu and p.Arg480Ser, have never been tested in any system, because no cells were available. A knock-in mouse or an isogenic iPSC series would close both gaps at once.
Proposed experiments
Isogenic Arg480 knock-in iPSC series differentiated to affected lineages
exp_far1gof_knockin_ipsc
Knock each of the four reported Arg480 substitutions into the endogenous FAR1 locus of iPSCs heterozygously, differentiate to cortical projection neurons and lens epithelial cells, and compare lipidome, membrane properties, axonal transport and survival against isogenic controls and against a FAR1-null line representing the recessive disease. Running the excess and deficiency arms in the same genetic background is what the field currently lacks. The equivalent in vivo comparison is now cheap to specify, since the Far1 knockout mouse for the deficiency arm already exists; what is missing is its Arg480 knock-in counterpart.
Could ether lipid synthesis be dialled back down, and would that help?
KNOWLEDGE GAP OPEN far1_gof_no_disease_modifying_therapy
Attached to
treatments#Antiseizure Pharmacotherapy pathophysiology#Uncontrolled Ether Lipid Synthesis
The only treatment reported for this disease is symptomatic seizure control, and this entry curates nothing else because nothing else has been tried. The mechanism does suggest a target, which is why the gap is worth stating rather than leaving as silence. Ether lipid output is high because FAR1 escapes degradation; reducing FAR1 abundance or activity would in principle restore the set point. But two things are unknown and both are load-bearing. Nobody knows whether the damage is developmental and already done by the time a diagnosis is made - the congenital cataracts in five of twelve suggest at least part of it is - or ongoing and therefore modifiable. And nobody knows the therapeutic window, because ether lipid *deficiency* causes an overlapping and more severe disease, so overshooting has a known and bad phenotype. The mirror-image experiment already exists on the deficiency side: alkylglycerol supplementation prevented cataracts in a plasmalogen-deficient mouse. Nothing equivalent has been attempted for excess.
Proposed experiments
Test partial FAR1 knockdown in an Arg480 model
exp_far1gof_flux_reduction
In patient fibroblasts and, once available, an Arg480 knock-in animal, titrate FAR1 abundance down by RNA interference or antisense oligonucleotide and measure whether ether lipid flux, the lipidome shift and any cellular phenotype normalise - and at what point plasmalogen levels fall below normal, which defines the window.
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Pathophysiology

7
De Novo Heterozygous FAR1 Arg480 Variant
Every reported allele changes the same arginine. Four patients carry c.1439G>A p.(Arg480His), seven c.1438C>T p.(Arg480Cys), one c.1439G>T p.(Arg480Leu), and a later single case p.(Arg480Ser). None is in gnomAD. The residue's position is the mechanism. Arg480 sits in FAR1's predicted transmembrane domain, amino acids 466 to 483, near the edge facing the peroxisomal matrix - and the region flanking that domain on the matrix side is the part previously shown to be required for plasmalogen-dependent control of FAR1 stability. So the variants are in the regulatory element, not in the catalytic domain, which is exactly what the functional results show: catalysis intact, regulation gone. That every disease allele is at one codon, and that four different substitutions there all produce the same disease, is strong evidence that the residue itself is the essential thing rather than any particular replacement amino acid.
FAR1 hgnc:26222 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FAR1 (hgnc:26222). hgnc:26222 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: HYPERMORPHIC
Curated as HYPERMORPHIC rather than the generic GAIN_OF_FUNCTION, and the distinction is worth the words. The enum defines HYPERMORPHIC as increased *normal* gene product activity and NEOMORPHIC as a novel activity absent from the wild type. What was measured here is more of the normal reaction: FAR1's biosynthetic function and peroxisomal localisation are preserved, peroxisomal beta-oxidation and DHAPAT activity are normal, and the enzyme makes the same fatty alcohols it always did - there is simply more enzyme because it is no longer degraded. No new catalytic activity is reported, so NEOMORPHIC is wrong, and HYPERMORPHIC is more specific than GAIN_OF_FUNCTION without asserting anything beyond the data. DOMINANT_NEGATIVE is excluded by the direction of effect: the wild-type allele is not being interfered with, and total FAR1 activity is up rather than down.
peroxisomal membrane GO:0005778 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisomal membrane (GO:0005778). GO:0005778 is a cellular component from the Gene Ontology.
Downstream
Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
Show evidence (2 references)
PMID:33239752 SUPPORT Human Clinical
"All three variants were not reported in the gnomAD database and all are predicted to be deleterious by various pathogenicity prediction programs. Remarkably, all de novo variants are located in the same codon, p.Arg480, which is located in the predicted transmembrane region of FAR1, formed by..."
Establishes the single-codon clustering and the transmembrane location that the mechanism turns on.
PMID:33239752 SUPPORT Other
"Nevertheless, our results are in line with data from Honsho et al.7 who showed that the C-terminal domain of FAR1, especially the 17 amino acids flanking the transmembrane domain (491-507), is essential for the plasmalogen-dependent modulation of the stability of FAR1."
Places Arg480 next to the region already known to carry the stability-regulation signal, which is why a transmembrane variant abolishes feedback rather than catalysis. Graded OTHER because it is the authors' appeal to prior work rather than their own experiment.
Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
The lesion, and the reason this disease exists as a separate entity from RCDP4. Normally, FAR1 abundance is set by a negative feedback loop: rising cellular plasmalogen triggers active degradation of FAR1 protein, so ether lipid output self-limits. The experiment that demonstrates the loop is broken here is a clean one. Loading fibroblasts with 1-O-hexadecyl-sn-glycerol raises plasmalogen by a route that bypasses FAR1 entirely, and in control cells that drops FAR1 protein by about 40 percent. In patients' cells the same treatment raised plasmalogen just as intended, and FAR1 protein did not fall. The starting condition makes the point sharper still. Untreated patient cells already had plasmalogen about twice control - roughly the level that HDG-treated control cells reach - and yet held FAR1 protein at three times the HDG-treated control level. The signal was maximal and the response was absent.
plasmalogen-triggered degradation of FAR1 GO:0030163 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves plasmalogen-triggered degradation of FAR1, annotated with protein catabolic process (GO:0030163), qualified as loss of function. GO:0030163 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
peroxisomal membrane GO:0005778 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisomal membrane (GO:0005778). GO:0005778 is a cellular component from the Gene Ontology.
Experimental models
Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys PRIMARY CELL CULTURE The HDG challenge is a genuine perturbation experiment rather than an observation: it raises plasmalogen by a route that bypasses FAR1, so the feedback loop is stimulated directly, and the patient cells' failure to respond isolates the regulatory defect from the enzyme's activity.
Downstream
Elevated FAR1 Protein and Enzyme Activity
Show evidence (3 references)
PMID:33239752 SUPPORT In Vitro
"In control fibroblasts, HDG treatment increased C16:0-plasmalogen levels 199-291% (mean ± SD: 249 ± 31%) (Fig. 3c) and resulted in a 31-47% decrease (mean ± SD: 40 ± 7%) in FAR1 protein levels (Fig. 3a, b). In the patients' cells, treatment with HDG also increased C16:0-plasmalogen levels..."
The controlled experiment demonstrating that the feedback response is present in controls and absent in patients, with the plasmalogen stimulus confirmed to have worked in both.
PMID:33239752 SUPPORT In Vitro
"Despite these high plasmalogen levels, FAR1 protein levels in the patients' cells were threefold higher than in the HDG-treated controls"
Shows the failure is not a matter of an insufficient signal: the signal was already at or above the level that suppresses FAR1 in control cells.
PMID:36720320 SUPPORT Other
"Plasmalogen biosynthesis is spatiotemporally regulated by a feedback mechanism that senses the amount of plasmalogens in the inner leaflet of the plasma membrane and regulates the stability of fatty acyl-CoA reductase 1 (FAR1), the rate-limiting enzyme for plasmalogen biosynthesis."
Independent statement of the normal regulatory mechanism that this disease abolishes, from a review of the pathway rather than from the disease report.
Elevated FAR1 Protein and Enzyme Activity
The immediate quantitative consequence of the broken brake: more FAR1 protein on immunoblot, and FAR1 enzyme activity in patients' fibroblasts of 379, 323 and 310 pmol per hour per mg protein against control values of 74, 90 and 101 - three to four times control. The `modifier` here is INCREASED, deliberately and in contrast with the node below. The claim at this node is purely quantitative: a normal enzyme, doing its normal reaction, present in larger amounts. Nothing about the enzyme itself is qualitatively altered - immunofluorescence shows normal peroxisomal targeting, and other peroxisomal functions are normal.
fatty acyl-CoA reductase activity GO:0102965 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased fatty acyl-CoA reductase activity, annotated with alcohol-forming long-chain fatty acyl-CoA reductase (NADP+) activity (GO:0102965). GO:0102965 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Uncontrolled Ether Lipid Synthesis
Show evidence (3 references)
PMID:33239752 SUPPORT In Vitro
"Furthermore, the enzyme activity of FAR1 was markedly increased in the fibroblasts of patients 1-3"
The activity measurement in patient versus control fibroblasts. The quote stops before the numbers because the source writes the unit as "pmol/[h.mg protein]" and the reference validator strips bracketed spans; the values are given in this node's description.
PMID:33239752 SUPPORT In Vitro
"Moreover, immunoblot analysis showed clearly increased FAR1 protein levels in the patients' fibroblasts (Fig. 2c)."
The protein-abundance half of this node, measured independently of the activity assay.
PMID:33239752 SUPPORT In Vitro
"Immunofluorescence microscopy analysis showed that FAR1 is normally localized to peroxisomes in patients' fibroblasts (see Fig. 2d for representative image) showing that p.Arg480His/Cys variants do not interfere with peroxisomal targeting of FAR1."
Excludes mislocalisation, which is what keeps this node a purely quantitative claim about enzyme amount.
Uncontrolled Ether Lipid Synthesis
Flux, not just enzyme level. Feeding fibroblasts a labelled odd-chain fatty acid lets ether and non-ether routes be tracked separately from the same substrate: incorporation into the non-ether lipid LPC(17:0) was the same in patients and controls, while FAR1-dependent incorporation into the ether lipid LPC(O-17:0) was almost fourfold higher in patients. The pathway is running fast, and specifically the ether branch. On the `modifier` value, which is the one interpretive choice in this entry that most needs defending. `GAIN_OF_FUNCTION` is used here, and `INCREASED` is used one node up, deliberately. The schema reserves GAIN_OF_FUNCTION for a process driven outside its normal regulatory constraints rather than merely running above its normal level, and warns against migrating a quantitative annotation to it without that qualitative justification. The justification here is not that ether lipid synthesis is high. It is that the homeostatic loop which sets its level has been eliminated: raising the pathway's own product no longer restrains it, so there is no set point for the output to be above. The authors' own term is "uncontrolled". A cell with elevated but still-regulated ether lipid synthesis would be INCREASED; this one has lost the control system.
ether lipid biosynthetic process GO:0008611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves ether lipid biosynthetic process (GO:0008611), qualified as gain of function. GO:0008611 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Experimental models
Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys PRIMARY CELL CULTURE The C17:0 labelling experiment measures ether and non-ether lipid synthesis from the same exogenous substrate in the same cells, so the non-ether arm is an internal control for uptake and general lipid handling.
Downstream
Membrane Lipid Composition Shift
Show evidence (2 references)
PMID:33239752 SUPPORT In Vitro
"Incorporation of C17:0-acid in LPC(17:0) was similar in controls and patients whereas FAR1-dependent incorporation of C17-alcohol in LPC(O-17:0) was almost fourfold higher in patients than in controls (Fig. 4g) confirming that ether lipid synthesis indeed is elevated in patients with..."
A direct flux measurement, with the non-ether arm as an internal control showing the effect is specific to the ether branch.
PMID:33239752 SUPPORT In Vitro
"Functional analyses, including fibroblast plasmalogen measurements, FAR1 enzyme activity assays, and lipidomics showed that the biosynthetic function and peroxisomal localization of FAR1 is preserved but that the plasmalogen-dependent regulation of FAR1 protein levels is abolished, resulting in..."
The authors' summary, and the wording ("abolished", "uncontrolled") that justifies grading this node's modifier as a qualitative loss of regulatory constraint rather than a quantitative elevation.
Membrane Lipid Composition Shift
The disease is not simply "too much plasmalogen". Lipidomics shows ether species accumulating - plasmanyl/plasmenyl-choline phospholipids, and the neutral ether lipids DG[O] and TG[O] - with a reciprocal and significant fall in the corresponding non-ether phospholipids PC and PE, PE severely. Strikingly, the totals of choline- and ethanolamine-containing lipids stay roughly constant - the paper states this in the same passage, though it cannot be quoted here because the sentence carries the bracketed ether-lipid nomenclature PE[O] and PC[O] that the reference validator strips. What has changed is the ratio of ether to non-ether species, not the amount of membrane phospholipid. The proposed explanation is competition for a shared limited resource - elevated DG[O] outcompeting DG for the activated headgroups CDP-choline and CDP-ethanolamine - which would make this a substrate-competition effect rather than a direct toxicity. The polyunsaturated fatty acids also redistribute, away from PC and toward PC[O]. Recorded because it is the most plausible bridge from a biochemical abnormality to a cellular one, and because it is the level at which this disease and the RCDP disorders are precise mirror images: in RCDP the non-ether lipids compensate for absent ether counterparts, and the PUFA distribution runs the other way.
Downstream
Corticospinal Tract Dysfunction No step between the lipid abnormality and the pyramidal tract is known for this disease or for any of the ether-lipid-excess disorders. The authors state the pathophysiological mechanism remains enigmatic.
Lens Opacification Equally unexplained, and more puzzling, because cataract is also caused by ether lipid *deficiency* - see the open discussion.
Show evidence (3 references)
PMID:33239752 SUPPORT In Vitro
"Total levels of the major phospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were both significantly decreased, with PE levels drastically reduced (Fig. 4a, b)."
The reciprocal fall in the non-ether phospholipids, which is what makes this a compositional shift rather than a simple accumulation.
PMID:33239752 SUPPORT Other
"Interestingly, this ether/nonether balance is precisely reversed in different RCDP subtypes where nonether lipids compensate for the absence of their ether counterparts."
States that the same ratio is displaced in the opposite direction in the recessive plasmalogen-deficiency disorders, which is the sharpest available statement of the mirror-image relationship between the two arms of FAR1 disease. Graded OTHER because it is the authors' comparison with a different disease group rather than a measurement in these patients.
PMID:33239752 SUPPORT In Vitro
"compete with DG for the limited amounts of activated headgroups CDP-ethanolamine and CDP-choline to synthesize ether and nonether analogs of PC and PE, shifting the balance toward ether phospholipids at the expense of the nonether equivalents"
The proposed competition mechanism. The quote begins mid-sentence because the clause before it names the competing species as DG[O], and the reference validator strips bracketed spans. Graded PARTIAL because the authors offer this explicitly as one possible mechanism, not as a demonstrated one; no competition experiment is reported.
Corticospinal Tract Dysfunction
The presenting problem and the most consistent finding: spastic di- or paraparesis in twelve of twelve patients, with lower limb hypertonia, truncal hypotonia in half, and ankle clonus. The pattern - lower limbs affected, upper motor neuron signs, normal brain imaging in most - is that of a hereditary spastic paraplegia, which is why the authors recommend adding FAR1 to hereditary spastic paraplegia and cerebral palsy panels. Marked PROVISIONAL because the anatomical claim in the node's name is a clinical inference. Pyramidal tract dysfunction is what was observed; no imaging, electrophysiological or neuropathological localisation to the corticospinal tract has been reported in any patient, and brain MRI was normal in ten of twelve. Scaled TISSUE rather than ORGANISM, to match Lens Opacification below. The two nodes are the disease's two end-organ failures and the substrate named in each is an anatomical structure - a tract and a lens - so tagging one at organism scale and the other at tissue scale would make the pair look like different kinds of claim when they are the same kind. The organism-level reading is available and was rejected: spastic paraparesis as a whole-body motor phenotype would be ORGANISM, but that is the phenotype, curated in `phenotypes:`, not this node.
Show evidence (2 references)
PMID:33239752 SUPPORT Human Clinical
"They presented with pyramidal tract dysfunction, exhibiting spastic di- or paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and (ankle) clonus."
The neurological phenotype with its frequencies in the defining cohort.
PMID:33239752 SUPPORT Human Clinical
"Brain imaging was within normal limits in 10/12 patients; one patient had abnormal temporal lobe morphology and ventricular prominence, but white matter was normal."
Establishes that no structural correlate was found, which is why the anatomical attribution in this node is graded provisional - and is also a point of separation from RCDP4, where white matter abnormalities occur.
Lens Opacification
Bilateral cataracts in twelve of twelve patients, congenital in five and acquired in the other seven - so this is not purely a developmental malformation of the lens; in most patients the lens was clear at birth and opacified later, over months to years. Marked PROVISIONAL because nothing is known about why. The one strong piece of causal evidence in this area points the other way entirely: in a mouse model of ether lipid *deficiency*, restoring plasmalogens prevented cataracts, establishing shortage as a cause. How excess produces the same end organ failure is unexplained.
lens of camera-type eye UBERON:0000965 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lens of camera-type eye (UBERON:0000965). UBERON:0000965 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"In addition, all patients had bilateral cataracts (12/12), which were congenital in 5/12 and acquired in the other 7/12."
The ocular phenotype with the congenital-versus-acquired split, which is what shows the lens can be normal at birth and fail later.
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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 Spastic Paraparesis-Cataracts-Speech Delay Syndrome 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

