Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

Abstract

Background: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. Materials and Methods: The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. Results: Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. Conclusions: The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.

Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder

“…We report a high frequency of seizures and/or abnormal EEGs, similar to previous studies [29][30][31] . The caregiver report of epilepsy is reliable and was verified by medical record review and/or review of clinical EEGs.…”

“…The most common clinical characteristics in our cohort were hypotonia, spasticity, difficulty with coordination, ataxia, seizures, neuropathy, optic nerve atrophy, cerebellar atrophy, and cognitive impairment, similar to the previous studies 1,[27][28][29][30][31] . This cohort which spans the age of 6 months to 58 years with an average age at follow-up of 9.1 years shows that some individuals are young and earlier in the disease course and are gaining developmental skills while others are losing skills and show signs of neurodegeneration.…”

“…From previous reports, cognitive function in individuals with KAND ranges from normal to profound intellectual disability 28,30,31,35 . We used standard cognitive and adaptive function assessments to quantify the cognitive profile.…”

Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells

“…Overall, our work suggests that inner ear deficits may contribute to phenotypes in human KAND patients. For example, KAND is associated with cerebellar ataxia, and although there is evidence of cerebellar atrophy in KAND patients, it is possible that there are also contributions from the inner ear, particularly the vestibular system where hair cells must maintain sustained release of synaptic vesicles for proper balance ( Paprocka et al, 2023 ). In the future it will be important to assess KAND patients carefully for hearing and balance deficits.…”

Striving for inclusivity: the crucial function of neurorehabilitation in the management of KIF1A syndrome

“…Activation of KIF1A occurs upon cargo binding, enabling transport along microtubules ( 1 ). Initially identified in 2011, these illnesses often went undiagnosed due to limited access to comprehensive genetic testing methods like full gene sequencing and exome sequencing ( 1 ), later on in the year 2022 the prevalence of KIF1A estimated as 3–10/100,000 ( 2 ). Recent findings reveal de-novo mutations linked to brain atrophy and progressive encephalopathy.…”