Objective: Expand upon the current phenotypic understanding of those with KIF1A-associated neurological disorder (KAND), including late onset progressive cerebellar ataxia (CA).

Background: KAND encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A, a gene that encodes an anterograde neuronal microtubule motor protein. (1) Variants in KIF1A were previously noted in families with autosomal recessive (AR) spastic paraparesis (SP) or sensory and autonomic neuropathy type-2. Evidence shows that heterozygous missense variants in the motor domain of KIF1A cause a phenotype that overlaps with the classic AR phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, SP, optic nerve atrophy, peripheral neuropathy, and epilepsy. (2)

Method: Retrospective chart review of a single case characterizing the presenting symptoms of a patient with KIF1Aheterozygous de novo missense variant.

Results: A 27-year-old female with history of cerebral palsy (CP), intellectual disability, bipolar disorder, anxiety, OCD, and ADHD presented with progressive balance and gait difficulty over 2 years. No history of pregnancy or birth complications; she did have delay in developmental milestones requiring early intervention. Since childhood, she reported mild baseline left hemibody motor deficits due to CP, though no changes in balance or gait. Her exam showed signs of CA including saccadic intrusions, bi-directional nystagmus, dysmetria, dysdiadochokinesia, and ataxic gait. Laboratory evaluation for reversible causes of ataxia was unrevealing. MRI Brain showed cerebellar atrophy, out of proportion to patients age. Initial genetic testing with a comprehensive ataxia panel (Athena Diagnostics) was negative. Whole exome sequencing (GeneDx) revealed a de novo heterozygous pathogenic variant (c. 173C>T, p.S58L) in the KIF1A gene.

Conclusion: We present a unique case of a pathogenic heterozygous de novo missense variant in the KIF1A gene (c.173 C>T, p.S58L) manifesting as late onset progressive CA. KAND are rare, though typically manifest as a pure form of SP.  Reports of this specific variant are limited, therefore this case expands upon the currently known phenotypic spectrum associated with pathogenic variants in this gene.  As a result, KAND should be considered in the differential diagnosis in those with progressive CA.

References: 1. Boyle L, Rao L, Kaur S, Fan X, Mebane C, Hamm L, Thornton A, Ahrendsen JT, Anderson MP, Christodoulou J, Gennerich A, Shen Y, Chung WK. Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder. HGG Adv. 2021 Apr 8;2(2):100026. doi: 10.1016/j.xhgg.2021.100026. Epub 2021 Jan 30. PMID: 33880452; PMCID: PMC8054982.

2. Lee JR, Srour M, Kim D, Hamdan FF, Lim SH, Brunel-Guitton C, Décarie JC, Rossignol E, Mitchell GA, Schreiber A, Moran R, Van Haren K, Richardson R, Nicolai J, Oberndorff KM, Wagner JD, Boycott KM, Rahikkala E, Junna N, Tyynismaa H, Cuppen I, Verbeek NE, Stumpel CT, Willemsen MA, de Munnik SA, Rouleau GA, Kim E, Kamsteeg EJ, Kleefstra T, Michaud JL. De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Hum Mutat. 2015 Jan;36(1):69-78. doi: 10.1002/humu.22709. Epub 2014 Nov 27. PMID: 25265257.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/late-onset-cerebellar-ataxia-in-a-patient-with-a-heterozygous-pathogenic-kif1a-mutation-a-case-report/