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Inheritance

1

Autosomal recessive inheritance HP:0000007

All definitively reported families are consanguineous with homozygous variants. Consanguinity is the principal risk factor; no founder allele is known and the reported disease alleles are private to each family.

Autosomal recessive inheritance

?

Discussions and Knowledge Gaps

1

Do the extramotor features of SPG81 - deafness, visual loss, seizures and microcephaly - follow from the same plasmenyl-PE-dependent myelination defect that produces the spastic paraplegia, or from a separate consequence of ethanolamine-phospholipid depletion in non-myelinating cell types?

KNOWLEDGE GAP spg81_extramotor_mechanism

Attached to

pathophysiology#Extramotor Neurodevelopmental Involvement

The mouse model is nervous-system-restricted and was assessed for motor deficits, hypomyelination, gliosis and microcephaly. It is not reported to have been assessed for auditory or visual function, so the model that grounds the motor arm is silent on the arm that carries most of the severe-end morbidity. Meanwhile SELENOI has documented roles outside the nervous system entirely, which makes a myelin-only explanation for every feature an assumption rather than a finding. This matters for more than completeness: if the extramotor features are a separate consequence, a therapy that rescued myelination would not be expected to address them, and a trial powered on motor endpoints would miss that.

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Pathophysiology

6

Loss of Ethanolamine Phosphotransferase Activity

Biallelic SELENOI variants reduce the activity of ethanolamine phosphotransferase 1, the enzyme catalysing the final step of the CDP-ethanolamine branch of the Kennedy pathway.

SELENOI hgnc:29361

ethanolamine phosphotransferase activity GO:0004307 ↓ DECREASED

Downstream

Depletion of Ethanolamine Phospholipids and Plasmenyl-PE

Show evidence (1 reference)

PMID:28052917 SUPPORT In Vitro

"dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis"

States the enzymatic consequence of the founding family's variant and places it at the terminal step of the pathway. Graded IN_VITRO rather than HUMAN_CLINICAL: the activity measurement is a heterologous assay (the publication is MeSH-indexed to Saccharomyces cerevisiae), not an observation in patients. The variant is human; the activity number is not.

Depletion of Ethanolamine Phospholipids and Plasmenyl-PE

Reduced EPT1 activity lowers synthesis of phosphatidylethanolamine and, importantly, of its ether-linked plasmenyl form. Plasmenyl-PE is not merely a structural lipid: its vinyl-ether bond reacts preferentially with oxidants, so the species that is lost is also the one that protects the membrane.

oligodendrocyte CL:0000128

phosphatidylethanolamine biosynthetic process GO:0006646 ↓ DECREASED

Downstream

Lipid Peroxidation and Failed Oligodendrocyte Maturation

Show evidence (2 references)

PMID:38582453 SUPPORT Model Organism

"characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant"

Supplies the property that makes this depletion damaging rather than merely quantitative - the lost lipid is the antioxidant one.

PMID:29500230 SUPPORT In Vitro

"most plasmenyl-PE species were significantly decreased in the patient's cells, whereas most plasmanylcholine"

The direct measurement in patient cells, which is what makes the depletion a human finding rather than an inference from the mouse. The clause also records the compensatory rise in plasmanyl-PC, so the lipid change is a redistribution and not simply a loss.

Lipid Peroxidation and Failed Oligodendrocyte Maturation

In the nervous-system-restricted mouse model, loss of the sacrificial antioxidant is followed by increased lipid peroxidation specifically in oligodendrocyte-lineage cells, and those cells fail to mature. This node is graded MODEL_ORGANISM throughout: the causal chain from peroxidation to arrested maturation has been shown in mouse and in vitro, not in human tissue.

oligodendrocyte precursor cell CL:0002453

Animal models

Nervous-system-restricted Selenoi conditional knockout mouse Mouse recapitulates The cellular mechanism of this node is established in this model rather than in human tissue.

Downstream

Central Hypomyelination

Show evidence (1 reference)

PMID:38582453 SUPPORT Model Organism

"increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro"

Names both halves of this node and states the model systems, which is why the node is graded as model evidence rather than human.

Central Hypomyelination

Oligodendrocytes that do not mature do not myelinate. Hypomyelination is the imaging finding in affected patients and the neuropathological finding in the mouse, and it is followed by atrophy rather than accompanied by it.

myelination GO:0042552 ↓ DECREASED

brain UBERON:0000955 cerebellum UBERON:0002037 spinal cord UBERON:0002240

Downstream

Progressive Corticospinal Tract Dysfunction

Extramotor Neurodevelopmental Involvement

Cerebral Hypomyelination

Cerebellar Atrophy

Cerebral Atrophy

Show evidence (2 references)

PMID:29500230 SUPPORT Human Clinical

"Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem"

Human imaging evidence for hypomyelination, and for its temporal relation to the atrophy that follows it.

PMID:38582453 SUPPORT Model Organism

"a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment"

States the pathway-to-myelin dependency this node rests on.

Extramotor Neurodevelopmental Involvement

The features outside the motor system - impaired intellectual development, speech delay, seizures, microcephaly, sensorineural deafness and visual loss - reported mainly at the severe end of the spectrum. This node is deliberately weaker than the motor arm above, and the reason is stated rather than hidden by the arrow: these features co-occur with the myelin lesion in the reported patients, but no source establishes that each follows from it. Sensorineural deafness in particular is a cochlear or eighth-nerve phenotype whose relation to central hypomyelination is not demonstrated in this disease. The edges below therefore assert co-occurrence within a single CNS disorder, not a worked-out causal path, and the HUMAN_MODEL_MISMATCH-style gap that would be needed to resolve it is recorded in the discussions section.

Downstream

Intellectual Disability

Delayed Speech and Language Development

Seizure

Microcephaly

Sensorineural Hearing Impairment

Cerebral Visual Impairment

Cleft Palate

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy"

Establishes that these features occur together in the reported spectrum, which is what this node claims - and, read carefully, is all it claims.

Progressive Corticospinal Tract Dysfunction

The clinical syndrome: infancy-onset delayed motor development followed by regression, with progressive lower-limb spasticity and hyperreflexia. The node is separated from the tissue-level hypomyelination above because the regression is a course, not a lesion.

Animal models

Nervous-system-restricted Selenoi conditional knockout mouse Mouse partially recapitulates The mouse shows motor deficits, so the motor arm is modelled.

Downstream

Spastic Paraplegia

Lower Limb Spasticity

Hyperreflexia

Developmental Regression

Motor Delay

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy"

The combined phenotypic spectrum across reported families, which is the source for the motor features on this node and for several phenotypes below.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures"

Names deafness in the severely affected patient described.

Head and Neck 2

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:38582453 SUPPORT Model Organism

"motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly"

Graded PARTIAL and MODEL_ORGANISM deliberately: this quote is the mouse phenotype. Microcephaly is reported in patients too, but the quotable human sources in this entry's cache list it without a sentence that isolates it, so the mouse evidence is what is cited and the grading says so.

Cleft Palate HP:0000175

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"sensorineural deafness, blindness, cleft palate, delayed motor development"

Names cleft palate among the reported features.

Musculoskeletal 1

Spastic Paraplegia HP:0001258

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures"

Names the defining feature and establishes that the presentation is complicated rather than pure.

Nervous System 9

Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy"

Names hyperreflexia, the upper-motor-neuron sign accompanying the spasticity.

Motor Delay HP:0001270

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"delayed motor development, regression of motor skills"

Names the delay, and in the same clause the regression that follows it - the two are curated separately because they are different claims about the course.

Developmental Regression HP:0002376

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"delayed motor development, regression of motor skills, impaired intellectual development"

States the regression explicitly rather than leaving it inferred from a progressive course.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"impaired intellectual development, poor speech and language acquisition"

Names impaired intellectual development among the reported features.

Delayed Speech and Language Development HP:0000750

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"poor speech and language acquisition"

Names the speech and language deficit.

Seizure HP:0001250

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures"

Names seizures among the features of the severely affected patient.

Cerebral Hypomyelination HP:0006808

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem"

The imaging finding that grounds the tissue-level node above in human patients rather than only in the mouse.

Cerebellar Atrophy HP:0001272

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem"

States the cerebellar predominance of the atrophy and that it follows the hypomyelination.

Cerebral Atrophy HP:0002059

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"white matter abnormalities and cerebral and cerebellar atrophy"

Names cerebral atrophy alongside the cerebellar atrophy already curated, from the combined spectrum across reported families.

Other 2

Lower Limb Spasticity HP:0002061

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy"

Names spasticity among the features reported across families.

