Abstract Details

Title Classification of Mutations in TUBB4A: A New Spectrum of Disease

Topic Child Neurology and Developmental Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-031

Objective To conduct a subtype analysis of children with mutations in the β-tubulin gene, TUBB4A, including canonical Hypomyelination with Atrophy of the Basal Ganglia (H-ABC).

Background TUBB4A associated leukodystrophy is now known to encompass a spectrum of presentations, but limited data is available on genotype-phenotype correlations or distinct cohorts within this disorder.

Design/Methods We retrospectively extracted clinical data from individuals with TUBB4A mutations including genotype, age at onset, clinical signs at presentation, maximum motor milestone, GMFCS score (Gross Motor Functional Classification), and evaluated time to specific clinical milestones, including gastrostomy placement. Kaplan Meier was used for survival analysis. Wilcoxon rank sum test distinguished differences between subtypes.

Results Three clinically distinct subtypes emerged amongst 125 individuals. Type I is a rare, milder presentation with onset between 6-24 months and preservation of walking into the fifth decade. Type II (70% of total) presents between birth and 4 years with a median age of onset at 9.5 months. The best achieved motor milestone is at least supported (95%) or independent walking (63%). Independent ambulation was lost by 25 years, with a median age of 8. The canonical H-ABC p.Asp249Asn mutation (32% of total) was closely associated with Type II. Individuals carrying p.Asp249Asn were more likely to reach independent ambulation, but lost ambulation and needed gastrostomy placement sooner within the Type II cohort (p<0.0001). Type III (24%) is an early-onset presentation before 9 months. Common features include hypotonia, developmental delay, and nystagmus. Type III patients need gastrostomy placement significantly sooner than p.Asp249Asn individuals (p<0.0001), and these individuals have severe developmental outcomes. Other recurrent mutations were rare, limiting analysis of their contribution to subgroups.

Conclusions We expand upon the known phenotypic spectrum of TUBB4A mutations, highlighting three distinct clinical subsets in a spectrum of disease with limited phenotype correlation to regionally clustered locations of TUBB4A mutations.

Authors/Disclosures
Brittany A. Charsar, MD, PhD (Children's Hospital of Philadelphia) PRESENTER	No disclosure on file
	No disclosure on file
Zachary Cross	No disclosure on file
Omar Sherbini	No disclosure on file
Julia Kramer-Golinkoff	No disclosure on file
	No disclosure on file
Marjo Van Der Knaap, MD, PhD (VU University Medical Center)	The institution of Marjo Van Der Knaap, MD, PhD has received research support from Calico. The institution of Marjo Van Der Knaap, MD, PhD has received research support from Ionis.
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia)	An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.

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