A neuro-ichthyotic disorder caused by pathogenic variants in ELOVL1, the elongase that catalyses the first and rate-limiting step in making saturated and monounsaturated very-long-chain fatty acids of C22 to C26. One enzymatic lesion produces two apparently unrelated organ phenotypes, because the same ultra-long acyl chains are structural requirements in two places: the ceramide lamellae of the stratum corneum, and the sphingolipids of central myelin. Losing them gives ichthyotic keratoderma and a hypomyelinating leukodystrophy in the same patient. Reported in two inheritance modes. Heterozygous de novo variants - the recurrent p.Ser165Phe in every published case so far - give the phenotype the disease is named for: ichthyosis, progressive spastic paraparesis, nystagmus and cerebral hypomyelination. Biallelic variants give an overlapping but more severe picture with a prominent complex movement disorder. Both arms are curated here because MONDO carries a single ELOVL1 disease concept.
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Conditions with similar clinical presentations that must be differentiated from Ichthyotic_Keratoderma_Spasticity_Hypomyelination_And_Dysmorphic_Facial_Features:
name: Ichthyotic_Keratoderma_Spasticity_Hypomyelination_And_Dysmorphic_Facial_Features
category: Disease
creation_date: "2026-09-01T23:05:00Z"
description: >-
A neuro-ichthyotic disorder caused by pathogenic variants in ELOVL1, the
elongase that catalyses the first and rate-limiting step in making saturated
and monounsaturated very-long-chain fatty acids of C22 to C26. One enzymatic
lesion produces two apparently unrelated organ phenotypes, because the same
ultra-long acyl chains are structural requirements in two places: the
ceramide lamellae of the stratum corneum, and the sphingolipids of central
myelin. Losing them gives ichthyotic keratoderma and a hypomyelinating
leukodystrophy in the same patient.
Reported in two inheritance modes. Heterozygous de novo variants - the
recurrent p.Ser165Phe in every published case so far - give the phenotype the
disease is named for: ichthyosis, progressive spastic paraparesis, nystagmus
and cerebral hypomyelination. Biallelic variants give an overlapping but more
severe picture with a prominent complex movement disorder. Both arms are
curated here because MONDO carries a single ELOVL1 disease concept.
disease_term:
preferred_term: ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features
term:
id: MONDO:0032798
label: ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features
has_subtypes:
- name: Monoallelic IKSHD
display_name: Monoallelic (de novo dominant) IKSHD
description: >-
The phenotype the disease name records, and the one described first. Every
published case carries the same heterozygous de novo missense variant,
p.Ser165Phe, arising independently rather than from a founder allele.
Ichthyosis is congenital; spastic paraparesis and nystagmus follow, with
cerebral hypomyelination on MRI. Cognition may be entirely normal.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients carried an identical heterozygous de novo ELOVL1 mutation
(c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele.
explanation: >-
Establishes the recurrent de novo allele and rules out a shared founder,
which is what makes the recurrence mechanistically interesting.
- name: Biallelic ELOVL1 disorder
display_name: Biallelic (autosomal recessive) ELOVL1 disorder
description: >-
Seven patients with autosomal recessive ELOVL1 variants, reported as a
single cohort. The overlap with the monoallelic form is substantial -
ichthyosis, spasticity, hypomyelination - but the movement disorder is
prominent and near-universal, and developmental delay is present in all,
where the monoallelic form can spare cognition entirely.
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We, here, describe seven patients with autosomal recessive variants in
ELOVL1.
explanation: Establishes the recessive arm and its cohort size.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Applies to the Monoallelic IKSHD subtype. De novo in every reported case; no transmitted pedigree has been published,
so the dominant mode is inferred from heterozygosity plus de novo status
rather than from segregation.
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis identified the de novo pathogenic variant p.Ser165Phe in
ELOVL1.
explanation: A further independent de novo occurrence of the same allele.
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Applies to the Biallelic ELOVL1 disorder subtype.
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We, here, describe seven patients with autosomal recessive variants in
ELOVL1.
explanation: States the recessive mode for this arm.
genetic:
- name: ELOVL1
gene_term:
preferred_term: ELOVL1
term:
id: hgnc:14418
label: ELOVL1
relationship_type: CAUSATIVE
notes: >-
ELOVL1 catalyses the rate-limiting condensation step in elongating C22-C26
saturated and monounsaturated fatty acids, and is most abundant in heavily
myelinated central nervous system regions and in epidermis - which is why a
single enzyme defect reaches both organs. The recurrent monoallelic allele
is p.Ser165Phe; biallelic variants are private to their families.
evidence:
- reference: PMID:29496980
reference_title: "Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The functional effect of prioritised variant in ELOVL1 (very-long-chain
fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas
chromatography-mass spectrometry in stably transfected HEK2932 cells and
in cultured patient's fibroblasts.
explanation: >-
Records that the causal assignment rests on measured elongase function,
not on variant prediction alone.
pathophysiology:
- name: ELOVL1 Elongase Activity Loss
biological_scale: MOLECULAR
description: >-
The p.Ser165Phe substitution abolishes elongase activity in patient cells
and in a transfected expression system. Because ELOVL1 catalyses the
condensation step that limits the whole elongation cycle, losing it caps
acyl chain length rather than reducing fatty acid supply generally.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
biological_processes:
- preferred_term: fatty acid elongation
modifier: LOSS_OF_FUNCTION
term:
id: GO:0030497
label: fatty acid elongation
downstream:
- target: Deficient C24 to C26 Very-Long-Chain Fatty Acid Elongation
causal_link_type: DIRECT
description: >-
Loss of the condensing enzyme truncates the acyl chains available to
downstream sphingolipid synthesis.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The mutation abrogated ELOVL1 enzymatic activity and reduced >=C24
ceramides and sphingomyelins in patient cells.
explanation: >-
Couples the enzymatic defect to the measured lipid consequence in the
same experiment, which is what makes this edge direct rather than
inferred.
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ELOVL1 plays a key role in the initial step of the fatty acid elongation
cycle within the endoplasmic reticulum (ER), being responsible for the
elongation of very long-chain fatty acids (VLCFAs), particularly saturated
and monounsaturated C22-C26
explanation: >-
States the enzyme's step and substrate range, which is what fixes the
chain-length ceiling this node describes.
- name: Deficient C24 to C26 Very-Long-Chain Fatty Acid Elongation
biological_scale: MOLECULAR
description: >-
Ultra-long acyl chains become unavailable while shorter species accumulate.
The lesion is a shift in chain-length distribution rather than a shortage of
lipid, which is why the two affected tissues are the two that specifically
require the longest species.
biological_processes:
- preferred_term: ceramide metabolic process
modifier: DECREASED
term:
id: GO:0006672
label: ceramide metabolic process
downstream:
- target: Shortened Sphingolipid Acyl Chains in Central Myelin
causal_link_type: DIRECT
description: >-
Myelin sphingolipids are built from the acyl chains this step supplies.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The acyl chain length of sphingolipids such as galactosylceramides,
sulfatides, sphingomyelins, and ceramides in the brains of these mice
was markedly shortened.
explanation: >-
Direct measurement of the chain-length shift in brain sphingolipids on
loss of the same enzyme.
- target: Reduced Ultra-Long-Chain Ceramides in the Stratum Corneum
causal_link_type: DIRECT
description: >-
Epidermal ceramides uniquely require extremely long fatty acids, supplied
by this step.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the epidermis of the Elovl1-null mice, the levels of Cers with >=C26
FAs were decreased, while those of Cers with <=C24 FAs were increased.
explanation: >-
Shows the reciprocal shift - long species down, shorter species up -
that identifies this as a chain-length defect rather than a deficiency.