Cerebral Visual Impairment HP:0100704

Show evidence (1 reference)

PMID:29500230 SUPPORT Human Clinical

"severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures"

Graded PARTIAL because the source states blindness without localising it, while the bound term asserts a cerebral origin.

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Genetic Associations

1

SELENOI

Gene: SELENOI hgnc:29361 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36942482 SUPPORT Human Clinical

"homozygous, synonymous variant in the SELENOI gene"

Establishes the allele class that motivates the note above.

PMID:36942482 SUPPORT Human Clinical

"disrupt normal splicing and lead to skipping of exon 2"

Gives the mechanism by which a synonymous change is pathogenic, which is the reason it cannot be filtered out on protein consequence.

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External Assertions

1

OMIM spastic paraplegia 81 record

OMIM disease record OMIM:618768

The OMIM record MONDO:0032905 xrefs. Recorded here because DiseaseMappings carries only ICD-10-CM, ICD-11, MONDO and NCIT slots, so there is nowhere in mappings for an OMIM identity to go.

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Biochemical Markers

1

Fibroblast ethanolamine phosphotransferase activity

Show evidence (3 references)

PMID:28052917 SUPPORT Human Clinical

"in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways"

States why blood PE is a poor diagnostic biomarker despite a genuine enzymatic defect - the compensation is the finding, and it is what sends the assay to fibroblasts.

PMID:29500230 SUPPORT In Vitro

"In vitro EPT activity, as well as the rate of biosynthesis of ethanolamine glycerophospholipids, was markedly reduced in cultures of the patient's skin fibroblasts"

The fibroblast assay this entry names as the informative readout, measured in a patient rather than proposed.

PMID:28052917 SUPPORT Human Clinical

"alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients"

Graded PARTIAL: it establishes that species-level changes are detectable in patients, but the sentence above qualifies how far a blood measurement can be trusted.

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Prevalence

1

Published cases worldwide

Cases In Literature Ultra Rare

Roughly three consanguineous families reported since 2017 (Oman, Israel, India), plus a fourth carrying a homozygous missense variant of uncertain significance. No point prevalence has been estimated and Orphanet lists none. This record states the measure type as a case count rather than converting it into a rate, because there is no denominator to convert against - which is the same reason no phenotype in this entry carries a frequency.

Show evidence (1 reference)

PMID:36942482 SUPPORT Human Clinical

"with only two families reported to date"

The count at the time of that report, which is the order of magnitude this record encodes. It is quoted rather than paraphrased so the figure stays attached to its date.

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Animal Models

1

Nervous-system-restricted Selenoi conditional knockout mouse

Constitutive deletion is embryonic lethal, so the model that exists at all is a conditional one. That constraint is not incidental: it means the model can speak to what SELENOI loss does to the nervous system, and cannot speak to what it does anywhere else.

Species

Mouse

Genotype

Nervous-system-restricted Selenoi conditional knockout

Publication

PMID:38582453

Pathograph links

Lipid Peroxidation and Failed Oligodendrocyte Maturation recapitulates fidelity: high The cellular mechanism of this node is established in this model rather than in human tissue.

Limitations: The measurements are murine. No human tissue equivalent exists for the peroxidation or the maturation arrest.

Readouts

Lipid peroxidation in oligodendrocyte-lineage cells

Direction: INCREASED

Interpretation: The oxidative injury predicted by loss of the sacrificial antioxidant, measured in the lineage that myelinates.

Show evidence (1 reference)

PMID:38582453 SUPPORT Model Organism

"increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro"

Reports the measurement and its direction in both in vivo and in vitro settings.

Show evidence (1 reference)

PMID:38582453 SUPPORT Model Organism

"developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia"

Establishes the model as informative for this disease and states the lethality constraint that forced the conditional design.

Progressive Corticospinal Tract Dysfunction partially recapitulates fidelity: moderate The mouse shows motor deficits, so the motor arm is modelled.

Limitations: Partial rather than full for a reason that matters to this entry: the reported murine assessment covers motor deficits, hypomyelination, gliosis and microcephaly, and is not reported to cover auditory or visual function. The model therefore grounds the motor arm while being silent on the extramotor arm that carries most of the severe-end morbidity in patients - which is exactly what the knowledge gap below asks about. It also cannot represent the intellectual disability and speech impairment that define the human disorder clinically.

Show evidence (1 reference)

PMID:38582453 SUPPORT Model Organism

"motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly"

Lists what the model was shown to reproduce - and, read as a closed list, what it was not assessed for.

{ }

Source YAML

click to show

name: Spastic Paraplegia 81
creation_date: "2026-08-28T17:20:00Z"
category: Mendelian
description: >-
  Spastic paraplegia 81 is an autosomal recessive complicated hereditary spastic
  paraplegia caused by biallelic loss-of-function variants in SELENOI, which
  encodes ethanolamine phosphotransferase 1 (EPT1). SELENOI catalyses the final
  step of the CDP-ethanolamine branch of the Kennedy pathway, condensing
  CDP-ethanolamine with a diacylglycerol or alkyl-acylglycerol to make
  phosphatidylethanolamine and its ether-linked form, plasmenyl-PE. The disease
  is therefore a disorder of ether-lipid homeostasis rather than of a
  motor-neuron-specific protein, and its central lesion is in myelin: the
  ether-linked plasmenyl-PE species that SELENOI makes are required for normal
  myelination and also act as sacrificial antioxidants, so their loss produces
  hypomyelination together with lipid peroxidation in the oligodendrocyte
  lineage. Onset is in infancy, with delayed motor development, subsequent
  regression, progressive lower-limb spasticity and impaired intellectual
  development; the severe end of the reported spectrum adds sensorineural
  deafness, visual loss, seizures, microcephaly and orofacial clefting.
parents:
  - Hereditary Spastic Paraplegia
  - Inborn Error of Metabolism
synonyms:
  - SPG81
  - spastic paraplegia 81, autosomal recessive
  - autosomal recessive spastic paraplegia type 81
  - SELENOI-related hereditary spastic paraplegia
disease_term:
  preferred_term: spastic paraplegia 81, autosomal recessive
  term:
    id: MONDO:0032905
    label: spastic paraplegia 81, autosomal recessive
notes: >-
  Evidence-base caveat, stated up front because it governs the whole entry.
  Roughly three consanguineous families have been reported since 2017, plus a
  fourth carrying a homozygous missense variant of uncertain significance. There
  is no cohort and no natural-history series, so no phenotype in this entry
  carries a frequency value. The problem is the absence of a denominator, not
  the number of families, and a frequency band inferred from "reported in most
  published patients" would be a number no source states.

  Gene identifier correction. The deep-research report committed alongside this
  entry gives the causal gene as HGNC:30396. That identifier is SELENOS, a
  different selenoprotein. SELENOI is hgnc:29361, which is what this entry uses.
  The error is recorded here rather than silently fixed because it is not
  detectable by existence checking - HGNC:30396 resolves to a real gene, so the
  report's own term-validation block passed it - and the next curator reading
  that report will meet the same wrong identifier.

  No treatments section, and the reason rather than the omission. There is no
  disease-modifying therapy; management is symptomatic - antispasticity agents,
  physical, occupational and speech therapy, seizure control, sensory and
  orthopaedic support. That is a curatable fact and would normally be recorded.
  It is not recorded here because none of the four cached references states it:
  all four are molecular or case-level papers, and no management source for this
  disorder was locatable that could be quoted exactly. Asserting a treatment
  list without a citable source is the failure mode this project's evidence
  rules exist to prevent, so the section is absent and this note is the
  substitute. A curator who finds a management reference should add it.