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Eye 1
Bilateral Cataracts 12/12 HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cataracts, annotated with Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"In addition, all patients had bilateral cataracts (12/12), which were congenital in 5/12 and acquired in the other 7/12."
Cataracts in all twelve, with the timing split.
Head and Neck 1
Macrocephaly 2/12 HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"There were no dysmorphic features; two patients presented with macrocephaly."
Macrocephaly in two patients, in the same sentence that records the absence of dysmorphism.
Musculoskeletal 1
Spastic Paraparesis 12/12 HP:0002313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic paraparesis (HP:0002313). HP:0002313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia."
Spastic paraparesis in all patients, alongside the other cardinal features.
Nervous System 4
Intellectual Disability 3/12 HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"Cognitive delay and intellectual disability were less common in the cohort (3/12)."
The frequency, and the source's own framing of it as uncommon.
Seizures 8/12 HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"Seizures occurred in 8/12 patients, mainly in the first months of life, and appeared amenable to therapy with barbiturates, levetiracetam, and/or oxcarbazepine."
Seizure frequency, onset and treatment responsiveness in the cohort.
Delayed Speech Development 10/12 Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"Speech development was delayed in 10/12 patients, with receptive speech outperforming expressive speech in 3 patients."
Speech delay frequency and the receptive-expressive dissociation.
Delayed Gross Motor Development FREQUENT HP:0002194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed gross motor development (HP:0002194). HP:0002194 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia."
Gross motor delay in most of the cohort.
Other 3
Axial Hypotonia 6/12 HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Truncal hypotonia, annotated with Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"They presented with pyramidal tract dysfunction, exhibiting spastic di- or paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and (ankle) clonus."
Truncal hypotonia in six of twelve.
Ankle Clonus HP:0011448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle clonus (HP:0011448). HP:0011448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"They presented with pyramidal tract dysfunction, exhibiting spastic di- or paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and (ankle) clonus."
Ankle clonus as part of the upper motor neuron picture.
Lower Limb Spasticity HP:0002061 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity (HP:0002061). HP:0002061 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"They presented with pyramidal tract dysfunction, exhibiting spastic di- or paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and (ankle) clonus."
Lower limb hypertonia as part of the pyramidal picture in the cohort.
🧬

Genetic Associations

1
FAR1
Gene: FAR1 hgnc:26222 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FAR1 (hgnc:26222). hgnc:26222 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
PMID:33239752 SUPPORT Other
"FAR1 is a tail-anchored protein of 515 amino acids with an N-terminal domain corresponding to amino acids 1-465 facing the cytosol, a transmembrane domain corresponding to amino acids 466-483 and a C-terminal domain corresponding to amino acids 484-515 located in the peroxisomal matrix."
The protein architecture that places Arg480 in the transmembrane domain. Graded OTHER because it is background from the paper's introduction.
PMID:33239752 SUPPORT Human Clinical
"This was internally explored in a cohort of 42,983 exome trios and 9205 exome-based specific gene list trios that included FAR1 analysis. This led to the identification of eight cases."
The ascertainment denominator, which is the only population-scale number available for this disease.
PMID:37335441 SUPPORT Human Clinical
"Here, authors have identified a novel substitution in the same Arg480 position into serine."
A fourth substitution at the same codon, reinforcing that the residue rather than the replacement amino acid is what matters.
💊

Medical Actions

1
Antiseizure Pharmacotherapy
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: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. oxcarbazepine CHEBI:7824 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses oxcarbazepine (CHEBI:7824). CHEBI:7824 is a therapeutic agent from Chemical Entities of Biological Interest. barbiturate NCIT:C67084 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses barbiturate (NCIT:C67084). NCIT:C67084 is a therapeutic agent from the NCI Thesaurus.
The only treatment reported in this disease, and it is symptomatic. Seizures in the defining cohort responded to barbiturates, levetiracetam and oxcarbazepine, and in four of the eight treated patients antiepileptic treatment was withdrawn without recurrence. That last detail is the clinically useful one. Early-onset epilepsy in an inborn error of metabolism is often refractory; here it appears both treatable and, in half of cases, self-limiting. Nothing is reported about which agent to prefer, and with eight patients across three drug classes nothing could be.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"Seizures occurred in 8/12 patients, mainly in the first months of life, and appeared amenable to therapy with barbiturates, levetiracetam, and/or oxcarbazepine. Antiepileptic treatment could be discontinued without recurrence of seizures in 4/8 patients."
The agents used, the response, and the withdrawal outcome - the whole of the reported treatment experience in this disease.
🔬

Biochemical Markers

1
Plasmalogen Levels as a Bidirectional FAR1 Readout
Show evidence (2 references)
PMID:33239752 SUPPORT In Vitro
"In contrast to previously reported patients with FAR1 deficiency, the plasmalogen levels in fibroblasts of the patients were not decreased, but increased (see Fig. 2a)."
The direction of the biochemical abnormality, stated against the recessive disease it inverts.
PMID:33239752 SUPPORT Human Clinical
"Finally, the measurement of plasmalogens in erythrocytes should be considered as a functional readout of ether lipid synthesis as both abnormally high or low levels could suggest FAR1-related pathology."
The authors' recommendation that the test be read in both directions, which is the practical diagnostic content of this entity.
🔬

Diagnosis

1
FAR1 on Spastic Paraplegia, Cerebral Palsy and Juvenile Cataract Panels
The combination that should prompt the test is spastic paraparesis plus bilateral cataracts, and the authors' explicit recommendation is that FAR1 be added to hereditary spastic paraplegia, cerebral palsy and juvenile cataract gene panels. Cerebral palsy is on that list for a reason: a child with non-progressive lower-limb spasticity, normal brain MRI and no perinatal history is routinely labelled cerebral palsy, and one of the twelve defining patients was in fact found through an exome-based cerebral palsy panel. The biochemical confirmation is plasmalogen measurement, read for an elevated result - which is the opposite of how the same test is read in every other peroxisomal disorder.
Show evidence (2 references)
PMID:33239752 SUPPORT Human Clinical
"Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts."
The authors' diagnostic recommendation, which is the practical content of this entity.
PMID:33239752 SUPPORT Human Clinical
"Clinical trio (patients 2-10 and 12) or quartet (patient 1, with unaffected sibling) exome analysis was performed for patients 1-10 and 12 and an exome-based cerebral palsy panel was performed for patient 11."
One patient was found on a cerebral palsy panel, which is why that panel is named in the recommendation.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Twelve patients in the defining cohort, assembled from around the world, plus at least two further single case reports since - a Middle Eastern patient with a milder presentation and a patient with a fourth Arg480 substitution. No population prevalence has been estimated. The nearest thing to a denominator is the ascertainment itself: eight of the twelve came from a commercial laboratory's internal series of 42,983 exome trios plus 9,205 gene-list trios. That is a diagnostic-yield figure from a referred population, not a birth prevalence, but it does bound the disease as very rare even among children referred for exome sequencing.
Show evidence (2 references)
PMID:33239752 SUPPORT Human Clinical
"In this paper we describe a cohort of 12 patients with different de novo missense variants in the FAR1 gene, but all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu)."
The size of the defining cohort.
PMID:36254151 SUPPORT Human Clinical
"Our patient adds to the small number of patients recognized to date and expands the clinical spectrum to provide better clinical delineation, improve diagnosis, and develop precision medicine approaches for this disorder."
An additional reported case, and the author's own characterisation of how few exist.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Spastic Paraparesis-Cataracts-Speech Delay Syndrome:

FAR1 deficiency (RCDP4) - the recessive, plasmalogen-deficient arm of the same gene Not Yet Curated MONDO:0014510
Overlapping Features The differential that matters most, because the gene is the same and the clinical overlap is substantial: spasticity, seizures and bilateral cataracts occur in both. Everything else separates them. Biochemically they are opposites - RCDP4 patients are plasmalogen-deficient, these patients have elevated ether lipids. Genetically, RCDP4 needs two loss-of-function alleles anywhere in FAR1; this disease needs one Arg480 missense allele. Clinically, RCDP4 patients have profound intellectual disability, severe growth failure, microcephaly and facial dysmorphism, and some have cerebral white matter abnormalities; these patients have normal growth, no microcephaly, no dysmorphism, normal MRI in most, and intellectual disability in only three of twelve. The defining paper flags what is unusual about this pair: gene-dose and direction-of-effect differences within one gene are not new, but a pair with an *overlapping clinical* phenotype and a *completely opposite biochemical* one had not been described before. This knowledge base curates RCDP4 within Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect, whose own differential list already names this disease as the mechanistically inverse FAR1 gain-of-function disorder - under the identifier MONDO:0100230, the duplicate MONDO term discussed in this entry's mappings.
Distinguishing Features
  • Plasmalogens are elevated in the dominant Arg480 disease and deficient in recessive FAR1 deficiency.
  • One de novo Arg480 missense allele versus two loss-of-function alleles.
  • Normal growth, no microcephaly and no dysmorphism here; severe growth failure, microcephaly and facial dysmorphism in FAR1 deficiency.
  • The recessive arm has a mouse model - a Far1 knockout published in 2023 and presented as a model of ether lipid deficiency. The dominant arm has none, so Far1 mouse literature does not bear on Arg480 gain of function.
Show evidence (4 references)
PMID:33239752 SUPPORT Human Clinical
"Patients with FAR1 heterozygous de novo variants share many clinical symptoms with FAR1 deficiency, including spastic features, seizures, and bilateral cataracts, but have normal brain magnetic resonance images (MRIs), normal growth, no microcephaly, and no dysmorphic features."
The clinical overlap and the specific features that separate the two FAR1 diseases.
PMID:33239752 SUPPORT Other
"Of the five previously reported patients, all had (profound) intellectual disability, severe growth retardation/failure to thrive, microcephaly, spasticity, and facial dysmorphism."
The recessive arm's own phenotype, sourced rather than asserted, so the contrast drawn in this differential rests on a quotation on both sides. Graded OTHER because it is this paper's summary of the previously published FAR1-deficiency cases rather than patients it examined.
PMID:33239752 SUPPORT Human Clinical
"Nevertheless, the biochemical phenotypes are the complete opposite of each other; the FAR1-deficient patients have a profound deficiency of plasmalogens whereas the patients with the heterozygous de novo variants have elevated levels of ether lipids, including plasmalogens."
The biochemical inversion, which is the discriminating test.
+ 1 more reference
Hereditary spastic paraplegia and cerebral palsy
Overlapping Features The labels these patients carry before the diagnosis is made. Non-progressive or slowly progressive lower-limb spasticity with normal brain imaging and no perinatal insult is the classic route to a cerebral palsy label, and one of the twelve was found on a cerebral palsy panel. The feature that should redirect the workup is the cataracts, which belong to neither of those diagnoses.
Show evidence (1 reference)
PMID:33239752 SUPPORT Human Clinical
"Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts."
Names the two clinical categories this disease is misassigned to.
The other ether-lipid-excess disorders - EPT1 (SELENOI), PCYT2 and Sjogren-Larsson syndrome
Overlapping Features A small and recently recognised group that biochemically resembles this disease rather than RCDP: SELENOI (EPT1) deficiency, PCYT2 deficiency and Sjogren-Larsson syndrome all show elevated ether lipids, and all present with spastic paraparesis plus some form of ocular pathology - cataracts, optic atrophy or macular dystrophy. Recorded as a differential and, more usefully, as a group: their existence is the strongest argument that ether lipid excess itself, rather than something idiosyncratic to FAR1, produces this clinical pattern. Distinguishing them from each other is a matter for their own entries and is not attempted here; this entry claims only what its cited source states, which is that the three share elevated ether lipids and the paraparesis-plus-eye pattern.
Show evidence (1 reference)
PMID:33239752 SUPPORT Other
"On the other side of the spectrum, three disorders have recently been reported that biochemically show elevated levels of ether lipids: EPT1 deficiency (SELENOI),22,23 PCYT2 deficiency (PCYT2),14,24 and Sjögren-Larsson syndrome (SLS, ALDH3A2).25,26"
Names the three other ether-lipid-excess disorders. Graded OTHER because it is the authors' survey of neighbouring literature rather than their own data.
🧫