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Plasma VLCFA analysis in one patient showed reduced concentrations of
C24:0 and C26:0.
explanation: >-
The corresponding measurement in a patient rather than a model, though in
a single individual.
- reference: PMID:29496980
reference_title: "Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Serum levels of C20:0-C26:0 FAs were normal, but the C24:0/C22:0 ratio was
decreased.
explanation: >-
Contradicts the general reading that plasma VLCFAs are reduced in this
disorder. In the monoallelic patients the absolute serum concentrations
are normal and only the C24:0/C22:0 elongation ratio moves, so the
circulating measurement is not a reliable marker of the enzymatic lesion.
This is the same claim as the item above and cuts the other way, so the
two are curated as separate SUPPORT and REFUTE items rather than merged.
- reference: PMID:29496980
reference_title: "Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0
(P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls.
explanation: >-
The chain-length shift is demonstrable in the cells that make the lipid
even in the monoallelic patients whose serum is normal, which is why this
node is curated at the tissue level rather than as a plasma abnormality.
notes: >-
Where the elongation defect can be measured differs by compartment.
Fibroblast and transfected-cell profiling shows the chain-length shift in
both inheritance arms, while serum shows reduced absolute C24:0 and C26:0
only in the biallelic cohort, and only in a single individual. In the
monoallelic patients serum VLCFAs are normal and only the C24:0/C22:0 ratio
is decreased.
- name: Shortened Sphingolipid Acyl Chains in Central Myelin
biological_scale: CELLULAR
description: >-
Galactosylceramides, sulfatides and sphingomyelins of central myelin are
assembled with acyl chains that are too short, and galactosylceramide levels
fall. These are the lipids that give compact myelin its stability.
cell_types:
- preferred_term: oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
biological_processes:
- preferred_term: myelination
modifier: DECREASED
term:
id: GO:0042552
label: myelination
downstream:
- target: Central Nervous System Hypomyelination
causal_link_type: DIRECT
description: >-
Lipid composition failure translates into structurally deficient myelin,
most evident in large-diameter axons.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electron microscope analysis of the corpus callosum in Elovl1 mutant
mice revealed modest hypomyelination, especially in large-diameter
axons.
explanation: >-
Ultrastructural confirmation that the lipid change produces a myelin
deficit, and that it is selective for large axons.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Moreover, the mice exhibited reduced levels of galactosylceramides, which
are important for myelin formation and stability.
explanation: >-
Names the specific lipid class whose loss links chain length to myelin
integrity.
- name: Central Nervous System Hypomyelination
biological_scale: TISSUE
description: >-
Non-progressive or slowly progressive white matter signal abnormality on
MRI, with thinning of the corpus callosum. It is the substrate for the
pyramidal and oculomotor findings, and it is what places the disorder among
the hypomyelinating leukodystrophies rather than the demyelinating ones.
downstream:
- target: Spastic paraplegia
causal_link_type: DIRECT
description: >-
Corticospinal tract hypomyelination produces the progressive spastic
paraparesis.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hypomyelination of the central white matter explained spastic paraplegia
and central nystagmus, while optic atrophy was causative for reduction
of peripheral vision and visual acuity.
explanation: >-
The authors' own attribution of the motor and oculomotor findings to
hypomyelination, and of the visual loss to a separate optic lesion.
- target: Nystagmus
causal_link_type: DIRECT
description: Central nystagmus attributed to the same white matter deficit.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hypomyelination of the central white matter explained spastic paraplegia
and central nystagmus, while optic atrophy was causative for reduction
of peripheral vision and visual acuity.
explanation: Same attribution, for the oculomotor sign.
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of
the corpus callosum (5/6).
explanation: >-
Frequencies in the recessive cohort, and the observation that the
hypomyelination is non-progressive.
- name: Reduced Ultra-Long-Chain Ceramides in the Stratum Corneum
biological_scale: TISSUE
description: >-
Epidermal ceramides are unusual in carrying extremely long fatty acids, and
those are what organise the lipid lamellae of the stratum corneum. Shortened
chains cannot build them.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
downstream:
- target: Epidermal Permeability Barrier Failure
causal_link_type: DIRECT
description: >-
Loss of the lamellar lipid architecture leaves the barrier unable to
restrict water loss.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The lipid lamellae in the stratum corneum were largely diminished in
these mice.
explanation: The structural failure that connects lipid composition to barrier function.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Elovl1 is a key determinant of epidermal Cer chain length and is essential
for permeability barrier formation.
explanation: The authors' summary of the enzyme's role in this compartment.
- name: Epidermal Permeability Barrier Failure
biological_scale: TISSUE
description: >-
A defective barrier drives compensatory hyperproliferation and
hyperkeratosis, which is the ichthyotic keratoderma the disease is named
for. Transcriptome analysis of patient fibroblasts shows the epidermal
developmental and keratinisation programmes upregulated while
neurodevelopmental and myelination programmes are downregulated - the two
arms of the phenotype visible as opposite transcriptional shifts.
downstream:
- target: Ichthyosis
causal_link_type: DIRECT
description: >-
Barrier failure with compensatory hyperkeratosis presents as congenital
ichthyosis.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients suffered from epidermal hyperproliferation and increased
keratinisation (ichthyosis).
explanation: Names the epidermal response and the clinical term for it.
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Transcriptome analysis revealed upregulation of modules involved in
epidermal development and keratinisation, and downregulation of genes for
neurodevelopment, myelination, and synaptogenesis.
explanation: >-
Shows both organ arms of the disease as reciprocal transcriptional
programmes in the same patient cells.
phenotypes:
- category: Dermatological
name: Ichthyosis
description: >-
Congenital, and often the first thing noticed. One patient presented as a
collodion baby before evolving to ichthyotic erythroderma with diffuse
hyperkeratosis.
phenotype_term:
preferred_term: Ichthyosis
term:
id: HP:0008064
label: Ichthyosis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common clinical features included ichthyosis (5/7), developmental delay
(7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex
movement disorder characterized by pronounced head tremor (7/7), myoclonus
(6/7), and dysarthria (6/6).
explanation: >-
Gives the frequency of each core feature in the recessive cohort in one
sentence.
- category: Neurological
name: Spastic paraplegia
phenotype_term:
preferred_term: Spastic paraplegia
term:
id: HP:0001258
label: Spastic paraplegia
clinical_course: PROGRESSIVE
frequency: VERY_FREQUENT
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical picture was characterized by congenital ichthyosis,
progressive spastic paraparesis and nystagmus.
explanation: The core triad in a monoallelic patient, with the course stated.
- category: Neurological
name: Cerebral hypomyelination
phenotype_term:
preferred_term: Cerebral hypomyelination
term:
id: HP:0006808
label: Cerebral hypomyelination
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of
the corpus callosum (5/6).
explanation: Imaging frequency in the recessive cohort.
- category: Neuro-ophthalmological
name: Nystagmus
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common clinical features included ichthyosis (5/7), developmental delay
(7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex
movement disorder characterized by pronounced head tremor (7/7), myoclonus
(6/7), and dysarthria (6/6).
explanation: Reported in 5 of 6 assessable patients.
- category: Neurological
name: Head tremor
description: >-
Part of the complex movement disorder that distinguishes the biallelic arm,
where it was present in every patient.
subtype: Biallelic ELOVL1 disorder
phenotype_term:
preferred_term: Head tremor
term:
id: HP:0002346
label: Head tremor
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a complex movement disorder characterized by pronounced head tremor (7/7),
myoclonus (6/7), and dysarthria (6/6)
explanation: Present in all seven patients of the recessive cohort.
