TUBA4A-related Disorder

Mendelian MONDO:0014531 Pathograph 12 Show in embeddings browser hereditary neurological disease neuromuscular disease neurodegenerative disease

TUBA4A-related disorder is the tubulinopathy that is not a brain malformation and, in most reported families, not a central nervous system disease at all. TUBA4A encodes an alpha-tubulin 4A isotype whose disease associations have widened repeatedly since it was first linked to familial amyotrophic lateral sclerosis and frontotemporal dementia. It now spans three phenotypic groups: the original ALS/FTD neurodegenerative presentations; hereditary spastic ataxia with variable age of onset; and - newly delineated in 2026 - the myo-tubulinopathies, in which a myopathy occurs with no CNS involvement whatsoever. The myopathy arm is the reason this entry exists as a distinct concept rather than as an ALS subtype. In a 31-individual, 19-family multicentre series, 17 families presented with myopathy and no CNS disease or history of it. Two further families showed cerebellar ataxia and epilepsy alongside proximal and axial weakness with protein aggregation, which the authors define as a multisystem proteinopathy - the first association of TUBA4A with that entity. Inheritance is likewise not what an ALS gene would predict: alongside autosomal dominant transmission and de novo variants, three probands had recessive homozygous variants whose heterozygous carriers were asymptomatic. The disease_term is MONDO's ALS type 22, which is the only MONDO concept for this gene; it under-describes the entry, and the mapping caveat is recorded in the notes. Muscle involvement is predominantly axial and paraspinal, creatine kinase ranges from normal to highly elevated, cardiac function is preserved across the reported cohort, and biopsies show heterogeneous myopathic change including nemaline bodies, core-like regions and internal nuclei with accumulations positive for TDP-43, p62 and TUBA4A itself.

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2
Inheritance
3
Pathophys.
8
Phenotypes
1
Gaps
12
Pathograph
1
Genes
2
Medical Actions
5
References
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
The predominant mode: heterozygous missense variants transmitted dominantly or arising de novo.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A"
Documents dominant transmission in four families of the multicentre myo-tubulinopathy cohort.
Autosomal recessive inheritance HP:0000007
A minority but genuine mode, and a departure from what the gene's ALS association would predict: three probands carried homozygous variants while their heterozygous carrier relatives were asymptomatic.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic"
Establishes a recessive mode with unaffected heterozygous carriers, widening the inheritance model beyond dominant/de novo.
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Discussions and Knowledge Gaps

1
What determines whether a TUBA4A variant produces isolated myopathy, spastic ataxia, ALS/FTD, or multisystem proteinopathy?
KNOWLEDGE GAP OPEN gap_tuba4a_phenotype_determination
Attached to
pathophysiology#Altered Alpha-Tubulin 4A (TUBA4A) Function pathophysiology#Skeletal Muscle Myopathic Change
TUBA4A now spans four clinical territories, and the striking fact is the proportions: 17 of 19 families in the largest series had myopathy with no CNS involvement at all, in a gene originally described as an ALS gene. Something determines the tissue that fails. There is a real lead - variant domain position correlates with both the pattern of muscle involvement and the extent of microtubule disruption - but that analysis was run within the myopathy cohort, so it explains variation inside the muscle arm rather than the choice between muscle and CNS. Inheritance adds a second unexplained axis: the same gene carries dominant, de novo and recessive alleles, and a recessive allele with unaffected heterozygous carriers implies a different mechanism from a dominant de novo one. Resolving this needs the domain-position analysis extended across all four phenotype groups, with tissue-specific expression or isotype-compensation data to explain why muscle tolerates or fails to tolerate a given lesion differently from motor neurons.
Show evidence (2 references)
PMID:41678358 SUPPORT Human Clinical
"Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease."
The proportion that makes tissue selectivity the central question for this gene.
PMID:41678358 SUPPORT In Vitro
"Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption."
The partial answer available - domain position predicts muscle pattern - which does not yet extend to the muscle-versus-CNS choice.
⚙