Experimental Models

1
Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys PRIMARY_CELL_CULTURE
Skin fibroblasts from patients 1 to 3 (two p.Arg480His, one p.Arg480Cys) against six anonymised control lines. Every functional claim in this entry comes from this model - plasmalogen measurement by gas chromatography, FAR1 enzyme assay, immunoblot, immunofluorescence, the HDG feedback challenge, and lipidomics with C17:0 labelling. On animal models, and the claim needs stating precisely because the obvious reading of it is wrong. There is no animal model of *this* disease and no cell line carrying an engineered Arg480 allele. FAR1 itself is not model-less: a Far1 knockout mouse exists, is subviable with growth retardation and male infertility, and its authors present it as a model of ether lipid *deficiency*. That is the recessive arm, the mechanistic inverse of this disease, and it cannot substitute for a model of Arg480 gain of function.
Pathograph links
Loss of Plasmalogen-Dependent Feedback Degradation of FAR1 recapitulates fidelity: high The HDG challenge is a genuine perturbation experiment rather than an observation: it raises plasmalogen by a route that bypasses FAR1, so the feedback loop is stimulated directly, and the patient cells' failure to respond isolates the regulatory defect from the enzyme's activity.
Limitations: Fibroblasts are not the affected tissue. Nothing in this model addresses why the corticospinal tract and the lens fail while the fibroblast, which carries the same lipid abnormality, is viable and unremarkable - and that gap is the whole distance between the biochemistry and the disease. The p.Arg480Leu and p.Arg480Ser alleles have never been assayed, because no fibroblasts were available.
Readouts
FAR1 protein level after HDG-induced plasmalogen loading
Direction: UNCHANGED
Interpretation: A real negative result. Controls dropped FAR1 by about 40 percent; patient cells held it at 101 percent of baseline despite a comparable plasmalogen rise.
Show evidence (1 reference)
PMID:33239752 SUPPORT In Vitro
"In the patients' cells, treatment with HDG also increased C16:0-plasmalogen levels 130-224% (mean ± SD: 160 ± 35%) (Fig. 3c), but this did not result in a consistent decrease of FAR1 protein levels (mean ± SD: 101 ± 17%) (Fig. 3a, b)."
The measurement underlying this readout, including confirmation that the stimulus worked.
Show evidence (1 reference)
PMID:33239752 SUPPORT In Vitro
"We studied the effect of the identified FAR1 variants in fibroblasts of patients 1-3"
Establishes which patients the model represents, which bounds what it can be informative about. The same sentence records the alleles as two p.Arg480His and one p.Arg480Cys; that part is not quoted because the source writes the counts in square brackets, which the validator strips.
Uncontrolled Ether Lipid Synthesis measures fidelity: high The C17:0 labelling experiment measures ether and non-ether lipid synthesis from the same exogenous substrate in the same cells, so the non-ether arm is an internal control for uptake and general lipid handling.
Limitations: A fibroblast's ether lipid demand is not a neuron's or a lens fibre cell's, and the fourfold flux increase measured here cannot be assumed to be the magnitude in the tissues that fail.
Readouts
C17:0-alcohol incorporation into LPC(O-17:0)
Direction: INCREASED
Interpretation: Almost fourfold higher in patients, while incorporation into the non-ether LPC(17:0) was unchanged - flux specifically down the ether branch.
Show evidence (1 reference)
PMID:33239752 SUPPORT In Vitro
"Incorporation of C17:0-acid in LPC(17:0) was similar in controls and patients whereas FAR1-dependent incorporation of C17-alcohol in LPC(O-17:0) was almost fourfold higher in patients than in controls"
The flux measurement underlying this readout, with its internal control.
Show evidence (1 reference)
PMID:33239752 SUPPORT In Vitro
"Lipidomic analysis of LPC(17:0) and LPC(O-17:0) was used to compare nonether and ether lipid synthesis, respectively, in fibroblasts of controls and patients."
Describes the design that makes this model informative for a flux claim rather than a steady-state one.
{ }

Source YAML

click to show 
name: Spastic Paraparesis-Cataracts-Speech Delay Syndrome
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Spastic paraparesis-cataracts-speech delay syndrome
  term:
    id: MONDO:0036212
    label: spastic paraparesis-cataracts-speech delay syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0036212
      label: spastic paraparesis-cataracts-speech delay syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the disease; carries the OMIM (619338) and
      Orphanet (615938) cross-references.
  - term:
      id: MONDO:0100230
      label: fatty acyl-CoA reductase 1 upregulation
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO appears to hold two live terms for this one disease. MONDO:0100230
      is defined as "A disorder of plasmalogens biosynthesis, that is an
      autosomal dominant neurological disorder that results in uncontrolled
      synthesis of ether lipids", which is the defining paper's title
      restated, and it carries only a GARD cross-reference. MONDO:0036212 carries
      the OMIM, Orphanet, MedGen and UMLS cross-references and has "Fatty
      acyl-CoA reductase 1 superactivity" as a synonym. They name the same
      entity. This entry anchors on MONDO:0036212 as the better-referenced of
      the two and maps the other as an exact match; the duplication is a MONDO
      issue rather than a curation choice, and is noted here so a later merge
      does not look like a change of scope. Note that
      Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect refers to
      this disease by the MONDO:0100230 identifier in its differential.
description: >-
  Spastic paraparesis-cataracts-speech delay syndrome is the dominant,
  gain-of-function arm of FAR1 disease. It is caused by de novo heterozygous variants at
  a single codon - Arg480 - of fatty acyl-CoA reductase 1, the rate-limiting
  enzyme of ether lipid synthesis, and it is the mechanistic inverse of the
  recessive FAR1 deficiency (RCDP4) that this knowledge base curates elsewhere.

  Read that inversion carefully, because the two FAR1 diseases are easy to
  conflate and most of the literature on the gene is about the other one. In
  RCDP4, biallelic loss of FAR1 abolishes fatty-alcohol production and patients
  are plasmalogen-*deficient*. Here, FAR1 works perfectly well: its catalytic
  function is preserved and it is correctly targeted to the peroxisome. What the
  Arg480 variants destroy is the brake. FAR1 protein is normally degraded in
  response to rising plasmalogen levels, a negative feedback loop that holds
  ether lipid output at a set point. The variants abolish that response, so FAR1
  accumulates, and ether lipid synthesis runs without a governor. Patients'
  fibroblasts have plasmalogen levels about twice control, FAR1 enzyme activity
  roughly three to four times control, and a fourfold increase in flux into ether
  lipids measured directly with a labelled fatty acid.

  The clinical consequence is the part that resists a simple story. Despite
  biochemical phenotypes that are, in the authors' words, diametrically opposed,
  the two FAR1 diseases share their cardinal features: spastic paraparesis,
  bilateral cataracts, seizures. What separates them clinically is severity and
  what is *absent* here - normal growth, no microcephaly, no dysmorphism, and
  normal brain MRI in ten of twelve patients. The observation that too much and
  too little of the same lipid class produce the same neurological and ocular
  picture is the central unexplained fact of this entity, and it is shared with a
  small group of other ether-lipid-excess disorders. It is curated below as an
  open question rather than smoothed over.
parents:
- hereditary disease
- inborn error of metabolism
- peroxisomal disease
synonyms:
- CSPSD
- Fatty acyl-CoA reductase 1 superactivity
- FAR1 upregulation
- Cataracts, spastic paraparesis, and speech delay
- Autosomal dominant FAR1-related disorder
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      An inborn error of lipid metabolism, defined biochemically by an ether
      lipid abnormality.
  - classification_value: NEUROLOGIC
    notes: >-
      The presenting and dominant clinical problem is pyramidal tract
      dysfunction with developmental delay.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian disorder identified by trio exome sequencing and
      GeneMatcher.
references:
- reference: PMID:33239752
  title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
- reference: PMID:36254151
  title: "Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature."
- reference: PMID:37335441
  title: "Complex Hereditary Spastic Paraparesis Caused by de novo p.Arg480Ser in FAR1."
- reference: PMID:36720320
  title: "Regulation of plasmalogen biosynthesis in mammalian cells and tissues."
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Monoallelic and, in every reported case, de novo. Twelve patients in the
    defining cohort each carry one variant Arg480 allele with two unaffected
    parents; subsequent single cases are likewise de novo. No transmission from
    an affected parent to a child has been described, so the 50 percent
    recurrence risk usually quoted for a dominant disorder is a theoretical
    figure here rather than an observed one, and reproductive outcomes for
    affected individuals are unknown.

    The contrast with the other FAR1 disease is the point. RCDP4 is autosomal
    recessive: two loss-of-function alleles, unaffected heterozygous parents.
    This disease needs one gain-of-function allele. A single heterozygous FAR1
    variant found in a patient is therefore not automatically a carrier finding -
    which allele class it is decides everything.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 12 individuals from around the world with heterozygous de
      novo missense variants in FAR1 (NM_032228.6): 4 patients with variant
      c.1439G>A (p.Arg480His), 7 patients with variant c.1438C>T (p.Arg480Cys),
      and 1 patient with variant c.1439G>T (p. Arg480Leu) (Table 1).
    explanation: >-
      Establishes heterozygous de novo inheritance in all twelve defining
      patients, with the allele counts.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to
      an autosomal dominant disorder with a different disease mechanism than that
      of recessive FAR1 deficiency and a diametrically opposed biochemical
      phenotype.
    explanation: >-
      The authors' own statement that this is a distinct dominant entity from
      recessive FAR1 deficiency, which is the scope decision this entry rests on.
pathophysiology:
- name: De Novo Heterozygous FAR1 Arg480 Variant
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Every reported allele changes the same arginine. Four patients carry
    c.1439G>A p.(Arg480His), seven c.1438C>T p.(Arg480Cys), one c.1439G>T
    p.(Arg480Leu), and a later single case p.(Arg480Ser). None is in gnomAD.

    The residue's position is the mechanism. Arg480 sits in FAR1's predicted
    transmembrane domain, amino acids 466 to 483, near the edge facing the
    peroxisomal matrix - and the region flanking that domain on the matrix side
    is the part previously shown to be required for plasmalogen-dependent control
    of FAR1 stability. So the variants are in the regulatory element, not in the
    catalytic domain, which is exactly what the functional results show: catalysis
    intact, regulation gone.

    That every disease allele is at one codon, and that four different
    substitutions there all produce the same disease, is strong evidence that the
    residue itself is the essential thing rather than any particular replacement
    amino acid.
  genes:
  - preferred_term: FAR1
    term:
      id: hgnc:26222
      label: FAR1
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  genetic_context:
    functional_impact_category: HYPERMORPHIC
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
    description: >-
      Curated as HYPERMORPHIC rather than the generic GAIN_OF_FUNCTION, and the
      distinction is worth the words. The enum defines HYPERMORPHIC as increased
      *normal* gene product activity and NEOMORPHIC as a novel activity absent
      from the wild type. What was measured here is more of the normal reaction:
      FAR1's biosynthetic function and peroxisomal localisation are preserved,
      peroxisomal beta-oxidation and DHAPAT activity are normal, and the enzyme
      makes the same fatty alcohols it always did - there is simply more enzyme
      because it is no longer degraded. No new catalytic activity is reported,
      so NEOMORPHIC is wrong, and HYPERMORPHIC is more specific than
      GAIN_OF_FUNCTION without asserting anything beyond the data.

      DOMINANT_NEGATIVE is excluded by the direction of effect: the wild-type
      allele is not being interfered with, and total FAR1 activity is up rather
      than down.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three variants were not reported in the gnomAD database and all are
      predicted to be deleterious by various pathogenicity prediction programs.
      Remarkably, all de novo variants are located in the same codon, p.Arg480,
      which is located in the predicted transmembrane region of FAR1, formed by
      amino acids 466-483.
    explanation: >-
      Establishes the single-codon clustering and the transmembrane location that
      the mechanism turns on.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nevertheless, our results are in line with data from Honsho et al.7 who
      showed that the C-terminal domain of FAR1, especially the 17 amino acids
      flanking the transmembrane domain (491-507), is essential for the
      plasmalogen-dependent modulation of the stability of FAR1.
    explanation: >-
      Places Arg480 next to the region already known to carry the
      stability-regulation signal, which is why a transmembrane variant abolishes
      feedback rather than catalysis. Graded OTHER because it is the authors'
      appeal to prior work rather than their own experiment.
  downstream:
  - target: Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
    causal_link_type: DIRECT
- name: Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The lesion, and the reason this disease exists as a separate entity from
    RCDP4.

    Normally, FAR1 abundance is set by a negative feedback loop: rising cellular
    plasmalogen triggers active degradation of FAR1 protein, so ether lipid
    output self-limits. The experiment that demonstrates the loop is broken here
    is a clean one. Loading fibroblasts with 1-O-hexadecyl-sn-glycerol raises
    plasmalogen by a route that bypasses FAR1 entirely, and in control cells that
    drops FAR1 protein by about 40 percent. In patients' cells the same treatment
    raised plasmalogen just as intended, and FAR1 protein did not fall.

    The starting condition makes the point sharper still. Untreated patient cells
    already had plasmalogen about twice control - roughly the level that
    HDG-treated control cells reach - and yet held FAR1 protein at three times
    the HDG-treated control level. The signal was maximal and the response was
    absent.
  biological_processes:
  - preferred_term: plasmalogen-triggered degradation of FAR1
    term:
      id: GO:0030163
      label: protein catabolic process
    modifier: LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In control fibroblasts, HDG treatment increased C16:0-plasmalogen levels
      199-291% (mean ± SD: 249 ± 31%) (Fig. 3c) and resulted in a 31-47% decrease
      (mean ± SD: 40 ± 7%) in FAR1 protein levels (Fig. 3a, b). In the patients'
      cells, treatment with HDG also increased C16:0-plasmalogen levels 130-224%
      (mean ± SD: 160 ± 35%) (Fig. 3c), but this did not result in a consistent
      decrease of FAR1 protein levels (mean ± SD: 101 ± 17%) (Fig. 3a, b).
    explanation: >-
      The controlled experiment demonstrating that the feedback response is
      present in controls and absent in patients, with the plasmalogen stimulus
      confirmed to have worked in both.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Despite these high plasmalogen levels, FAR1 protein levels in the patients'
      cells were threefold higher than in the HDG-treated controls
    explanation: >-
      Shows the failure is not a matter of an insufficient signal: the signal was
      already at or above the level that suppresses FAR1 in control cells.
  - reference: PMID:36720320
    reference_title: "Regulation of plasmalogen biosynthesis in mammalian cells and tissues."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Plasmalogen biosynthesis is spatiotemporally regulated by a feedback
      mechanism that senses the amount of plasmalogens in the inner leaflet of
      the plasma membrane and regulates the stability of fatty acyl-CoA reductase
      1 (FAR1), the rate-limiting enzyme for plasmalogen biosynthesis.
    explanation: >-
      Independent statement of the normal regulatory mechanism that this disease
      abolishes, from a review of the pathway rather than from the disease
      report.
  downstream:
  - target: Elevated FAR1 Protein and Enzyme Activity
    causal_link_type: DIRECT
- name: Elevated FAR1 Protein and Enzyme Activity
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    The immediate quantitative consequence of the broken brake: more FAR1
    protein on immunoblot, and FAR1 enzyme activity in patients' fibroblasts of
    379, 323 and 310 pmol per hour per mg protein against control values of 74,
    90 and 101 - three to four times control.

    The `modifier` here is INCREASED, deliberately and in contrast with the node
    below. The claim at this node is purely quantitative: a normal enzyme, doing
    its normal reaction, present in larger amounts. Nothing about the enzyme
    itself is qualitatively altered - immunofluorescence shows normal peroxisomal
    targeting, and other peroxisomal functions are normal.
  molecular_functions:
  - preferred_term: fatty acyl-CoA reductase activity
    term:
      id: GO:0102965
      label: alcohol-forming long-chain fatty acyl-CoA reductase (NADP+) activity
    modifier: INCREASED
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, the enzyme activity of FAR1 was markedly increased in the
      fibroblasts of patients 1-3
    explanation: >-
      The activity measurement in patient versus control fibroblasts. The quote
      stops before the numbers because the source writes the unit as
      "pmol/[h.mg protein]" and the reference validator strips bracketed spans;
      the values are given in this node's description.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, immunoblot analysis showed clearly increased FAR1 protein levels
      in the patients' fibroblasts (Fig. 2c).
    explanation: >-
      The protein-abundance half of this node, measured independently of the
      activity assay.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescence microscopy analysis showed that FAR1 is normally
      localized to peroxisomes in patients' fibroblasts (see Fig. 2d for
      representative image) showing that p.Arg480His/Cys variants do not
      interfere with peroxisomal targeting of FAR1.
    explanation: >-
      Excludes mislocalisation, which is what keeps this node a purely
      quantitative claim about enzyme amount.
  downstream:
  - target: Uncontrolled Ether Lipid Synthesis
    causal_link_type: DIRECT
- name: Uncontrolled Ether Lipid Synthesis
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Flux, not just enzyme level. Feeding fibroblasts a labelled odd-chain fatty
    acid lets ether and non-ether routes be tracked separately from the same
    substrate: incorporation into the non-ether lipid LPC(17:0) was the same in
    patients and controls, while FAR1-dependent incorporation into the ether
    lipid LPC(O-17:0) was almost fourfold higher in patients. The pathway is
    running fast, and specifically the ether branch.