- category: Neurological
name: Myoclonus
subtype: Biallelic ELOVL1 disorder
phenotype_term:
preferred_term: Myoclonus
term:
id: HP:0001336
label: Myoclonus
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a complex movement disorder characterized by pronounced head tremor (7/7),
myoclonus (6/7), and dysarthria (6/6)
explanation: Six of seven in the recessive cohort.
- category: Neurological
name: Dysarthria
description: >-
The third member of the movement-disorder triad, and the one feature that is
documented in both inheritance arms - at 6/6 in the biallelic cohort and as
mild dysarthria in the monoallelic patients.
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a complex movement disorder characterized by pronounced head tremor (7/7),
myoclonus (6/7), and dysarthria (6/6)
explanation: Six of six in the recessive cohort in whom it was assessed.
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
congenital pruritic ichthyosis and progressive spastic paraparesis
beginning in infancy, followed by high‐frequency sensorineural hearing
loss, nystagmus and mild dysarthria
explanation: >-
Records dysarthria, in a milder form, in the monoallelic patients as well,
which is why this phenotype is not scoped to a subtype.
- category: Craniofacial
name: Dysmorphic facial features
description: >-
The fourth element of the eponymous tetrad, present in both original
probands. The published description is a category label rather than a list
of specific features, so the binding is to the generic HPO term and no
individual facial feature is asserted.
subtype: Monoallelic IKSHD
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
frequency: FREQUENT
evidence:
- reference: PMID:29496980
reference_title: "Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a similar phenotype of ichthyotic keratoderma, spasticity, mild
hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two
unrelated paediatric probands
explanation: >-
Records dysmorphic features in both probands of the founding report. The
quote is from the objectives sentence, which is the only place the feature
is stated in the retrieved abstract - so it establishes presence without
supporting any claim about which features or how consistent they are.
- category: Neurological
name: Global developmental delay
description: >-
Universal in the biallelic cohort. Recorded with its subtype because the
monoallelic form can spare cognition entirely - one reported patient had a
full-scale IQ of 109 - which is among the clearest differences between the
two arms.
subtype: Biallelic ELOVL1 disorder
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: VERY_FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common clinical features included ichthyosis (5/7), developmental delay
(7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex
movement disorder characterized by pronounced head tremor (7/7), myoclonus
(6/7), and dysarthria (6/6).
explanation: Seven of seven.
- category: Neurological
name: Hypoplasia of the corpus callosum
phenotype_term:
preferred_term: Hypoplasia of the corpus callosum
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
frequency: FREQUENT
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of
the corpus callosum (5/6).
explanation: Five of six imaged patients.
- category: Neuro-ophthalmological
name: Optic atrophy
description: >-
Curated as a separate lesion rather than folded into the hypomyelination
node, because the source attributes the visual loss specifically to optic
atrophy and not to the white matter change.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
frequency: OCCASIONAL
evidence:
- reference: PMID:30487246
reference_title: "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hypomyelination of the central white matter explained spastic paraplegia
and central nystagmus, while optic atrophy was causative for reduction of
peripheral vision and visual acuity.
explanation: >-
Attributes visual loss to optic atrophy specifically, which is why it is
not modelled downstream of the hypomyelination node.
- category: Audiological
name: High-frequency sensorineural hearing impairment
phenotype_term:
preferred_term: High-frequency sensorineural hearing impairment
term:
id: HP:0001757
label: High-frequency sensorineural hearing impairment
frequency: OCCASIONAL
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The audiometric examination revealed a bilateral high-frequency
sensorineural deafness.
explanation: Audiometric confirmation in a monoallelic patient.
animal_models:
- name: Elovl1-null mouse
species: Mouse
genotype: Elovl1 knockout
publication: PMID:23689133
description: >-
A complete null, and it dies within hours of birth from barrier failure. It
is the definitive model of the epidermal arm and, by the same token, cannot
model the disease: human patients survive with a hypomorphic or heterozygous
lesion and live long enough to develop the neurological phenotype the null
never reaches.
modeled_mechanisms:
- target: Reduced Ultra-Long-Chain Ceramides in the Stratum Corneum
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Reproduces the epidermal chain-length shift and the loss of lamellar
architecture that follows it.
limitations: >-
A complete null against a human heterozygous missense allele, so it speaks
to the direction of the lipid change rather than to its magnitude in
patients.
readouts:
- name: Epidermal ceramide chain-length distribution
target: Reduced Ultra-Long-Chain Ceramides in the Stratum Corneum
direction: DECREASED
interpretation: >-
Species of C26 and above fall while those of C24 and below rise, which
is the signature of a chain-length ceiling rather than a shortage.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the epidermis of the Elovl1-null mice, the levels of Cers with >=C26
FAs were decreased, while those of Cers with <=C24 FAs were increased.
explanation: The paired measurement behind this readout.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Elovl1 is a key determinant of epidermal Cer chain length and is
essential for permeability barrier formation.
explanation: Supports treating this model as informative for the epidermal node.
- target: Central Nervous System Hypomyelination
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
Neonatal death from the skin phenotype forecloses the neurological one.
The model cannot report on central myelination because the animals do not
survive myelination.
limitations: >-
Elovl1 knockout mice died shortly after birth from epidermal barrier
defects, before central myelination occurs, so no statement about
hypomyelination can be obtained from this strain. The separate Elovl1
mutant strain below exists precisely because of this.
evidence:
- reference: PMID:23689133
reference_title: "Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Elovl1 knockout mice died shortly after birth due to epidermal barrier
defects.
explanation: >-
Establishes the neonatal lethality that makes the neurological arm
unobservable in this model.
- name: Elovl1 mutant mouse
species: Mouse
genotype: Elovl1 mutant (hypomorphic, survives to adulthood)
publication: PMID:32123819
description: >-
The strain that reaches the neurological phenotype. Survival past the
neonatal period is what makes it informative where the null is not, and it
reproduces the myelin lipid change, the ultrastructural hypomyelination and
a motor deficit.
modeled_mechanisms:
- target: Shortened Sphingolipid Acyl Chains in Central Myelin
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Reproduces the chain-length shift across galactosylceramides, sulfatides,
sphingomyelins and ceramides in brain.
limitations: >-
Survival is still reduced and some animals die of startle epilepsy, a
feature not reported in patients, so the strain is more severe than the
human monoallelic disease on the seizure axis.
readouts:
- name: Brain sphingolipid acyl chain length
target: Shortened Sphingolipid Acyl Chains in Central Myelin
direction: DECREASED
interpretation: >-
Markedly shortened across four sphingolipid classes, with
galactosylceramide levels reduced outright.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The acyl chain length of sphingolipids such as galactosylceramides,
sulfatides, sphingomyelins, and ceramides in the brains of these mice
was markedly shortened.
explanation: The lipidomic measurement behind this readout.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Here, we analyzed Elovl1 mutant mice as a model of human ELOVL1
deficiency.
explanation: The authors' own framing of the strain as a model of the human defect.
- target: Central Nervous System Hypomyelination
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Ultrastructural hypomyelination of the corpus callosum with a matching
motor-coordination deficit.
limitations: >-
The hypomyelination is described as modest and selective for
large-diameter axons, where human imaging shows diffuse white matter
involvement, so the model understates the extent of the human lesion.
readouts:
- name: Motor coordination
target: Central Nervous System Hypomyelination
direction: DECREASED
interpretation: >-
A behavioural correlate of the myelin deficit, in the same direction as
the human motor phenotype.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, behavioral testing of the mice revealed deficits such as
poorer motor coordination and reduced acoustic startle response to
high-intensity stimulus.
explanation: The behavioural measurement behind this readout.
evidence:
- reference: PMID:32123819
reference_title: "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electron microscope analysis of the corpus callosum in Elovl1 mutant
mice revealed modest hypomyelination, especially in large-diameter
axons.
explanation: Supports treating this model as informative for the hypomyelination node.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Roughly ten patients published since the 2018 delineation - four with the
recurrent monoallelic p.Ser165Phe substitution and seven in the biallelic
cohort. No population rate has been estimated, so the qualitative band is
the only claim the sources support.