  Scope. Several other hereditary spastic paraplegia entries exist in this
  knowledge base. SPG81 is curated as its own Disease rather than a subtype
  because the lesion is a distinct enzymatic step in a distinct pathway
  (ether-lipid synthesis) rather than a further allele of a shared
  axonal-transport or mitochondrial mechanism, and because the phenotype is
  complicated rather than pure.
external_assertions:
  - name: OMIM spastic paraplegia 81 record
    source: OMIM
    assertion_type: disease_record
    external_id: OMIM:618768
    url: https://omim.org/entry/618768
    description: >-
      The OMIM record MONDO:0032905 xrefs. Recorded here because DiseaseMappings
      carries only ICD-10-CM, ICD-11, MONDO and NCIT slots, so there is nowhere
      in mappings for an OMIM identity to go.
inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      All definitively reported families are consanguineous with homozygous
      variants. Consanguinity is the principal risk factor; no founder allele is
      known and the reported disease alleles are private to each family.
pathophysiology:
  - name: Loss of Ethanolamine Phosphotransferase Activity
    biological_scale: MOLECULAR
    description: >-
      Biallelic SELENOI variants reduce the activity of ethanolamine
      phosphotransferase 1, the enzyme catalysing the final step of the
      CDP-ethanolamine branch of the Kennedy pathway.
    genes:
      - preferred_term: SELENOI
        term:
          id: hgnc:29361
          label: SELENOI
    molecular_functions:
      - preferred_term: ethanolamine phosphotransferase activity
        term:
          id: GO:0004307
          label: ethanolaminephosphotransferase activity
        modifier: DECREASED
    downstream:
      - target: Depletion of Ethanolamine Phospholipids and Plasmenyl-PE
    evidence:
      - reference: PMID:28052917
        reference_title: "A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          dramatically reduces the enzymatic activity of EPT1, thereby hindering
          the final step in phosphatidylethanolamine synthesis
        explanation: >-
          States the enzymatic consequence of the founding family's variant and
          places it at the terminal step of the pathway. Graded IN_VITRO rather
          than HUMAN_CLINICAL: the activity measurement is a heterologous assay
          (the publication is MeSH-indexed to Saccharomyces cerevisiae), not an
          observation in patients. The variant is human; the activity number is
          not.
  - name: Depletion of Ethanolamine Phospholipids and Plasmenyl-PE
    biological_scale: CELLULAR
    description: >-
      Reduced EPT1 activity lowers synthesis of phosphatidylethanolamine and,
      importantly, of its ether-linked plasmenyl form. Plasmenyl-PE is not
      merely a structural lipid: its vinyl-ether bond reacts preferentially with
      oxidants, so the species that is lost is also the one that protects the
      membrane.
    cell_types:
      - preferred_term: oligodendrocyte
        term:
          id: CL:0000128
          label: oligodendrocyte
    biological_processes:
      - preferred_term: phosphatidylethanolamine biosynthetic process
        term:
          id: GO:0006646
          label: phosphatidylethanolamine biosynthetic process
        modifier: DECREASED
    downstream:
      - target: Lipid Peroxidation and Failed Oligodendrocyte Maturation
    evidence:
      - reference: PMID:38582453
        reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          characterized by a vinyl ether bond that preferentially reacts with
          oxidants, thus serves as a sacrificial antioxidant
        explanation: >-
          Supplies the property that makes this depletion damaging rather than
          merely quantitative - the lost lipid is the antioxidant one.
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          most plasmenyl-PE species were significantly decreased in the
          patient's cells, whereas most plasmanylcholine
        explanation: >-
          The direct measurement in patient cells, which is what makes the
          depletion a human finding rather than an inference from the mouse.
          The clause also records the compensatory rise in plasmanyl-PC, so the
          lipid change is a redistribution and not simply a loss.
  - name: Lipid Peroxidation and Failed Oligodendrocyte Maturation
    biological_scale: CELLULAR
    description: >-
      In the nervous-system-restricted mouse model, loss of the sacrificial
      antioxidant is followed by increased lipid peroxidation specifically in
      oligodendrocyte-lineage cells, and those cells fail to mature. This node
      is graded MODEL_ORGANISM throughout: the causal chain from peroxidation to
      arrested maturation has been shown in mouse and in vitro, not in human
      tissue.
    cell_types:
      - preferred_term: oligodendrocyte precursor cell
        term:
          id: CL:0002453
          label: oligodendrocyte precursor cell
    downstream:
      - target: Central Hypomyelination
    evidence:
      - reference: PMID:38582453
        reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          increased lipid peroxidation in oligodendrocyte lineage cells and
          disrupted oligodendrocyte maturation both in vivo and in vitro
        explanation: >-
          Names both halves of this node and states the model systems, which is
          why the node is graded as model evidence rather than human.
  - name: Central Hypomyelination
    biological_scale: TISSUE
    description: >-
      Oligodendrocytes that do not mature do not myelinate. Hypomyelination is
      the imaging finding in affected patients and the neuropathological finding
      in the mouse, and it is followed by atrophy rather than accompanied by it.
    biological_processes:
      - preferred_term: myelination
        term:
          id: GO:0042552
          label: myelination
        modifier: DECREASED
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
      - preferred_term: cerebellum
        term:
          id: UBERON:0002037
          label: cerebellum
      - preferred_term: spinal cord
        term:
          id: UBERON:0002240
          label: spinal cord
    downstream:
      - target: Progressive Corticospinal Tract Dysfunction
      - target: Extramotor Neurodevelopmental Involvement
      - target: Cerebral Hypomyelination
      - target: Cerebellar Atrophy
      - target: Cerebral Atrophy
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Neuroimaging revealed hypomyelination, followed by brain atrophy
          mainly in the cerebellum and brainstem
        explanation: >-
          Human imaging evidence for hypomyelination, and for its temporal
          relation to the atrophy that follows it.
      - reference: PMID:38582453
        reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          a critical role for SELENOI-derived plasmenyl-PE in myelination that
          is of paramount importance for neurodevelopment
        explanation: >-
          States the pathway-to-myelin dependency this node rests on.
  - name: Extramotor Neurodevelopmental Involvement
    biological_scale: ORGANISM
    description: >-
      The features outside the motor system - impaired intellectual development,
      speech delay, seizures, microcephaly, sensorineural deafness and visual
      loss - reported mainly at the severe end of the spectrum.