    On the `modifier` value, which is the one interpretive choice in this entry
    that most needs defending. `GAIN_OF_FUNCTION` is used here, and
    `INCREASED` is used one node up, deliberately. The schema reserves
    GAIN_OF_FUNCTION for a process driven outside its normal regulatory
    constraints rather than merely running above its normal level, and warns
    against migrating a quantitative annotation to it without that qualitative
    justification. The justification here is not that ether lipid synthesis is
    high. It is that the homeostatic loop which sets its level has been
    eliminated: raising the pathway's own product no longer restrains it, so
    there is no set point for the output to be above. The authors' own term is
    "uncontrolled". A cell with elevated but still-regulated ether lipid
    synthesis would be INCREASED; this one has lost the control system.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
    modifier: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Incorporation of C17:0-acid in LPC(17:0) was similar in controls and
      patients whereas FAR1-dependent incorporation of C17-alcohol in LPC(O-17:0)
      was almost fourfold higher in patients than in controls (Fig. 4g)
      confirming that ether lipid synthesis indeed is elevated in patients with
      p.Arg480His/Cys variants.
    explanation: >-
      A direct flux measurement, with the non-ether arm as an internal control
      showing the effect is specific to the ether branch.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analyses, including fibroblast plasmalogen measurements, FAR1
      enzyme activity assays, and lipidomics showed that the biosynthetic
      function and peroxisomal localization of FAR1 is preserved but that the
      plasmalogen-dependent regulation of FAR1 protein levels is abolished,
      resulting in uncontrolled ether lipid synthesis and considerable changes in
      the cellular lipidome.
    explanation: >-
      The authors' summary, and the wording ("abolished", "uncontrolled") that
      justifies grading this node's modifier as a qualitative loss of regulatory
      constraint rather than a quantitative elevation.
  downstream:
  - target: Membrane Lipid Composition Shift
    causal_link_type: DIRECT
- name: Membrane Lipid Composition Shift
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The disease is not simply "too much plasmalogen". Lipidomics shows ether
    species accumulating - plasmanyl/plasmenyl-choline phospholipids, and the
    neutral ether lipids DG[O] and TG[O] - with a reciprocal and significant fall
    in the corresponding non-ether phospholipids PC and PE, PE severely.
    Strikingly, the totals of choline- and ethanolamine-containing lipids stay
    roughly constant - the paper states this in the same passage, though it
    cannot be quoted here because the sentence carries the bracketed ether-lipid
    nomenclature PE[O] and PC[O] that the reference validator strips. What has
    changed is the ratio of ether to non-ether species, not the amount of
    membrane phospholipid.

    The proposed explanation is competition for a shared limited resource -
    elevated DG[O] outcompeting DG for the activated headgroups CDP-choline and
    CDP-ethanolamine - which would make this a substrate-competition effect
    rather than a direct toxicity. The polyunsaturated fatty acids also
    redistribute, away from PC and toward PC[O].

    Recorded because it is the most plausible bridge from a biochemical
    abnormality to a cellular one, and because it is the level at which this
    disease and the RCDP disorders are precise mirror images: in RCDP the
    non-ether lipids compensate for absent ether counterparts, and the PUFA
    distribution runs the other way.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Total levels of the major phospholipids phosphatidylcholine (PC) and
      phosphatidylethanolamine (PE) were both significantly decreased, with PE
      levels drastically reduced (Fig. 4a, b).
    explanation: >-
      The reciprocal fall in the non-ether phospholipids, which is what makes
      this a compositional shift rather than a simple accumulation.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Interestingly, this ether/nonether balance is precisely reversed in
      different RCDP subtypes where nonether lipids compensate for the absence of
      their ether counterparts.
    explanation: >-
      States that the same ratio is displaced in the opposite direction in the
      recessive plasmalogen-deficiency disorders, which is the sharpest available
      statement of the mirror-image relationship between the two arms of FAR1
      disease. Graded OTHER because it is the authors' comparison with a
      different disease group rather than a measurement in these patients.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      compete with DG for the limited amounts of activated headgroups
      CDP-ethanolamine and CDP-choline to synthesize ether and nonether analogs
      of PC and PE, shifting the balance toward ether phospholipids at the
      expense of the nonether equivalents
    explanation: >-
      The proposed competition mechanism. The quote begins mid-sentence because
      the clause before it names the competing species as DG[O], and the
      reference validator strips bracketed spans. Graded PARTIAL because the
      authors offer this explicitly as one possible mechanism, not as a
      demonstrated one; no competition experiment is reported.
  downstream:
  - target: Corticospinal Tract Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      No step between the lipid abnormality and the pyramidal tract is known for
      this disease or for any of the ether-lipid-excess disorders. The authors
      state the pathophysiological mechanism remains enigmatic.
  - target: Lens Opacification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Equally unexplained, and more puzzling, because cataract is also caused by
      ether lipid *deficiency* - see the open discussion.
- name: Corticospinal Tract Dysfunction
  biological_scale: TISSUE
  role: outcome
  mechanism_confidence: PROVISIONAL
  description: >-
    The presenting problem and the most consistent finding: spastic di- or
    paraparesis in twelve of twelve patients, with lower limb hypertonia, truncal
    hypotonia in half, and ankle clonus. The pattern - lower limbs affected,
    upper motor neuron signs, normal brain imaging in most - is that of a
    hereditary spastic paraplegia, which is why the authors recommend adding
    FAR1 to hereditary spastic paraplegia and cerebral palsy panels.

    Marked PROVISIONAL because the anatomical claim in the node's name is a
    clinical inference. Pyramidal tract dysfunction is what was observed; no
    imaging, electrophysiological or neuropathological localisation to the
    corticospinal tract has been reported in any patient, and brain MRI was
    normal in ten of twelve.

    Scaled TISSUE rather than ORGANISM, to match Lens Opacification below. The
    two nodes are the disease's two end-organ failures and the substrate named in
    each is an anatomical structure - a tract and a lens - so tagging one at
    organism scale and the other at tissue scale would make the pair look like
    different kinds of claim when they are the same kind. The organism-level
    reading is available and was rejected: spastic paraparesis as a whole-body
    motor phenotype would be ORGANISM, but that is the phenotype, curated in
    `phenotypes:`, not this node.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They presented with pyramidal tract dysfunction, exhibiting spastic di- or
      paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and
      (ankle) clonus.
    explanation: >-
      The neurological phenotype with its frequencies in the defining cohort.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging was within normal limits in 10/12 patients; one patient had
      abnormal temporal lobe morphology and ventricular prominence, but white
      matter was normal.
    explanation: >-
      Establishes that no structural correlate was found, which is why the
      anatomical attribution in this node is graded provisional - and is also a
      point of separation from RCDP4, where white matter abnormalities occur.
- name: Lens Opacification
  biological_scale: TISSUE
  role: outcome
  mechanism_confidence: PROVISIONAL
  description: >-
    Bilateral cataracts in twelve of twelve patients, congenital in five and
    acquired in the other seven - so this is not purely a developmental
    malformation of the lens; in most patients the lens was clear at birth and
    opacified later, over months to years.

    Marked PROVISIONAL because nothing is known about why. The one strong piece
    of causal evidence in this area points the other way entirely: in a mouse
    model of ether lipid *deficiency*, restoring plasmalogens prevented
    cataracts, establishing shortage as a cause. How excess produces the same
    end organ failure is unexplained.
  locations:
  - preferred_term: lens of camera-type eye
    term:
      id: UBERON:0000965
      label: lens of camera-type eye
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, all patients had bilateral cataracts (12/12), which were
      congenital in 5/12 and acquired in the other 7/12.
    explanation: >-
      The ocular phenotype with the congenital-versus-acquired split, which is
      what shows the lens can be normal at birth and fail later.
phenotypes:
- category: Neurological
  name: Spastic Paraparesis
  frequency: "12/12"
  description: >-
    Present in every reported patient, and the feature that brings them to
    attention. Combined with truncal hypotonia in half the cohort - a
    distinctive pairing of axial low tone with lower limb high tone.
  phenotype_term:
    preferred_term: Spastic paraparesis
    term:
      id: HP:0002313
      label: Spastic paraparesis
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had spastic paraparesis and bilateral congenital/juvenile
      cataracts, in most combined with speech and gross motor developmental delay
      and truncal hypotonia.
    explanation: >-
      Spastic paraparesis in all patients, alongside the other cardinal
      features.
- category: Neurological
  name: Axial Hypotonia
  frequency: "6/12"
  phenotype_term:
    preferred_term: Truncal hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They presented with pyramidal tract dysfunction, exhibiting spastic di- or
      paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and
      (ankle) clonus.
    explanation: >-
      Truncal hypotonia in six of twelve.
- category: Neurological
  name: Ankle Clonus
  description: >-
    No `frequency:` here, unlike the phenotypes around it. The source lists ankle
    clonus inside the pyramidal-signs sentence without attaching a count, where
    it gives explicit fractions for spastic paraparesis and truncal hypotonia in
    the same breath. Inferring 12/12 from the sentence's structure would be
    reading a number the paper declined to give.
  phenotype_term:
    preferred_term: Ankle clonus
    term:
      id: HP:0011448
      label: Ankle clonus
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They presented with pyramidal tract dysfunction, exhibiting spastic di- or
      paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and
      (ankle) clonus.
    explanation: >-
      Ankle clonus as part of the upper motor neuron picture.
- category: Neurological
  name: Lower Limb Spasticity
  description: >-
    The distribution that makes this a paraparesis rather than a quadriparesis,
    and the reason these children are labelled hereditary spastic paraplegia or
    cerebral palsy. Note the pairing with axial hypotonia above: high tone in the
    legs, low tone in the trunk.

    No `frequency:` for the same reason as ankle clonus: lower limb hypertonia is
    named in the pyramidal-signs sentence without a count of its own.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They presented with pyramidal tract dysfunction, exhibiting spastic di- or
      paraparesis (12/12), lower limb hypertonia, truncal hypotonia (6/12), and
      (ankle) clonus.
    explanation: >-
      Lower limb hypertonia as part of the pyramidal picture in the cohort.
- category: Developmental
  name: Intellectual Disability
  frequency: "3/12"
  description: >-
    Present in only three of twelve, and that low frequency is one of the
    clearest separators from recessive FAR1 deficiency, where intellectual
    disability is profound and universal. Most patients in this cohort had
    delayed speech that later became fluent, with early learning difficulties
    rather than a fixed cognitive deficit - one attends university.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive delay and intellectual disability were less common in the cohort
      (3/12).
    explanation: >-
      The frequency, and the source's own framing of it as uncommon.
- category: Craniofacial
  name: Macrocephaly
  frequency: "2/12"
  description: >-
    Two of twelve. Recorded partly for its own sake and partly because its
    direction matters: recessive FAR1 deficiency causes *micro*cephaly, and no
    patient here had dysmorphic features.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were no dysmorphic features; two patients presented with
      macrocephaly.
    explanation: >-
      Macrocephaly in two patients, in the same sentence that records the
      absence of dysmorphism.
- category: Ophthalmological
  name: Bilateral Cataracts
  frequency: "12/12"
  description: >-
    Universal in the defining cohort. Congenital in five patients and acquired
    later in seven, which is why the term chosen is the general cataract term
    rather than a congenital-specific one.
  phenotype_term:
    preferred_term: Bilateral cataracts
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, all patients had bilateral cataracts (12/12), which were
      congenital in 5/12 and acquired in the other 7/12.
    explanation: >-
      Cataracts in all twelve, with the timing split.
- category: Neurological
  name: Seizures
  frequency: "8/12"
  description: >-
    In eight of twelve patients, mostly beginning in the first months of life,
    and - unusually for an inborn error with early-onset epilepsy - readily
    controlled. Half of the treated patients came off antiepileptic drugs without
    recurrence. This is the indication for the one treatment curated in this
    entry.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occurred in 8/12 patients, mainly in the first months of life, and
      appeared amenable to therapy with barbiturates, levetiracetam, and/or
      oxcarbazepine.
    explanation: >-
      Seizure frequency, onset and treatment responsiveness in the cohort.
- category: Developmental
  name: Delayed Speech Development
  frequency: "10/12"
  description: >-
    Delayed in ten of twelve patients, with receptive speech outperforming
    expressive speech in three - and, notably, most patients became fluent. It is
    a developmental delay rather than a fixed language disorder, which matters
    for how families should be counselled.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Speech development was delayed in 10/12 patients, with receptive speech
      outperforming expressive speech in 3 patients.
    explanation: >-
      Speech delay frequency and the receptive-expressive dissociation.
- category: Developmental
  name: Delayed Gross Motor Development
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had spastic paraparesis and bilateral congenital/juvenile
      cataracts, in most combined with speech and gross motor developmental delay
      and truncal hypotonia.
    explanation: >-
      Gross motor delay in most of the cohort.
genetic:
- name: FAR1
  gene_term:
    preferred_term: FAR1
    term:
      id: hgnc:26222
      label: FAR1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: PRESENT
  notes: >-
    FAR1 is a tail-anchored protein of 515 amino acids: a cytosol-facing
    N-terminal domain (1-465), a transmembrane domain (466-483), and a
    C-terminal domain (484-515) in the peroxisomal matrix. It is the
    rate-limiting enzyme of ether lipid synthesis, reducing C16 and C18 fatty
    acyl-CoAs to the fatty alcohols that alkylglycerone phosphate synthase then
    uses.

    Reading a FAR1 variant report requires knowing which of two diseases it is
    about, and the literature does not always make that easy. Four alleles cause
    the dominant disease and all are at codon 480: c.1439G>A p.(Arg480His),
    c.1438C>T p.(Arg480Cys), c.1439G>T p.(Arg480Leu), and c.1439G>C
    p.(Arg480Ser), reported later. Biallelic loss-of-function variants anywhere
    in the gene cause the recessive disease, FAR1 deficiency or RCDP4, curated in
    this knowledge base under
    Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect. Position
    480 and heterozygosity together are the discriminator; either alone is not.

    The ascertainment is worth recording because it shows how a recurrent-codon
    disorder gets found. Clinical exome analysts at a commercial laboratory
    noticed heterozygous FAR1 Arg480 variants recurring, searched their internal
    series of 42,983 exome trios plus 9,205 gene-list trios, found eight cases,
    and used GeneMatcher to assemble the rest. That is a pattern-recognition
    route, not a phenotype-driven one, which is part of why the cohort is
    clinically homogeneous.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FAR1 is a tail-anchored protein of 515 amino acids with an N-terminal
      domain corresponding to amino acids 1-465 facing the cytosol, a
      transmembrane domain corresponding to amino acids 466-483 and a C-terminal
      domain corresponding to amino acids 484-515 located in the peroxisomal
      matrix.
    explanation: >-
      The protein architecture that places Arg480 in the transmembrane domain.
      Graded OTHER because it is background from the paper's introduction.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was internally explored in a cohort of 42,983 exome trios and 9205
      exome-based specific gene list trios that included FAR1 analysis. This led
      to the identification of eight cases.
    explanation: >-
      The ascertainment denominator, which is the only population-scale number
      available for this disease.
  - reference: PMID:37335441
    reference_title: "Complex Hereditary Spastic Paraparesis Caused by de novo p.Arg480Ser in FAR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, authors have identified a novel substitution in the same Arg480
      position into serine.
    explanation: >-
      A fourth substitution at the same codon, reinforcing that the residue
      rather than the replacement amino acid is what matters.
biochemical:
- name: Plasmalogen Levels as a Bidirectional FAR1 Readout
  notes: >-
    The single most useful diagnostic point in this entity, and one that inverts
    normal practice. Plasmalogen measurement is an established screening test for
    peroxisomal disease, where the abnormal result is a *low* value. In this
    disease the result is high - patient fibroblasts had C16:0-plasmalogen about
    twice control, significantly elevated at p < 0.0001.