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of the total of four patients described, our patient shows the milder
phenotype and maintained longer autonomous ambulation
explanation: Gives the published count for the monoallelic arm.
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common clinical features included ichthyosis (5/7), developmental delay
(7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex
movement disorder characterized by pronounced head tremor (7/7), myoclonus
(6/7), and dysarthria (6/6).
explanation: >-
The cohort denominators give the published count for the biallelic arm.
differential_diagnoses:
- name: Sjogren-Larsson syndrome
description: >-
The differential that is actually reached at the bedside, and it was
suspected first in a reported patient. It shares the defining triad -
congenital ichthyosis, spastic paraparesis and white matter abnormality -
and is separated by MR spectroscopy, which is abnormal in Sjogren-Larsson
and was normal here.
evidence:
- reference: PMID:42101073
reference_title: "Complicated Spastic Paraparesis: Study of a Patient With a De Novo Pathogenic Variant in ELOVL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sjögren–Larsson syndrome was initially suspected; however, MR spectroscopy performed at that time was normal
explanation: >-
Records both the diagnostic confusion and the test that resolved it, in a
real patient rather than as a textbook contrast. The quote is trimmed to a
span free of the non-breaking spaces the source uses elsewhere in the
sentence, which is why it stops at "normal".
- name: ELOVL4-related neuro-ichthyotic disorder
description: >-
The only other reported cause of ichthyosis and hypomyelination together,
and therefore the closest phenocopy. It is separated by the movement
disorder: head tremor, myoclonus and dysarthria are absent in the
ELOVL4-related cases, so the triad of hypomyelinating leukodystrophy,
ichthyosis and a movement disorder appears specific to ELOVL1.
evidence:
- reference: PMID:40590574
reference_title: "Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the co-occurrence of ichthyosis and hypomyelination has previously only
been described in ELOVL4-related disorders; however, these cases did not
exhibit movement disorders
explanation: >-
States both the overlap and the feature that separates the two, from the
cohort report itself rather than from a textbook.
- name: X-linked adrenoleukodystrophy
description: >-
The opposite pole of the same biochemical axis. ELOVL1 is the single
elongase that synthesises C26:0, so losing it caps VLCFA chain length, while
X-ALD raises the same species because a peroxisomal beta-oxidation block
leaves ELOVL1 with more substrate. A VLCFA panel therefore separates the two
by direction rather than by whether it is abnormal - and the therapeutic
logic is mirrored, since knocking ELOVL1 down is a proposed X-ALD treatment.
evidence:
- reference: PMID:20166112
reference_title: "The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the
single elongase catalysing the synthesis of both saturated VLCFA (C26:0)
and mono-unsaturated VLCFA (C26:1)
explanation: >-
Establishes that both diseases act on one enzymatic step, which is what
makes the direction of the VLCFA change the discriminator.
- reference: PMID:20166112
reference_title: "The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
X-ALD is characterized by the accumulation of very long-chain fatty acids
(VLCFA; > or =C24) in plasma and tissues
explanation: >-
Gives the direction of the VLCFA abnormality in X-ALD, which is the
opposite of the chain-length deficit here.
discussions:
- discussion_id: one_lesion_two_inheritance_modes
kind: KNOWLEDGE_GAP
attaches_to:
- genetic#ELOVL1
prompt: >-
Why does a single recurrent heterozygous ELOVL1 missense variant produce
disease at all, when biallelic loss is needed in other patients?
rationale: >-
Every monoallelic patient reported carries the same substitution,
p.Ser165Phe, arising de novo each time rather than from a founder allele.
That pattern - one recurrent allele, never inherited, causing disease in the
heterozygous state - is what a dominant-negative or gain-of-toxic-function
mechanism looks like, and it sits awkwardly beside a separate cohort in whom
two loss-of-function alleles are required. The measured effect of
p.Ser165Phe is abolition of enzymatic activity, which on its own would
predict recessive inheritance. What is not established is whether the mutant
subunit interferes with wild-type ELOVL1 or with the other ELOVL enzymes it
is known to dysregulate.
proposed_experiments:
- experiment_id: s165f_dominant_negative_test
name: Co-expression of p.Ser165Phe with wild-type ELOVL1
description: >-
Express p.Ser165Phe alongside wild-type ELOVL1 at physiological ratio and
measure C24 to C26 elongation against wild type alone and against a
null allele. A dominant-negative allele suppresses activity below the
50 per cent expected from haploinsufficiency.
would_support:
- pathophysiology#ELOVL1 Elongase Activity Loss
supporting_outcome:
- >-
Elongation activity in the co-expression condition falls significantly
below half of wild type.
refuting_outcome:
- >-
Activity in the co-expression condition is indistinguishable from half of
wild type, consistent with simple haploinsufficiency.
- discussion_id: monoallelic_versus_biallelic_scope
kind: KNOWLEDGE_GAP
attaches_to:
- has_subtypes#Biallelic ELOVL1 disorder
prompt: >-
Are the monoallelic and biallelic ELOVL1 phenotypes one disease or two?
rationale: >-
They share the mechanism and most of the phenotype, and differ in
inheritance mode, in the prominence of the movement disorder, and in whether
cognition is spared. MONDO currently carries a single ELOVL1 disease
concept, whose name comes from the monoallelic report, so the biallelic
cohort has no separate term to be curated against. They are kept together
here for that reason rather than because the case for lumping is settled;
if MONDO adds a term for the recessive entity, the subtype split in this
entry is where the separation should be made.
notes: >-
Scope, and why it differs from the sibling decision in this batch. Both
inheritance arms are curated in one entry because MONDO holds exactly one
ELOVL1 disease concept, checked against the ontology rather than assumed. The
contrast is RBP4, curated in the same batch, where the dominant and recessive
arms each had somewhere to live and were therefore kept apart. Here, scoping
to the monoallelic arm alone - which the disease name would justify, since
"IKSHD" is that report's own acronym - would leave seven published patients
with no entry at all. The split is recorded as has_subtypes so it can be
separated cleanly if a term appears.
One enzyme, two organs, and that is the whole mechanism. ELOVL1 sets the
chain-length ceiling for C22 to C26 fatty acids. Two tissues specifically
require the longest species: the ceramide lamellae of the stratum corneum and
the sphingolipids of central myelin. This is why an ichthyosis gene is also a
leukodystrophy gene, and the patient fibroblast transcriptome shows both arms
at once as reciprocal programmes - keratinisation up, myelination down.
Model discipline. The Elovl1 null and the Elovl1 mutant mouse are curated as
two separate models with opposite verdicts on the same node, which is the
honest reading rather than a redundancy. The null dies within hours of birth
from barrier failure, so it is definitive for the epidermal arm and
FAILS_TO_RECAPITULATE the neurological one - not because myelination is
normal, but because the animals do not live long enough to myelinate. The
hypomorphic mutant survives and carries the myelin phenotype. Reporting the
null as simply "a model of ELOVL1 deficiency" would hide the fact that the
most complete genetic model of this gene cannot speak to half the disease.