      This node is deliberately weaker than the motor arm above, and the reason
      is stated rather than hidden by the arrow: these features co-occur with
      the myelin lesion in the reported patients, but no source establishes that
      each follows from it. Sensorineural deafness in particular is a cochlear
      or eighth-nerve phenotype whose relation to central hypomyelination is not
      demonstrated in this disease. The edges below therefore assert
      co-occurrence within a single CNS disorder, not a worked-out causal path,
      and the HUMAN_MODEL_MISMATCH-style gap that would be needed to resolve it
      is recorded in the discussions section.
    downstream:
      - target: Intellectual Disability
      - target: Delayed Speech and Language Development
      - target: Seizure
      - target: Microcephaly
      - target: Sensorineural Hearing Impairment
      - target: Cerebral Visual Impairment
      - target: Cleft Palate
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          sensorineural deafness, blindness, cleft palate, delayed motor
          development, regression of motor skills, impaired intellectual
          development, poor speech and language acquisition, spasticity,
          hyperreflexia, white matter abnormalities and cerebral and cerebellar
          atrophy
        explanation: >-
          Establishes that these features occur together in the reported
          spectrum, which is what this node claims - and, read carefully, is all
          it claims.
  - name: Progressive Corticospinal Tract Dysfunction
    biological_scale: ORGANISM
    description: >-
      The clinical syndrome: infancy-onset delayed motor development followed by
      regression, with progressive lower-limb spasticity and hyperreflexia. The
      node is separated from the tissue-level hypomyelination above because the
      regression is a course, not a lesion.
    downstream:
      - target: Spastic Paraplegia
      - target: Lower Limb Spasticity
      - target: Hyperreflexia
      - target: Developmental Regression
      - target: Motor Delay
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          sensorineural deafness, blindness, cleft palate, delayed motor
          development, regression of motor skills, impaired intellectual
          development, poor speech and language acquisition, spasticity,
          hyperreflexia, white matter abnormalities and cerebral and cerebellar
          atrophy
        explanation: >-
          The combined phenotypic spectrum across reported families, which is
          the source for the motor features on this node and for several
          phenotypes below.
phenotypes:
  - name: Spastic Paraplegia
    category: Neurologic
    phenotype_term:
      preferred_term: Spastic paraplegia
      term:
        id: HP:0001258
        label: Spastic paraplegia
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe complicated hereditary spastic paraplegia,
          sensorineural-deafness, blindness, and seizures
        explanation: >-
          Names the defining feature and establishes that the presentation is
          complicated rather than pure.
  - name: Lower Limb Spasticity
    category: Neurologic
    phenotype_term:
      preferred_term: Lower limb spasticity
      term:
        id: HP:0002061
        label: Lower limb spasticity
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          spasticity, hyperreflexia, white matter abnormalities and cerebral and
          cerebellar atrophy
        explanation: >-
          Names spasticity among the features reported across families.
  - name: Hyperreflexia
    category: Neurologic
    phenotype_term:
      preferred_term: Hyperreflexia
      term:
        id: HP:0001347
        label: Hyperreflexia
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          spasticity, hyperreflexia, white matter abnormalities and cerebral and
          cerebellar atrophy
        explanation: >-
          Names hyperreflexia, the upper-motor-neuron sign accompanying the
          spasticity.
  - name: Motor Delay
    category: Neurologic
    phenotype_term:
      preferred_term: Motor delay
      term:
        id: HP:0001270
        label: Motor delay
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          delayed motor development, regression of motor skills
        explanation: >-
          Names the delay, and in the same clause the regression that follows
          it - the two are curated separately because they are different claims
          about the course.
  - name: Developmental Regression
    category: Neurologic
    phenotype_term:
      preferred_term: Developmental regression
      term:
        id: HP:0002376
        label: Developmental regression
    description: >-
      Motor skills are acquired and then lost. This is what makes the disorder
      neurodegenerative as well as neurodevelopmental, and it is the feature
      that distinguishes the course from a static hypomyelinating disorder.
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          delayed motor development, regression of motor skills, impaired
          intellectual development
        explanation: >-
          States the regression explicitly rather than leaving it inferred from
          a progressive course.
  - name: Intellectual Disability
    category: Neurologic
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          impaired intellectual development, poor speech and language
          acquisition
        explanation: >-
          Names impaired intellectual development among the reported features.
  - name: Delayed Speech and Language Development
    category: Neurologic
    phenotype_term:
      preferred_term: Delayed speech and language development
      term:
        id: HP:0000750
        label: Delayed speech and language development
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          poor speech and language acquisition
        explanation: >-
          Names the speech and language deficit.
  - name: Sensorineural Hearing Impairment
    category: Sensory
    phenotype_term:
      preferred_term: Sensorineural hearing impairment
      term:
        id: HP:0000407
        label: Sensorineural hearing impairment
    description: >-
      Reported at the severe end of the spectrum rather than in every patient.
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe complicated hereditary spastic paraplegia,
          sensorineural-deafness, blindness, and seizures
        explanation: >-
          Names deafness in the severely affected patient described.
  - name: Cerebral Visual Impairment
    category: Sensory
    phenotype_term:
      preferred_term: Cerebral visual impairment
      term:
        id: HP:0100704
        label: Cerebral visual impairment
    description: >-
      The reported visual loss is central rather than ocular. Note the source
      wording is "blindness", which does not by itself localise the lesion; the
      HP term is chosen on the basis that the reported neuroimaging shows
      cerebral rather than retinal pathology, and a curator preferring the
      unlocalised term would be reasonable.
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe complicated hereditary spastic paraplegia,
          sensorineural-deafness, blindness, and seizures
        explanation: >-
          Graded PARTIAL because the source states blindness without localising
          it, while the bound term asserts a cerebral origin.
  - name: Seizure
    category: Neurologic
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe complicated hereditary spastic paraplegia,
          sensorineural-deafness, blindness, and seizures
        explanation: >-
          Names seizures among the features of the severely affected patient.
  - name: Cerebral Hypomyelination
    category: Neurologic
    phenotype_term:
      preferred_term: Cerebral hypomyelination
      term:
        id: HP:0006808
        label: Cerebral hypomyelination
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Neuroimaging revealed hypomyelination, followed by brain atrophy
          mainly in the cerebellum and brainstem
        explanation: >-
          The imaging finding that grounds the tissue-level node above in human
          patients rather than only in the mouse.
  - name: Cerebellar Atrophy
    category: Neurologic
    phenotype_term:
      preferred_term: Cerebellar atrophy
      term:
        id: HP:0001272
        label: Cerebellar atrophy
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Neuroimaging revealed hypomyelination, followed by brain atrophy
          mainly in the cerebellum and brainstem
        explanation: >-
          States the cerebellar predominance of the atrophy and that it follows
          the hypomyelination.
  - name: Microcephaly
    category: Craniofacial
    phenotype_term:
      preferred_term: Microcephaly
      term:
        id: HP:0000252
        label: Microcephaly
    evidence:
      - reference: PMID:38582453
        reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          motor deficits and neuropathology including hypomyelination, elevated
          reactive gliosis, and microcephaly
        explanation: >-
          Graded PARTIAL and MODEL_ORGANISM deliberately: this quote is the
          mouse phenotype. Microcephaly is reported in patients too, but the
          quotable human sources in this entry's cache list it without a
          sentence that isolates it, so the mouse evidence is what is cited and
          the grading says so.
  - name: Cerebral Atrophy
    category: Neurologic
    phenotype_term:
      preferred_term: Cerebral atrophy
      term:
        id: HP:0002059
        label: Cerebral atrophy
      clinical_course: PROGRESSIVE
    description: >-
      Atrophy follows the hypomyelination rather than accompanying it, which is
      why it is curated as a separate phenotype from the hypomyelination above.
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          white matter abnormalities and cerebral and cerebellar atrophy
        explanation: >-
          Names cerebral atrophy alongside the cerebellar atrophy already
          curated, from the combined spectrum across reported families.
  - name: Cleft Palate
    category: Craniofacial
    phenotype_term:
      preferred_term: Cleft palate
      term:
        id: HP:0000175
        label: Cleft palate
    description: >-
      An orofacial clefting phenotype, reported with bifid uvula at the milder
      end of the same spectrum. Its presence is the feature least obviously
      explained by a myelination defect, which is part of what the extramotor
      knowledge gap is about.
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          sensorineural deafness, blindness, cleft palate, delayed motor
          development
        explanation: >-
          Names cleft palate among the reported features.

genetic:
  - name: SELENOI
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    gene_term:
      preferred_term: SELENOI
      term:
        id: hgnc:29361
        label: SELENOI
    notes: >-
      Disease alleles reported to date are private to each consanguineous
      family and act by disrupting splicing or otherwise reducing enzyme
      activity. One is a synonymous change that would be dismissed on protein
      consequence alone: it disrupts splicing and removes exon 2. That is the
      clinically material point in this section - a synonymous variant in
      SELENOI is not automatically benign.

      Constitutive knockout is embryonic lethal in mouse, which implies that
      surviving human genotypes retain partial activity. The entry does not
      claim a genotype-phenotype correlation, because with three families there
      is no basis for one.
    inheritance:
      - name: Autosomal recessive inheritance
        inheritance_term:
          preferred_term: Autosomal recessive inheritance
          term:
            id: HP:0000007
            label: Autosomal recessive inheritance
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          homozygous, synonymous variant in the SELENOI gene
        explanation: >-
          Establishes the allele class that motivates the note above.
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          disrupt normal splicing and lead to skipping of exon 2
        explanation: >-
          Gives the mechanism by which a synonymous change is pathogenic, which
          is the reason it cannot be filtered out on protein consequence.
biochemical:
  - name: Fibroblast ethanolamine phosphotransferase activity
    notes: >-
      The cellular enzyme assay is the informative biochemical readout, and the
      reason is worth recording: blood phosphatidylethanolamine is not, because
      alternate pathways compensate for EPT1 inactivity there.
    evidence:
      - reference: PMID:28052917
        reference_title: "A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          in blood EPT1 inactivity may be compensated for, in part, via
          alternate biochemical pathways
        explanation: >-
          States why blood PE is a poor diagnostic biomarker despite a genuine
          enzymatic defect - the compensation is the finding, and it is what
          sends the assay to fibroblasts.
      - reference: PMID:29500230
        reference_title: "EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In vitro EPT activity, as well as the rate of biosynthesis of
          ethanolamine glycerophospholipids, was markedly reduced in cultures of
          the patient's skin fibroblasts
        explanation: >-
          The fibroblast assay this entry names as the informative readout,
          measured in a patient rather than proposed.
      - reference: PMID:28052917
        reference_title: "A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          alteration to levels of specific phosphatidylethanolamine fatty acyl
          species in patients
        explanation: >-
          Graded PARTIAL: it establishes that species-level changes are
          detectable in patients, but the sentence above qualifies how far a
          blood measurement can be trusted.
discussions:
  - discussion_id: spg81_extramotor_mechanism
    kind: KNOWLEDGE_GAP
    prompt: >-
      Do the extramotor features of SPG81 - deafness, visual loss, seizures and
      microcephaly - follow from the same plasmenyl-PE-dependent myelination
      defect that produces the spastic paraplegia, or from a separate
      consequence of ethanolamine-phospholipid depletion in non-myelinating cell
      types?
    attaches_to:
      - pathophysiology#Extramotor Neurodevelopmental Involvement
    rationale: >-
      The mouse model is nervous-system-restricted and was assessed for motor
      deficits, hypomyelination, gliosis and microcephaly. It is not reported to
      have been assessed for auditory or visual function, so the model that
      grounds the motor arm is silent on the arm that carries most of the
      severe-end morbidity. Meanwhile SELENOI has documented roles outside the
      nervous system entirely, which makes a myelin-only explanation for every
      feature an assumption rather than a finding.

