THG1L-Related Disorder

🔗

Mappings

MONDO

MONDO:0032923 spinocerebellar ataxia, autosomal recessive 28

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease is caused by biallelic pathogenic THG1L variants, reported both as homozygous (p.Val55Ala, p.Leu294Pro) and compound heterozygous genotypes.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:37670026 SUPPORT Human Clinical

"Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."

A compound-heterozygous patient confirms the autosomal recessive mode of inheritance alongside the earlier homozygous families.

◆

Subtypes

2

SCAR28 / ATX-THG1L (p.Val55Ala)

The classic, comparatively milder end of the spectrum, defined by homozygous p.Val55Ala in Ashkenazi Jewish families: early-onset but largely non-progressive cerebellar ataxia with developmental delay, dysarthria, pyramidal signs, and cerebellar atrophy/hypoplasia.

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"Previously, three siblings with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy on brain magnetic resonance imaging (MRI) were reported to carry homozygous V55A mutations in THG1L."

Defines the p.Val55Ala classic presentation.

Severe epileptic encephalopathy (p.Val55Ala / p.Cys51Trp)

The severe end of the spectrum, best documented in p.Val55Ala/p.Cys51Trp compound heterozygotes: profound developmental delay, microcephaly, intractable epilepsy, and cerebellar hypoplasia, often with early death. Ataxia was not documented in these patients — plausibly because profound delay, epilepsy, and early death preclude gait assessment rather than because the cerebellar process is absent (cerebellar hypoplasia is shared with the classic end). A homozygous p.Leu294Pro patient sits at a similar severe pole. This is modeled as a severity-gated subtype of one disorder, not a separate disease: the MONDO/ClinGen nosology proposal (monarch-initiative/mondo#10172, PR 10477) carves the same spectrum into an umbrella plus subtypes.

Show evidence (2 references)

PMID:33682303 SUPPORT Human Clinical

"presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia"

Defines the severe compound-heterozygous presentation, which retains the shared cerebellar hypoplasia.

PMID:30214071 SUPPORT Human Clinical

"The index (14DG0824) in family 91 was born with intrauterine growth restriction (IUGR) and diffuse cerebral and cerebellar atrophy (Table S3). Exome sequencing revealed a novel missense variant in THG1L that is predicted to be pathogenic"

The primary report of the severe THG1L case later identified as p.Leu294Pro independently anchors a disease pole with prenatal growth restriction and diffuse cerebral and cerebellar atrophy.

◈

Mechanistic Hypotheses

1

THG1L Loss and Mitochondrial Dysfunction Model

thg1l_mitochondrial_dysfunction_model CANONICAL

Evidence balance 2 support

THG1L is a mitochondrial protein with two candidate disease-relevant activities: catalysis of the 3'-5' (G-1) addition of guanine to the 5'-end of tRNA-histidine (mitochondrial tRNA maturation), and participation in mitochondrial fusion via interaction with MFN2. Loss of function disturbs the mitochondrial network and is proposed to deprive cerebellar Purkinje dendrites of mitochondria, causing Purkinje cell degeneration and granule cell apoptosis.

Pathograph links

THG1L Loss of Function -> Mitochondrial Network Disruption INDIRECT KNOWN INTERMEDIATES THG1L loss lowers MFN2 GTP loading (loss of its mitofusin GEF activity), disturbing the mitochondrial network and producing abnormal fragmentation and distribution in patient cells. Intermediates: reduced MFN2 GTP loading due to loss of THG1L mitofusin-GEF activity

Mitochondrial Network Disruption -> Cerebellar Purkinje and Granule Cell Degeneration INDIRECT UNKNOWN INTERMEDIATES Mitochondrial network disruption is proposed to deprive cerebellar Purkinje dendrites of mitochondria, causing Purkinje cell degeneration and granule cell apoptosis, as seen in MFN2-deficient mice.

Mitochondrial Network Disruption -> Severe Neurodevelopmental and Epileptic Encephalopathy INDIRECT UNKNOWN INTERMEDIATES When residual THG1L function falls below a threshold (e.g. p.Val55Ala in trans with the more severe p.Cys51Trp allele), mitochondrial dysfunction extends beyond the cerebellum to a severe global neurodevelopmental and epileptogenic process. This is modeled as a severity-gated distal branch of the same trunk rather than a separate mechanism: the severe cases still carry the shared cerebellar hypoplasia.

Show evidence (2 references)

PMID:31168944 SUPPORT In Vitro

"tRNA-histidine guanylyltransferase 1 like (THG1L) localizes to the mitochondrion and catalyzes the 3'-5' addition of guanine to the 5'-end of tRNA-histidine."

Establishes the mitochondrial localization and canonical enzymatic activity of THG1L.

PMID:27307223 SUPPORT In Vitro

"THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2."

Establishes the alternative MFN2-dependent mitochondrial-fusion role implicated in the p.Val55Ala mechanism.

?

Discussions and Knowledge Gaps

2

Which molecular function of THG1L drives cerebellar disease: its MFN2-dependent mitochondrial-fusion role, or its mitochondrial tRNA-histidine (G-1) maturation activity?

KNOWLEDGE GAP OPEN disc_thg1l_function_gap

Attached to

pathophysiology#THG1L Loss of Function

THG1L has two separable activities: a tRNA-His guanylyltransferase (enzyme) and a mitofusin GEF that enhances MFN2 GTP loading. For p.Val55Ala the in vitro guanylyltransferase activity is preserved, so disease in that allele tracks the MFN2/fusion (GEF) arm; a compound-heterozygous case instead framed the mechanism as abnormal mitochondrial tRNA modification (the enzymatic arm). Which activity is rate-limiting — and whether it differs by allele — remains unresolved, and this same functional dichotomy is the axis on which the mild-vs-severe spectrum (disc_thg1l_nosology_spectrum) most likely turns: fusion-selective loss (mild) vs additional enzymatic loss (severe). A single allele-resolved functional assay would inform both gaps.