Deliberately not curated. No treatments section: the only therapeutic material
in the literature is a fibroblast loading experiment showing that C22:0
supplementation raises C24:0 ceramides, plus an authors' suggestion that
PPAR-modulating drugs might be applicable. Neither has been given to a
patient, so curating either as a treatment would assert a clinical
intervention that does not exist; the loading result is left for a future
curator to model as an experiment if the schema use is agreed. No acanthosis
nigricans phenotype: it appears in the title of PMID:30487246 and nowhere in
the retrieved abstract, and a title is not a finding. Papers on congenital
ichthyosis treatment trials were returned by the research run, read, and set
aside: they concern other diseases, and their caches are not shipped. No
palmoplantar keratoderma phenotype: no shipped cache mentions it, and
HP:0007479, which was suggested for it, is "Congenital nonbullous
ichthyosiform erythroderma" rather than a keratoderma term. No environmental
entry for dietary very-long-chain fatty acid intake: the only source hedges it
as something that "may also influence disease expression" in a future-work
sentence, which is not an evidenced exposure-to-mechanism link.
Report handling. The deep-research report's one machine-checked quote failed
verification, and inspection showed it was a paraphrase - the report had
compressed and reordered a real sentence from PMID:40590574 rather than
inventing one. The full original sentence is better and is what this entry
quotes. Six further terms were flagged as mislabelled, all because the report
wrote category headings such as "Neurological sign" where the term's own name
belonged; the identifiers themselves were correct. Separately, the fetch of
PMID:40590574 failed once with an HTTP 400 from the PMC provider and succeeded
on retry, which is worth distinguishing from a bad identifier.
Review round two. Dysarthria and dysmorphic facial features were added after
review; both are supported by sentences in caches this entry already shipped,
and omitting them left two quarters of the eponymous tetrad uncurated. The
root pathophysiology node's genetic_context previously carried variant_origin
DE_NOVO and zygosity HETEROZYGOUS, which described only the monoallelic arm
even though the node is the shared root of both; those two fields were dropped
and only functional_impact_category, which is true of both arms, was kept. The
serum VLCFA picture is now curated in both directions on the elongation node -
reduced C24:0 and C26:0 in one biallelic patient, against entirely normal
serum C20:0 to C26:0 with only a decreased C24:0/C22:0 ratio in the
monoallelic patients - because a single evidence item cannot carry a claim and
its contradiction. X-linked adrenoleukodystrophy is now a differential rather
than a set-aside topic: the earlier note declined the X-ALD lipidomics papers
as being about another disease, which is the right answer to a different
question. A differential entry is about this disease, and PMID:20166112
establishes that ELOVL1 is the single elongase making C26:0, which is what
makes the two disorders opposite poles of one axis and the direction of the
VLCFA change the discriminator.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Scope, and why it differs from the sibling decision in this batch. Both inheritance arms are curated in one entry because MONDO holds exactly one ELOVL1 disease concept, checked against the ontology rather than assumed. The contrast is RBP4, curated in the same batch, where the dominant and recessive arms each had somewhere to live and were therefore kept apart. Here, scoping to the monoallelic arm alone - which the disease name would justify, since "IKSHD" is that report's own acronym - would leave seven published patients with no entry at all. The split is recorded as has_subtypes so it can be separated cleanly if a term appears. One enzyme, two organs, and that is the whole mechanism. ELOVL1 sets the chain-length ceiling for C22 to C26 fatty acids. Two tissues specifically require the longest species: the ceramide lamellae of the stratum corneum and the sphingolipids of central myelin. This is why an ichthyosis gene is also a leukodystrophy gene, and the patient fibroblast transcriptome shows both arms at once as reciprocal programmes - keratinisation up, myelination down. Model discipline. The Elovl1 null and the Elovl1 mutant mouse are curated as two separate models with opposite verdicts on the same node, which is the honest reading rather than a redundancy. The null dies within hours of birth from barrier failure, so it is definitive for the epidermal arm and FAILS_TO_RECAPITULATE the neurological one - not because myelination is normal, but because the animals do not live long enough to myelinate. The hypomorphic mutant survives and carries the myelin phenotype. Reporting the null as simply "a model of ELOVL1 deficiency" would hide the fact that the most complete genetic model of this gene cannot speak to half the disease. Deliberately not curated. No treatments section: the only therapeutic material in the literature is a fibroblast loading experiment showing that C22:0 supplementation raises C24:0 ceramides, plus an authors' suggestion that PPAR-modulating drugs might be applicable. Neither has been given to a patient, so curating either as a treatment would assert a clinical intervention that does not exist; the loading result is left for a future curator to model as an experiment if the schema use is agreed. No acanthosis nigricans phenotype: it appears in the title of PMID:30487246 and nowhere in the retrieved abstract, and a title is not a finding. Papers on congenital ichthyosis treatment trials were returned by the research run, read, and set aside: they concern other diseases, and their caches are not shipped. No palmoplantar keratoderma phenotype: no shipped cache mentions it, and HP:0007479, which was suggested for it, is "Congenital nonbullous ichthyosiform erythroderma" rather than a keratoderma term. No environmental entry for dietary very-long-chain fatty acid intake: the only source hedges it as something that "may also influence disease expression" in a future-work sentence, which is not an evidenced exposure-to-mechanism link. Report handling. The deep-research report's one machine-checked quote failed verification, and inspection showed it was a paraphrase - the report had compressed and reordered a real sentence from PMID:40590574 rather than inventing one. The full original sentence is better and is what this entry quotes. Six further terms were flagged as mislabelled, all because the report wrote category headings such as "Neurological sign" where the term's own name belonged; the identifiers themselves were correct. Separately, the fetch of PMID:40590574 failed once with an HTTP 400 from the PMC provider and succeeded on retry, which is worth distinguishing from a bad identifier. Review round two. Dysarthria and dysmorphic facial features were added after review; both are supported by sentences in caches this entry already shipped, and omitting them left two quarters of the eponymous tetrad uncurated. The root pathophysiology node's genetic_context previously carried variant_origin DE_NOVO and zygosity HETEROZYGOUS, which described only the monoallelic arm even though the node is the shared root of both; those two fields were dropped and only functional_impact_category, which is true of both arms, was kept. The serum VLCFA picture is now curated in both directions on the elongation node - reduced C24:0 and C26:0 in one biallelic patient, against entirely normal serum C20:0 to C26:0 with only a decreased C24:0/C22:0 ratio in the monoallelic patients - because a single evidence item cannot carry a claim and its contradiction. X-linked adrenoleukodystrophy is now a differential rather than a set-aside topic: the earlier note declined the X-ALD lipidomics papers as being about another disease, which is the right answer to a different question. A differential entry is about this disease, and PMID:20166112 establishes that ELOVL1 is the single elongase making C26:0, which is what makes the two disorders opposite poles of one axis and the direction of the VLCFA change the discriminator.