Pathophysiology

3
Altered Alpha-Tubulin 4A (TUBA4A) Function
Missense variants alter the alpha-tubulin 4A isotype. Patient-derived fibroblasts carrying distinct TUBA4A missense variants show significant alterations in microtubule organization and dynamics, and in silico and in vitro work indicates the variants cause protein abnormalities that may differentially affect microtubule dynamics. Domain position matters: variant location within TUBA4A correlates both with the pattern of muscle involvement and with the extent of microtubule disruption, so this is one of the few tubulin genes where a structure-phenotype relationship has been measured directly.
TUBA4A hgnc:12407 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TUBA4A (hgnc:12407). hgnc:12407 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: UNKNOWN
The myopathy and spastic-ataxia cohorts considered at this node carry missense variants. The broader ALS literature also includes one nonsense, one splice-site and one frameshift variant, so missense is not an accurate locus-wide description. The mechanism class remains unresolved: the same gene carries dominant, de novo and recessive alleles, and a recessive allele whose heterozygous carriers are unaffected may behave differently from a dominant de novo allele. A single functional_impact_category is therefore unlikely to be correct across the full phenotypic spectrum.
microtubule cytoskeleton organization GO:0000226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated microtubule cytoskeleton organization (GO:0000226). GO:0000226 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Skeletal Muscle Myopathic Change Perturbed microtubule function in skeletal muscle produces the myopathic phenotype that dominates the reported cohort.
Motor Neuron and Cerebellar Dysfunction TUBA4A perturbation is associated with CNS dysfunction rather than, or in addition to, myopathy in a minority of the myopathy cohort and in separate neurological cohorts.
Show evidence (4 references)
PMID:38884572 SUPPORT In Vitro
"Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity."
Direct measurement of the microtubule lesion in patient cells across three distinct variants.
PMID:41678358 SUPPORT In Vitro
"Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics."
Supports the molecular lesion and its non-uniformity across variants.
PMID:41678358 SUPPORT In Vitro
"Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption."
Establishes a measured relationship between variant domain, microtubule disruption and clinical pattern.
+ 1 more reference
Skeletal Muscle Myopathic Change
The dominant arm. Muscle involvement is predominantly axial and paraspinal. Biopsies show heterogeneous myopathic changes - myofibre size variation, nemaline bodies, core-like regions and internal nuclei - with immunohistochemical accumulations positive for TDP-43, p62 and TUBA4A itself. The protein accumulations are what connect this arm to the proteinopathy branch rather than leaving it a structural myopathy. Creatine kinase is variable from normal to highly elevated, and cardiac function was preserved across the whole reported cohort.
muscle structure development GO:0061061 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated muscle structure development (GO:0061061). GO:0061061 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Myopathy The clinical myopathy phenotype.
Elevated Creatine Kinase Variable CK elevation reflects the myopathic process.
Show evidence (4 references)
PMID:41678358 SUPPORT Human Clinical
"Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei."
Reports the histopathological substrate of this node.
PMID:38413182 SUPPORT Human Clinical
"The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles."
Provides independent histopathologic support from two congenital-myopathy patients carrying the recurrent de novo p.Leu227Phe variant.
PMID:41678358 SUPPORT Human Clinical
"Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6)."
Documents the protein aggregates, including TUBA4A itself, that link the myopathy to the proteinopathy phenotype.
+ 1 more reference
Motor Neuron and Cerebellar Dysfunction
The neurological arm, and historically the first to be recognised. TUBA4A has a ClinGen Moderate relationship with autosomal dominant ALS22, and a segregating missense variant has been reported in one extended family with FTD. A separate 448-proband ataxia screen plus a 100,000 Genomes burden analysis support a hereditary spastic-ataxia association with variable age of onset. In the myo-tubulinopathy cohort, CNS involvement appeared in two of nineteen families, coexisting with muscle weakness and protein aggregation - the combination the authors call a multisystem proteinopathy.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Cerebellar Ataxia Cerebellar involvement.
Spasticity Corticospinal involvement.
Multisystem Proteinopathy Coexisting neurodegenerative and neuromuscular features with protein aggregation define the multisystem proteinopathy presentation.
Epilepsy Epilepsy in the CNS-involved myo-tubulinopathy families.
Amyotrophic Lateral Sclerosis The ClinGen Moderate autosomal dominant ALS22 relationship.
Frontotemporal Dementia Familial FTD reported with a segregating TUBA4A variant.
Show evidence (3 references)
PMID:38884572 SUPPORT Human Clinical
"Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia."
Establishes the spastic ataxia phenotype and its genetic support across 12 patients.
CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z SUPPORT Other
"In summary, there is moderate evidence to support this gene-disease relationship."
Records the current expert-panel assessment of the ALS arm rather than relying on an article's historical summary of the association.
PMID:34169147 SUPPORT Human Clinical
"We identified a likely pathogenic variant in TUBA4A segregating with disease."
Supports the FTD arm with segregation in an extended family; it does not establish a Definitive FTD relationship by itself.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for TUBA4A-related Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Metabolism 1
Elevated Creatine Kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"Creatine kinase levels were variable, ranging from normal to highly elevated."
Reports the CK range, including normal values.
Musculoskeletal 2
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease."
Establishes isolated myopathy as the majority presentation in the cohort.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38884572 SUPPORT Human Clinical
"we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation"
Reports spasticity as a presenting feature of the CNS arm.
Nervous System 4
Cerebellar Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation."
Documents ataxia in the CNS-involved minority of the cohort.
Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation."
Documents epilepsy in the multisystem presentations.
Amyotrophic Lateral Sclerosis HP:0007354 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amyotrophic lateral sclerosis (HP:0007354). HP:0007354 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z SUPPORT Other
"At least 14 variants have been reported in relation to ALS (mostly missense, as well as one nonsense, one splice site, and one frameshift)."
Directly documents reported TUBA4A-associated ALS cases; the separate external assertion records the expert-panel Moderate classification.
Frontotemporal Dementia HP:0002145 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontotemporal dementia (HP:0002145). HP:0002145 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34169147 SUPPORT Human Clinical
"In this study we demonstrate segregation of a likely pathogenic TUBA4A variant in a family with FTD without concomitant ALS."
Documents the segregating FTD-only family while avoiding a stronger validity claim than one pedigree supports.
Other 1
Multisystem Proteinopathy
HPO has no suitable term for multisystem proteinopathy, so this phenotype is deliberately left unbound rather than assigned an ALS term that would assert a phenotype not reported for every patient.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy."
Defines the entity and its constituent features.
🧬