Proposed experiments

Allele-resolved assay of THG1L guanylyltransferase vs mitofusin-GEF activity

exp_thg1l_allele_resolved_function

For each disease allele (p.Val55Ala, p.Cys51Trp, p.Leu294Pro, and the compound-heterozygous combinations), measure the two THG1L activities independently: (1) in vitro tRNA-His G-1 addition (guanylyltransferase), as in Edvardson 2016; and (2) MFN2 GTP-loading / mitochondrial-fusion rescue in a THG1L-null cell background (GEF activity), as in Hickey 2014. Test whether severity tracks combined residual function (dosage/threshold, supporting one disorder with a severity-gated subtype) or whether the severe alleles selectively ablate the enzymatic arm while sparing the GEF arm (a functional branch that would argue for splitting).

Show evidence (1 reference)

PMID:27307223 SUPPORT In Vitro

"tRNAHis guanylyltransferase activity was excluded by the normal in vitro G-1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation."

Shows the enzymatic activity was intact for p.Val55Ala, motivating the fusion-role hypothesis.

Is the THG1L severity spectrum a dosage/threshold effect on one shared mechanism (lump), or does a specific allele (e.g. p.Cys51Trp) confer a qualitatively distinct molecular lesion that would justify splitting into separate diseases?

KNOWLEDGE GAP OPEN disc_thg1l_nosology_spectrum

Attached to

has_subtypes#Severe pathophysiology#Severe Neurodevelopmental and Epileptic Encephalopathy

MONDO/ClinGen (monarch-initiative/mondo#10172, PR 10477) propose an umbrella "THG1L-related disorder" with a mild SCAR28 subtype and a severe epileptic-encephalopathy subtype. dismech models this as one pathograph with a severity-gated distal branch rather than two diseases, because the severe p.Val55Ala/p.Cys51Trp compound heterozygotes retain the shared cerebellar hypoplasia (the "no ataxia" is plausibly ascertainment — profound delay, intractable epilepsy, and early death preclude gait testing), and no functional data show p.Cys51Trp ablates a different THG1L activity than the hypomorphic, guanylyltransferase-sparing p.Val55Ala. That points to allele dosage / residual function crossing a threshold, not a mechanistic branch. The open question is whether direct functional characterization of p.Cys51Trp (enzymatic vs MFN2-fusion effect) confirms the dosage model or instead reveals a distinct lesion that would warrant a split. Note the compound-heterozygous label alone does not predict severity: a different compound-het genotype (Han 2023, c.224A>G/c.369-8T>G) gave only moderate ataxia.

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"expand the phenotypic spectrum of THG1L-related disorders to include severe epileptic encephalopathy"

Frames the severe end as an extension of one THG1L phenotypic spectrum, supporting a lump-with-subtypes model over a split.

⚙

Pathophysiology

4

THG1L Loss of Function

THG1L is a bifunctional protein with two separable activities, and disease can in principle arise from loss of either. (1) A tRNA-histidine guanylyltransferase that catalyzes the ancestral 3'-5' addition of a single guanylate (G-1) to the 5' end of tRNA-His after RNase P cleavage (GTP donor, ATP-activated 5' end, two catalytic Mg2+; active as a homotetramer), acting in both cytosol and mitochondrion and required for tRNA-His identity and translational fidelity. (2) A moonlighting mitofusin guanyl-nucleotide exchange factor at the mitochondrial outer membrane that binds MFN1/MFN2, enhances MFN2 GTP loading, and promotes mitochondrial fusion. Critically the two functions dissociate by allele: for p.Val55Ala the in vitro guanylyltransferase activity is preserved and disease tracks the impaired MFN2/fusion (GEF) role, whereas other alleles may compromise the enzymatic arm — the axis on which the mild-vs-severe spectrum likely turns.

THG1L Loss and Mitochondrial Dysfunction Model

THG1L hgnc:26053

tRNA 5'-end processing GO:0099116 ↓ DECREASED mitochondrial fusion GO:0008053 ↓ DECREASED stress-induced mitochondrial fusion GO:1990046 ↓ DECREASED

tRNA guanylyltransferase activity GO:0008193 ↓ DECREASED MFN2 guanyl-nucleotide exchange factor activity GO:0005085 ↓ DECREASED

Downstream

Mitochondrial Network Disruption THG1L loss lowers MFN2 GTP loading (loss of its mitofusin GEF activity), disturbing the mitochondrial network and producing abnormal fragmentation and distribution in patient cells.

Show evidence (4 references)

PMID:37670026 SUPPORT Human Clinical

"Dysfunction of THG1L results in abnormal mitochondrial tRNA modification and neurodevelopmental disorders."

Directly frames THG1L dysfunction as impairing mitochondrial tRNA modification with a neurodevelopmental consequence.

PMID:27307223 SUPPORT In Vitro

"tRNAHis guanylyltransferase activity was excluded by the normal in vitro G-1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation."

For p.Val55Ala the enzymatic activity was intact in vitro, so this allele's mechanism is attributed to the MFN2/fusion role rather than loss of guanylyltransferase activity.

PMID:21059936 SUPPORT In Vitro

"tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleotidyl transferase"

Establishes THG1L's ancestral tRNA-His guanylyltransferase activity as a unique 3'-5' nucleotidyl transferase.

+ 1 more reference

Mitochondrial Network Disruption

Impaired THG1L function disrupts the mitochondrial network in patient cells, with abnormal fragmentation and perinuclear confinement under conditions requiring oxidative phosphorylation.

THG1L Loss and Mitochondrial Dysfunction Model

Purkinje cell CL:0000121

cerebellum UBERON:0002037

Downstream

Cerebellar Purkinje and Granule Cell Degeneration Mitochondrial network disruption is proposed to deprive cerebellar Purkinje dendrites of mitochondria, causing Purkinje cell degeneration and granule cell apoptosis, as seen in MFN2-deficient mice.

Severe Neurodevelopmental and Epileptic Encephalopathy When residual THG1L function falls below a threshold (e.g. p.Val55Ala in trans with the more severe p.Cys51Trp allele), mitochondrial dysfunction extends beyond the cerebellum to a severe global neurodevelopmental and epileptogenic process. This is modeled as a severity-gated distal branch of the same trunk rather than a separate mechanism: the severe cases still carry the shared cerebellar hypoplasia.

Show evidence (1 reference)

PMID:27307223 SUPPORT In Vitro

"Abnormal mitochondrial fragmentation, including mitochondria accumulation around the nuclei and confinement of the mitochondrial network to the nuclear vicinity, was observed when patient fibroblasts were cultured in galactose containing medium."

Directly documents the disturbed mitochondrial network in patient fibroblasts.