      This matters for more than completeness: if the extramotor features are a
      separate consequence, a therapy that rescued myelination would not be
      expected to address them, and a trial powered on motor endpoints would
      miss that.
prevalence:
  - population: Published cases worldwide
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >-
      Roughly three consanguineous families reported since 2017 (Oman, Israel,
      India), plus a fourth carrying a homozygous missense variant of uncertain
      significance. No point prevalence has been estimated and Orphanet lists
      none. This record states the measure type as a case count rather than
      converting it into a rate, because there is no denominator to convert
      against - which is the same reason no phenotype in this entry carries a
      frequency.
    evidence:
      - reference: PMID:36942482
        reference_title: "A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          with only two families reported to date
        explanation: >-
          The count at the time of that report, which is the order of magnitude
          this record encodes. It is quoted rather than paraphrased so the
          figure stays attached to its date.
animal_models:
  - name: Nervous-system-restricted Selenoi conditional knockout mouse
    species: Mouse
    genotype: Nervous-system-restricted Selenoi conditional knockout
    publication: PMID:38582453
    description: >-
      Constitutive deletion is embryonic lethal, so the model that exists at all
      is a conditional one. That constraint is not incidental: it means the
      model can speak to what SELENOI loss does to the nervous system, and
      cannot speak to what it does anywhere else.
    modeled_mechanisms:
      - target: Lipid Peroxidation and Failed Oligodendrocyte Maturation
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          The cellular mechanism of this node is established in this model
          rather than in human tissue.
        limitations: >-
          The measurements are murine. No human tissue equivalent exists for the
          peroxidation or the maturation arrest.
        readouts:
          - name: Lipid peroxidation in oligodendrocyte-lineage cells
            target: Lipid Peroxidation and Failed Oligodendrocyte Maturation
            direction: INCREASED
            interpretation: >-
              The oxidative injury predicted by loss of the sacrificial
              antioxidant, measured in the lineage that myelinates.
            evidence:
              - reference: PMID:38582453
                reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  increased lipid peroxidation in oligodendrocyte lineage cells
                  and disrupted oligodendrocyte maturation both in vivo and in
                  vitro
                explanation: >-
                  Reports the measurement and its direction in both in vivo and
                  in vitro settings.
        evidence:
          - reference: PMID:38582453
            reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              developed a mouse model of nervous system-restricted SELENOI
              deficiency that circumvents embryonic lethality caused by
              constitutive deletion and recapitulates phenotypic features of
              hereditary spastic paraplegia
            explanation: >-
              Establishes the model as informative for this disease and states
              the lethality constraint that forced the conditional design.
      - target: Progressive Corticospinal Tract Dysfunction
        relationship: PARTIALLY_RECAPITULATES
        fidelity: MODERATE
        description: >-
          The mouse shows motor deficits, so the motor arm is modelled.
        limitations: >-
          Partial rather than full for a reason that matters to this entry: the
          reported murine assessment covers motor deficits, hypomyelination,
          gliosis and microcephaly, and is not reported to cover auditory or
          visual function. The model therefore grounds the motor arm while being
          silent on the extramotor arm that carries most of the severe-end
          morbidity in patients - which is exactly what the knowledge gap below
          asks about. It also cannot represent the intellectual disability and
          speech impairment that define the human disorder clinically.
        evidence:
          - reference: PMID:38582453
            reference_title: "Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              motor deficits and neuropathology including hypomyelination,
              elevated reactive gliosis, and microcephaly
            explanation: >-
              Lists what the model was shown to reproduce - and, read as a
              closed list, what it was not assessed for.

📚

References & Deep Research

Deep Research

1

OpenScientist ▸

Spastic Paraplegia 81 (SPG81): A Comprehensive Disease Characteristics Report

openscientist-autonomous 12 citations 2026-08-28T17:11:38.531189

Spastic Paraplegia 81 (SPG81): A Comprehensive Disease Characteristics Report

Disease: Spastic Paraplegia 81 (SPG81) OMIM: #618768 | MONDO: 0032905 | UMLS: C5394033 Causal gene: SELENOI (EPT1) | Inheritance: Autosomal recessive | Category: Mendelian

Summary

Spastic Paraplegia 81 (SPG81) is an ultra-rare, autosomal recessive complicated hereditary spastic paraplegia (HSP) caused by biallelic loss-of-function variants in SELENOI (also known as EPT1 or SELI). SELENOI encodes ethanolamine phosphotransferase 1, the enzyme that catalyzes the final step of the CDP-ethanolamine branch of the Kennedy pathway, converting CDP-ethanolamine and diacylglycerol (or alkyl-acylglycerol) into phosphatidylethanolamine (PE) and its ether-linked form plasmenyl-PE (a plasmalogen). These ethanolamine phospholipids are indispensable membrane constituents, and plasmenyl-PE in particular is critical for myelination and serves as a sacrificial antioxidant in oligodendrocytes.

Loss of SELENOI activity therefore produces a neurodevelopmental disorder characterized by infancy-onset, progressive lower-limb spasticity, delayed motor development with subsequent motor regression, impaired intellectual development, and hypomyelination with brain and cerebellar atrophy. Severely affected individuals additionally develop sensorineural deafness, cortical/ocular visual loss, seizures, microcephaly, and orofacial anomalies (bifid uvula/cleft palate). Mechanistically, a nervous-system–restricted Selenoi-deficient mouse recapitulates the human phenotype—hypomyelination, reactive gliosis, microcephaly, and motor deficits—driven by increased lipid peroxidation and impaired maturation of oligodendrocyte-lineage cells. The disease thus represents a disorder of ether-lipid/plasmalogen homeostasis affecting central nervous system myelination.

SPG81 is exceedingly rare: only about three definitive consanguineous families (from Oman, Israel, and India) have been reported since 2017, plus a fourth candidate family (Korea) carrying a homozygous missense variant of uncertain significance. There is no disease-specific or disease-modifying therapy; management is entirely supportive (antispasticity agents, physical/occupational/speech therapy, seizure control, and sensory/orthopedic support). SELENOI also has pleiotropic roles beyond the CNS—in T-cell activation and Th17 differentiation, adipocyte differentiation, tumorigenesis, embryogenesis, and liver physiology—and emerging data link SELENOI/PE dysregulation to motor-neuron degeneration and TDP-43 pathology in ALS, broadening the disease relevance of this pathway.

Key Findings

Finding 1 — SPG81 is caused by biallelic loss-of-function variants in SELENOI (EPT1), disrupting the Kennedy pathway

SPG81 arises from biallelic (homozygous) loss-of-function variants in SELENOI, the gene encoding ethanolamine phosphotransferase 1 (EPT1). The founding report by Ahmed et al. (2017, Brain) identified a homozygous SELENOI/EPT1 variant in a consanguineous family with complicated autosomal recessive HSP and demonstrated that the variant "dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis." SELENOI catalyzes the third and final reaction of the CDP-ethanolamine branch of the Kennedy pathway (CDP-ethanolamine + diacylglycerol/alkyl-acylglycerol → PE / plasmanyl-PE).

Disease identifiers: OMIM #618768; gene SELENOI (HGNC:30396; aliases EPT1, SELI); locus chromosome 2p23.3; NCBI Gene 85465; Ensembl ENSG00000112782; UniProt Q9C0D9.

PMID: 28052917: "associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine."

PMID: 28052917: "the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis."

PMID: 27645994: "SELENOI (selenoprotein I, SELI, EPT1)" — confirming gene nomenclature and synonyms.

This finding establishes the causal gene, its enzymatic role, and loss-of-function as the molecular disease mechanism.

Finding 2 — SELENOI-derived plasmenyl-PE is essential for myelination; deficiency causes hypomyelination, lipid peroxidation, and microcephaly

The central mechanistic insight is that SELENOI-derived plasmenyl-PE (a plasmalogen) is essential for myelination, and its deficiency produces the neuropathology of SPG81. Nunes et al. (2024) generated a nervous-system–restricted Selenoi-deficient mouse (necessary because constitutive knockout is embryonic lethal) that faithfully recapitulated HSP features. Brain lipid composition alterations "coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly," with "increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro." Plasmenyl-PE contains a vinyl-ether bond that "preferentially reacts with oxidants" and thus acts as a sacrificial antioxidant, protecting membranes from peroxidative damage.

PMID: 38582453: "motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly."

PMID: 38582453: "increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro."

PMID: 38582453: "a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment."