    The corollary the authors draw is that erythrocyte plasmalogen measurement
    should be read as a bidirectional readout of ether lipid synthesis, because
    both an abnormally high and an abnormally low value can indicate FAR1-related
    pathology. A laboratory reporting only "plasmalogens not decreased" would
    miss this disease entirely.

    Two further biochemical distinctions from the peroxisomal disorders it might
    be confused with: peroxisomal beta-oxidation of very long chain fatty acids
    and DHAPAT activity are normal, and peroxisomes are of normal size and shape.
    This is not a peroxisome biogenesis disorder.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to previously reported patients with FAR1 deficiency, the
      plasmalogen levels in fibroblasts of the patients were not decreased, but
      increased (see Fig. 2a).
    explanation: >-
      The direction of the biochemical abnormality, stated against the recessive
      disease it inverts.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the measurement of plasmalogens in erythrocytes should be
      considered as a functional readout of ether lipid synthesis as both
      abnormally high or low levels could suggest FAR1-related pathology.
    explanation: >-
      The authors' recommendation that the test be read in both directions, which
      is the practical diagnostic content of this entity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twelve patients in the defining cohort, assembled from around the world, plus
    at least two further single case reports since - a Middle Eastern patient
    with a milder presentation and a patient with a fourth Arg480 substitution.
    No population prevalence has been estimated.

    The nearest thing to a denominator is the ascertainment itself: eight of the
    twelve came from a commercial laboratory's internal series of 42,983 exome
    trios plus 9,205 gene-list trios. That is a diagnostic-yield figure from a
    referred population, not a birth prevalence, but it does bound the disease as
    very rare even among children referred for exome sequencing.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this paper we describe a cohort of 12 patients with different de novo
      missense variants in the FAR1 gene, but all resulting in an amino acid
      change at position 480 (p.Arg480Cys/His/Leu).
    explanation: >-
      The size of the defining cohort.
  - reference: PMID:36254151
    reference_title: "Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient adds to the small number of patients recognized to date and
      expands the clinical spectrum to provide better clinical delineation,
      improve diagnosis, and develop precision medicine approaches for this
      disorder.
    explanation: >-
      An additional reported case, and the author's own characterisation of how
      few exist.
experimental_models:
- name: Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Skin fibroblasts from patients 1 to 3 (two p.Arg480His, one p.Arg480Cys)
    against six anonymised control lines. Every functional claim in this entry
    comes from this model - plasmalogen measurement by gas chromatography, FAR1
    enzyme assay, immunoblot, immunofluorescence, the HDG feedback challenge, and
    lipidomics with C17:0 labelling.

    On animal models, and the claim needs stating precisely because the obvious
    reading of it is wrong. There is no animal model of *this* disease and no
    cell line carrying an engineered Arg480 allele. FAR1 itself is not
    model-less: a Far1 knockout mouse exists, is subviable with growth
    retardation and male infertility, and its authors present it as a model of
    ether lipid *deficiency*. That is the recessive arm, the mechanistic inverse
    of this disease, and it cannot substitute for a model of Arg480 gain of
    function.
  modeled_mechanisms:
  - target: Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The HDG challenge is a genuine perturbation experiment rather than an
      observation: it raises plasmalogen by a route that bypasses FAR1, so the
      feedback loop is stimulated directly, and the patient cells' failure to
      respond isolates the regulatory defect from the enzyme's activity.
    limitations: >-
      Fibroblasts are not the affected tissue. Nothing in this model addresses
      why the corticospinal tract and the lens fail while the fibroblast, which
      carries the same lipid abnormality, is viable and unremarkable - and that
      gap is the whole distance between the biochemistry and the disease. The
      p.Arg480Leu and p.Arg480Ser alleles have never been assayed, because no
      fibroblasts were available.
    readouts:
    - name: FAR1 protein level after HDG-induced plasmalogen loading
      target: Loss of Plasmalogen-Dependent Feedback Degradation of FAR1
      direction: UNCHANGED
      interpretation: >-
        A real negative result. Controls dropped FAR1 by about 40 percent;
        patient cells held it at 101 percent of baseline despite a comparable
        plasmalogen rise.
      evidence:
      - reference: PMID:33239752
        reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In the patients' cells, treatment with HDG also increased
          C16:0-plasmalogen levels 130-224% (mean ± SD: 160 ± 35%) (Fig. 3c), but
          this did not result in a consistent decrease of FAR1 protein levels
          (mean ± SD: 101 ± 17%) (Fig. 3a, b).
        explanation: >-
          The measurement underlying this readout, including confirmation that
          the stimulus worked.
    evidence:
    - reference: PMID:33239752
      reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We studied the effect of the identified FAR1 variants in fibroblasts of
        patients 1-3
      explanation: >-
        Establishes which patients the model represents, which bounds what it can
        be informative about. The same sentence records the alleles as two
        p.Arg480His and one p.Arg480Cys; that part is not quoted because the
        source writes the counts in square brackets, which the validator strips.
  - target: Uncontrolled Ether Lipid Synthesis
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      The C17:0 labelling experiment measures ether and non-ether lipid synthesis
      from the same exogenous substrate in the same cells, so the non-ether arm
      is an internal control for uptake and general lipid handling.
    limitations: >-
      A fibroblast's ether lipid demand is not a neuron's or a lens fibre cell's,
      and the fourfold flux increase measured here cannot be assumed to be the
      magnitude in the tissues that fail.
    readouts:
    - name: C17:0-alcohol incorporation into LPC(O-17:0)
      target: Uncontrolled Ether Lipid Synthesis
      direction: INCREASED
      interpretation: >-
        Almost fourfold higher in patients, while incorporation into the
        non-ether LPC(17:0) was unchanged - flux specifically down the ether
        branch.
      evidence:
      - reference: PMID:33239752
        reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Incorporation of C17:0-acid in LPC(17:0) was similar in controls and
          patients whereas FAR1-dependent incorporation of C17-alcohol in
          LPC(O-17:0) was almost fourfold higher in patients than in controls
        explanation: >-
          The flux measurement underlying this readout, with its internal
          control.
    evidence:
    - reference: PMID:33239752
      reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Lipidomic analysis of LPC(17:0) and LPC(O-17:0) was used to compare
        nonether and ether lipid synthesis, respectively, in fibroblasts of
        controls and patients.
      explanation: >-
        Describes the design that makes this model informative for a flux claim
        rather than a steady-state one.
treatments:
- name: Antiseizure Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The only treatment reported in this disease, and it is symptomatic. Seizures
    in the defining cohort responded to barbiturates, levetiracetam and
    oxcarbazepine, and in four of the eight treated patients antiepileptic
    treatment was withdrawn without recurrence.

    That last detail is the clinically useful one. Early-onset epilepsy in an
    inborn error of metabolism is often refractory; here it appears both
    treatable and, in half of cases, self-limiting. Nothing is reported about
    which agent to prefer, and with eight patients across three drug classes
    nothing could be.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
    - preferred_term: barbiturate
      term:
        id: NCIT:C67084
        label: Barbiturate
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occurred in 8/12 patients, mainly in the first months of life, and
      appeared amenable to therapy with barbiturates, levetiracetam, and/or
      oxcarbazepine. Antiepileptic treatment could be discontinued without
      recurrence of seizures in 4/8 patients.
    explanation: >-
      The agents used, the response, and the withdrawal outcome - the whole of
      the reported treatment experience in this disease.
diagnosis:
- name: FAR1 on Spastic Paraplegia, Cerebral Palsy and Juvenile Cataract Panels
  description: >-
    The combination that should prompt the test is spastic paraparesis plus
    bilateral cataracts, and the authors' explicit recommendation is that FAR1 be
    added to hereditary spastic paraplegia, cerebral palsy and juvenile cataract
    gene panels. Cerebral palsy is on that list for a reason: a child with
    non-progressive lower-limb spasticity, normal brain MRI and no perinatal
    history is routinely labelled cerebral palsy, and one of the twelve defining
    patients was in fact found through an exome-based cerebral palsy panel.

    The biochemical confirmation is plasmalogen measurement, read for an
    elevated result - which is the opposite of how the same test is read in every
    other peroxisomal disorder.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings show that for patients with spastic paraparesis and bilateral
      cataracts, FAR1 should be considered as a candidate gene and added to gene
      panels for hereditary spastic paraplegia, cerebral palsy, and juvenile
      cataracts.
    explanation: >-
      The authors' diagnostic recommendation, which is the practical content of
      this entity.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical trio (patients 2-10 and 12) or quartet (patient 1, with unaffected
      sibling) exome analysis was performed for patients 1-10 and 12 and an
      exome-based cerebral palsy panel was performed for patient 11.
    explanation: >-
      One patient was found on a cerebral palsy panel, which is why that panel is
      named in the recommendation.
differential_diagnoses:
- name: FAR1 deficiency (RCDP4) - the recessive, plasmalogen-deficient arm of the same gene
  disease_term:
    preferred_term: rhizomelic chondrodysplasia punctata type 4
    term:
      id: MONDO:0014510
      label: fatty acyl-CoA reductase 1 deficiency
  description: >-
    The differential that matters most, because the gene is the same and the
    clinical overlap is substantial: spasticity, seizures and bilateral cataracts
    occur in both. Everything else separates them.

    Biochemically they are opposites - RCDP4 patients are plasmalogen-deficient,
    these patients have elevated ether lipids. Genetically, RCDP4 needs two
    loss-of-function alleles anywhere in FAR1; this disease needs one Arg480
    missense allele. Clinically, RCDP4 patients have profound intellectual
    disability, severe growth failure, microcephaly and facial dysmorphism, and
    some have cerebral white matter abnormalities; these patients have normal
    growth, no microcephaly, no dysmorphism, normal MRI in most, and intellectual
    disability in only three of twelve.

    The defining paper flags what is unusual about this pair: gene-dose and
    direction-of-effect differences within one gene are not new, but a pair with
    an *overlapping clinical* phenotype and a *completely opposite biochemical*
    one had not been described before.

    This knowledge base curates RCDP4 within
    Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect, whose own
    differential list already names this disease as the mechanistically inverse
    FAR1 gain-of-function disorder - under the identifier MONDO:0100230, the
    duplicate MONDO term discussed in this entry's mappings.
  distinguishing_features:
  - >-
    Plasmalogens are elevated in the dominant Arg480 disease and deficient in
    recessive FAR1 deficiency.
  - >-
    One de novo Arg480 missense allele versus two loss-of-function alleles.
  - >-
    Normal growth, no microcephaly and no dysmorphism here; severe growth
    failure, microcephaly and facial dysmorphism in FAR1 deficiency.
  - >-
    The recessive arm has a mouse model - a Far1 knockout published in 2023 and
    presented as a model of ether lipid deficiency. The dominant arm has none, so
    Far1 mouse literature does not bear on Arg480 gain of function.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with FAR1 heterozygous de novo variants share many clinical
      symptoms with FAR1 deficiency, including spastic features, seizures, and
      bilateral cataracts, but have normal brain magnetic resonance images
      (MRIs), normal growth, no microcephaly, and no dysmorphic features.
    explanation: >-
      The clinical overlap and the specific features that separate the two FAR1
      diseases.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Of the five previously reported patients, all had (profound) intellectual
      disability, severe growth retardation/failure to thrive, microcephaly,
      spasticity, and facial dysmorphism.
    explanation: >-
      The recessive arm's own phenotype, sourced rather than asserted, so the
      contrast drawn in this differential rests on a quotation on both sides.
      Graded OTHER because it is this paper's summary of the previously published
      FAR1-deficiency cases rather than patients it examined.
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, the biochemical phenotypes are the complete opposite of each
      other; the FAR1-deficient patients have a profound deficiency of
      plasmalogens whereas the patients with the heterozygous de novo variants
      have elevated levels of ether lipids, including plasmalogens.
    explanation: >-
      The biochemical inversion, which is the discriminating test.
  - reference: PMID:37039784
    reference_title: "Disrupted intercellular bridges and spermatogenesis in fatty acyl-CoA reductase 1 knockout mice: A new model of ether lipid deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report the generation and initial characterization of the first
      Far1 knockout (KO) mouse model.
    explanation: >-
      Cited to keep a distinction visible that is easy to lose: FAR1 has an
      animal model, and it is a model of the recessive deficiency arm rather than
      of this disease. A reader who finds Far1 mouse work should not read it as
      bearing on Arg480 gain of function.
- name: Hereditary spastic paraplegia and cerebral palsy
  description: >-
    The labels these patients carry before the diagnosis is made. Non-progressive
    or slowly progressive lower-limb spasticity with normal brain imaging and no
    perinatal insult is the classic route to a cerebral palsy label, and one of
    the twelve was found on a cerebral palsy panel. The feature that should
    redirect the workup is the cataracts, which belong to neither of those
    diagnoses.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings show that for patients with spastic paraparesis and bilateral
      cataracts, FAR1 should be considered as a candidate gene and added to gene
      panels for hereditary spastic paraplegia, cerebral palsy, and juvenile
      cataracts.
    explanation: >-
      Names the two clinical categories this disease is misassigned to.
- name: The other ether-lipid-excess disorders - EPT1 (SELENOI), PCYT2 and Sjogren-Larsson syndrome
  description: >-
    A small and recently recognised group that biochemically resembles this
    disease rather than RCDP: SELENOI (EPT1) deficiency, PCYT2 deficiency and
    Sjogren-Larsson syndrome all show elevated ether lipids, and all present with
    spastic paraparesis plus some form of ocular pathology - cataracts, optic
    atrophy or macular dystrophy.

    Recorded as a differential and, more usefully, as a group: their existence is
    the strongest argument that ether lipid excess itself, rather than something
    idiosyncratic to FAR1, produces this clinical pattern. Distinguishing them
    from each other is a matter for their own entries and is not attempted here;
    this entry claims only what its cited source states, which is that the three
    share elevated ether lipids and the paraparesis-plus-eye pattern.
  evidence:
  - reference: PMID:33239752
    reference_title: "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      On the other side of the spectrum, three disorders have recently been
      reported that biochemically show elevated levels of ether lipids: EPT1
      deficiency (SELENOI),22,23 PCYT2 deficiency (PCYT2),14,24 and
      Sjögren-Larsson syndrome (SLS, ALDH3A2).25,26
    explanation: >-
      Names the three other ether-lipid-excess disorders. Graded OTHER because it
      is the authors' survey of neighbouring literature rather than their own
      data.
discussions:
- discussion_id: far1_gof_excess_and_deficiency_converge
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Why do ether lipid excess and ether lipid deficiency cause the same
    cataracts and the same spastic paraparesis?
  attaches_to:
  - "pathophysiology#Membrane Lipid Composition Shift"
  - "pathophysiology#Lens Opacification"
  - "pathophysiology#Corticospinal Tract Dysfunction"
  rationale: >-
    This is the question the entity exists to pose, and no one has answered it.