Genetic Associations

1
TUBA4A (Causative)
Gene: TUBA4A (alpha-tubulin 4A) hgnc:12407 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TUBA4A (alpha-tubulin 4A), annotated with TUBA4A (hgnc:12407). hgnc:12407 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:41678358 SUPPORT Human Clinical
"In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families."
The multicentre cohort that establishes the breadth of TUBA4A disease alleles.
PMID:38413182 SUPPORT Human Clinical
"We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy."
Supplies independent recurrence and de novo evidence for the congenital myopathy arm.
PMID:38884572 SUPPORT Human Clinical
"Identification of an additional five unrelated patients carrying de novo missense mutations, including three impacting the same residue (Pro173) clearly indicates TUBA4A causal role in the disease."
Supports causality for the monoallelic spastic-ataxia arm.
+ 2 more references
🗃️

External Assertions

2
ClinGen TUBA4A-amyotrophic lateral sclerosis type 22 gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
ClinGen's Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation Expert Panel classifies the autosomal dominant TUBA4A-amyotrophic lateral sclerosis type 22 relationship as Moderate under SOP11, recurated 2025-03-27. This supports the ALS arm while making clear that it is not yet a Definitive relationship.
Show evidence (1 reference)
CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z SUPPORT Other
"In summary, there is moderate evidence to support this gene-disease relationship."
Records the expert-panel strength of the TUBA4A-ALS22 relationship.
ClinGen TUBA4A-autosomal dominant macrothrombocytopenia gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z
Recorded only as an anti-conflation guard. ClinGen's Hemostasis/Thrombosis Gene Curation Expert Panel classifies the TUBA4A-autosomal dominant macrothrombocytopenia relationship as Limited and explicitly curates it separately from ALS because the phenotypes and proposed mechanisms differ.
Show evidence (1 reference)
CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z SUPPORT Other
"Based on differences in phenotype and proposed molecular mechanisms these disease entiteis have been considered seperately and the relationship to ALS was curated by the ALS GCEP."
Provides expert-panel support for keeping macrothrombocytopenia outside this neuromuscular and neurodegenerative entry.
💊

Medical Actions

2
Supportive Care and Surveillance Context
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
The cited phenotype cohort did not evaluate a disorder-specific intervention, so this entry represents management as supportive care rather than naming a disease-modifying therapy. Cardiac function remained preserved across that cohort; this is relevant context for individualized surveillance planning, but it does not establish that surveillance can be reduced.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"Cardiac function remained preserved across the cohort."
Supports only the cardiac cohort observation and its surveillance context; the study did not test a supportive-care intervention.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counselling is complicated here in a way it is not for most tubulinopathies, because the inheritance model is genuinely mixed - dominant transmission, de novo variants, and recessive homozygous variants with asymptomatic heterozygous carriers all occur in the same gene. Recurrence risk cannot be quoted from the gene alone.
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic;..."
The recessive families are why recurrence risk must be established per family rather than assumed dominant.
🔬

Diagnosis

2
Muscle biopsy
Biopsy can show heterogeneous myopathic change with nemaline bodies, core-like regions and internal nuclei. In the 2026 cohort, immunohistochemistry found accumulations positive for TDP-43 in two samples, p62 in five and TUBA4A in six; their diagnostic sensitivity and specificity have not been established.
muscle biopsy NCIT:C15189 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6)."
Reports the immunohistochemical findings that support the diagnosis.
Molecular genetic testing
Sequencing identifies the TUBA4A missense variant. Because most reported individuals have no CNS involvement, TUBA4A must be on the differential for axial myopathy and not only for ALS - which is the practical message of the 2026 cohort.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41678358 SUPPORT Human Clinical
"These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement."
States the diagnostic implication directly, including that CNS involvement is not required.
{ }

