SEPSECS Deficiency

Metabolic Disorder Pathograph 4 Show in embeddings browser Selenoprotein Biosynthesis Disorder Trace Element Metabolism Disorder

SEPSECS deficiency is an autosomal recessive selenocysteine biosynthesis disorder caused by biallelic SEPSECS variants. SEPSECS (O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase) catalyzes the final conversion of Sep-tRNA(Sec) to Sec-tRNA(Sec), the only route to human selenoprotein generation. Disruption of this step produces a severe neurodevelopmental and neurodegenerative phenotype, classically progressive cerebello-cerebral atrophy or pontocerebellar hypoplasia type 2D, with profound developmental delay, microcephaly, hypotonia evolving to spasticity, and progressive cerebellar atrophy.

Ask OpenScientist

Ask a research question about SEPSECS Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
3
Pathophys.
6
Phenotypes
4
Pathograph
1
Genes
🏷

Classifications

👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20920667 SUPPORT Human Clinical
"We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry."
Directly states autosomal recessive inheritance for SEPSECS-related PCCA.
⚙

Pathophysiology

3
SEPSECS Sec-tRNA synthesis defect
SEPSECS catalyzes the final tRNA-dependent step that converts Sep-tRNA(Sec) to Sec-tRNA(Sec). Pathogenic variants therefore impair Sec-tRNA formation before selenocysteine can be inserted into nascent proteins.
SEPSECS hgnc:30605
L-selenocysteine biosynthetic process GO:0016260 ↓ DECREASED
Downstream
Selenoprotein generation failure Defective Sec-tRNA formation blocks the route to selenoprotein generation.
Show evidence (1 reference)
PMID:19608919 SUPPORT In Vitro
"O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) catalyzes the final step of selenocysteine formation by a poorly understood tRNA-dependent mechanism."
Defines the enzyme step disrupted by SEPSECS deficiency.
Selenoprotein generation failure
Failed Sec-tRNA formation prevents production of selenoproteins that depend on cotranslational selenocysteine insertion.
selenocysteine incorporation GO:0001514 ↓ DECREASED
Downstream
Cerebellocerebral neurodevelopmental injury Loss of selenoprotein generation preferentially manifests as early-onset brain and cerebellar developmental-neurodegenerative disease.
Show evidence (1 reference)
PMID:20920667 SUPPORT Human Clinical
"Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans."
Establishes selenoprotein generation failure as the downstream biochemical consequence.
Cerebellocerebral neurodevelopmental injury
SEPSECS deficiency causes early brain involvement with progressive cerebellar and cerebral pathology, producing developmental delay, microcephaly, hypotonia, spasticity, and progressive atrophy.
neuron CL:0000540 glial cell CL:0000125
brain UBERON:0000955 cerebellum UBERON:0002037
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Mutations in the human O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase gene (SEPSECS) are associated with progressive cerebello-cerebral atrophy (PCCA), also known as pontocerebellar hypoplasia type 2D (PCH2D)."
Supports the cerebellocerebral disease pattern caused by SEPSECS deficiency.
⬡

Pathograph

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

Phenotypes

6
Head and Neck 1
Microcephaly Microcephaly HP:0000252
Course: PROGRESSIVE
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Early-onset profound developmental delay, progressive microcephaly, and hypotonia that develops toward severe spasticity have been previously reported with SEPSECS mutations."
Supports progressive microcephaly as part of the phenotype.
Musculoskeletal 2
Hypotonia evolving to spasticity Hypotonia HP:0001252
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Early-onset profound developmental delay, progressive microcephaly, and hypotonia that develops toward severe spasticity have been previously reported with SEPSECS mutations."
Supports hypotonia with progression toward spasticity.
Spasticity Spasticity HP:0001257
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Early-onset profound developmental delay, progressive microcephaly, and hypotonia that develops toward severe spasticity have been previously reported with SEPSECS mutations."
Supports severe spasticity in the SEPSECS phenotype.
Nervous System 3
Progressive cerebellar atrophy Cerebellar atrophy HP:0001272
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:26888482 SUPPORT Human Clinical
"We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations"
Supports progressive cerebellar atrophy in biallelic SEPSECS disease.
Cerebellar hypoplasia Cerebellar hypoplasia HP:0001321
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Mutations in the human O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase gene (SEPSECS) are associated with progressive cerebello-cerebral atrophy (PCCA), also known as pontocerebellar hypoplasia type 2D (PCH2D)."
Supports pontocerebellar hypoplasia/cerebellar hypoplasia as part of the SEPSECS clinical spectrum.
Global developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
DOI:10.3389/fped.2021.805575 SUPPORT Human Clinical
"Early-onset profound developmental delay, progressive microcephaly, and hypotonia that develops toward severe spasticity have been previously reported with SEPSECS mutations."
Supports developmental delay in SEPSECS deficiency.
🧬