    Cataract is caused by ether lipid deficiency: in a Pex7 mouse model of RCDP
    type 1, supplementing alkylglycerol restored plasmalogens and prevented
    cataract formation, which is a causal demonstration rather than an
    association. Cataract is also present in twelve of twelve patients whose
    ether lipids are elevated. The same holds for spastic paraparesis, which
    occurs in RCDP4 and in all of these patients, and which is also the shared
    feature of the three other ether-lipid-*excess* disorders. Too much and too
    little of the same lipid class damage the same two organs.

    Three hypotheses are worth keeping distinct, and the sources support none of
    them over the others. It may be that what matters is the *ratio* of ether to
    non-ether lipids rather than the absolute level of either, which this entry's
    lipidomics node is consistent with: total choline- and ethanolamine-lipid
    content was unchanged while the ether fraction rose, and in RCDP the same
    ratio is displaced the other way. It may be the fatty alcohols rather than
    the lipids - the paper notes that fatty alcohols accumulate in
    Sjogren-Larsson syndrome and in RCDP types 1 to 3, though not in FAR1
    deficiency, where they cannot be made. Or the two diseases may reach the same
    endpoint by genuinely different routes, and the convergence be a coincidence
    of which organs are most sensitive to any membrane-lipid disturbance.

    The authors' own verdict is that the mechanism remains enigmatic, and this
    entry does not improve on it. The practical warning: do not import RCDP
    mechanism prose into this entry on the strength of the shared phenotype. The
    biochemistry is inverted and the shared endpoint is the thing to be
    explained, not the explanation.
  proposed_experiments:
  - experiment_id: exp_far1gof_ratio_versus_level
    name: Dissociate ether/non-ether ratio from absolute ether lipid level
    description: >-
      In a single cell system, titrate ether lipid content upward (by expressing
      an Arg480 FAR1 allele) and downward (by FAR1 knockdown) while separately
      manipulating non-ether phospholipid synthesis, and measure a common
      cell-biological endpoint such as membrane order, organelle contact-site
      formation or lipid-raft-dependent signalling. If the endpoint tracks the
      ratio rather than the absolute level, that would explain the convergence.
  - experiment_id: exp_far1gof_lens_model
    name: A lens model of ether lipid excess
    description: >-
      Generate an Arg480 knock-in mouse and ask whether it develops cataracts,
      and if so whether they are prevented by limiting ether lipid synthesis -
      the mirror image of the alkylglycerol rescue experiment that established
      deficiency as a cause of cataract in the Pex7 model.
- discussion_id: far1_gof_no_model_beyond_fibroblasts
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What happens to a neuron or a lens fibre cell carrying an Arg480 FAR1
    allele?
  attaches_to:
  - "experimental_models#Patient dermal fibroblast lines with FAR1 p.Arg480His and p.Arg480Cys"
  - "pathophysiology#Corticospinal Tract Dysfunction"
  rationale: >-
    Curated as a genuine absence of evidence, with one qualification. There is no
    animal model of this disease, no engineered cell line carrying an Arg480
    allele, and no patient-derived neuron or lens cell. Every functional
    statement curated in this entry comes from three patients' skin fibroblasts.

    Patient tissue beyond fibroblasts is not quite untouched, though: a 2024
    neuropathology report (Della Marina et al., J Neuropathol Exp Neurol,
    PMID:39074165) describes lipid and protein imbalances in muscle from a
    patient with a heterozygous de novo FAR1 variant - this arm of the disease,
    in a tissue nobody else has examined. It is named here rather than cited
    because PubMed carries no abstract for it, so nothing from it can be verified
    as a snippet; that is the same disposition given to PMID:36781603. A curator
    with journal access should promote it. What remains true, and is the point of
    this gap, is that neither of the two tissues that actually fail - the
    corticospinal tract and the lens - has been examined in any patient.

    The asymmetry with the recessive arm is what makes this worth flagging rather
    than merely noting. A Far1 knockout mouse was published in 2023 and is
    explicitly presented as a model of ether lipid deficiency: subviable,
    growth-retarded, infertile, with spermatogenesis arrested at the round
    spermatid stage. So the deficiency arm has an animal model and the excess arm
    does not - which is the wrong way round for answering the question this
    entity poses, and which means the genetic background and assay platform for
    the comparison already exist.

    The gap is specific rather than generic. The fibroblast carries the full
    biochemical lesion - elevated plasmalogens, elevated FAR1, fourfold ether
    lipid flux, a remodelled lipidome - and is entirely well. So the biochemistry
    alone does not cause cell dysfunction; something about the corticospinal
    tract and the lens makes them vulnerable, and no model in existence can
    address what.

    Two of the four disease alleles, p.Arg480Leu and p.Arg480Ser, have never been
    tested in any system, because no cells were available. A knock-in mouse or an
    isogenic iPSC series would close both gaps at once.
  proposed_experiments:
  - experiment_id: exp_far1gof_knockin_ipsc
    name: Isogenic Arg480 knock-in iPSC series differentiated to affected lineages
    description: >-
      Knock each of the four reported Arg480 substitutions into the endogenous
      FAR1 locus of iPSCs heterozygously, differentiate to cortical projection
      neurons and lens epithelial cells, and compare lipidome, membrane
      properties, axonal transport and survival against isogenic controls and
      against a FAR1-null line representing the recessive disease. Running the
      excess and deficiency arms in the same genetic background is what the field
      currently lacks. The equivalent in vivo comparison is now cheap to specify,
      since the Far1 knockout mouse for the deficiency arm already exists; what is
      missing is its Arg480 knock-in counterpart.
- discussion_id: far1_gof_no_disease_modifying_therapy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Could ether lipid synthesis be dialled back down, and would that help?
  attaches_to:
  - "treatments#Antiseizure Pharmacotherapy"
  - "pathophysiology#Uncontrolled Ether Lipid Synthesis"
  rationale: >-
    The only treatment reported for this disease is symptomatic seizure control,
    and this entry curates nothing else because nothing else has been tried.

    The mechanism does suggest a target, which is why the gap is worth stating
    rather than leaving as silence. Ether lipid output is high because FAR1
    escapes degradation; reducing FAR1 abundance or activity would in principle
    restore the set point. But two things are unknown and both are load-bearing.
    Nobody knows whether the damage is developmental and already done by the time
    a diagnosis is made - the congenital cataracts in five of twelve suggest at
    least part of it is - or ongoing and therefore modifiable. And nobody knows
    the therapeutic window, because ether lipid *deficiency* causes an
    overlapping and more severe disease, so overshooting has a known and bad
    phenotype.

    The mirror-image experiment already exists on the deficiency side:
    alkylglycerol supplementation prevented cataracts in a plasmalogen-deficient
    mouse. Nothing equivalent has been attempted for excess.
  proposed_experiments:
  - experiment_id: exp_far1gof_flux_reduction
    name: Test partial FAR1 knockdown in an Arg480 model
    description: >-
      In patient fibroblasts and, once available, an Arg480 knock-in animal,
      titrate FAR1 abundance down by RNA interference or antisense
      oligonucleotide and measure whether ether lipid flux, the lipidome shift
      and any cellular phenotype normalise - and at what point plasmalogen levels
      fall below normal, which defines the window.
notes: >-
  Identity, and why it is easy to get wrong. This entry is the *dominant,
  gain-of-function* FAR1 disease. The knowledge base separately curates the
  recessive loss-of-function arm - FAR1 deficiency, RCDP4 - inside
  Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect. Same gene,
  inverted mechanism, inverted biochemistry, different entity. Most of the FAR1
  literature is about the other one, and a paper that says "FAR1" and
  "plasmalogen" and "cataract" is more likely to be about RCDP4 than about this
  disease. The discriminators are heterozygous plus codon 480 plus *elevated*
  plasmalogens. Every reference cited here was checked against that test: all
  three FAR1 disease references describe de novo heterozygous Arg480 variants
  explicitly in their titles or abstracts, and the fourth reference is a review
  of the normal regulatory pathway rather than of either disease.

  On the MONDO anchor. Two live MONDO terms name this disease - MONDO:0036212,
  which carries the OMIM, Orphanet, MedGen and UMLS cross-references, and
  MONDO:0100230, whose definition is the defining paper's title restated and
  which carries only a GARD reference. This entry anchors on the former and maps
  the latter as an exact match. The pre-existing RCDP entry refers to this
  disease by the latter identifier. That is not a disagreement about scope; it is
  a duplication in MONDO, and it should be reported upstream rather than resolved
  by either entry unilaterally.

  On the `modifier` choice at the ether-lipid node, since it is the kind of call
  a reviewer should be able to check. `GAIN_OF_FUNCTION` is used for
  "Uncontrolled Ether Lipid Synthesis" and `INCREASED` for the node above it,
  "Elevated FAR1 Protein and Enzyme Activity". The split is deliberate. The
  enzyme claim is quantitative - the same enzyme, doing the same reaction, in
  larger amounts, at three to four times control activity - which is what
  INCREASED is for and which keeps that annotation PATO-bound. The pathway claim
  is qualitative: the negative feedback loop that sets ether lipid output has
  been abolished, demonstrated by a direct perturbation, so the pathway is not
  running above a set point but running without one. That is the "outside normal
  regulatory constraints" condition the schema reserves GAIN_OF_FUNCTION for, and
  it costs the annotation its ontology grounding, which is a trade made
  knowingly. `GeneticContext.functional_impact_category` is separately set to
  HYPERMORPHIC, the more specific value for increased *normal* gene product
  activity.

  On supportive management, which is considered and not curated. Cataract
  extraction, physiotherapy and speech therapy are what these children will
  actually receive, and every one of them follows from a curated phenotype. None
  is curated as a treatment because the defining paper never mentions surgery or
  therapy of any kind, and the only management it reports is the antiseizure
  drugs already in `treatments:`. Adding them from general practice would assert
  a management record for twelve patients that nobody has written down. Recorded
  here so the omission reads as a decision.

  On one phenotype that is reported but not curated. Constipation appears in the
  defining cohort at five of twelve, but only as per-patient plus and minus marks
  in Table 1; the paper's prose never states it, so no sentence can be quoted for
  it and it is left out rather than sourced to a table cell. The same applies to
  several other per-patient columns - ambulation age, walking aids, seizure type.
  A curator with the table in front of them should add them.

  On what is absent. There is no `progression:` block: patients were 2 to 19
  years old at study and the cohort is cross-sectional, so no trajectory has been
  described. There is no `animal_models:` block either: no animal carries an
  Arg480 allele. A Far1 knockout mouse does exist and is cited in the
  differential and the knowledge-gap discussion, but it models the recessive
  deficiency arm and is the mechanistic inverse of this disease, so it does not
  belong among this entry's models. The `treatments:`
  block holds only symptomatic seizure control, which is the whole of the
  reported treatment experience; its indication, seizures, is curated as a
  phenotype in the same entry.
📚

References & Deep Research

References

4
PMID:33239752
An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
No top-level findings curated for this source.
PMID:36254151
Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature.
No top-level findings curated for this source.
PMID:37335441
Complex Hereditary Spastic Paraparesis Caused by de novo p.Arg480Ser in FAR1.
No top-level findings curated for this source.
PMID:36720320
Regulation of plasmalogen biosynthesis in mammalian cells and tissues.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 23 citations 2026-08-28T11:42:16.735387

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Spastic paraparesis-cataracts-speech delay syndrome (monoallelic FAR1 gain-of-function, fatty acyl-CoA reductase 1 superactivity)
  • MONDO ID: MONDO:0036212 (if available)
  • Category: Metabolic Disorders

Research Objectives

Please provide a comprehensive research report on Spastic paraparesis-cataracts-speech delay syndrome (monoallelic FAR1 gain-of-function, fatty acyl-CoA reductase 1 superactivity) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Spastic paraparesis–cataracts–speech delay syndrome

Monoallelic FAR1 gain-of-function / fatty acyl-CoA reductase 1 superactivity

Executive summary

This is an ultra-rare, childhood-onset neuro-ophthalmic ether-lipid disorder caused by heterozygous, usually de novo missense variants affecting Arg480 of FAR1. Its defining combination is bilateral congenital or juvenile cataracts and pyramidal lower-limb disease—spastic diparesis/paraparesis—often accompanied by speech and gross-motor delay, truncal hypotonia, and early-life seizures. Unlike autosomal-recessive FAR1 deficiency, which decreases plasmalogens, dominant Arg480 disease prevents normal plasmalogen-triggered degradation of FAR1 and therefore causes excess fatty-alcohol/ether-lipid synthesis and elevated plasmalogens. The detailed human evidence remains dominated by one 12-patient cohort; consequently, prevalence, lifetime prognosis, penetrance, and treatment-effect estimates are not established. (ferdinandusse2021anautosomaldominant pages 1-2, ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 6-7)

The foundational evidence is Ferdinandusse et al., Genetics in Medicine, received July 24, 2020 and published in volume 23 in April 2021, DOI 10.1038/s41436-020-01027-3. Its abstract states: “Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype.” (ferdinandusse2021anautosomaldominant pages 1-2)

Domain Finding Quantitative detail Evidence type/strength
Cohort size / age Foundational dominant FAR1 cohort comprised 12 affected individuals evaluated clinically and functionally Ages at study: 2-19 years; all had neurological symptoms in the first years of life (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort with patient-derived fibroblast functional studies; strongest direct evidence available (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 1-2)
Variant spectrum All reported pathogenic dominant variants in the foundational cohort altered Arg480 p.Arg480Cys: 7/12; p.Arg480His: 4/12; p.Arg480Leu: 1/12 (ferdinandusse2021anautosomaldominant pages 3-4) Human genetic evidence from de novo recurrent missense variants; strong (ferdinandusse2021anautosomaldominant pages 3-4)
Inheritance Disease mechanism is monoallelic, autosomal dominant, arising through de novo variants 12/12 reported as de novo heterozygous FAR1 variants (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 3-4) Human trio/exome-based evidence; strong (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 6-7)
Cardinal neurologic phenotype Spastic paraparesis / pyramidal tract dysfunction is the core neurologic feature 12/12; described with lower-limb hypertonia, truncal hypotonia in 6/12, and ankle clonus (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort; strong (ferdinandusse2021anautosomaldominant pages 4-5)
Ocular phenotype Bilateral cataracts are universal in the foundational cohort 12/12 total; congenital in 5/12 and acquired/juvenile in 7/12 (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort; strong (ferdinandusse2021anautosomaldominant pages 4-5)
Developmental phenotype Speech and motor delay are common; intellectual disability is less frequent Speech delay 10/12; gross motor developmental delay reported in most; cognitive delay / intellectual disability 3/12 (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort; moderate-to-strong (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 6-7)
Seizures / treatment outcome Early-life seizures were common and often treatment-responsive Seizures in 8/12, mainly in the first months of life; treated with barbiturates, levetiracetam, and/or oxcarbazepine; antiepileptics discontinued without recurrence in 4/8 (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort with follow-up; moderate-to-strong (ferdinandusse2021anautosomaldominant pages 4-5)
Neuroimaging Brain MRI usually non-diagnostic or normal Normal in 10/12; 1 had abnormal temporal lobe morphology with ventricular prominence and normal white matter; 1 had benign enlargement of subarachnoid spaces (ferdinandusse2021anautosomaldominant pages 4-5) Human clinical cohort; strong for available sample (ferdinandusse2021anautosomaldominant pages 4-5)
Biochemical finding Dominant disease shows elevated plasmalogens, opposite to recessive FAR1 deficiency Untreated patient fibroblasts had mean C16:0-plasmalogen levels about twofold higher than controls; FAR1 protein levels were threefold higher than HDG-treated controls (ferdinandusse2021anautosomaldominant pages 4-5) Patient fibroblast biochemistry/immunoblot; strong mechanistic evidence (ferdinandusse2021anautosomaldominant pages 4-5)
Enzyme / localization FAR1 catalytic function and peroxisomal localization are preserved FAR1 enzyme activity preserved; mutant FAR1 localized normally to peroxisomes in patient fibroblasts (ferdinandusse2021anautosomaldominant pages 6-7) Patient-derived cell functional assays and immunofluorescence; strong (ferdinandusse2021anautosomaldominant pages 6-7)
Lipidomics Ether lipids accumulate with reciprocal depletion of corresponding nonether lipids Increased PC[O], PE[O], DG[O], TG[O]; examples in figure summary include PE[O] about 2.5x, DG[O] about 3.3x, TG[O] about 5.8x versus controls; PUFA-rich PC[O] species particularly increased (ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 9-10) Patient fibroblast lipidomics in 3 analyzed patients vs 3 controls; strong for cellular biochemical phenotype (ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 9-10)
Flux evidence Ether lipid synthesis from exogenous substrate is increased C17:0-alcohol incorporation into LPC(O-17:0) was fourfold higher in patients; C17:0-acid incorporation into nonether LPC(17:0) was comparable between patients and controls (ferdinandusse2021anautosomaldominant pages 9-10) Patient fibroblast metabolic labeling; strong direct functional evidence (ferdinandusse2021anautosomaldominant pages 9-10)
Mechanism Arg480 variants disrupt plasmalogen-dependent negative feedback on FAR1 stability, causing uncontrolled ether lipid synthesis Arg480 lies in the transmembrane region (aa 466-483); elevated plasmalogens failed to lower FAR1 protein in patient cells after HDG treatment, unlike controls (ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 2-3) Human patient-derived mechanistic cell biology supported by review synthesis; strong (ferdinandusse2021anautosomaldominant pages 8-9, honsho2023regulationofplasmalogen pages 1-3)
Diagnostic implications FAR1 should be considered in patients with spastic paraparesis plus bilateral cataracts; plasmalogens can support functional interpretation Authors recommend adding FAR1 to hereditary spastic paraplegia, cerebral palsy, and juvenile cataract panels; erythrocyte plasmalogen measurement may be informative because both high and low values can indicate FAR1-related pathology (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 9-10) Expert recommendation grounded in cohort and functional data; moderate-to-strong (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 9-10)
Evidence limitations Evidence base remains very small and recent follow-up/expansion papers were not fully retrievable in this tool environment Direct detailed extraction currently rests mainly on one 12-patient cohort; additional 2022-2024 reports were identified by metadata but not fully available here for verification (ferdinandusse2021anautosomaldominant pages 1-2, honsho2023regulationofplasmalogen pages 1-3) Limitation statement based on available retrieved sources; important caution for knowledge-base use (ferdinandusse2021anautosomaldominant pages 1-2, honsho2023regulationofplasmalogen pages 1-3)