Source YAML

click to show 
name: TUBA4A-related Disorder
creation_date: "2026-08-20T16:30:00Z"
category: Mendelian
disease_term:
  preferred_term: amyotrophic lateral sclerosis type 22
  term:
    id: MONDO:0014531
    label: amyotrophic lateral sclerosis type 22
description: >-
  TUBA4A-related disorder is the tubulinopathy that is not a brain malformation
  and, in most reported families, not a central nervous system disease at all.
  TUBA4A encodes an alpha-tubulin 4A isotype whose disease associations have
  widened repeatedly since it was first linked to familial amyotrophic lateral
  sclerosis and frontotemporal dementia. It now spans three phenotypic groups:
  the original ALS/FTD neurodegenerative presentations; hereditary spastic ataxia
  with variable age of onset; and - newly delineated in 2026 - the
  myo-tubulinopathies, in which a myopathy occurs with no CNS involvement
  whatsoever.

  The myopathy arm is the reason this entry exists as a distinct concept rather
  than as an ALS subtype. In a 31-individual, 19-family multicentre series, 17
  families presented with myopathy and no CNS disease or history of it. Two
  further families showed cerebellar ataxia and epilepsy alongside proximal and
  axial weakness with protein aggregation, which the authors define as a
  multisystem proteinopathy - the first association of TUBA4A with that entity.
  Inheritance is likewise not what an ALS gene would predict: alongside autosomal
  dominant transmission and de novo variants, three probands had recessive
  homozygous variants whose heterozygous carriers were asymptomatic.