Severe Neurodevelopmental and Epileptic Encephalopathy

The severe end of the THG1L spectrum, documented in p.Val55Ala/p.Cys51Trp compound heterozygotes: profound developmental delay, microcephaly, intractable epilepsy, and cerebellar hypoplasia, often with early death. Present only when residual THG1L function is lowest, consistent with a dosage/threshold effect on the shared mitochondrial mechanism.

Downstream

Microcephaly The severe branch includes microcephaly.

Epileptic Encephalopathy The severe branch includes intractable epilepsy / epileptic encephalopathy.

Profound Global Developmental Delay The severe branch includes profound developmental delay.

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"expand the phenotypic spectrum of THG1L-related disorders to include severe epileptic encephalopathy"

Establishes the severe epileptic encephalopathy as an extension of the same THG1L phenotypic spectrum.

Cerebellar Purkinje and Granule Cell Degeneration

Cerebellar Purkinje neurons and granule cells are the proposed cellular targets, with Purkinje cell body degeneration and granule cell apoptosis driving loss of cerebellar cortical output.

Purkinje cell CL:0000121 cerebellar granule cell CL:0001031

cerebellum UBERON:0002037

Downstream

Cerebellar Atrophy Cerebellar neuron loss manifests as cerebellar atrophy or hypoplasia on brain MRI.

Ataxia Loss of cerebellar cortical output produces the core cerebellar ataxia phenotype.

Show evidence (1 reference)

PMID:27307223 SUPPORT Model Organism

"This may result in lack of mitochondria in the cerebellar Purkinje dendrites, with degeneration of Purkinje cell bodies and apoptosis of granule cells, as reported for MFN2 deficient mice."

Names Purkinje and granule cells as the proposed degenerating cerebellar populations.

⬡

Pathograph

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

●

Phenotypes

10

Head and Neck 2

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia"

Microcephaly is documented in the severe compound-heterozygous cohort.

Micrognathia OCCASIONAL HP:0000347

Show evidence (1 reference)

CGGV:assertion_c1568d1e-8fef-4666-80e1-7cee60e94863-2025-09-10T160000.000Z SUPPORT Other

"Dysmorphic features like microcephaly and micrognathia have been reported but in a minority of cases."

The ClinGen curation supports micrognathia as an occasional feature while not resolving its allele or subtype association.

Nervous System 6

Ataxia VERY_FREQUENT HP:0001251

Onset: CHILDHOOD

Show evidence (2 references)

PMID:27307223 SUPPORT Human Clinical

"three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI"

Cerebellar signs (ataxia) were present in all three founding-family siblings.

PMID:37670026 SUPPORT Human Clinical

"in THG1L in a 6-year-old boy with moderate cerebellar ataxia."

A compound-heterozygous patient also presented with cerebellar ataxia.

Cerebellar Atrophy VERY_FREQUENT HP:0001272

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"All three individuals displayed cerebellar ataxia, dysarthria, developmental delay, pyramidal signs, and cerebellar hypoplasia versus atrophy on brain magnetic resonance imaging (MRI)."

Documents cerebellar atrophy/hypoplasia on brain MRI.

Cerebellar Hypoplasia FREQUENT HP:0001321

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"All three individuals displayed cerebellar ataxia, dysarthria, developmental delay, pyramidal signs, and cerebellar hypoplasia versus atrophy on brain magnetic resonance imaging (MRI)."

Cerebellar hypoplasia was noted alongside atrophy on MRI.

Dysarthria FREQUENT HP:0001260

Show evidence (1 reference)

PMID:27307223 SUPPORT Human Clinical

"three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI"

Dysarthria was present in the founding-family siblings.

Global Developmental Delay VERY_FREQUENT HP:0001263

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:27307223 SUPPORT Human Clinical

"three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI"

Developmental delay was present in the founding-family siblings.

Profound Global Developmental Delay HP:0012736

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia"

Profound developmental delay is documented in the severe compound-heterozygous cohort.

Other 2

Pyramidal Signs FREQUENT Abnormal pyramidal sign HP:0007256

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"Previously, three siblings with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy on brain magnetic resonance imaging (MRI) were reported to carry homozygous V55A mutations in THG1L."

Pyramidal signs are documented in the reported patients.

Epileptic Encephalopathy HP:0200134

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia"

Intractable epilepsy is documented in the severe compound-heterozygous cohort.

🧬

Genetic Associations

1

THG1L (Causal biallelic variant)

Gene: THG1L hgnc:26053

Show evidence (4 references)

PMID:27307223 SUPPORT Human Clinical

"we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine guanylyltransferase 1 like) gene in three siblings"

Identifies THG1L as the causal gene via the founding homozygous variant.

PMID:30214071 SUPPORT Human Clinical

"The index (14DG0824) in family 91 was born with intrauterine growth restriction (IUGR) and diffuse cerebral and cerebellar atrophy (Table S3). Exome sequencing revealed a novel missense variant in THG1L that is predicted to be pathogenic"

This primary report directly anchors the severe THG1L case later identified as p.Leu294Pro, which had previously been cited only through a subsequent phenotype paper.

PMID:37670026 SUPPORT Human Clinical

"The variant c.224A > G was demonstrated to downregulate its RNA and protein expression, and c.369-8 T > G resulted in a 7 bp insertion before exon 3."

Functionally characterizes the compound-heterozygous alleles as loss-of-function.

+ 1 more reference

💊

Medical Actions

1

Cardiac, hepatic, and auditory monitoring

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because the natural history and risk of multisystem mitochondrial disease remain uncertain, reported patients should receive close clinical monitoring of cardiac, liver, and auditory function. The source does not define evidence-based monitoring intervals.

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"Given the risk of the former, close monitoring of multiple systems— particularly cardiac, liver, and auditory functions—is warranted in these patients."

The phenotype paper directly recommends multisystem monitoring while leaving modality and interval unspecified.

🔬

Diagnosis

1

Molecular diagnosis by next-generation sequencing

Children with congenital ataxia can be evaluated with an ataxia or mitochondrial-disease next-generation sequencing panel and preferably clinical whole-exome sequencing. Identification of biallelic pathogenic or likely pathogenic THG1L variants supports the diagnosis in the appropriate clinical context.

clinical whole-exome sequencing NCIT:C101295

Results: Biallelic pathogenic or likely pathogenic THG1L variants are consistent with THG1L-related disorder; variant interpretation remains important because ClinGen currently classifies the gene-disease relationship as Limited.