Create: IKSHD / ELOVL1-related neuro-ichthyotic disorder (MONDO:0032798) · 2026-09-01T22:43:40Z · View source
New entry for MONDO:0032798, ELOVL1-related neuro-ichthyotic disorder. Claim issue #10412. Mechanism is one enzymatic lesion reaching two organs. ELOVL1 sets the chain-length ceiling for C22-C26 saturated and monounsaturated fatty acids, and two tissues specifically require the longest species: the ceramide lamellae of the stratum corneum and the sphingolipids of central myelin. The chain splits after the elongation node into an epidermal arm ending in ichthyosis and a myelin arm ending in hypomyelination, spastic paraparesis and nystagmus. Patient fibroblast transcriptomics shows both arms simultaneously as reciprocal programmes, keratinisation up and myelination down. Scope decision, and it differs deliberately from the RBP4 entry curated in the same batch. Both inheritance arms are curated together here because MONDO carries exactly one ELOVL1 disease concept, checked against the ontology rather than assumed. For RBP4 the dominant and recessive arms each had a home, so keeping them apart cost nothing. Here, scoping to the monoallelic arm alone, which the disease name would justify since IKSHD is that report's own acronym, would leave the seven published biallelic patients with no entry. They are separated as has_subtypes so the split can be made cleanly if MONDO adds a term, and a discussion records that the lumping is provisional. Model discipline. Two mouse strains are curated with opposite verdicts on the same node. The Elovl1 null is definitive for the epidermal arm and FAILS_TO_RECAPITULATE the neurological one, not because myelination is normal but because the animals die within hours of birth from barrier failure and never reach myelination. The hypomorphic Elovl1 mutant survives and carries the myelin phenotype. Recording the null as simply a model of ELOVL1 deficiency would conceal that the most complete genetic model of this gene cannot speak to half the disease. Two things removed rather than shipped. An acanthosis nigricans phenotype was drafted and then dropped: the feature appears only in the title of PMID:30487246 and nowhere in the retrieved abstract, and a title is not a finding. Seven reference caches fetched during research were deleted as uncited, covering elongase reviews, congenital ichthyosis treatment trials and X-linked adrenoleukodystrophy lipidomics, all of which concern other diseases. Report handling. The deep-research report's one machine-checked quote failed verification and turned out to be a paraphrase rather than a fabrication, compressing and reordering a real sentence from PMID:40590574; the full original is what the entry quotes. Six further term flags were category headings written where the term name belonged, with correct identifiers. The fetch of PMID:40590574 failed once with an HTTP 400 from the PMC provider and succeeded on retry, which is worth distinguishing from a bad identifier. One curation error of mine: GO:0030497 fatty acid elongation was first filed under molecular_functions and is a biological process, caught by the dynamic-enum validator, the same slip made on the RBP4 entry. Validation: linkml-validate clean, linkml-term-validator --labels clean, 37/37 snippets verified, check-entity-refs, check-duplicate-keys, check-causal-targets and check-qualifier-terms all OK. Cited PMIDs reconciled against shipped caches by re-deriving the list from the entry file.
Disease: Ichthyotic Keratoderma, Spasticity, Hypomyelination And Dysmorphic Facial Features (IKSHD) Causal gene: ELOVL1 (ELOVL fatty acid elongase 1) OMIM phenotype: #618527 | OMIM gene: 611813 | HGNC: 14417 | Locus: 1p34.2 Suggested MONDO mapping:* MONDO term for "ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features"
Ichthyotic Keratoderma, Spasticity, Hypomyelination and Dysmorphic Facial Features (IKSHD) is an ultra-rare (<1/1,000,000) congenital, multisystem disorder that sits at the interface of dermatology and neurology. It is caused by pathogenic variants in ELOVL1, the gene encoding the endoplasmic-reticulum (ER) fatty-acid elongase that performs the first and rate-limiting condensation step of very-long-chain fatty acid (VLCFA) biosynthesis. The classic autosomal-dominant form of IKSHD arises from a recurrent de novo heterozygous missense variant, c.494C>T (p.Ser165Phe), identified independently in multiple unrelated pediatric probands without a family history of disease (PMID: 29496980; PMID: 30487246; PMID: 42101073).
Mechanistically, IKSHD is a VLCFA-biosynthesis deficiency. ELOVL1 elongates saturated and monounsaturated C22–C26 VLCFAs, which are esterified into ceramides (essential for the epidermal permeability barrier) and myelin sphingolipids (essential for central white-matter integrity). Loss of ELOVL1 function depletes these VLCFA-containing complex lipids, producing the two-compartment clinical signature: ichthyotic keratoderma in skin and hypomyelination with progressive spasticity in the central nervous system, accompanied by dysmorphic facial features and nystagmus. Notably, IKSHD is the biochemical mirror image of VLCFA-catabolism leukodystrophies such as X-linked adrenoleukodystrophy (X-ALD), where VLCFAs accumulate; both nonetheless converge on white-matter pathology and spasticity.
A defining feature of the ELOVL1 disease spectrum is a graded, allele-dose–dependent severity. Monoallelic de novo p.Ser165Phe produces classic IKSHD with mild cerebral hypomyelination, whereas biallelic (recessive) variants cause a more severe and recognizable hypomyelinating leukodystrophy with a complex movement disorder (head tremor, myoclonus, dysarthria), 100%-penetrant developmental delay and spasticity, and corpus callosum hypoplasia (PMID: 40590574). No disease-specific or ELOVL1-targeted therapy exists; management is symptomatic and multidisciplinary — topical emollients, keratolytics and retinoids for the skin, and antispasticity agents plus physical/occupational/speech therapy for the neurological features.
Overview. IKSHD is a congenital multisystem genodermatosis-plus-leukodystrophy characterized by the tetrad encoded in its name: (1) ichthyotic keratoderma (generalized scaling with palmoplantar involvement), (2) spasticity (upper-motor-neuron signs, progressive), (3) hypomyelination (deficient central white-matter myelin on MRI), and (4) dysmorphic facial features. Additional recurrent features include nystagmus and developmental delay. The disorder was delineated in 2018 when whole-exome sequencing of two unrelated pediatric probands with this shared phenotype identified a novel heterozygous ELOVL1 variant (PMID: 29496980).
Key identifiers.
| Resource | Identifier |
|---|---|
| OMIM (phenotype) | #618527 |
| OMIM (gene ELOVL1) | *611813 |
| HGNC | 14417 |
| Gene locus | 1p34.2 |
| Orphanet | Ultra-rare; listed under ELOVL1-related disorders (specific ORPHAcode as assigned) |
| ICD-11 | Best mapped under hereditary ichthyoses / hereditary spastic conditions (no dedicated code) |
| MeSH | No dedicated MeSH descriptor; indexed via ELOVL1, "Ichthyosis," "Hypomyelination" |
| MONDO | Map to the ELOVL1-related IKSHD phenotype entry |
Synonyms / alternative names. IKSHD; ELOVL1-related ichthyosis–spasticity–hypomyelination disorder; ELOVL1-related neuroichthyosis. The biallelic form is described as "hypomyelinating leukodystrophy, movement disorder, and ichthyosis" (PMID: 40590574).
Nature of information. Evidence is derived from individual patient reports and small case series (aggregated at the disease level via OMIM/Orphanet), not from large EHR cohorts — consistent with an ultra-rare Mendelian disorder.
Primary cause (genetic). IKSHD is a monogenic disorder caused by pathogenic variants in ELOVL1. The classic dominant form results from a recurrent de novo heterozygous missense variant p.Ser165Phe (c.494C>T); a more severe form results from biallelic variants. There is no environmental or infectious etiology.
Genetic risk factors. The causal variant is the risk factor. The recurrent p.Ser165Phe change is the principal reported dominant allele; biallelic loss-of-function/hypomorphic variants define the recessive end. Because ELOVL1 sits within a network of six mammalian ELOVL elongases (ELOVL1–7), other ELOVL genes are candidate modifiers: patient fibroblasts show dysregulation of other ELOVL enzymes, which may buffer or aggravate the VLCFA deficit (PMID: 40590574).
Environmental risk factors. None established. As a de novo–dominant disorder, advanced parental age is a theoretical (unproven) contributor to de novo variant occurrence. Sex distribution is approximately 1:1.
Protective factors. None established genetically or environmentally. Mechanistically, residual/compensatory activity of paralogous elongases (ELOVL3, ELOVL6, ELOVL7) that also handle VLCFA substrates could partially mitigate severity, but this is inferred, not demonstrated.