  The disease_term is MONDO's ALS type 22, which is the only MONDO concept for
  this gene; it under-describes the entry, and the mapping caveat is recorded in
  the notes. Muscle involvement is predominantly axial and paraspinal, creatine
  kinase ranges from normal to highly elevated, cardiac function is preserved
  across the reported cohort, and biopsies show heterogeneous myopathic change
  including nemaline bodies, core-like regions and internal nuclei with
  accumulations positive for TDP-43, p62 and TUBA4A itself.
parents:
- hereditary neurological disease
- neuromuscular disease
- neurodegenerative disease
references:
- reference: PMID:41678358
  title: Missense variants in TUBA4A cause myo-tubulinopathies.
- reference: PMID:38884572
  title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
- reference: PMID:38413182
  title: Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation.
- reference: PMID:34169147
  title: Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.
- reference: PMID:30760556
  title: An essential role for α4A-tubulin in platelet biogenesis.
external_assertions:
- name: ClinGen TUBA4A-amyotrophic lateral sclerosis type 22 gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z"
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
  description: >-
    ClinGen's Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation
    Expert Panel classifies the autosomal dominant TUBA4A-amyotrophic lateral
    sclerosis type 22 relationship as Moderate under SOP11, recurated
    2025-03-27. This supports the ALS arm while making clear that it is not yet
    a Definitive relationship.
  evidence:
  - reference: CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
    reference_title: TUBA4A / amyotrophic lateral sclerosis type 22 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is moderate evidence to support this gene-disease
      relationship.
    explanation: >-
      Records the expert-panel strength of the TUBA4A-ALS22 relationship.
- name: ClinGen TUBA4A-autosomal dominant macrothrombocytopenia gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z"
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z
  description: >-
    Recorded only as an anti-conflation guard. ClinGen's Hemostasis/Thrombosis
    Gene Curation Expert Panel classifies the TUBA4A-autosomal dominant
    macrothrombocytopenia relationship as Limited and explicitly curates it
    separately from ALS because the phenotypes and proposed mechanisms differ.
  evidence:
  - reference: CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z
    reference_title: TUBA4A / autosomal dominant macrothrombocytopenia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Based on differences in phenotype and proposed molecular mechanisms these disease entiteis have been considered seperately and the relationship to ALS was curated by the ALS GCEP."  # codespell:ignore-line
    explanation: >-
      Provides expert-panel support for keeping macrothrombocytopenia outside
      this neuromuscular and neurodegenerative entry.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The predominant mode: heterozygous missense variants transmitted dominantly
    or arising de novo.
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four families demonstrated autosomal dominant transmission through
      heterozygous variants in TUBA4A
    explanation: >-
      Documents dominant transmission in four families of the multicentre
      myo-tubulinopathy cohort.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A minority but genuine mode, and a departure from what the gene's ALS
    association would predict: three probands carried homozygous variants while
    their heterozygous carrier relatives were asymptomatic.
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      three probands had recessive inheritance due to homozygous variants, while
      the respective heterozygous carriers were asymptomatic
    explanation: >-
      Establishes a recessive mode with unaffected heterozygous carriers,
      widening the inheritance model beyond dominant/de novo.
pathophysiology:
- name: Altered Alpha-Tubulin 4A (TUBA4A) Function
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    Missense variants alter the alpha-tubulin 4A isotype. Patient-derived
    fibroblasts carrying distinct TUBA4A missense variants show significant
    alterations in microtubule organization and dynamics, and in silico and in
    vitro work indicates the variants cause protein abnormalities that may
    differentially affect microtubule dynamics. Domain position matters: variant
    location within TUBA4A correlates both with the pattern of muscle involvement
    and with the extent of microtubule disruption, so this is one of the few
    tubulin genes where a structure-phenotype relationship has been measured
    directly.
  genetic_context:
    functional_impact_category: UNKNOWN
    variant_origin: GERMLINE
    description: >-
      The myopathy and spastic-ataxia cohorts considered at this node carry
      missense variants. The broader ALS literature also includes one nonsense,
      one splice-site and one frameshift variant, so missense is not an accurate
      locus-wide description. The mechanism class remains unresolved: the same
      gene carries dominant, de novo and recessive alleles, and a recessive allele
      whose heterozygous carriers are unaffected may behave differently from a
      dominant de novo allele. A single functional_impact_category is therefore
      unlikely to be correct across the full phenotypic spectrum.
  genes:
  - preferred_term: TUBA4A
    term:
      id: hgnc:12407
      label: TUBA4A
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:38884572
    reference_title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cultured fibroblasts from three patients harbouring distinct TUBA4A
      missense showed significant alterations in microtubule organization and
      dynamics, providing insight of TUBA4A variants pathogenicity.
    explanation: >-
      Direct measurement of the microtubule lesion in patient cells across three
      distinct variants.
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Complementary in silico and in vitro investigations suggested that the
      identified TUBA4A variants cause significant protein abnormalities and may
      differentially impact microtubule dynamics.
    explanation: >-
      Supports the molecular lesion and its non-uniformity across variants.
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Correlation analyses integrating clinical severity, variant location, and
      mechanistic readouts further demonstrated that domain specificity within
      TUBA4A influences both the pattern of muscle involvement and the extent of
      microtubule disruption.
    explanation: >-
      Establishes a measured relationship between variant domain, microtubule
      disruption and clinical pattern.
  - reference: CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
    reference_title: TUBA4A / amyotrophic lateral sclerosis type 22 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TUBA4A mutants appear to disrupt microtubule dynamics and stability through
      a dominant-negative mechanism, however there is an absence of functional
      data from primary tissue of TUBA4A mutation carriers.
    explanation: >-
      Supports a candidate dominant-negative mechanism for ALS-associated
      variants while preserving ClinGen's explicit primary-tissue limitation.
  downstream:
  - target: Skeletal Muscle Myopathic Change
    description: >-
      Perturbed microtubule function in skeletal muscle produces the myopathic
      phenotype that dominates the reported cohort.
  - target: Motor Neuron and Cerebellar Dysfunction
    description: >-
      TUBA4A perturbation is associated with CNS dysfunction rather than, or in
      addition to, myopathy in a minority of the myopathy cohort and in separate
      neurological cohorts.
- name: Skeletal Muscle Myopathic Change
  biological_scale: TISSUE
  description: >-
    The dominant arm. Muscle involvement is predominantly axial and paraspinal.
    Biopsies show heterogeneous myopathic changes - myofibre size variation,
    nemaline bodies, core-like regions and internal nuclei - with
    immunohistochemical accumulations positive for TDP-43, p62 and TUBA4A itself.
    The protein accumulations are what connect this arm to the proteinopathy