Show evidence (1 reference)

PMID:31168944 SUPPORT Human Clinical

"We would therefore recommend genetic evaluation with at least a next-generation sequencing panel covering these genes and, preferably, WES in any child presenting with congenital ataxia"

This clinical phenotype paper directly recommends panel or whole-exome testing for children with congenital ataxia.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Ultra-rare, concentrated in the Ashkenazi Jewish population. Reported patients include the founding p.Val55Ala homozygous families, four further p.Val55Ala homozygous siblings and three p.Val55Ala/p.Cys51Trp compound heterozygotes (Rabin 2021), a p.Leu294Pro patient, and a compound heterozygous ataxia patient (Han 2023). Both key Ashkenazi alleles are low-frequency and no p.Val55Ala homozygotes were found in ExAC/gnomAD.

Show evidence (2 references)

PMID:33682303 SUPPORT Human Clinical

"was found in 40 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 668"

Quantifies the Ashkenazi Jewish carrier frequency of the severe p.Cys51Trp allele in a 26,731-person screen.

PMID:31168944 SUPPORT Human Clinical

"A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals"

Quantifies the Ashkenazi Jewish carrier frequency for the founding p.Val55Ala allele.

⚖️

Clinical Burden

Variable

The phenotype spans a severity spectrum on one shared mechanism: p.Val55Ala homozygotes have early-onset but largely non-progressive cerebellar ataxia with mild developmental delay and near-normal cognition, while compound heterozygotes carrying p.Val55Ala plus the more severe p.Cys51Trp allele present at the catastrophic end (profound developmental delay, microcephaly, intractable epilepsy, cerebellar hypoplasia, and early death). Burden ranges from motor/speech disability to a lethal epileptic encephalopathy.

Show evidence (1 reference)

PMID:33682303 SUPPORT Human Clinical

"presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia"

The compound-heterozygous cohort defines the severe end of the burden spectrum, while the same report's homozygous siblings define the mild end.