PMID: 38582453: "characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant."

Complementary human/in-vitro work by Horibata et al. (2018) established that EPT1/SELENOI is critical for neural development and maintenance of plasmalogens. Together these define the cellular mechanism: oligodendrocyte dysfunction and oxidative membrane damage → hypomyelination → progressive neurodegeneration.

Finding 3 — SELENOI is a bifunctional selenoprotein with roles beyond the CNS

SELENOI is one of the 25 human selenoproteins and is unusual in being a bifunctional enzyme. Li et al. (2023) describe two distinct biochemical functions—"PE regulation and antioxidant potential"—conferred respectively by its N-terminal CDP-alcohol phosphotransferase domain and its C-terminal selenocysteine (Sec) residue. This dual functionality underlies its involvement in "neurological diseases (especially hereditary spastic paraplegia), T cell activation, tumorigenesis, and adipocyte differentiation." The essentiality of the gene is underscored by embryonic lethality of the constitutive knockout, meaning only partial (hypomorphic) loss of function is compatible with survival, consistent with SPG81 being caused by residual-activity alleles.

PMID: 36963501: "neurological diseases (especially hereditary spastic paraplegia), T cell activation, tumorigenesis, and adipocyte differentiation."

PMID: 36007576: "Deletion of SELENOI in mice is embryonic lethal."

PMID: 40107406: "how Selenoi loss-of-function affects embryogenesis, neurodevelopment, the immune system and liver physiology."

Finding 4 — Clinical phenotype: infancy-onset complicated HSP with spasticity, intellectual disability, and sensory/neuroimaging abnormalities

Across the reported families, SPG81 presents as an infancy-onset complicated HSP. Per OMIM #618768 / MONDO:0032905, it is an "autosomal recessive neurologic disorder with onset in infancy... delayed motor development, progressive spasticity... impaired intellectual development and speech delay," with additional features in some patients including bifid uvula, microcephaly, seizures, and variable ocular anomalies. The most severely affected patient reported had cortical visual loss, sensorineural deafness, and achievement of almost no developmental milestones.

Sarma et al. (2023) summarize the combined phenotypic spectrum: "sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy." Horibata et al. (2018) described a patient with "severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures. Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem."

PMID: 29500230: "severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures. Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem."

PMID: 36942482: "sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy."

Suggested HPO terms: Spastic paraplegia (HP:0001258), Lower limb spasticity (HP:0002061), Hyperreflexia (HP:0001347), Intellectual disability (HP:0001249), Motor delay (HP:0001270), Developmental regression (HP:0002376), Sensorineural hearing impairment (HP:0000407), Cortical visual impairment (HP:0100704), Seizure (HP:0001250), Microcephaly (HP:0000252), Cerebellar atrophy (HP:0001272), Cerebral atrophy (HP:0002059), Cerebral hypomyelination (HP:0006808), Bifid uvula (HP:0000193), Cleft palate (HP:0000175), Speech delay (HP:0000750).

Finding 5 — Variant spectrum: rare biallelic splice-disrupting/LOF SELENOI variants in consanguineous families

All definitive families are autosomal recessive with homozygous variants. Sarma et al. (2023) noted "only two families reported to date" at the time and identified "a homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys))" that was found to "disrupt normal splicing and lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids [NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)]." Horibata (2018) identified a novel exon-skipping mutation, and Ahmed (2017) identified a variant that dramatically reduces EPT1 activity. Disease-causing alleles are private/family-specific; SELENOI has ~101 ClinVar submissions dominated by VUS/benign population variants.

PMID: 36942482: "homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys))."

PMID: 36942482: "disrupt normal splicing and lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids."

PMID: 36942482: "with only two families reported to date."

Finding 6 — Lipidomic biomarker signature: reduced polyunsaturated PE and plasmenyl-PE with compensatory shifts

Horibata et al. (2018) quantified phospholipids by LC-MS/MS in patient fibroblasts and EPT1-knockout HeLa cells, finding markedly reduced in-vitro EPT activity, decreased biosynthesis of ethanolamine glycerophospholipids, reduced polyunsaturated PE species (38:6, 38:4, 40:6, 40:5, 40:4), and significant decreases in most plasmenyl-PE species, while most plasmanyl-PC species increased (a compensatory shift). Ahmed et al. (2017) found in patient blood "alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients," although "in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways"—explaining why blood PE is a poor diagnostic biomarker despite the enzymatic defect. A cellular (fibroblast) EPT activity assay and tissue lipidomics are the most informative biochemical readouts.

PMID: 28052917: "alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients."

PMID: 28052917: "in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways."

Finding 7 — SELENOI-dependent ethanolamine phospholipid synthesis drives T-cell metabolic reprogramming and Th17 differentiation (immune pleiotropy)

Beyond the CNS, SELENOI has immunologic roles. Ma et al. (2021) showed that SELENOI knockout in mouse T cells led to "reduced de novo synthesis of PE and plasmenyl PE during activation and impaired proliferation," with reduced AMPK activation, ATP accumulation, and reduced GPI-anchor synthesis/attachment. Ma et al. (2022) demonstrated that SELENOI KO "skewed differentiation away from pathogenic Th17 cells" toward tolerogenic phenotypes (Foxp3+/IL-10+), and that T-cell-specific KO mice in the EAE autoimmune model showed "diminished clinical symptoms, reduced CNS pathology and decreased T cell infiltration." These immune roles are relevant for understanding the broader biology of the gene, though their contribution to the SPG81 neurologic phenotype is not established.

PMID: 33484950: "reduced de novo synthesis of PE and plasmenyl PE during activation and impaired proliferation."

PMID: 35916034: "skewed differentiation away from pathogenic Th17 cells."

PMID: 35916034: "diminished clinical symptoms, reduced CNS pathology and decreased T cell infiltration."

Finding 8 — Model organisms: constitutive KO embryonic lethal; nervous-system conditional KO recapitulates HSP; cellular models available

The mouse ortholog is Selenoi (Mus musculus, NCBI Taxon 10090). Constitutive/global knockout is embryonic lethal, so faithful modeling required conditional (nervous-system–restricted) knockout, which recapitulates SPG81 features. Cellular models include patient-derived skin fibroblasts and EPT1-KO HeLa cells, both reproducing the lipid defect.

PMID: 38582453: "developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia."

PMID: 36007576: "Deletion of SELENOI in mice is embryonic lethal."

PMID: 40107406: "global and conditional knockout (KO) of the Selenoi gene in mice."

Finding 9 — Epidemiology, prognosis, and management

SPG81 is ultra-rare: fewer than ~10 patients from 3 consanguineous families (Oman, Israel, India) have been published since 2017; prevalence/incidence are not formally estimated (Orphanet lists no point prevalence). Inheritance is autosomal recessive; both sexes are affected; consanguinity is the principal risk factor; there is no known founder allele, and carrier frequency for pathogenic alleles is presumably very low (SELENOI LOF is depleted in gnomAD). Prognosis is poor: infancy onset, progressive course with motor regression, and severe neurodevelopmental disability; the severe end of the spectrum features near-absent developmental milestones, blindness, and deafness. No cure or disease-modifying therapy exists; management is supportive/symptomatic (antispasticity agents such as baclofen/tizanidine, physical/occupational/speech therapy, antiepileptics, sensory aids, nutritional and orthopedic support). Genetic counseling, carrier testing, and prenatal/preimplantation genetic testing are indicated for at-risk consanguineous families once the familial variant is known.

PMID: 36942482: "recently identified, rare autosomal recessive disease, caused by biallelic pathogenic variants in the SELENOI gene."

PMID: 29500230: "severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures."

Finding 10 — Fourth candidate family expands variant spectrum to a homozygous missense VUS (p.Pro266Leu)

Lee et al. (2026, Korea) reported a consanguineous family of six siblings; the index patient and a younger brother carried a homozygous SELENOI c.797C>T (p.Pro266Leu) variant of uncertain significance, interpreted in the context of an SPG81-like phenotype (significant lower-limb weakness, spasticity, developmental delay). Notably, other siblings' phenotypes were explained by different genes (LAMA1 p.Gln1527Ter → Poretti-Boltshauser syndrome; a de novo SATB2 VUS), illustrating intrafamilial genetic heterogeneity. This is the first reported homozygous SELENOI missense candidate variant, contrasting with the splice-affecting/in-frame-deletion alleles of the three prior definitive families.

PMID: 42446524: "We report a family of six siblings born to asymptomatic consanguineous parents, in which three siblings exhibited overlapping spastic paraplegia phenotypes with developmental delay."

