TUBB4A – Hypomyelinating Leukodystrophy 6 (H-ABC)

TUBB4A encodes the brain-specific β-tubulin isotype and is associated with autosomal dominant hypomyelinating leukodystrophy 6, also known as hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (Disease). Affected individuals present in infancy or childhood with motor developmental delay, extrapyramidal signs, spasticity, cerebellar atrophy and diffuse CNS hypomyelination on MRI (PMID:24785942).

Genetic evidence: H-ABC is caused by heterozygous de novo or dominantly inherited TUBB4A missense variants supporting an autosomal dominant inheritance mode. In a cohort of 42 patients harboring TUBB4A mutations, the recurrent c.745G>A (p.Asp249Asn) variant was found in 25 cases, and 13 additional distinct missense changes were identified, all but three confirmed de novo ([PMID:24785942]). A series of 12 patients further expanded the spectrum with c.745G>A recurrent in five and three novel variants in five individuals ([PMID:26643067]). Familial segregation of c.1023C>G (p.Phe341Leu) in three affected members demonstrates transmission in a multigenerational pedigree ([PMID:37867417]).

Variant spectrum: Over 40 pathogenic missense variants have been described. Besides the common p.Asp249Asn allele, case reports include c.785G>A (p.Arg262His) in an infant with PMD-like presentation ([PMID:24974158]), c.1088T>C (p.Met363Thr) in pediatric hypomyelination without basal ganglia atrophy ([PMID:35661708]), and the familial c.1023C>G (p.Phe341Leu) variant in adult-onset spastic paraplegia ([PMID:37867417]).

Phenotypic spectrum: H-ABC patients exhibit infantile hypotonia, motor delay, dystonia, ataxia and cognitive impairment, often with extrapyramidal movement abnormalities and progressive cerebellar atrophy. MRI shows diffuse cerebral hypomyelination with variable basal ganglia involvement; putaminal and cerebellar volume loss can evolve over years ([PMID:24785942], [PMID:26643067]).

Functional evidence: In vitro studies of TUBB4A mutations demonstrate impaired microtubule dynamics and defective oligodendrocyte morphology for hypomyelination-associated alleles (e.g., p.Asp249Asn, p.Arg2Gln) and distinct effects on motor protein interactions ([PMID:28973395], [PMID:24850488]). A knock-in mouse model carrying p.Asp249Asn recapitulates progressive tremor, dystonia, oligodendrocyte loss and neuronal degeneration, confirming dominant toxic gain-of-function as the mechanism ([PMID:32463361]).

Integration & Clinical Utility: The definitive gene–disease association is supported by over 60 unrelated probands, recurrent de novo variants, segregation in families and concordant functional and animal data. Genetic testing for TUBB4A missense variants is recommended in infants and children with unexplained hypomyelination and basal ganglia or cerebellar atrophy to guide prognosis, management and counseling.

Key Take-home: Autosomal dominant TUBB4A sequencing enables definitive diagnosis of H-ABC and informs anticipatory guidance and targeted research efforts.

References

• Brain | 2014 | Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. PMID:24785942
• European Journal of Paediatric Neurology | 2016 | TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients. PMID:26643067
• Neurology | 2014 | Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies. PMID:24850488
• Human Molecular Genetics | 2017 | TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes. PMID:28973395
• eLife | 2020 | TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model. PMID:32463361

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