Genetic Associations

1
SEPSECS pathogenic variants (Loss-of-function)
Gene: SEPSECS hgnc:30605
Show evidence (1 reference)
PMID:26888482 SUPPORT Human Clinical
"We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2."
Supports biallelic SEPSECS variants as the causal genetic basis.
{ }

Source YAML

click to show 
name: SEPSECS Deficiency
creation_date: "2026-07-06T05:15:58Z"
category: Metabolic Disorder
parents:
- Selenoprotein Biosynthesis Disorder
- Trace Element Metabolism Disorder
description: >-
  SEPSECS deficiency is an autosomal recessive selenocysteine biosynthesis
  disorder caused by biallelic SEPSECS variants. SEPSECS
  (O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase) catalyzes the final
  conversion of Sep-tRNA(Sec) to Sec-tRNA(Sec), the only route to human
  selenoprotein generation. Disruption of this step produces a severe
  neurodevelopmental and neurodegenerative phenotype, classically progressive
  cerebello-cerebral atrophy or pontocerebellar hypoplasia type 2D, with
  profound developmental delay, microcephaly, hypotonia evolving to spasticity,
  and progressive cerebellar atrophy.
synonyms:
- O-phosphoseryl-tRNA(Sec) selenium transferase deficiency
- O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase deficiency
- SEPSECS-related progressive cerebello-cerebral atrophy
- pontocerebellar hypoplasia type 2D
notes: >-
  WP-079 seed identifiers: OMIM:613811 and ORPHA:2524. No exact local MONDO
  disease term was resolved, so disease_term is intentionally left unbound.
external_assertions:
- name: OMIM SEPSECS deficiency record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:613811
  url: https://omim.org/entry/613811
  description: OMIM phenotype record corresponding to SEPSECS deficiency.
- name: Orphanet pontocerebellar hypoplasia type 2D record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2524
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2524
  description: Orphanet structured disease record for the SEPSECS-related pontocerebellar hypoplasia/PCCA phenotype.
classifications:
  icimd_category:
  - classification_value: trace_element_other
    notes: >-
      ICIMD category 22, "Disorders of trace elements and metals", other
      trace-element metabolism. SEPSECS deficiency disrupts the selenium
      incorporation step in selenocysteine biosynthesis needed for
      selenoproteins.
    evidence:
    - reference: PMID:20920667
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both founder mutations, common in these two populations, disrupt the
        sole route to the biosynthesis of the 21st amino acid, Sec, and thus to
        the generation of selenoproteins in humans.
      explanation: >-
        Supports trace-element classification through disrupted selenocysteine
        biosynthesis and selenoprotein generation.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20920667
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that SepSecS mutations cause autosomal-recessive
      progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan
      ancestry.
    explanation: >-
      Directly states autosomal recessive inheritance for SEPSECS-related PCCA.
genetic:
- name: SEPSECS pathogenic variants
  gene_term:
    preferred_term: SEPSECS
    term:
      id: hgnc:30605
      label: SEPSECS
  association: Loss-of-function
  presence: Positive
  notes: >-
    Biallelic SEPSECS variants impair the enzyme that completes
    Sec-tRNA(Sec) formation, disrupting the only human route to
    selenoprotein biosynthesis.
  evidence:
  - reference: PMID:26888482
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two new families with progressive cerebellar atrophy, and by
      whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G
      (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G
      (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2.
    explanation: >-
      Supports biallelic SEPSECS variants as the causal genetic basis.
pathophysiology:
- name: SEPSECS Sec-tRNA synthesis defect
  description: >-
    SEPSECS catalyzes the final tRNA-dependent step that converts Sep-tRNA(Sec)
    to Sec-tRNA(Sec). Pathogenic variants therefore impair Sec-tRNA formation
    before selenocysteine can be inserted into nascent proteins.
  genes:
  - preferred_term: SEPSECS
    term:
      id: hgnc:30605
      label: SEPSECS
  biological_processes:
  - preferred_term: L-selenocysteine biosynthetic process
    term:
      id: GO:0016260
      label: L-selenocysteine biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: selenocysteine
    term:
      id: CHEBI:9093
      label: selenocysteine
  evidence:
  - reference: PMID:19608919
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) catalyzes the
      final step of selenocysteine formation by a poorly understood
      tRNA-dependent mechanism.
    explanation: >-
      Defines the enzyme step disrupted by SEPSECS deficiency.
  downstream:
  - target: Selenoprotein generation failure
    description: >-
      Defective Sec-tRNA formation blocks the route to selenoprotein
      generation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20920667
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both founder mutations, common in these two populations, disrupt the