    branch rather than leaving it a structural myopathy. Creatine kinase is
    variable from normal to highly elevated, and cardiac function was preserved
    across the whole reported cohort.
  biological_processes:
  - preferred_term: muscle structure development
    term:
      id: GO:0061061
      label: muscle structure development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsies showed heterogenous myopathic changes, including myofibre
      size variation, nemaline bodies, core-like regions, and internal nuclei.
    explanation: Reports the histopathological substrate of this node.
  - reference: PMID:38413182
    reference_title: Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prominent myopathological changes in both patients were muscle fibres
      with focal myofibrillar disorganisation and rimmed vacuoles.
    explanation: >-
      Provides independent histopathologic support from two congenital-myopathy
      patients carrying the recurrent de novo p.Leu227Phe variant.
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical analysis revealed protein accumulations positive for
      TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6).
    explanation: >-
      Documents the protein aggregates, including TUBA4A itself, that link the
      myopathy to the proteinopathy phenotype.
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical phenotypes ranged from mild to severe myopathy, predominantly
      affecting the axial and paraspinal muscles.
    explanation: Establishes the distribution and severity range of muscle involvement.
  downstream:
  - target: Myopathy
    description: The clinical myopathy phenotype.
  - target: Elevated Creatine Kinase
    description: Variable CK elevation reflects the myopathic process.
- name: Motor Neuron and Cerebellar Dysfunction
  biological_scale: TISSUE
  description: >-
    The neurological arm, and historically the first to be recognised.
    TUBA4A has a ClinGen Moderate relationship with autosomal dominant ALS22,
    and a segregating missense variant has been reported in one extended family
    with FTD. A separate 448-proband ataxia screen plus a 100,000 Genomes burden
    analysis support a hereditary spastic-ataxia association with variable age
    of onset. In the myo-tubulinopathy cohort, CNS involvement appeared in two of
    nineteen families, coexisting with muscle weakness and protein aggregation -
    the combination the authors call a multisystem proteinopathy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:38884572
    reference_title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taken together, we report 12 patients presenting with spasticity and/or
      cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense
      mutation, including five confirmed de novo cases and a mutation previously
      reported in a large family presenting with spastic ataxia.
    explanation: >-
      Establishes the spastic ataxia phenotype and its genetic support across 12
      patients.
  - reference: CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
    reference_title: TUBA4A / amyotrophic lateral sclerosis type 22 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is moderate evidence to support this gene-disease
      relationship.
    explanation: >-
      Records the current expert-panel assessment of the ALS arm rather than
      relying on an article's historical summary of the association.
  - reference: PMID:34169147
    reference_title: Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a likely pathogenic variant in TUBA4A segregating with
      disease.
    explanation: >-
      Supports the FTD arm with segregation in an extended family; it does not
      establish a Definitive FTD relationship by itself.
  downstream:
  - target: Cerebellar Ataxia
    description: Cerebellar involvement.
  - target: Spasticity
    description: Corticospinal involvement.
  - target: Multisystem Proteinopathy
    description: >-
      Coexisting neurodegenerative and neuromuscular features with protein
      aggregation define the multisystem proteinopathy presentation.
  - target: Epilepsy
    description: Epilepsy in the CNS-involved myo-tubulinopathy families.
  - target: Amyotrophic Lateral Sclerosis
    description: The ClinGen Moderate autosomal dominant ALS22 relationship.
  - target: Frontotemporal Dementia
    description: Familial FTD reported with a segregating TUBA4A variant.
phenotypes:
- name: Myopathy
  description: >-
    Proximal and axial muscle weakness, predominantly affecting axial and
    paraspinal muscles, ranging from mild to severe with onset from congenital to
    late adulthood. This is the presenting and often only feature.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Remarkably, individuals in 17 families presented with a myopathy without
      any CNS involvement or history of such disease.
    explanation: >-
      Establishes isolated myopathy as the majority presentation in the cohort.
- name: Elevated Creatine Kinase
  description: >-
    Creatine kinase is unhelpfully variable - normal in some individuals and
    highly elevated in others - so a normal CK does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Creatine kinase levels were variable, ranging from normal to highly
      elevated.
    explanation: Reports the CK range, including normal values.
- name: Cerebellar Ataxia
  description: >-
    Cerebellar ataxia, present in the spastic-ataxia presentation and in the two
    multisystem proteinopathy families.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the remaining two families, we observed probands with cerebellar ataxia
      and epilepsy accompanying proximal and axial muscle weakness along with
      protein aggregation.
    explanation: Documents ataxia in the CNS-involved minority of the cohort.
- name: Spasticity
  description: Corticospinal involvement with spasticity, in the spastic ataxia presentation.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:38884572
    reference_title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report 12 patients presenting with spasticity and/or cerebellar ataxia
      and harbouring a predicted pathogenic TUBA4A missense mutation
    explanation: Reports spasticity as a presenting feature of the CNS arm.
- name: Multisystem Proteinopathy
  description: >-
    The coexistence of neuromuscular and neurodegenerative features with protein
    aggregation. The 2026 cohort establishes the first association between TUBA4A
    and multisystem proteinopathy.
  notes: >-
    HPO has no suitable term for multisystem proteinopathy, so this phenotype is
    deliberately left unbound rather than assigned an ALS term that would assert
    a phenotype not reported for every patient.
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The coexistence of neuromuscular and neurodegenerative features with
      protein aggregation defines a multisystem proteinopathy.
    explanation: Defines the entity and its constituent features.
- name: Epilepsy
  description: >-
    Epilepsy accompanied cerebellar ataxia and axial/proximal weakness in the two
    CNS-involved families in the 2026 myo-tubulinopathy cohort.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the remaining two families, we observed probands with cerebellar ataxia
      and epilepsy accompanying proximal and axial muscle weakness along with
      protein aggregation.
    explanation: Documents epilepsy in the multisystem presentations.
- name: Amyotrophic Lateral Sclerosis
  description: >-
    The historically first neurodegenerative presentation and the phenotype to
    which this entry's MONDO term refers. ClinGen classifies the autosomal
    dominant TUBA4A-ALS22 relationship as Moderate.
  phenotype_term:
    preferred_term: Amyotrophic lateral sclerosis
    term:
      id: HP:0007354
      label: Amyotrophic lateral sclerosis
  evidence:
  - reference: CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
    reference_title: TUBA4A / amyotrophic lateral sclerosis type 22 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At least 14 variants have been reported in relation to ALS (mostly
      missense, as well as one nonsense, one splice site, and one frameshift).
    explanation: >-
      Directly documents reported TUBA4A-associated ALS cases; the separate
      external assertion records the expert-panel Moderate classification.
- name: Frontotemporal Dementia
  description: >-