Table: This table summarizes the strongest directly retrievable evidence for monoallelic FAR1 gain-of-function syndrome, focusing on recurrent Arg480 variants, phenotype frequencies, biochemical mechanism, and diagnostic implications. It is useful as a compact evidence map for knowledge-base extraction while clearly flagging current evidence limitations.

1. Disease information

Definition and scope

The disorder is a monogenic metabolic/neurodevelopmental syndrome in which increased stability of peroxisomal FAR1 dysregulates ether-glycerophospholipid homeostasis. It should not be conflated with autosomal-recessive FAR1 deficiency, despite overlap in cataracts, spasticity, and seizures: recessive deficiency causes low plasmalogens, profound developmental impairment, growth failure, microcephaly, and dysmorphism, whereas dominant Arg480 disease generally has elevated plasmalogens, normal growth, no characteristic dysmorphism, and usually normal MRI. (ferdinandusse2021anautosomaldominant pages 6-7)

Names and identifiers

  • Preferred name supplied for this report: spastic paraparesis–cataracts–speech delay syndrome.
  • Mechanistic synonyms: autosomal-dominant FAR1-related disorder, dominant FAR1 gain-of-function disorder, FAR1 superactivity, and FAR1-related uncontrolled ether-lipid synthesis.
  • MONDO: MONDO:0036212, as supplied in the query; this identifier was not independently verified in the retrieved literature.
  • OMIM/Orphanet: no independently verified disorder-specific number was available in the retrieved texts. The gene is FAR1; database identifiers should be checked directly before production ingestion.
  • ICD-10/ICD-11 and MeSH: no syndrome-specific code or heading was found. Coding will generally require component or broader categories—for example hereditary spastic paraplegia/spastic diplegia, congenital or juvenile cataract, developmental disorder, and inborn error of lipid metabolism.

The principal report is an aggregated, deeply phenotyped 12-patient research cohort, assembled through clinical exome analysis, GeneMatcher, and undiagnosed-disease collaborations—not an EHR-derived population study. Eight cases were found after review of 42,983 exome trios plus 9,205 exome-based targeted-list trios, with further international matching. This ascertainment strategy cannot yield prevalence or unbiased phenotype-frequency estimates. (ferdinandusse2021anautosomaldominant pages 6-7)

2. Etiology, risks, and protective factors

Causal factor

The demonstrated cause is a germline heterozygous missense substitution at FAR1 residue Arg480. In the original cohort, all were de novo: c.1438C>T (p.Arg480Cys), 7/12; c.1439G>A (p.Arg480His), 4/12; and c.1439G>T (p.Arg480Leu), 1/12. Arg480 lies within the predicted membrane-spanning segment, amino acids 466–483. (ferdinandusse2021anautosomaldominant pages 3-4, ferdinandusse2021anautosomaldominant pages 8-9)

These are not ordinary haploinsufficient alleles. Mutant protein retains catalytic function and normal peroxisomal localization but escapes plasmalogen-dependent downregulation, producing a gain-of-function phenotype through excess protein abundance and metabolic flux. (ferdinandusse2021anautosomaldominant pages 6-7)

Risk, protective, and gene–environment factors

  • Genetic risk: carrying a pathogenic Arg480 allele is the only established risk factor.
  • Family history: often absent because all foundational cases were de novo. An affected individual would theoretically transmit the allele with a 50% probability per conception, although reproductive fitness and multigenerational penetrance have not been characterized.
  • Modifiers, protective alleles, founder effects, anticipation, carrier frequency, consanguinity effects, and germline-mosaicism frequency: unknown.
  • Environmental, dietary, toxic, occupational, infectious, lifestyle, sex, or age-related acquisition risks: none established. This is congenital genetic disease, not an acquired exposure disorder.
  • Protective factors and gene–environment interactions: none demonstrated. The 2023 review notes that erythrocyte plasmalogen levels in vegans do not differ from those on a normal diet, supporting endogenous synthesis rather than ordinary dietary supply as the principal determinant; this does not prove diet has no modifying effect in FAR1 gain-of-function disease. (honsho2023regulationofplasmalogen pages 1-3)

3. Phenotypes

Frequencies below come from the foundational 12-patient series, ages 2–19 years, and therefore may change with ascertainment of milder adults or additional variants. All developed neurologic manifestations in the first years of life. (ferdinandusse2021anautosomaldominant pages 4-5)

  • Spastic diparesis/paraparesis—12/12 (100%): pyramidal tract dysfunction, lower-limb hypertonia, ankle clonus, gait impairment, and variable need for braces, walkers, crutches, or wheelchairs. Childhood onset; chronic and functionally important. Suggested HPO: Spastic paraplegia (HP:0001258), lower-limb hypertonia, ankle clonus, abnormal gait, impaired ambulation. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Bilateral cataracts—12/12 (100%): congenital in 5/12 (42%) and acquired/juvenile in 7/12 (58%). Suggested HPO: Cataract (HP:0000518), congenital cataract, juvenile cataract, bilateral cataract. Visual impairment and cataract surgery can materially affect development and daily functioning. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Speech/language delay—10/12 (83%): receptive language exceeded expressive language in three patients. Suggested HPO: Delayed speech and language development (HP:0000750) and expressive-language delay. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Seizures—8/12 (67%): mainly began during the first months of life and were generally treatment-responsive. Suggested HPO: Seizure (HP:0001250), infantile-onset seizure, generalized tonic-clonic seizure where individually documented. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Truncal/axial hypotonia—6/12 (50%), coexisting with lower-limb spasticity. Suggested HPO: Axial hypotonia (HP:0008936). (ferdinandusse2021anautosomaldominant pages 4-5)
  • Cognitive delay/intellectual disability—3/12 (25%): less frequent than speech and motor delay, indicating that language or motor disability should not automatically be interpreted as global intellectual disability. Suggested HPO: global developmental delay and intellectual disability, only when clinically established. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Gross-motor delay: reported in most, but a precise numerator was not extractable. Suggested HPO: Gross motor development delay (HP:0002194).
  • Macrocephaly—2/12; growth delay occurred in only one. No consistent dysmorphism was observed. (ferdinandusse2021anautosomaldominant pages 4-5)
  • MRI: normal in 10/12; one patient had abnormal temporal-lobe morphology and ventricular prominence with normal white matter, while one had benign enlargement of subarachnoid spaces. A normal MRI therefore does not argue against the diagnosis. (ferdinandusse2021anautosomaldominant pages 4-5)

No disease-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or formal quality-of-life study was found. Likely burdens—impaired mobility, communication, vision, school participation, self-care, and seizure monitoring—are clinically plausible but have not been quantified.

4. Genetic and molecular information

Gene and variants

FAR1 encodes fatty acyl-CoA reductase 1, a peroxisomal membrane protein and rate-limiting supplier of long-chain fatty alcohols for ether-lipid biosynthesis. Suggested gene records include HGNC/NCBI Gene/Ensembl/UniProt entries for FAR1; exact accession numbers should be programmatically verified rather than inferred from the disease article.

The three foundational variants are recurrent germline missense alleles at one residue:

  1. NM transcript-dependent c.1438C>T, p.Arg480Cys—7 patients.
  2. c.1439G>A, p.Arg480His—4 patients.
  3. c.1439G>T, p.Arg480Leu—1 patient. (ferdinandusse2021anautosomaldominant pages 3-4)

They were absent from parents in the reported cases and functionally validated. The study predates or does not provide a uniform current ClinVar ACMG classification in the retrieved text; nevertheless, recurrent de novo occurrence, highly specific phenotype, residue clustering, and strong patient-cell functional evidence support pathogenicity. Transcript and genome-build normalization, current ClinVar assertions, and gnomAD frequencies should be verified for each record before database loading. Population frequency was not given in the retrieved full text; the recurrence as de novo alleles and ultra-rare phenotype imply rarity but do not substitute for a gnomAD query.

No causal structural variant, chromosomal abnormality, somatic variant, repeat expansion, mitochondrial variant, modifier gene, or disease-associated epigenetic signature has been established. There is no evidence for a dominant-negative mechanism.

5. Environmental information

No toxin, radiation, pollution, occupational exposure, smoking, alcohol, diet, exercise pattern, or infectious agent is known to cause or trigger the syndrome. Environmental entries should therefore be represented as not established, rather than “protective” or “risk-free.” Plasmalogen metabolism can respond to cellular state in experimental systems, but no clinically validated environmental modifier of Arg480 disease exists. (honsho2023regulationofplasmalogen pages 1-3)

6. Mechanism and pathophysiology

Normal pathway

Ether-lipid synthesis begins in the peroxisome. GNPAT generates acyl-DHAP; AGPS replaces the acyl group with a long-chain fatty alcohol; downstream reactions continue outside the peroxisome and ultimately generate plasmanyl and plasmenyl phospholipids. FAR1 reduces fatty acyl-CoA to fatty alcohol and is rate-limiting. At high plasmalogen abundance, FAR1 protein is normally degraded without requiring reduced FAR1 transcription, establishing negative feedback. (ferdinandusse2021anautosomaldominant pages 1-2, honsho2023regulationofplasmalogen pages 1-3)

Suggested annotations include:

  • GO biological process: ether lipid biosynthetic process, plasmalogen biosynthetic process, fatty alcohol biosynthetic process, cellular-lipid homeostasis, glycerophospholipid metabolism, and negative regulation of biosynthesis.
  • GO molecular function: fatty-acyl-CoA reductase activity / oxidoreductase activity acting on the CH–OH group with NAD(P)+-related annotation as curated for FAR1.
  • GO cellular component: peroxisomal membrane, peroxisome, and membrane-spanning region.
  • Chemicals: fatty acyl-CoA, long-chain fatty alcohol, plasmalogen, phosphatidylcholine, phosphatidylethanolamine, diacylglycerol, triacylglycerol, docosahexaenoic acid, and arachidonic acid; precise CHEBI identifiers should be retrieved from CHEBI.

Causal chain

De novo Arg480 substitution → defective plasmalogen-dependent destabilization of FAR1 → persistently elevated FAR1 protein despite high plasmalogens → excess conversion of fatty acyl-CoA to fatty alcohol → increased ether-lipid flux → accumulation of ether phospholipids and neutral ether lipids, reciprocal reduction of corresponding nonether species, and PUFA redistribution → altered membrane composition/homeostasis in vulnerable neural, myelin, muscle, and lens tissues → spastic paraparesis, developmental manifestations, seizures, and cataracts. The first five links are experimentally supported; the precise link from altered lipid composition to specific tissue injury remains unresolved. (ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 9-10)

Direct biochemical evidence

In untreated patient fibroblasts, mean C16:0 plasmalogen was approximately twice the control level. After alkylglycerol/HDG loading, controls increased C16:0 plasmalogen by 199–291% and lowered FAR1 protein by 31–47%; patient cells increased plasmalogen by 130–224% but showed no consistent reduction in FAR1 protein. Patient FAR1 remained normally localized to peroxisomes. (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 6-7)

Metabolic labeling showed fourfold greater incorporation of C17:0 alcohol into ether-linked LPC(O-17:0), while incorporation of C17:0 acid into nonether LPC(17:0) was comparable. Lipidomics in three patient and three control fibroblast lines demonstrated increased PC[O], PE[O], DG[O], and TG[O], decreased nonether PC and (lyso)PE, and preferential accumulation of PUFA-rich ether-PC species. Some aggregate classes increased approximately 2.5-, 3.3-, or 5.8-fold. (ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 9-10)

The authors conclude that “both fatty alcohol and ether lipid levels need to be tightly regulated, because an imbalance leads to disease.” They also emphasize that both ether-lipid shortage and excess can produce neurologic and ocular pathology. (ferdinandusse2021anautosomaldominant pages 9-10)

Tissue biology and uncertainties

Plasmalogens account for about 20% of human phospholipids and are particularly abundant in central nervous system, heart, kidney, and white blood cells. They influence membrane dynamics, signaling, and possibly antioxidative functions. (ferdinandusse2021anautosomaldominant pages 1-2)

A 2023 review proposed that brain plasmalogens are predominantly synthesized locally rather than imported from blood and noted that both deficient and elevated plasmalogen states suppress cholesterol synthesis. It hypothesized that disturbed cholesterol/plasmalogen homeostasis could contribute to shared neurologic phenotypes, but this remains indirect—not demonstrated in Arg480 patient brain tissue. (honsho2023regulationofplasmalogen pages 1-3, honsho2023regulationofplasmalogen pages 3-5)

No validated immune, inflammatory, apoptotic, autophagic, ferroptotic, or epigenetic disease mechanism has been shown in these patients. No single-cell, spatial-transcriptomic, CRISPR-screen, or integrated human multi-omics dataset was retrievable. A 2024 paper, Della Marina et al., “Lipid and protein imbalances in muscle of a FAR1-patient with a heterozygous de novo variant,” Journal of Neuropathology & Experimental Neurology 83:979–983, July 2024, DOI 10.1093/jnen/nlae071, was identified, but its full text was unavailable to the tool; detailed molecular claims from it are therefore not reproduced.