{ }

Source YAML

click to show

name: THG1L-Related Disorder
creation_date: "2026-07-23T00:00:00Z"
description: >-
  THG1L-related disorder is an autosomal recessive mitochondrial
  cerebellar ataxia caused by biallelic pathogenic variants in THG1L
  (tRNA-histidine guanylyltransferase 1 like), also cataloged as
  spinocerebellar ataxia, autosomal recessive 28 (SCAR28) / ATX-THG1L.
  THG1L localizes to the mitochondrion, catalyzes the 3'-5' addition of
  guanine to the 5'-end of tRNA-histidine, and additionally participates
  in mitochondrial fusion through its interaction with MFN2. Loss of
  function is proposed to injure cerebellar Purkinje and granule cells,
  producing early-onset, largely non-progressive cerebellar ataxia with
  developmental delay, dysarthria, pyramidal signs, and cerebellar atrophy
  or hypoplasia on brain MRI. The disorder is ultra-rare: the founding
  reports describe homozygous p.Val55Ala in Ashkenazi Jewish families, a
  more severely affected homozygous p.Leu294Pro patient, and a
  compound-heterozygous Chinese patient with moderate ataxia. The gene
  carries only a Limited ClinGen gene-disease validity classification,
  reflecting the small number of reported families.
category: Mendelian
synonyms:
- SCAR28
- spinocerebellar ataxia, autosomal recessive 28
- THG1L-related autosomal recessive congenital cerebellar ataxia
- ATX-THG1L
- THG1L-related cerebellar ataxia
parents:
- Mendelian Disorder
- Neurological Disorder
- Mitochondrial Disorder
disease_term:
  preferred_term: THG1L-related autosomal recessive congenital cerebellar ataxia
  term:
    id: MONDO:0032923
    label: spinocerebellar ataxia, autosomal recessive 28
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032923
      label: spinocerebellar ataxia, autosomal recessive 28
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    The phenotype spans a severity spectrum on one shared mechanism: p.Val55Ala
    homozygotes have early-onset but largely non-progressive cerebellar ataxia
    with mild developmental delay and near-normal cognition, while compound
    heterozygotes carrying p.Val55Ala plus the more severe p.Cys51Trp allele
    present at the catastrophic end (profound developmental delay, microcephaly,
    intractable epilepsy, cerebellar hypoplasia, and early death). Burden ranges
    from motor/speech disability to a lethal epileptic encephalopathy.
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with profound developmental delays, microcephaly, intractable
      epilepsy, and cerebellar hypoplasia
    explanation: >-
      The compound-heterozygous cohort defines the severe end of the burden
      spectrum, while the same report's homozygous siblings define the mild end.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Disease is caused by biallelic pathogenic THG1L variants, reported both
    as homozygous (p.Val55Ala, p.Leu294Pro) and compound heterozygous
    genotypes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37670026
    reference_title: "Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."
    explanation: >-
      A compound-heterozygous patient confirms the autosomal recessive mode of
      inheritance alongside the earlier homozygous families.
mechanistic_hypotheses:
- hypothesis_group_id: thg1l_mitochondrial_dysfunction_model
  hypothesis_label: THG1L Loss and Mitochondrial Dysfunction Model
  status: CANONICAL
  description: >-
    THG1L is a mitochondrial protein with two candidate disease-relevant
    activities: catalysis of the 3'-5' (G-1) addition of guanine to the
    5'-end of tRNA-histidine (mitochondrial tRNA maturation), and
    participation in mitochondrial fusion via interaction with MFN2. Loss of
    function disturbs the mitochondrial network and is proposed to deprive
    cerebellar Purkinje dendrites of mitochondria, causing Purkinje cell
    degeneration and granule cell apoptosis.
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      tRNA-histidine guanylyltransferase 1 like (THG1L) localizes to the
      mitochondrion and catalyzes the 3'-5' addition of guanine to the
      5'-end of tRNA-histidine.
    explanation: >-
      Establishes the mitochondrial localization and canonical enzymatic
      activity of THG1L.
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2."
    explanation: >-
      Establishes the alternative MFN2-dependent mitochondrial-fusion role
      implicated in the p.Val55Ala mechanism.
pathophysiology:
- name: THG1L Loss of Function
  biological_scale: MOLECULAR
  description: >-
    THG1L is a bifunctional protein with two separable activities, and disease
    can in principle arise from loss of either. (1) A tRNA-histidine
    guanylyltransferase that catalyzes the ancestral 3'-5' addition of a single
    guanylate (G-1) to the 5' end of tRNA-His after RNase P cleavage (GTP donor,
    ATP-activated 5' end, two catalytic Mg2+; active as a homotetramer), acting
    in both cytosol and mitochondrion and required for tRNA-His identity and
    translational fidelity. (2) A moonlighting mitofusin guanyl-nucleotide
    exchange factor at the mitochondrial outer membrane that binds MFN1/MFN2,
    enhances MFN2 GTP loading, and promotes mitochondrial fusion. Critically the
    two functions dissociate by allele: for p.Val55Ala the in vitro
    guanylyltransferase activity is preserved and disease tracks the impaired
    MFN2/fusion (GEF) role, whereas other alleles may compromise the enzymatic
    arm — the axis on which the mild-vs-severe spectrum likely turns.
  genes:
  - preferred_term: THG1L
    term:
      id: hgnc:26053
      label: THG1L
  molecular_functions:
  - preferred_term: tRNA guanylyltransferase activity
    term:
      id: GO:0008193
      label: tRNA guanylyltransferase activity
    modifier: DECREASED
  - preferred_term: MFN2 guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: tRNA 5'-end processing
    term:
      id: GO:0099116
      label: tRNA 5'-end processing
    modifier: DECREASED
  - preferred_term: mitochondrial fusion
    term:
      id: GO:0008053
      label: mitochondrial fusion
    modifier: DECREASED
  - preferred_term: stress-induced mitochondrial fusion
    term:
      id: GO:1990046
      label: stress-induced mitochondrial fusion
    modifier: DECREASED
  evidence:
  - reference: PMID:37670026
    reference_title: "Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysfunction of THG1L results in abnormal mitochondrial tRNA modification and neurodevelopmental disorders."
    explanation: >-
      Directly frames THG1L dysfunction as impairing mitochondrial tRNA
      modification with a neurodevelopmental consequence.
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "tRNAHis guanylyltransferase activity was excluded by the normal in vitro G-1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation."
    explanation: >-
      For p.Val55Ala the enzymatic activity was intact in vitro, so this
      allele's mechanism is attributed to the MFN2/fusion role rather than
      loss of guanylyltransferase activity.
  - reference: PMID:21059936
    reference_title: "tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleotidyl transferase, shares unexpected structural homology with canonical 5'-3' DNA polymerases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleotidyl transferase"
    explanation: >-
      Establishes THG1L's ancestral tRNA-His guanylyltransferase activity as a
      unique 3'-5' nucleotidyl transferase.
  - reference: PMID:25008184
    reference_title: "IHG-1 increases mitochondrial fusion and bioenergetic function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as
      a guanine nucleotide exchange factor
    explanation: >-
      Establishes the moonlighting mitofusin GEF activity — THG1L/IHG-1
      enhances MFN2 GTP loading — that underlies the fusion role.
  downstream:
  - target: Mitochondrial Network Disruption
    description: >-
      THG1L loss lowers MFN2 GTP loading (loss of its mitofusin GEF activity),
      disturbing the mitochondrial network and producing abnormal fragmentation
      and distribution in patient cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced MFN2 GTP loading due to loss of THG1L mitofusin-GEF activity
    hypothesis_groups:
    - thg1l_mitochondrial_dysfunction_model
    evidence:
    - reference: PMID:25008184