Finding 11 — SELENOI/PE dysregulation links to motor-neuron degeneration and TDP-43 pathology in ALS

Isik et al. (2025) found that in human ALS brain, "PE levels were significantly decreased in the disease-affected motor cortex of ALS compared to controls and were inversely associated with disease duration," while PE was unaltered in the disease-unaffected cerebellum. "SELENOI expression was dysregulated only in the motor cortex," the SELENOI–TDP-43 correlation was lost, and "knockdown of SELENOI expression in neuronal cells caused an upregulation of TDP-43 expression." The authors explicitly note that "SELENOI is important in motor neuron development and function, as demonstrated in hereditary spastic paraplegia," linking the SPG81 pathway to broader motor-neuron disease.

PMID: 41002422: "PE levels were significantly decreased in the disease-affected motor cortex of ALS compared to controls and were inversely associated with disease duration."

PMID: 41002422: "SELENOI is important in motor neuron development and function, as demonstrated in hereditary spastic paraplegia."

Mechanistic Model / Interpretation

SPG81 is fundamentally a disorder of ether-lipid (plasmalogen) homeostasis affecting CNS myelination. The causal chain runs from a genetic defect in a single enzymatic step to a progressive neurodevelopmental/neurodegenerative phenotype:

Biallelic LOF SELENOI (EPT1)  [chr 2p23.3]
  │
  ▼
Reduced ethanolamine phosphotransferase activity
(final step of CDP-ethanolamine / Kennedy pathway)
  │
  ▼
↓ Phosphatidylethanolamine (PE)  &  ↓↓ plasmenyl-PE (plasmalogen)
   (compensatory ↑ plasmanyl-PC in some tissues)
  │
  ├──────────────► Loss of "sacrificial antioxidant" (vinyl-ether bond)
  │                          │
  ▼                          ▼
Impaired oligodendrocyte      ↑ Lipid peroxidation in
maturation                    oligodendrocyte-lineage cells
  │                          │
  └──────────┬───────────────┘
     ▼
HYPOMYELINATION + reactive gliosis + microcephaly
     │
     ▼
   Progressive spasticity, motor regression, intellectual
   disability, sensorineural deafness, visual loss, seizures,
   cerebral/cerebellar atrophy

Upstream vs downstream: The upstream trigger is the enzymatic deficiency and consequent depletion of ethanolamine phospholipids (especially plasmenyl-PE). Downstream consequences are oligodendrocyte-lineage lipid peroxidation and maturation failure, producing hypomyelination and, over time, neurodegeneration/atrophy.

Cell types and processes involved: Oligodendrocytes/oligodendrocyte precursor cells (CL:0000128 oligodendrocyte; CL:0002453 oligodendrocyte precursor cell) are the key effector cells; upper motor neurons and corticospinal tract axons (long descending tracts) manifest the classic HSP length-dependent "dying-back" degeneration. Suggested GO terms: phosphatidylethanolamine biosynthetic process (GO:0006646), CDP-ethanolamine pathway (GO:0006657), ether lipid biosynthetic process (GO:0008611), myelination (GO:0042552), oligodendrocyte differentiation (GO:0048709), response to oxidative stress (GO:0006979), ethanolamine phosphotransferase activity (GO:0004307). Cellular components: endoplasmic reticulum membrane (GO:0005789), myelin sheath (GO:0043209).

Anatomical structures (UBERON): brain (UBERON:0000955), cerebellum (UBERON:0002037), brainstem (UBERON:0002298), cerebral white matter (UBERON:0002316), corticospinal tract (UBERON:0005425), spinal cord (UBERON:0002240). Body system: central nervous system (UBERON:0001017). Lateralization is bilateral and symmetric, as typical of HSP.

CHEBI entities: phosphatidylethanolamine (CHEBI:16038), plasmenyl-ethanolamine/plasmalogen (CHEBI:52590), CDP-ethanolamine (CHEBI:57876), selenocysteine (CHEBI:16633).

Level	Structure/process affected	Ontology suggestion
Organ	Brain, cerebellum, brainstem	UBERON:0000955, 0002037, 0002298
System	Central nervous system (corticospinal tracts)	UBERON:0001017, 0005425
Tissue	Cerebral/cerebellar white matter (myelin)	UBERON:0002316
Cell	Oligodendrocytes, OPCs; upper motor neurons	CL:0000128, CL:0002453
Subcellular	ER membrane; myelin sheath	GO:0005789, GO:0043209
Molecule	↓PE, ↓plasmenyl-PE; ↑lipid peroxidation	CHEBI:16038, 52590

Evidence Base

PMID	Title (abbrev.)	Role in this report	Evidence type
28052917	A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis	Founding paper: causal gene, LOF mechanism, blood PE alterations	Human clinical + biochemical
29500230	EPT1 (selenoprotein I) is critical for neural development and plasmalogen maintenance	Severe phenotype, neuroimaging, fibroblast/HeLa lipidomics	Human clinical + in vitro
36942482	A novel homozygous synonymous splicing variant in SELENOI causes SPG81	Third family; exact variant nomenclature; splice mechanism; rarity	Human clinical + molecular
38582453	Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination	Conditional-KO mouse recapitulates HSP; plasmenyl-PE/myelination mechanism	Model organism
36007576	Selenoprotein I (Selenoi) as a critical enzyme in the CNS	Embryonic lethality of global KO	Model organism / review
36963501	Biology and Roles in Diseases of Selenoprotein I	Bifunctionality; pleiotropic disease roles	Review
40107406	Insights from selenoprotein I mouse models	Multi-organ roles from KO models	Review
27645994	Selenoprotein Gene Nomenclature	Confirms SELENOI = SELI = EPT1	Reference
33484950	Ethanolamine phospholipid synthesis via SELENOI in T-cell activation	Immune role; PE/plasmenyl-PE in T cells	Model organism / in vitro
34681834	Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation	Review of immune metabolic reprogramming	Review
35916034	SELENOI deficiency in T cells promotes tolerance, decreases Th17 pathology	Th17/EAE immune findings	Model organism
42446524	HSP in three siblings with distinct genetic mutations	Fourth candidate family; missense VUS; intrafamilial heterogeneity	Human clinical
41002422	Dysregulation of SELENOI associated with TDP-43 neuropathology in ALS	Broader motor-neuron disease relevance	Human + in vitro
32142958	Transcriptional status of selenoproteins in skin cancer cell lines	SELENOI upregulation in BRAF/NRAS-mutant melanoma (tumor pleiotropy)	In vitro / computational

Coherence of evidence: Human genetic/clinical reports (28052917, 29500230, 36942482, 42446524) converge on biallelic SELENOI LOF causing complicated HSP. The mouse conditional-KO study (38582453) provides the definitive mechanistic bridge—directly demonstrating that plasmenyl-PE loss causes hypomyelination via oligodendrocyte lipid peroxidation—and no study contradicts this model. The ALS study (41002422) and immune studies (33484950, 35916034) extend the pathway's relevance without challenging the core SPG81 mechanism.

Section-by-Section Data Compilation

1. Disease Information

Complicated autosomal recessive HSP with infancy onset. Identifiers: OMIM #618768; MONDO:0032905; UMLS C5394033; gene SELENOI (HGNC:30396). Synonyms: SPG81; spastic paraplegia 81, autosomal recessive; SELENOI/EPT1-related HSP. Source type: aggregated disease-level resources (OMIM, Orphanet) plus individual case reports; no EHR/registry data.

2. Etiology

Causal factor: genetic (biallelic LOF SELENOI). Genetic risk factor: homozygous pathogenic SELENOI alleles. Environmental risk factor: none identified; consanguinity is the dominant risk factor (all definitive families are consanguineous). Protective factors: none characterized. Gene–environment interactions: none documented. It is a monogenic Mendelian disorder.

3. Phenotypes

See Finding 4 and HPO term list. Onset: infancy (congenital/pediatric). Severity: variable but generally severe; progression: progressive with motor regression. Core features (spasticity, hyperreflexia, motor delay, intellectual disability) appear consistent across families; sensory (deafness, blindness), seizures, microcephaly, and orofacial anomalies are variable. Quality of life is severely impacted, with loss of ambulation and profound developmental disability at the severe end.

4. Genetic/Molecular Information

Causal gene: SELENOI (EPT1), 2p23.3, NM_033505.4. Variant types: splice-disrupting synonymous (c.126G>A → exon 2 skipping → p.Tyr20_Lys42del), exon-skipping, activity-reducing alleles; plus a candidate missense (c.797C>T, p.Pro266Leu, VUS). Classification: pathogenic/likely pathogenic in definitive families; VUS for the missense candidate. Origin: germline. Functional consequence: loss of function (reduced enzyme activity). Allele frequency: private/family-specific; LOF depleted in gnomAD. Modifier/epigenetic/chromosomal: none reported.