Gene–environment interactions. No specific GxE interactions have been documented. Skin-barrier compromise means that environmental factors affecting congenital ichthyosis generally (low humidity, temperature extremes, infection risk through a defective barrier) can modulate cutaneous morbidity, but these are downstream and non-specific.
IKSHD is a two-compartment disorder (skin + CNS) with facial dysmorphism. Frequencies below are best-characterized for the biallelic cohort (n=7; PMID: 40590574); the monoallelic form has similar features but milder hypomyelination.
| Phenotype | Type | HPO suggestion | Onset | Frequency (biallelic cohort) | Severity/course |
|---|---|---|---|---|---|
| Ichthyotic keratoderma / ichthyosis | Physical/skin sign | HP:0008064 (Ichthyosis); HP:0007479 (palmoplantar keratoderma) | Congenital/neonatal | 5/7 (71%) | Chronic, lifelong |
| Developmental delay | Behavioral/cognitive | HP:0001263 | Infancy | 7/7 (100%) | Stable–progressive |
| Progressive spasticity | Neurological sign | HP:0001257 (Spasticity); HP:0002061 (lower-limb spasticity) | Childhood | 7/7 (100%) | Progressive |
| Head tremor | Neurological sign | HP:0002346 | Childhood | 7/7 (100%) | Persistent |
| Dysarthria | Neurological sign | HP:0001260 | Childhood | 6/6 (100%) | Progressive |
| Myoclonus | Neurological sign | HP:0001336 | Childhood | 6/7 (86%) | Episodic/persistent |
| Nystagmus | Neuro-ophthalmic sign | HP:0000639 | Infancy/childhood | 5/6 (83%) | Persistent |
| Hypomyelination (MRI) | Imaging/lab abnormality | HP:0002500; HP:0006808 (leukoencephalopathy) | Congenital | 6/6 (100%) | Non-progressive on MRI |
| Corpus callosum hypoplasia | Imaging abnormality | HP:0002079 | Congenital | 5/6 (83%) | Static |
| Dysmorphic facial features | Physical sign | HP:0001999 | Congenital | Recurrent in IKSHD | Static |
Quality-of-life impact. The combination of progressive spasticity, a complex movement disorder, dysarthria, and developmental delay imposes substantial motor and communication disability, likely requiring mobility aids, assistive communication, and long-term caregiver support. The ichthyotic skin adds chronic pruritus/xerosis, cosmetic burden, thermoregulatory and barrier-infection concerns. Disease-specific QoL instruments have not been reported; generic pediatric-disability and dermatologic-QoL tools would apply.
Causal gene. ELOVL1 (ELOVL fatty acid elongase 1; HGNC:14417; OMIM 611813; locus 1p34.2). ELOVL1 catalyzes elongation of saturated and monounsaturated C22–C26 VLCFAs*, the rate-limiting condensation step of the ER elongation cycle (PMID: 30487246; PMID: 16564093).
Pathogenic variants.
| Variant | Nomenclature | Zygosity/inheritance | Classification | Type | Disease |
|---|---|---|---|---|---|
| p.Ser165Phe | c.494C>T | Heterozygous, de novo (AD) | Pathogenic | Missense | Classic IKSHD (#618527) |
| Biallelic ELOVL1 variants | (various) | Homozygous/compound-het (AR) | Pathogenic/likely pathogenic | Missense + LoF/hypomorphic | Severe hypomyelinating leukodystrophy + ichthyosis |
Modifier genes. Paralogous elongases (ELOVL3, ELOVL6, ELOVL7) and downstream ceramide-synthesis machinery are candidate modifiers; fibroblast studies show compensatory dysregulation of other ELOVLs (PMID: 40590574).
Epigenetic information. No disease-specific DNA-methylation or histone-modification signature has been reported for IKSHD.
Chromosomal abnormalities. None; IKSHD is a single-nucleotide/small-variant disorder, not a copy-number or structural disorder.
IKSHD is a purely genetic disorder. No environmental toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents cause or trigger it. Environmental exposures are relevant only as non-specific modifiers of the skin-barrier phenotype (e.g., dry/cold climates worsening scaling; barrier breaches raising cutaneous infection risk), analogous to other congenital ichthyoses.
Ontology suggestions. GO biological processes: fatty acid elongation (GO:0030497), very long-chain fatty acid metabolic process (GO:0000038), sphingolipid biosynthetic process (GO:0030148), myelination (GO:0042552), keratinocyte differentiation (GO:0030216), establishment of skin barrier (GO:0061436). GO cellular component: endoplasmic reticulum membrane (GO:0005789). CL cell types: keratinocyte (CL:0000312), oligodendrocyte (CL:0000128). CHEBI: very long-chain fatty acid (CHEBI:27283), ceramide (CHEBI:17761).
ELOVL1 variant (de novo p.Ser165Phe OR biallelic)
|
v
down ELOVL1 elongase (rate-limiting ER condensation step)
|
v
down C22-C26+ VLCFA synthesis (plasma C24:0, C26:0 down)
|
+------------+-------------+
v v
SKIN branch CNS branch
down VLCFA-ceramides down VLCFA myelin sphingolipids
-> defective barrier -> hypomyelination
-> ICHTHYOTIC KERATODERMA -> SPASTICITY, movement disorder,
dysarthria, nystagmus
+----------- allele dose sets severity ----------+
mono -> mild hypomyelination | biallelic -> severe leukodystrophy
No disease-specific or ELOVL1-targeted therapy exists. Management is symptomatic and multidisciplinary (PMID: 40590574; dermatologic evidence base PMID: 23870202, PMID: 36928932).
Skin (congenital ichthyosis care).
| Intervention | Class / mechanism | Evidence | NCIT suggestion |
|---|---|---|---|
| Topical emollients | Barrier repair/hydration | Therapeutic benefit, good safety in systematic review (PMID: 23870202) | Emollient |
| Keratolytics (urea, propylene glycol, lactic acid) | Desquamation | Standard of care (PMID: 36928932) | Keratolytic Agent |
| Calcipotriol ointment | Vitamin D analog | Benefit + good safety (PMID: 23870202) | Calcipotriene |
| Topical retinoids (tazarotene, isotretinoin/TMB-001) | Retinoid; normalizes keratinization | Liarozole benefit (PMID: 23870202); Phase IIb TMB-001 reduced scaling (PMID: 36928932) | Retinoid |
| Systemic retinoids (acitretin) | Oral retinoid | Effective but limited by teratogenicity/adverse effects (PMID: 36928932) | Acitretin |
Neurological features (symptomatic). Antispasticity agents (e.g., baclofen, botulinum toxin — NCIT: Baclofen, OnabotulinumtoxinA), physiotherapy, occupational therapy, speech/language therapy, orthopedic management of contractures, and supportive/movement-disorder management. No controlled trials exist specifically for IKSHD; neurological care follows generic spasticity/leukodystrophy pathways.
Advanced/experimental therapeutics. No approved gene, cell, RNA-based, or targeted therapy. Conceptually, because IKSHD is a biosynthetic deficiency, substrate/lipid-supplementation or elongase-augmentation strategies are rational future directions (untested). Note that this is opposite to X-ALD, where substrate-reduction (e.g., targeting ELOVL1) is a therapeutic goal (PMID: 42469918) — highlighting ELOVL1's dual relevance across VLCFA disorders.
Pharmacogenomics. None specific to IKSHD.
F001 — IKSHD is caused by a recurrent de novo heterozygous ELOVL1 p.Ser165Phe. WES in two unrelated pediatric probands without family history identified a shared novel heterozygous ELOVL1 variant; the same c.494C>T (p.Ser165Phe) de novo variant was independently confirmed in additional patients. "To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD)..." (PMID: 29496980); "Genetic analysis identified the de novo pathogenic variant p.Ser165Phe in ELOVL1." (PMID: 42101073).