        sole route to the biosynthesis of the 21st amino acid, Sec, and thus to
        the generation of selenoproteins in humans.
      explanation: >-
        Supports failed selenoprotein generation downstream of SEPSECS
        mutations.
- name: Selenoprotein generation failure
  description: >-
    Failed Sec-tRNA formation prevents production of selenoproteins that depend
    on cotranslational selenocysteine insertion.
  biological_processes:
  - preferred_term: selenocysteine incorporation
    term:
      id: GO:0001514
      label: selenocysteine incorporation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: selenocysteine
    term:
      id: CHEBI:9093
      label: selenocysteine
  evidence:
  - reference: PMID:20920667
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both founder mutations, common in these two populations, disrupt the sole
      route to the biosynthesis of the 21st amino acid, Sec, and thus to the
      generation of selenoproteins in humans.
    explanation: >-
      Establishes selenoprotein generation failure as the downstream biochemical
      consequence.
  downstream:
  - target: Cerebellocerebral neurodevelopmental injury
    description: >-
      Loss of selenoprotein generation preferentially manifests as early-onset
      brain and cerebellar developmental-neurodegenerative disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20920667
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We demonstrate that SepSecS mutations cause autosomal-recessive
        progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and
        Moroccan ancestry.
      explanation: >-
        Links SEPSECS mutations to the progressive cerebellocerebral phenotype.
- name: Cerebellocerebral neurodevelopmental injury
  description: >-
    SEPSECS deficiency causes early brain involvement with progressive
    cerebellar and cerebral pathology, producing developmental delay,
    microcephaly, hypotonia, spasticity, and progressive atrophy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the human O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase
      gene (SEPSECS) are associated with progressive cerebello-cerebral atrophy
      (PCCA), also known as pontocerebellar hypoplasia type 2D (PCH2D).
    explanation: >-
      Supports the cerebellocerebral disease pattern caused by SEPSECS
      deficiency.
phenotypes:
- name: Progressive cerebellar atrophy
  description: >-
    Progressive cerebellar atrophy is a recurrent neuroimaging phenotype in
    SEPSECS deficiency.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26888482
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two new families with progressive cerebellar atrophy, and by
      whole exome sequencing detected biallelic SEPSECS mutations
    explanation: >-
      Supports progressive cerebellar atrophy in biallelic SEPSECS disease.
- name: Cerebellar hypoplasia
  description: >-
    The SEPSECS phenotype has been described as pontocerebellar hypoplasia type
    2D in addition to progressive cerebello-cerebral atrophy.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the human O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase
      gene (SEPSECS) are associated with progressive cerebello-cerebral atrophy
      (PCCA), also known as pontocerebellar hypoplasia type 2D (PCH2D).
    explanation: >-
      Supports pontocerebellar hypoplasia/cerebellar hypoplasia as part of the
      SEPSECS clinical spectrum.
- name: Global developmental delay
  description: >-
    Severe early developmental delay is a core clinical presentation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early-onset profound developmental delay, progressive microcephaly, and
      hypotonia that develops toward severe spasticity have been previously
      reported with SEPSECS mutations.
    explanation: >-
      Supports developmental delay in SEPSECS deficiency.
- name: Microcephaly
  description: >-
    Progressive microcephaly has been reported in SEPSECS deficiency.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early-onset profound developmental delay, progressive microcephaly, and
      hypotonia that develops toward severe spasticity have been previously
      reported with SEPSECS mutations.
    explanation: >-
      Supports progressive microcephaly as part of the phenotype.
- name: Hypotonia evolving to spasticity
  description: >-
    Hypotonia can evolve toward severe spasticity over the disease course.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early-onset profound developmental delay, progressive microcephaly, and
      hypotonia that develops toward severe spasticity have been previously
      reported with SEPSECS mutations.
    explanation: >-
      Supports hypotonia with progression toward spasticity.
- name: Spasticity
  description: >-
    Spasticity develops as part of the motor phenotype.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: DOI:10.3389/fped.2021.805575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early-onset profound developmental delay, progressive microcephaly, and
      hypotonia that develops toward severe spasticity have been previously
      reported with SEPSECS mutations.
    explanation: >-
      Supports severe spasticity in the SEPSECS phenotype.