5. Environmental Information

No environmental, lifestyle, or infectious contributors. Purely genetic.

6. Mechanism / Pathophysiology

See Mechanistic Model. Pathway: CDP-ethanolamine branch of the Kennedy pathway (KEGG glycerophospholipid metabolism). Cellular processes: oligodendrocyte maturation failure, lipid peroxidation/oxidative stress, myelination defect. Protein dysfunction: loss of enzyme activity. Metabolic changes: ↓PE, ↓plasmenyl-PE. Immune involvement: pathway-level (T-cell PE synthesis, Th17) but not part of the SPG81 clinical picture. Transcriptomic/proteomic profiling of patient CNS tissue is not available.

7. Anatomical Structures Affected

See table in Mechanistic Model. Primary: CNS white matter/myelin, corticospinal tracts, cerebellum, brainstem. Secondary: sensory systems (auditory, visual). Bilateral, symmetric.

8. Temporal Development

Onset: infancy, insidious/chronic. Course: progressive with motor regression; chronic lifelong. No remission. Critical period likely the early postnatal myelination window.

9. Inheritance and Population

Autosomal recessive; consanguinity-driven; both sexes; ultra-rare (~3 definitive families, <10 patients); no founder effect; carrier frequency very low; penetrance appears complete in reported homozygotes; expressivity variable (severity ranges from moderate to profound).

10. Diagnostics

Genetic testing is definitive: WES/WGS or HSP gene panels including SELENOI; single-gene/familial variant testing once identified. Careful splice-variant interpretation is needed (synonymous variants can be pathogenic via splicing). Biochemical: fibroblast EPT activity assay and lipidomics (↓plasmenyl-PE) are supportive; blood PE is unreliable due to compensation. Imaging: MRI shows hypomyelination, cerebral/cerebellar atrophy. Differential diagnosis: other complicated HSPs, hypomyelinating leukodystrophies, peroxisomal plasmalogen-biosynthesis disorders (rhizomelic chondrodysplasia punctata), and other Kennedy-pathway/phospholipid disorders.

11. Outcome/Prognosis

Poor; progressive disability, motor regression, severe neurodevelopmental impairment; severe cases with blindness, deafness, near-absent milestones. No formal survival data. No disease-specific prognostic biomarkers established; earlier/more severe presentation and severe hypomyelination suggest worse outcome.

12. Treatment

No disease-specific/disease-modifying therapy. Supportive: antispasticity agents (baclofen, tizanidine, botulinum toxin), physical/occupational/speech therapy, antiepileptic drugs, hearing/visual aids, nutritional and orthopedic support. No pharmacogenomic, gene, cell, or RNA therapy exists. Theoretical/experimental directions (plasmalogen replacement, antioxidants) are unproven for SPG81. Suggested NCIT terms: Baclofen (C376), Physical Therapy (C15368), Occupational Therapy (C15218), Supportive Care (C15417).

13. Prevention

Primary prevention via genetic counseling for consanguineous families, carrier testing, and prenatal/preimplantation genetic testing once the familial variant is known. No population screening (ultra-rare). No immunization or behavioral prevention applicable.

14. Other Species / Natural Disease

Mouse ortholog Selenoi (NCBI Taxon 10090). No naturally occurring animal disease reported (no OMIA entry). Gene and pathway are evolutionarily conserved. Not zoonotic.

15. Model Organisms

Mouse: constitutive KO embryonic lethal; nervous-system–restricted conditional KO recapitulates HSP (hypomyelination, gliosis, microcephaly, motor deficits); T-cell-specific conditional KO for immune studies. Cellular: patient skin fibroblasts; EPT1-KO HeLa cells reproduce the lipid defect. Phenotype recapitulation of the neural conditional KO is high. Limitation: no model captures the full multi-sensory human phenotype; global-KO lethality prevents whole-organism study.

Limitations and Knowledge Gaps

Extreme rarity: Only ~3 definitive families (plus one candidate) exist, limiting genotype–phenotype correlation, penetrance/expressivity estimates, and natural-history data. No prevalence/incidence figures exist.
Missense candidate uncertain: The p.Pro266Leu allele (Lee 2026) remains a VUS; functional validation is lacking, and the family showed genetic heterogeneity, so SPG81 causation is not confirmed for that variant.
Biomarker limitations: Blood PE is compensated and unreliable; the most sensitive biochemical assays require patient fibroblasts, limiting non-invasive diagnosis.
No human CNS omics: Transcriptomic/proteomic/metabolomic profiling of patient brain tissue is unavailable; mechanistic detail derives largely from mouse and cell models.
No therapies tested: No preclinical or clinical therapeutic studies specific to SPG81; whether plasmalogen supplementation or antioxidants could help is untested.
Citation verification caveats: A few supporting snippets were flagged during curation (e.g., portions of PMID 29500230, 35916034 quotes); the core claims are corroborated across multiple sources, but exact-quote fidelity should be re-verified before database ingestion.

Proposed Follow-up Experiments / Actions

Functional validation of p.Pro266Leu: Express the missense variant in an EPT1-null cell system and measure ethanolamine phosphotransferase activity and plasmenyl-PE synthesis to resolve its VUS status.
International case aggregation: Use GeneMatcher/Matchmaker Exchange to identify additional families, enabling genotype–phenotype correlation and natural-history characterization.
Non-invasive biomarker development: Systematic plasma/CSF lipidomics (plasmalogen panels) across patients and carriers to establish a reliable diagnostic/monitoring biomarker.
Therapeutic proof-of-concept in the conditional-KO mouse: Test plasmalogen/ether-lipid precursor supplementation (e.g., alkyl-glycerols) and lipophilic antioxidants for rescue of hypomyelination and motor deficits.
iPSC-derived oligodendrocyte/organoid models: Generate patient iPSC-derived oligodendrocytes and cerebral organoids to study human oligodendrocyte maturation, lipid peroxidation, and candidate therapeutics.
Cross-disease pathway study: Given the ALS link (PMID 41002422), examine whether modulating SELENOI/PE affects TDP-43 handling in motor neurons—potentially uncovering shared therapeutic targets across SPG81 and motor-neuron disease.

Report compiled from 11 confirmed findings and 14 reviewed papers over a 5-iteration autonomous investigation. Evidence types span human clinical/genetic reports, model-organism (mouse conditional KO) studies, in-vitro/cellular assays, and computational/transcriptomic analyses.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	14
On topic	8
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	40
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	0
Terms whose name is worth a second look	1

Terms whose name is worth a second look

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

UBERON:0002316 (2 mentions) - the report calls it "Cerebral/cerebellar white matter (myelin)"; UBERON calls it white matter, and lists "neuronal white matter" among its other names

39 of 40 terms resolved to a current term; the rest could not be looked up either way.

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Biochemical Markers

Prevalence

Animal Models

Source YAML

References & Deep Research

Deep Research

Spastic Paraplegia 81 (SPG81): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — SPG81 is caused by biallelic loss-of-function variants in SELENOI (EPT1), disrupting the Kennedy pathway

Finding 2 — SELENOI-derived plasmenyl-PE is essential for myelination; deficiency causes hypomyelination, lipid peroxidation, and microcephaly

Finding 3 — SELENOI is a bifunctional selenoprotein with roles beyond the CNS

Finding 4 — Clinical phenotype: infancy-onset complicated HSP with spasticity, intellectual disability, and sensory/neuroimaging abnormalities

Finding 5 — Variant spectrum: rare biallelic splice-disrupting/LOF SELENOI variants in consanguineous families

Finding 6 — Lipidomic biomarker signature: reduced polyunsaturated PE and plasmenyl-PE with compensatory shifts

Finding 7 — SELENOI-dependent ethanolamine phospholipid synthesis drives T-cell metabolic reprogramming and Th17 differentiation (immune pleiotropy)

Finding 8 — Model organisms: constitutive KO embryonic lethal; nervous-system conditional KO recapitulates HSP; cellular models available

Finding 9 — Epidemiology, prognosis, and management

Finding 10 — Fourth candidate family expands variant spectrum to a homozygous missense VUS (p.Pro266Leu)

Finding 11 — SELENOI/PE dysregulation links to motor-neuron degeneration and TDP-43 pathology in ALS

Mechanistic Model / Interpretation

Evidence Base

Section-by-Section Data Compilation

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms whose name is worth a second look