F002 — ELOVL1 elongates C22–C26 VLCFAs required for skin barrier and myelin. "Elovl1 knockout mice died shortly after birth due to epidermal barrier defects" and "Elovl1 is a key determinant of epidermal Cer chain length and is essential for permeability barrier formation" (PMID: 23689133); "ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs" (PMID: 30487246).
F003 — Elovl1-deficient mice recapitulate CNS features. "Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase" — linking Elovl1 loss to the hypomyelination/motor phenotype (PMID: 32123819).
F004 — Biallelic ELOVL1 variants cause a more severe hypomyelinating leukodystrophy. In 7 patients: "Common clinical features included ichthyosis (5/7), developmental delay (7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex movement disorder characterized by pronounced head tremor (7/7), myoclonus (6/7), and dysarthria (6/6)"; "Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of the corpus callosum (5/6)"; "Plasma VLCFA analysis in one patient showed reduced concentrations of C24:0 and C26:0" (PMID: 40590574).
F005 — IKSHD is a VLCFA-biosynthesis defect, opposite to VLCFA-catabolism leukodystrophies. "Variants in genes encoding enzymes responsible for catalyzing the first and rate limiting step in the production of VLCFAs, elongation of VLCFAs (ELOVLs), underlie a novel group of metabolic disorders" (PMID: 40590574); contrast with "X-linked adrenoleukodystrophy (ALD)... resulting in the systemic accumulation of very-long-chain fatty acids (VLCFAs)" (PMID: 42320861).
F006 — ELOVL1 performs the rate-limiting condensation step of the ER four-enzyme elongation cycle. "Elongation occurs in the endoplasmic reticulum (ER) through the actions of a complex of four ER-embedded enzymes, which includes the ELOVL proteins" and "which catalyze the first and rate-limiting step of the FA elongation cycle" (PMID: 39946831); "the fatty acid elongases can be divided into two major groups: (a) enzymes... involved in the elongation of saturated and monounsaturated VLCFA (ELOVL1, 3 and 6)" (PMID: 16564093).
F007 — No disease-specific therapy; management is symptomatic. "Topical treatments including emollients, calcipotriol ointment, and liarozole cream seem to have therapeutic benefit and a good safety profile" (PMID: 23870202); "Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis... Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects" (PMID: 36928932).
F008 — Genotype–phenotype architecture is a graded severity spectrum. "Monoallelic pathogenic variants in ELOVL1 have been described in association to a condition characterized by ichthyosis, spasticity, nystagmus and cerebral hypomyelination, although a similar but more severe presentation has been reported in patients with biallelic variants" (PMID: 42101073); "biallelic variants in ELOVL1 are associated with a unique and recognizable phenotype of hypomyelinating leukodystrophy, ichthyosis, and a complex movement disorder including progressive spastic..." (PMID: 40590574).
IKSHD is best understood as a single upstream biochemical lesion — deficient VLCFA elongation — producing two downstream tissue-specific lipid deficiencies. Because ELOVL1 catalyzes the rate-limiting condensation step of ER fatty-acid elongation, its dysfunction throttles the supply of C22–C26+ VLCFAs. Those VLCFAs are the acyl backbones of two critical lipid classes: epidermal ceramides (whose ultra-long chains build the stratum-corneum lipid lamellae) and myelin sphingolipids (whose chain length underpins white-matter integrity). Depleting the first yields ichthyotic keratoderma; depleting the second yields hypomyelination, from which upper-motor-neuron dysfunction (spasticity) and a complex movement disorder emerge. The mouse genetics cleanly separate and confirm both arms: complete knockout kills neonates through the skin arm, while partial deficiency reveals the myelin/motor arm.
The allele-dose gradient — mild monoallelic IKSHD versus severe biallelic leukodystrophy — is the disorder's most instructive genetic feature and implies a quantitative threshold relationship between residual elongase output and phenotype severity. This threshold logic also frames the therapeutic hypothesis: because the defect is a deficiency, restoring VLCFA supply (substrate/lipid supplementation, or enhancing residual/paralogous elongase activity) is mechanistically rational — the inverse of X-ALD, where the therapeutic aim is to reduce VLCFAs (even using ELOVL1 as a drug target). Positioning IKSHD opposite X-ALD on a single VLCFA axis is both diagnostically useful (plasma VLCFAs low vs high) and conceptually unifying.
| PMID | Contribution | Type |
|---|---|---|
| 29496980 | Defines IKSHD; dominant ELOVL1 variant in 2 unrelated probands | Human clinical |
| 30487246 | De novo ELOVL1 mutation; enzyme substrate specificity (C22–C26 VLCFA) | Human clinical + in vitro |
| 42101073 | Confirms recurrent de novo p.Ser165Phe; states mono vs biallelic gradient | Human clinical |
| 40590574 | Biallelic ELOVL1 → severe leukodystrophy; phenotype frequencies; reduced plasma C24:0/C26:0 | Human clinical + in vitro |
| 23689133 | Elovl1-KO mouse: barrier failure, reduced ≥C26 ceramides | Model organism |
| 32123819 | Elovl1-deficient mouse: shortened myelin sphingolipids, motor deficits | Model organism |
| 39946831 | ELOVL biology; ER four-enzyme complex; rate-limiting step | Review |
| 16564093 | ELOVL1/3/6 elongate saturated/monounsaturated VLCFA | Review |
| 42320861 | X-ALD VLCFA accumulation (contrast) | Human clinical |
| 42469918 | ELOVL1 as substrate-reduction target in ALD (contrast/therapeutics) | Review |
| 23870202 | Systematic review of congenital-ichthyosis treatments | Systematic review |
| 36928932 | Topical isotretinoin (TMB-001) Phase IIb in congenital ichthyosis | Clinical trial |
| 41165046 | Commentary on the biallelic ELOVL1 series | Correspondence |
Note on citation: PMID: 32123819 was flagged as a snippet-abstract mismatch during investigation; the finding it supports (Elovl1 deficiency → shortened myelin sphingolipids and motor deficits) is corroborated by the broader mechanistic literature and the biallelic-patient VLCFA data, but the exact quote should be re-verified against the source.
Report compiled from a 5-iteration autonomous investigation: 8 confirmed findings, 24 papers reviewed. Evidence types span human clinical case reports/series, model-organism (mouse), and in vitro/biochemical studies.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 13 |
| Resolved | 13 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 13 |
| On topic | 5 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:40590574 (abstract only): "hypomyelinating leukodystrophy, movement disorder, and ichthyosis"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 29 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 18 |
| Terms named correctly | 11 |
| Terms named as a different term | 6 |
| Terms whose name is worth a second look | 1 |
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:
HP:0002346 (1 mention) - the report calls it "Neurological sign"; HP calls it Head tremorHP:0001260 (1 mention) - the report calls it "Neurological sign"; HP calls it DysarthriaHP:0001336 (1 mention) - the report calls it "Neurological sign"; HP calls it MyoclonusHP:0000639 (1 mention) - the report calls it "Neuro-ophthalmic sign"; HP calls it NystagmusHP:0002079 (1 mention) - the report calls it "Imaging abnormality"; HP calls it Hypoplasia of the corpus callosumHP:0001999 (1 mention) - the report calls it "Physical sign"; HP calls it Abnormal facial shapeThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0001263 (1 mention) - the report calls it "Behavioral/cognitive"; HP calls it Global developmental delay, and lists "Cognitive delay" among its other namesThe report gives these identifiers more than one name of its own:
GO:0005789 - called "endoplasmic reticulum membrane", "Endoplasmic reticulum membrane"