      reference_title: "IHG-1 increases mitochondrial fusion and bioenergetic function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as
        a guanine nucleotide exchange factor
      explanation: >-
        Identifies reduced MFN2 GTP loading as the molecular intermediate between
        THG1L loss and impaired fusion.
    - reference: PMID:27307223
      reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Abnormal mitochondrial fragmentation, including mitochondria
        accumulation around the nuclei and confinement of the mitochondrial
        network to the nuclear vicinity, was observed when patient fibroblasts
        were cultured in galactose containing medium.
      explanation: >-
        Patient fibroblasts show a disturbed mitochondrial network under
        obligatory oxidative phosphorylation.
- name: Mitochondrial Network Disruption
  biological_scale: CELLULAR
  description: >-
    Impaired THG1L function disrupts the mitochondrial network in patient
    cells, with abnormal fragmentation and perinuclear confinement under
    conditions requiring oxidative phosphorylation.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Abnormal mitochondrial fragmentation, including mitochondria
      accumulation around the nuclei and confinement of the mitochondrial
      network to the nuclear vicinity, was observed when patient fibroblasts
      were cultured in galactose containing medium.
    explanation: >-
      Directly documents the disturbed mitochondrial network in patient
      fibroblasts.
  downstream:
  - target: Cerebellar Purkinje and Granule Cell Degeneration
    description: >-
      Mitochondrial network disruption is proposed to deprive cerebellar
      Purkinje dendrites of mitochondria, causing Purkinje cell degeneration
      and granule cell apoptosis, as seen in MFN2-deficient mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - thg1l_mitochondrial_dysfunction_model
    evidence:
    - reference: PMID:27307223
      reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This may result in lack of mitochondria in the cerebellar Purkinje
        dendrites, with degeneration of Purkinje cell bodies and apoptosis of
        granule cells, as reported for MFN2 deficient mice.
      explanation: >-
        The proposed cerebellar mechanism is extrapolated from the MFN2-deficient
        mouse phenotype, so it is a model-supported hypothesis rather than a
        directly demonstrated human mechanism.
  - target: Severe Neurodevelopmental and Epileptic Encephalopathy
    description: >-
      When residual THG1L function falls below a threshold (e.g. p.Val55Ala in
      trans with the more severe p.Cys51Trp allele), mitochondrial dysfunction
      extends beyond the cerebellum to a severe global neurodevelopmental and
      epileptogenic process. This is modeled as a severity-gated distal branch
      of the same trunk rather than a separate mechanism: the severe cases still
      carry the shared cerebellar hypoplasia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - thg1l_mitochondrial_dysfunction_model
    evidence:
    - reference: PMID:33682303
      reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented with profound developmental delays, microcephaly, intractable
        epilepsy, and cerebellar hypoplasia
      explanation: >-
        The severe compound-heterozygous cases retain cerebellar hypoplasia
        (shared trunk) while adding microcephaly and intractable epilepsy,
        supporting a severity-gated distal extension rather than a distinct
        disease.
- name: Severe Neurodevelopmental and Epileptic Encephalopathy
  biological_scale: ORGANISM
  description: >-
    The severe end of the THG1L spectrum, documented in p.Val55Ala/p.Cys51Trp
    compound heterozygotes: profound developmental delay, microcephaly,
    intractable epilepsy, and cerebellar hypoplasia, often with early death.
    Present only when residual THG1L function is lowest, consistent with a
    dosage/threshold effect on the shared mitochondrial mechanism.
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      expand the phenotypic spectrum of THG1L-related disorders to include
      severe epileptic encephalopathy
    explanation: >-
      Establishes the severe epileptic encephalopathy as an extension of the
      same THG1L phenotypic spectrum.
  downstream:
  - target: Microcephaly
    description: The severe branch includes microcephaly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33682303
      reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented with profound developmental delays, microcephaly, intractable
        epilepsy, and cerebellar hypoplasia
      explanation: Microcephaly is documented in the severe compound-heterozygous cohort.
  - target: Epileptic Encephalopathy
    description: The severe branch includes intractable epilepsy / epileptic encephalopathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33682303
      reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented with profound developmental delays, microcephaly, intractable
        epilepsy, and cerebellar hypoplasia
      explanation: Intractable epilepsy is documented in the severe compound-heterozygous cohort.
  - target: Profound Global Developmental Delay
    description: The severe branch includes profound developmental delay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33682303
      reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented with profound developmental delays, microcephaly, intractable
        epilepsy, and cerebellar hypoplasia
      explanation: Profound developmental delay is documented in the severe compound-heterozygous cohort.
- name: Cerebellar Purkinje and Granule Cell Degeneration
  biological_scale: TISSUE
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    Cerebellar Purkinje neurons and granule cells are the proposed cellular
    targets, with Purkinje cell body degeneration and granule cell apoptosis
    driving loss of cerebellar cortical output.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This may result in lack of mitochondria in the cerebellar Purkinje
      dendrites, with degeneration of Purkinje cell bodies and apoptosis of
      granule cells, as reported for MFN2 deficient mice.
    explanation: >-
      Names Purkinje and granule cells as the proposed degenerating cerebellar
      populations.
  downstream:
  - target: Cerebellar Atrophy
    description: >-
      Cerebellar neuron loss manifests as cerebellar atrophy or hypoplasia on
      brain MRI.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31168944
      reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All three individuals displayed cerebellar ataxia, dysarthria,
        developmental delay, pyramidal signs, and cerebellar hypoplasia versus
        atrophy on brain magnetic resonance imaging (MRI).
      explanation: >-
        Documents cerebellar hypoplasia/atrophy on MRI as the structural
        consequence.
  - target: Ataxia
    description: >-
      Loss of cerebellar cortical output produces the core cerebellar ataxia
      phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27307223
      reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        three siblings who presented with cerebellar signs, developmental
        delay, dysarthria, and pyramidal signs and had cerebellar atrophy on
        brain MRI
      explanation: >-
        Establishes cerebellar signs (ataxia) as the core clinical manifestation.
phenotypes:
- name: Ataxia
  description: >-
    Early-onset cerebellar ataxia is the defining and universal neurologic
    feature across reported patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      three siblings who presented with cerebellar signs, developmental
      delay, dysarthria, and pyramidal signs and had cerebellar atrophy on
      brain MRI
    explanation: Cerebellar signs (ataxia) were present in all three founding-family siblings.
  - reference: PMID:37670026
    reference_title: "Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in THG1L in a 6-year-old boy with moderate cerebellar ataxia."
    explanation: A compound-heterozygous patient also presented with cerebellar ataxia.
- name: Cerebellar Atrophy
  description: >-
    Cerebellar atrophy (or hypoplasia) is the characteristic structural
    neuroimaging abnormality.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three individuals displayed cerebellar ataxia, dysarthria,