    Familial frontotemporal dementia without concomitant ALS has been reported
    with a segregating TUBA4A p.Arg105Cys variant and FTLD-TDP type A pathology.
  phenotype_term:
    preferred_term: Frontotemporal dementia
    term:
      id: HP:0002145
      label: Frontotemporal dementia
  evidence:
  - reference: PMID:34169147
    reference_title: Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we demonstrate segregation of a likely pathogenic TUBA4A
      variant in a family with FTD without concomitant ALS.
    explanation: >-
      Documents the segregating FTD-only family while avoiding a stronger
      validity claim than one pedigree supports.
genetic:
- name: TUBA4A
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TUBA4A (alpha-tubulin 4A)
    term:
      id: hgnc:12407
      label: TUBA4A
  notes: >-
    A single gene with an unusually wide reach: ALS and frontotemporal dementia,
    hereditary spastic ataxia, isolated congenital-to-adult myopathy, and
    multisystem proteinopathy - across dominant, de novo and recessive
    inheritance.
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this multi-centre study, we identified one previously reported and 12
      novel TUBA4A missense variants in 31 individuals from 19 unrelated
      families.
    explanation: >-
      The multicentre cohort that establishes the breadth of TUBA4A disease
      alleles.
  - reference: PMID:38413182
    reference_title: Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F)
      variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two
      unrelated patients with clinicopathologically diagnosed sporadic
      congenital myopathy.
    explanation: >-
      Supplies independent recurrence and de novo evidence for the congenital
      myopathy arm.
  - reference: PMID:38884572
    reference_title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of an additional five unrelated patients carrying de novo
      missense mutations, including three impacting the same residue (Pro173)
      clearly indicates TUBA4A causal role in the disease.
    explanation: Supports causality for the monoallelic spastic-ataxia arm.
  - reference: CGGV:assertion_7349d6e4-f351-4a8a-80f6-af62d3e716e5-2025-03-27T160000.000Z
    reference_title: TUBA4A / amyotrophic lateral sclerosis type 22 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is moderate evidence to support this gene-disease
      relationship.
    explanation: Supports the ALS22 arm at ClinGen's Moderate validity level.
  - reference: PMID:34169147
    reference_title: Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we demonstrate segregation of a likely pathogenic TUBA4A
      variant in a family with FTD without concomitant ALS.
    explanation: Supports the familial FTD arm with segregation evidence.
diagnosis:
- name: Muscle biopsy
  description: >-
    Biopsy can show heterogeneous myopathic change with nemaline bodies,
    core-like regions and internal nuclei. In the 2026 cohort,
    immunohistochemistry found accumulations positive for TDP-43 in two samples,
    p62 in five and TUBA4A in six; their diagnostic sensitivity and specificity
    have not been established.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical analysis revealed protein accumulations positive for
      TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6).
    explanation: Reports the immunohistochemical findings that support the diagnosis.
- name: Molecular genetic testing
  description: >-
    Sequencing identifies the TUBA4A missense variant. Because most reported
    individuals have no CNS involvement, TUBA4A must be on the differential for
    axial myopathy and not only for ALS - which is the practical message of the
    2026 cohort.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results underscore the importance of considering TUBA4A variants in
      the differential diagnosis of axial myopathies and multisystem
      proteinopathies, regardless of central nervous system (CNS) involvement.
    explanation: >-
      States the diagnostic implication directly, including that CNS involvement
      is not required.
treatments:
- name: Supportive Care and Surveillance Context
  description: >-
    The cited phenotype cohort did not evaluate a disorder-specific
    intervention, so this entry represents management as supportive care rather
    than naming a disease-modifying therapy. Cardiac function remained preserved
    across that cohort; this is relevant context for individualized surveillance
    planning, but it does not establish that surveillance can be reduced.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac function remained preserved across the cohort.
    explanation: >-
      Supports only the cardiac cohort observation and its surveillance context;
      the study did not test a supportive-care intervention.
- name: Genetic Counseling
  description: >-
    Counselling is complicated here in a way it is not for most tubulinopathies,
    because the inheritance model is genuinely mixed - dominant transmission, de
    novo variants, and recessive homozygous variants with asymptomatic
    heterozygous carriers all occur in the same gene. Recurrence risk cannot be
    quoted from the gene alone.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our cohort exhibited diverse genotypes and inheritance patterns: four families
      demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A,
      three probands had recessive inheritance due to homozygous variants, while the
      respective heterozygous carriers were asymptomatic; five probands carried de novo
      variants, and nine probands with heterozygous variants were classified as sporadic
      cases.
    explanation: >-
      The recessive families are why recurrence risk must be established per
      family rather than assumed dominant.
discussions:
- discussion_id: gap_tuba4a_phenotype_determination
  prompt: >-
    What determines whether a TUBA4A variant produces isolated myopathy, spastic
    ataxia, ALS/FTD, or multisystem proteinopathy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Alpha-Tubulin 4A (TUBA4A) Function
  - pathophysiology#Skeletal Muscle Myopathic Change
  rationale: >-
    TUBA4A now spans four clinical territories, and the striking fact is the
    proportions: 17 of 19 families in the largest series had myopathy with no CNS
    involvement at all, in a gene originally described as an ALS gene. Something
    determines the tissue that fails. There is a real lead - variant domain
    position correlates with both the pattern of muscle involvement and the extent
    of microtubule disruption - but that analysis was run within the myopathy
    cohort, so it explains variation inside the muscle arm rather than the choice
    between muscle and CNS. Inheritance adds a second unexplained axis: the same
    gene carries dominant, de novo and recessive alleles, and a recessive allele
    with unaffected heterozygous carriers implies a different mechanism from a
    dominant de novo one. Resolving this needs the domain-position analysis
    extended across all four phenotype groups, with tissue-specific expression or
    isotype-compensation data to explain why muscle tolerates or fails to tolerate
    a given lesion differently from motor neurons.
  evidence:
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Remarkably, individuals in 17 families presented with a myopathy without
      any CNS involvement or history of such disease.
    explanation: >-
      The proportion that makes tissue selectivity the central question for this
      gene.
  - reference: PMID:41678358
    reference_title: Missense variants in TUBA4A cause myo-tubulinopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Correlation analyses integrating clinical severity, variant location, and
      mechanistic readouts further demonstrated that domain specificity within
      TUBA4A influences both the pattern of muscle involvement and the extent of
      microtubule disruption.
    explanation: >-
      The partial answer available - domain position predicts muscle pattern -
      which does not yet extend to the muscle-versus-CNS choice.
notes: >-
  Created 2026-08-20 while closing out tubulin-family disease coverage, following
  docs/reports/tubulinopathies-grouping-review-2026-08-20.md, which flagged the
  2026 myo-tubulinopathy delineation as a genuinely new tubulin disease entity
  with no DisMech entry.