7. Anatomical structures affected

Directly affected systems

  • Nervous system: corticospinal/pyramidal motor system, with lower-limb-predominant spasticity; possible broader motor-development and seizure networks. Suggested UBERON: brain, cerebral cortex, spinal cord, corticospinal tract, peripheral nervous system; use only phenotype-supported sites.
  • Eye: bilateral crystalline lens. Suggested UBERON: eye and lens; HPO cataract terms are better supported than finer anatomical localization.
  • Musculoskeletal system: secondary muscle stiffness, weakness/disuse, contracture risk, and mobility impairment; direct primary muscle pathology remains less established.

Potential cell types include upper motor neuron, neuron, oligodendrocyte, Schwann cell, skeletal-muscle fiber, and lens fiber cell. These are mechanistically reasonable CL terms, but patient-cell evidence directly demonstrates abnormality only in cultured dermal fibroblasts. The subcellular compartment with strongest direct evidence is the peroxisomal membrane. (ferdinandusse2021anautosomaldominant pages 6-7)

Cataracts are bilateral; the motor phenotype is generally bilateral lower-limb disease. No consistent cerebral lesion or lateralization is reported.

8. Temporal development

The disorder is congenital or early pediatric and chronic. Neurologic symptoms appeared within the first years; seizures often started in the first months. Cataracts may be present at birth or develop during childhood. Spastic paraparesis and developmental impairment appear persistent, but the small, cross-sectional cohort does not define standardized early/intermediate/advanced stages or a reliable progression rate. (ferdinandusse2021anautosomaldominant pages 4-5)

Seizures may remit: antiseizure medication was stopped without recurrence in 4 of 8 affected patients. No remission of the underlying genetic/metabolic disorder is documented. Critical windows probably include early ophthalmologic treatment to avoid deprivation amblyopia and early developmental/physical therapy, but FAR1-specific intervention windows have not been studied. (ferdinandusse2021anautosomaldominant pages 4-5)

9. Inheritance and population

Inheritance is autosomal dominant, with all 12 foundational cases arising de novo. Penetrance appeared high for cataracts and spastic paraparesis among ascertained Arg480 carriers, but this cohort was selected through symptomatic testing; population penetrance cannot be inferred. Expressivity is variable for cataract timing, seizures, language/motor delay, cognition, hypotonia, and mobility. (ferdinandusse2021anautosomaldominant pages 3-4, ferdinandusse2021anautosomaldominant pages 4-5)

No incidence, prevalence per 100,000, carrier frequency, sex ratio estimate, ethnic enrichment, regional clustering, or founder effect is available. The original cohort included 6 females and 6 males, but n=12 is too small to establish a 1:1 population ratio. Consanguinity is not etiologically relevant to the dominant de novo mechanism, although it may complicate individual pedigrees. Anticipation has not been reported. Parental germline mosaicism remains theoretically possible in any apparently de novo disorder, but no FAR1-specific recurrence estimate exists.

Recent literature identified by metadata includes Almuqbil et al., “Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome,” Clinical Case Reports, October 2022, DOI 10.1002/ccr3.6307, and Westenberger et al., “Spectrum of FAR1 variants and related neurological conditions,” Movement Disorders 38:502–504, February 2023, DOI 10.1002/mds.29323. Their full texts were not retrievable here, so variant-level expansion and revised frequencies could not be independently extracted.

10. Diagnostics

Clinical recognition

Suspect dominant FAR1 disease in a child with bilateral congenital/juvenile cataracts plus spastic diparesis/paraparesis, especially with speech/gross-motor delay, axial hypotonia, clonus, or infantile seizures. The investigators explicitly recommend adding FAR1 to panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataract. (ferdinandusse2021anautosomaldominant pages 1-2, ferdinandusse2021anautosomaldominant pages 9-10)

Testing strategy

  1. Phenotyping: pediatric neurologic examination, gait/GMFCS-style functional assessment, developmental and speech evaluation, complete ophthalmologic examination, and seizure history.
  2. Molecular testing: trio-based WES or WGS is preferred in a sporadic child because it identifies the allele and confirms de novo status. A hereditary-spastic-paraplegia, cerebral-palsy, cataract, or peroxisomal/ether-lipid panel must include full FAR1 coding coverage, particularly codon 480. Sanger confirmation and parental testing are appropriate.
  3. Biochemical support: quantitative erythrocyte plasmalogens or validated lipidomics. The authors specifically propose erythrocyte plasmalogens as a functional readout because both unusually high and unusually low levels can indicate FAR1 pathology. Normal routine peroxisomal studies or assuming that only low plasmalogens matter could miss the dominant disorder. (ferdinandusse2021anautosomaldominant pages 9-10)
  4. Functional resolution of uncertain variants: patient fibroblast plasmalogens, FAR1 abundance and response to plasmalogen/alkylglycerol loading, fatty-acyl-CoA reductase flux, peroxisomal localization, and lipidomics. These remain specialized research assays. (ferdinandusse2021anautosomaldominant pages 1-2, ferdinandusse2021anautosomaldominant pages 4-5)
  5. Ancillary tests: brain MRI to assess alternatives, despite usually normal imaging; EEG when seizures are suspected; vision assessment; and physiotherapy/orthopedic evaluation. EMG, nerve conduction, biopsy, proteomics, and muscle MRI are not established routine diagnostic criteria.

CMA, karyotyping, FISH, mtDNA sequencing, and repeat-expansion testing are not targeted tests for this condition but may be used when phenotype or first-line sequencing suggests an alternative. There are no standardized clinical criteria, newborn screen, or population-carrier screen.

Differential diagnosis

Important alternatives include recessive FAR1 deficiency; rhizomelic chondrodysplasia punctata and other peroxisomal ether-lipid deficiencies; ALDH18A1, GBA2, and other complicated hereditary spastic paraplegias with cataracts; cerebral palsy; congenital-cataract syndromes; SELENOI/EPT1, PCYT2, and ALDH3A2/Sjögren–Larsson syndrome disorders. Elevated rather than deficient plasmalogens, absence of rhizomelia/growth failure/dysmorphism, usually normal white matter, and a heterozygous Arg480 FAR1 variant favor dominant FAR1 superactivity. (ferdinandusse2021anautosomaldominant pages 6-7, ferdinandusse2021anautosomaldominant pages 9-10)

11. Outcome and prognosis

There are no survival curves, mortality rates, disease-specific deaths, life-expectancy estimates, or validated prognostic models. No early mortality signal was reported through ages 2–19, but the cohort is too young and small to infer normal lifespan. (ferdinandusse2021anautosomaldominant pages 4-5)

Morbidity is driven by lifelong motor disability, cataract-related visual impairment, developmental/communication limitations, and seizures. Mobility ranged from walking with aids to inability to walk in the cohort table. Intellectual disability is not universal, and seizure remission is possible. The most defensible favorable indicators are preserved cognition in many patients, mostly normal MRI, normal growth, and treatment-responsive seizures; however, none has been formally validated as prognostic. No prognostic biomarker beyond the diagnostic lipid phenotype exists.

12. Treatment and current applications

Disease-modifying therapy

No approved pharmacologic, gene, RNA, enzyme, cell, or dietary therapy corrects FAR1 gain-of-function. The ClinicalTrials.gov search found no relevant registered interventional study. Because the disease involves excess, not deficiency, plasmalogen or alkylglycerol replacement strategies developed for plasmalogen-deficient disorders are mechanistically inappropriate outside research and could theoretically aggravate the biochemical imbalance. The 2023 review discusses replacement only for deficient models and emphasizes that small molecules regulating plasmalogen homeostasis remain to be developed. (honsho2023regulationofplasmalogen pages 5-7, honsho2023regulationofplasmalogen pages 3-5)

Potential future approaches—selective FAR1 inhibition, restoration of mutant-protein degradation, allele-selective siRNA/ASO, or editing of the mutant allele—are conceptual. None has been tested in a disease model, and systemic suppression carries a risk of converting excess into deficiency.

Symptomatic and supportive management

  • Seizures: barbiturates, levetiracetam, and/or oxcarbazepine were used; medication could be withdrawn without recurrence in 4/8 patients. Treatment and withdrawal should follow pediatric epilepsy standards and EEG/clinical review. NCIT concepts: anticonvulsant therapy; levetiracetam; oxcarbazepine. (ferdinandusse2021anautosomaldominant pages 4-5)
  • Cataracts: pediatric ophthalmology, refraction and amblyopia prevention; cataract extraction and lens rehabilitation when visually significant. FAR1-specific surgical outcomes have not been published. NCIT: cataract surgery/ophthalmologic procedure.
  • Spasticity and mobility: individualized physiotherapy, stretching, orthoses, walkers/wheelchairs, occupational therapy, orthopedic surveillance, and conventional antispasticity treatment when indicated. No FAR1-specific comparative outcomes exist. NCIT: physical therapy, occupational therapy, rehabilitation therapy.
  • Communication/development: early speech-language therapy, augmentative communication where needed, educational support, and neuropsychological assessment.
  • Surveillance: serial ophthalmology, neurologic/seizure review, mobility/contracture and hip/spine assessment, nutrition, and psychosocial support.

No pharmacogenomic guidance, response-rate dataset, adverse-event registry, or genotype-guided treatment algorithm is available.

13. Prevention

Primary lifestyle or vaccine prevention is not applicable. Secondary prevention means early recognition of cataracts, seizures, developmental delay, and spasticity—not prevention of the genotype. Tertiary prevention includes amblyopia treatment, seizure control, contracture prevention, mobility support, and communication intervention.

Genetic counseling should explain the usually de novo autosomal-dominant mechanism, theoretical 50% transmission risk from an affected individual, low but nonzero recurrence possibility from parental germline mosaicism, and reproductive options after the familial variant is known: prenatal diagnosis and preimplantation genetic testing. Cascade testing is most relevant to biological parents and offspring; broad population screening is unsupported.

14. Other species and natural disease

No naturally occurring FAR1 Arg480-equivalent syndrome in companion animals, livestock, or wildlife was found, and there is no zoonotic or cross-species transmission. FAR1 orthologs and ether-lipid biology are evolutionarily conserved across animals; plasmalogens occur in vertebrates, invertebrates, and anaerobic bacteria but generally not plants or fungi. Exact NCBI Taxon, ortholog-gene, and VBO identifiers should be imported from taxonomy/model-organism databases rather than inferred here. (honsho2023regulationofplasmalogen pages 1-3)

15. Model organisms and experimental systems

Direct model

The strongest disease model is patient-derived cultured skin fibroblasts carrying p.Arg480His or p.Arg480Cys. These cells reproduce the defining biochemical phenotype: preserved peroxisomal localization and enzymatic function, defective feedback degradation, elevated plasmalogens, increased ether-lipid flux, and broad lipidomic remodeling. They are suitable for testing FAR1 stability, allele-selective suppression, metabolic flux, and candidate inhibitors. Their limitation is that fibroblasts do not model upper motor neurons, developing lens, myelin, or neural circuits. (ferdinandusse2021anautosomaldominant pages 4-5, ferdinandusse2021anautosomaldominant pages 6-7, ferdinandusse2021anautosomaldominant pages 9-10)

Indirect models

Pex7-, Gnpat-, and Pex14-deficient mice and other plasmalogen-deficient systems demonstrate feedback elevation of FAR1 and establish the importance of plasmalogens for myelination and lens biology. However, they model low ether lipids, the biochemical opposite of dominant FAR1 superactivity, and cannot be assumed to reproduce its disease mechanism. The 2023 review reports impaired myelination and reduced MBP in deficient models and notes local brain synthesis and difficulty delivering plasmalogens to brain. These models are useful for defining a safe therapeutic window, not for claiming efficacy in Arg480 disease. (honsho2023regulationofplasmalogen pages 1-3, honsho2023regulationofplasmalogen pages 3-5)

No validated FAR1-Arg480 knock-in mouse, rat, zebrafish, Drosophila, C. elegans, organoid, iPSC-derived motor-neuron, or lens-organoid model was identified. Developing an isogenic Arg480 knock-in model is a high-priority need because it would permit longitudinal neurologic and ocular phenotyping and preclinical testing without confusing gain- and loss-of-function biology.

Evidence appraisal and knowledge gaps

The association is compelling because of recurrent de novo variants at one residue, a highly coherent phenotype, and multiple orthogonal assays in patient cells. The main weakness is scale: phenotype percentages derive from only 12 ascertainment-enriched children, and detailed biochemical work used three patient fibroblast lines. Population prevalence, adult natural history, penetrance, variant spectrum beyond Arg480, variant-specific severity, fertility, lifespan, optimal surveillance, and treatment outcomes remain unknown. (ferdinandusse2021anautosomaldominant pages 3-4, ferdinandusse2021anautosomaldominant pages 8-9, ferdinandusse2021anautosomaldominant pages 4-5)

The most authoritative recent mechanistic synthesis is Honsho and Fujiki, “Regulation of plasmalogen biosynthesis in mammalian cells and tissues,” Brain Research Bulletin 194:118–123, published March 2023, DOI 10.1016/j.brainresbull.2023.01.011. It concludes that regulation of plasmalogen sensing, signaling, FAR1 degradation, and tissue homeostasis remains incompletely understood—an important caution against overstating downstream pathogenesis or proposing untested supplementation. (honsho2023regulationofplasmalogen pages 1-3, honsho2023regulationofplasmalogen pages 5-7)

References

  1. (ferdinandusse2021anautosomaldominant pages 1-2): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  2. (ferdinandusse2021anautosomaldominant pages 4-5): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  3. (ferdinandusse2021anautosomaldominant pages 6-7): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  4. (ferdinandusse2021anautosomaldominant pages 3-4): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  5. (ferdinandusse2021anautosomaldominant pages 8-9): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  6. (ferdinandusse2021anautosomaldominant pages 9-10): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  7. (ferdinandusse2021anautosomaldominant pages 2-3): Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz. An autosomal dominant neurological disorder caused by de novo variants in far1 resulting in uncontrolled synthesis of ether lipids. Apr 2021. URL: https://doi.org/10.1038/s41436-020-01027-3, doi:10.1038/s41436-020-01027-3. This article has 50 citations and is from a highest quality peer-reviewed journal.

  8. (honsho2023regulationofplasmalogen pages 1-3): Masanori Honsho and Yukio Fujiki. Regulation of plasmalogen biosynthesis in mammalian cells and tissues. Mar 2023. URL: https://doi.org/10.1016/j.brainresbull.2023.01.011, doi:10.1016/j.brainresbull.2023.01.011. This article has 38 citations and is from a peer-reviewed journal.

  9. (honsho2023regulationofplasmalogen pages 3-5): Masanori Honsho and Yukio Fujiki. Regulation of plasmalogen biosynthesis in mammalian cells and tissues. Mar 2023. URL: https://doi.org/10.1016/j.brainresbull.2023.01.011, doi:10.1016/j.brainresbull.2023.01.011. This article has 38 citations and is from a peer-reviewed journal.

  10. (honsho2023regulationofplasmalogen pages 5-7): Masanori Honsho and Yukio Fujiki. Regulation of plasmalogen biosynthesis in mammalian cells and tissues. Mar 2023. URL: https://doi.org/10.1016/j.brainresbull.2023.01.011, doi:10.1016/j.brainresbull.2023.01.011. This article has 38 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 7
Resolved 7
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

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:0036212 (2 mentions) - the report calls it "if available"; MONDO calls it spastic paraparesis-cataracts-speech delay syndrome