      developmental delay, pyramidal signs, and cerebellar hypoplasia versus
      atrophy on brain magnetic resonance imaging (MRI).
    explanation: Documents cerebellar atrophy/hypoplasia on brain MRI.
- name: Cerebellar Hypoplasia
  description: >-
    In some patients the small cerebellum is described as hypoplastic rather
    than atrophic, reflecting the congenital onset.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three individuals displayed cerebellar ataxia, dysarthria,
      developmental delay, pyramidal signs, and cerebellar hypoplasia versus
      atrophy on brain magnetic resonance imaging (MRI).
    explanation: Cerebellar hypoplasia was noted alongside atrophy on MRI.
- name: Dysarthria
  description: Dysarthria is a recurrent speech manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      three siblings who presented with cerebellar signs, developmental
      delay, dysarthria, and pyramidal signs and had cerebellar atrophy on
      brain MRI
    explanation: Dysarthria was present in the founding-family siblings.
- name: Global Developmental Delay
  description: >-
    Developmental delay accompanies the cerebellar syndrome in reported
    patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      three siblings who presented with cerebellar signs, developmental
      delay, dysarthria, and pyramidal signs and had cerebellar atrophy on
      brain MRI
    explanation: Developmental delay was present in the founding-family siblings.
- name: Pyramidal Signs
  description: >-
    Corticospinal (pyramidal) tract signs are part of the neurologic
    presentation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: pyramidal signs
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously, three siblings with early onset cerebellar dysfunction,
      developmental delay, pyramidal signs, and cerebellar atrophy on brain
      magnetic resonance imaging (MRI) were reported to carry homozygous V55A
      mutations in THG1L.
    explanation: Pyramidal signs are documented in the reported patients.
- name: Microcephaly
  subtype: Severe
  description: >-
    Microcephaly is a distinguishing feature of the severe
    (p.Val55Ala/p.Cys51Trp) end of the spectrum and is not seen in the
    classic ataxia phenotype.
  phenotype_term:
    preferred_term: microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with profound developmental delays, microcephaly, intractable
      epilepsy, and cerebellar hypoplasia
    explanation: Microcephaly is documented in the severe compound-heterozygous cohort.
- name: Micrognathia
  description: >-
    Micrognathia is a dysmorphic feature reported in a minority of THG1L-related
    disorder cases. The available ClinGen summary does not assign it to a
    specific genotype.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: CGGV:assertion_c1568d1e-8fef-4666-80e1-7cee60e94863-2025-09-10T160000.000Z
    reference_title: "THG1L / spinocerebellar ataxia, autosomal recessive 28 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dysmorphic features like microcephaly and micrognathia have been reported
      but in a minority of cases.
    explanation: >-
      The ClinGen curation supports micrognathia as an occasional feature while
      not resolving its allele or subtype association.
- name: Epileptic Encephalopathy
  subtype: Severe
  description: >-
    Intractable epilepsy amounting to an epileptic encephalopathy defines the
    severe end of the spectrum; the classic p.Val55Ala phenotype is not
    epileptic.
  phenotype_term:
    preferred_term: intractable epilepsy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with profound developmental delays, microcephaly, intractable
      epilepsy, and cerebellar hypoplasia
    explanation: Intractable epilepsy is documented in the severe compound-heterozygous cohort.
- name: Profound Global Developmental Delay
  subtype: Severe
  description: >-
    The severe end shows profound developmental delay, in contrast to the
    mild/near-normal cognition of the classic phenotype.
  phenotype_term:
    preferred_term: profound global developmental delay
    term:
      id: HP:0012736
      label: Profound global developmental delay
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with profound developmental delays, microcephaly, intractable
      epilepsy, and cerebellar hypoplasia
    explanation: Profound developmental delay is documented in the severe compound-heterozygous cohort.
genetic:
- name: THG1L
  gene_term:
    preferred_term: THG1L
    term:
      id: hgnc:26053
      label: THG1L
  association: Causal biallelic variant
  notes: >-
    Reported disease-associated genotypes include homozygous p.Val55Ala
    (c.164T>C) in Ashkenazi Jewish families (mild ataxia end); compound
    heterozygous p.Val55Ala + p.Cys51Trp (severe epileptic-encephalopathy
    end); a homozygous p.Leu294Pro (c.881T>C) patient; and compound
    heterozygous c.224A>G / c.369-8T>G (moderate ataxia). p.Val55Ala spares
    the in vitro guanylyltransferase activity, so severity appears to track
    residual THG1L function (allele dosage) rather than a distinct molecular
    lesion. ClinGen classifies the THG1L-SCAR28 gene-disease relationship as
    Limited.
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine
      guanylyltransferase 1 like) gene in three siblings
    explanation: Identifies THG1L as the causal gene via the founding homozygous variant.
  - reference: PMID:30214071
    reference_title: "Genomic and phenotypic delineation of congenital microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index (14DG0824) in family 91 was born with intrauterine growth
      restriction (IUGR) and diffuse cerebral and cerebellar atrophy (Table S3).
      Exome sequencing revealed a novel missense variant in THG1L that is
      predicted to be pathogenic
    explanation: >-
      This primary report directly anchors the severe THG1L case later
      identified as p.Leu294Pro, which had previously been cited only through a
      subsequent phenotype paper.
  - reference: PMID:37670026
    reference_title: "Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant c.224A > G was demonstrated to downregulate its RNA and protein expression, and c.369-8 T > G resulted in a 7 bp insertion before exon 3."
    explanation: Functionally characterizes the compound-heterozygous alleles as loss-of-function.
  - reference: CGGV:assertion_c1568d1e-8fef-4666-80e1-7cee60e94863-2025-09-10T160000.000Z
    reference_title: "THG1L / spinocerebellar ataxia, autosomal recessive 28 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "THG1L | HGNC:26053 | spinocerebellar ataxia, autosomal recessive 28 | MONDO:0032923 | AR | Limited"
    explanation: ClinGen records a Limited gene-disease validity classification for THG1L-SCAR28.
has_subtypes:
- name: SCAR28 classic
  display_name: SCAR28 / ATX-THG1L (p.Val55Ala)
  description: >-
    The classic, comparatively milder end of the spectrum, defined by
    homozygous p.Val55Ala in Ashkenazi Jewish families: early-onset but
    largely non-progressive cerebellar ataxia with developmental delay,
    dysarthria, pyramidal signs, and cerebellar atrophy/hypoplasia.
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously, three siblings with early onset cerebellar dysfunction,
      developmental delay, pyramidal signs, and cerebellar atrophy on brain
      magnetic resonance imaging (MRI) were reported to carry homozygous V55A
      mutations in THG1L.
    explanation: Defines the p.Val55Ala classic presentation.
- name: Severe
  display_name: Severe epileptic encephalopathy (p.Val55Ala / p.Cys51Trp)
  description: >-
    The severe end of the spectrum, best documented in p.Val55Ala/p.Cys51Trp
    compound heterozygotes: profound developmental delay, microcephaly,
    intractable epilepsy, and cerebellar hypoplasia, often with early death.
    Ataxia was not documented in these patients — plausibly because profound
    delay, epilepsy, and early death preclude gait assessment rather than
    because the cerebellar process is absent (cerebellar hypoplasia is
    shared with the classic end). A homozygous p.Leu294Pro patient sits at a
    similar severe pole. This is modeled as a severity-gated subtype of one
    disorder, not a separate disease: the MONDO/ClinGen nosology proposal