  MAPPING CAVEAT. disease_term is MONDO:0014531, amyotrophic lateral sclerosis
  type 22, because that is the only MONDO concept for TUBA4A. It under-describes
  this entry substantially: the majority of reported individuals have myopathy
  with no CNS involvement, and MONDO has no concept for TUBA4A-related
  myo-tubulinopathy or for the multisystem proteinopathy presentation. This is an
  upstream ontology gap of the same family as the tubulinopathy-hierarchy gap
  recorded in monarch-initiative/dismech#9113. Curators reusing this
  disease_term should read the entry, not the term label.

  SCOPE GUARD. TUBA4A-related autosomal dominant macrothrombocytopenia has its
  own MONDO identity (MONDO:0015372) and a substantially independent
  platelet-biogenesis mechanism (PMID:30760556). ClinGen classifies that
  relationship as Limited and explicitly considers it separately from ALS based
  on phenotypic and proposed mechanistic differences. Under the separate-entry
  rule in docs/explanation/design-decisions.md section 2, that disease is not
  lumped into this neuromuscular/neurodegenerative entry despite the broad
  filename.

  Deliberately NOT a member of the Tubulinopathies grouping and NOT conformed to
  microtubule_dependent_neuronal_migration_failure: there is no cortical
  malformation and no neuronal migration defect in this disorder. The grouping's
  notes already record TUBA4A as out of scope.

  functional_impact_category is UNKNOWN by deliberate choice - a gene carrying
  dominant, de novo and recessive alleles in the same cohort is unlikely to have
  one mechanism class.

  All evidence snippets are quoted from cached abstracts.
📚

References & Deep Research

References

5
PMID:41678358
Missense variants in TUBA4A cause myo-tubulinopathies.
No top-level findings curated for this source.
PMID:38884572
De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
No top-level findings curated for this source.
PMID:38413182
Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation.
No top-level findings curated for this source.
PMID:34169147
Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.
No top-level findings curated for this source.
PMID:30760556
An essential role for α4A-tubulin in platelet biogenesis.
No top-level findings curated for this source.