    (monarch-initiative/mondo#10172, PR 10477) carves the same spectrum into
    an umbrella plus subtypes.
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with profound developmental delays, microcephaly, intractable
      epilepsy, and cerebellar hypoplasia
    explanation: >-
      Defines the severe compound-heterozygous presentation, which retains the
      shared cerebellar hypoplasia.
  - reference: PMID:30214071
    reference_title: "Genomic and phenotypic delineation of congenital microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index (14DG0824) in family 91 was born with intrauterine growth
      restriction (IUGR) and diffuse cerebral and cerebellar atrophy (Table S3).
      Exome sequencing revealed a novel missense variant in THG1L that is
      predicted to be pathogenic
    explanation: >-
      The primary report of the severe THG1L case later identified as
      p.Leu294Pro independently anchors a disease pole with prenatal growth
      restriction and diffuse cerebral and cerebellar atrophy.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare, concentrated in the Ashkenazi Jewish population. Reported
    patients include the founding p.Val55Ala homozygous families, four further
    p.Val55Ala homozygous siblings and three p.Val55Ala/p.Cys51Trp compound
    heterozygotes (Rabin 2021), a p.Leu294Pro patient, and a compound
    heterozygous ataxia patient (Han 2023). Both key Ashkenazi alleles are
    low-frequency and no p.Val55Ala homozygotes were found in ExAC/gnomAD.
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was found in 40 of the Ashkenazi Jewish individuals tested, with a
      carrier rate of 1 in 668
    explanation: >-
      Quantifies the Ashkenazi Jewish carrier frequency of the severe p.Cys51Trp
      allele in a 26,731-person screen.
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a
      cohort of 3,232 unrelated Ashkenazi Jewish individuals
    explanation: Quantifies the Ashkenazi Jewish carrier frequency for the founding p.Val55Ala allele.
diagnosis:
- name: Molecular diagnosis by next-generation sequencing
  description: >-
    Children with congenital ataxia can be evaluated with an ataxia or
    mitochondrial-disease next-generation sequencing panel and preferably
    clinical whole-exome sequencing. Identification of biallelic pathogenic or
    likely pathogenic THG1L variants supports the diagnosis in the appropriate
    clinical context.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    Biallelic pathogenic or likely pathogenic THG1L variants are consistent with
    THG1L-related disorder; variant interpretation remains important because
    ClinGen currently classifies the gene-disease relationship as Limited.
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We would therefore recommend genetic evaluation with at least a
      next-generation sequencing panel covering these genes and, preferably,
      WES in any child presenting with congenital ataxia
    explanation: >-
      This clinical phenotype paper directly recommends panel or whole-exome
      testing for children with congenital ataxia.
treatments:
- name: Cardiac, hepatic, and auditory monitoring
  description: >-
    Because the natural history and risk of multisystem mitochondrial disease
    remain uncertain, reported patients should receive close clinical
    monitoring of cardiac, liver, and auditory function. The source does not
    define evidence-based monitoring intervals.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31168944
    reference_title: "Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the risk of the former, close monitoring of multiple systems—
      particularly cardiac, liver, and auditory functions—is warranted in these
      patients.
    explanation: >-
      The phenotype paper directly recommends multisystem monitoring while
      leaving modality and interval unspecified.
discussions:
- discussion_id: disc_thg1l_function_gap
  prompt: >-
    Which molecular function of THG1L drives cerebellar disease: its
    MFN2-dependent mitochondrial-fusion role, or its mitochondrial
    tRNA-histidine (G-1) maturation activity?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#THG1L Loss of Function
  rationale: >-
    THG1L has two separable activities: a tRNA-His guanylyltransferase (enzyme)
    and a mitofusin GEF that enhances MFN2 GTP loading. For p.Val55Ala the in
    vitro guanylyltransferase activity is preserved, so disease in that allele
    tracks the MFN2/fusion (GEF) arm; a compound-heterozygous case instead
    framed the mechanism as abnormal mitochondrial tRNA modification (the
    enzymatic arm). Which activity is rate-limiting — and whether it differs by
    allele — remains unresolved, and this same functional dichotomy is the axis
    on which the mild-vs-severe spectrum (disc_thg1l_nosology_spectrum) most
    likely turns: fusion-selective loss (mild) vs additional enzymatic loss
    (severe). A single allele-resolved functional assay would inform both gaps.
  proposed_experiments:
  - experiment_id: exp_thg1l_allele_resolved_function
    name: Allele-resolved assay of THG1L guanylyltransferase vs mitofusin-GEF activity
    description: >-
      For each disease allele (p.Val55Ala, p.Cys51Trp, p.Leu294Pro, and the
      compound-heterozygous combinations), measure the two THG1L activities
      independently: (1) in vitro tRNA-His G-1 addition (guanylyltransferase),
      as in Edvardson 2016; and (2) MFN2 GTP-loading / mitochondrial-fusion
      rescue in a THG1L-null cell background (GEF activity), as in Hickey 2014.
      Test whether severity tracks combined residual function (dosage/threshold,
      supporting one disorder with a severity-gated subtype) or whether the
      severe alleles selectively ablate the enzymatic arm while sparing the GEF
      arm (a functional branch that would argue for splitting).
  evidence:
  - reference: PMID:27307223
    reference_title: "A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "tRNAHis guanylyltransferase activity was excluded by the normal in vitro G-1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation."
    explanation: Shows the enzymatic activity was intact for p.Val55Ala, motivating the fusion-role hypothesis.
- discussion_id: disc_thg1l_nosology_spectrum
  prompt: >-
    Is the THG1L severity spectrum a dosage/threshold effect on one shared
    mechanism (lump), or does a specific allele (e.g. p.Cys51Trp) confer a
    qualitatively distinct molecular lesion that would justify splitting into
    separate diseases?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Severe
  - pathophysiology#Severe Neurodevelopmental and Epileptic Encephalopathy
  rationale: >-
    MONDO/ClinGen (monarch-initiative/mondo#10172, PR 10477) propose an
    umbrella "THG1L-related disorder" with a mild SCAR28 subtype and a severe
    epileptic-encephalopathy subtype. dismech models this as one pathograph
    with a severity-gated distal branch rather than two diseases, because the
    severe p.Val55Ala/p.Cys51Trp compound heterozygotes retain the shared
    cerebellar hypoplasia (the "no ataxia" is plausibly ascertainment — profound
    delay, intractable epilepsy, and early death preclude gait testing), and no
    functional data show p.Cys51Trp ablates a different THG1L activity than the
    hypomorphic, guanylyltransferase-sparing p.Val55Ala. That points to allele
    dosage / residual function crossing a threshold, not a mechanistic branch.
    The open question is whether direct functional characterization of
    p.Cys51Trp (enzymatic vs MFN2-fusion effect) confirms the dosage model or
    instead reveals a distinct lesion that would warrant a split. Note the
    compound-heterozygous label alone does not predict severity: a different
    compound-het genotype (Han 2023, c.224A>G/c.369-8T>G) gave only moderate
    ataxia.
  evidence:
  - reference: PMID:33682303
    reference_title: "Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      expand the phenotypic spectrum of THG1L-related disorders to include
      severe epileptic encephalopathy
    explanation: >-
      Frames the severe end as an extension of one THG1L phenotypic spectrum,
      supporting a lump-with-subtypes model over a split.

THG1L-Related Disorder

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Clinical Burden

Source YAML