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. 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. 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. The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.

KIF1A, a gene that encodes a neuron-specific motor protein, plays important roles in cargo transport along neurites. Variants in KIF1A have been described in three different disorders, and neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment syndrome (NESCAVS) is the severest phenotype. A 3-year-old girl was born at term with a birth weight of 2590 g. At five months of age, she visited our hospital due to developmental delay. An EEG showed multiple epileptic discharge, and a nerve conduction study showed severe axonopathy of both motor and sensory nerves. We performed exome sequencing and identified a de novo heterozygous missense variant in KIF1A (NM_001244008.1: c. 757G > A, p.E253K). At six months of age, she developed acute encephalopathy, multiple organ failure and disseminated intravascular coagulation, necessitating intensive care. Her brain CT showed severe brain edema, followed by profound brain atrophy. We diagnosed hemorrhagic shock and encephalopathy syndrome (HSES) according to the clinico-radiological features. Currently, she is bed-ridden, and requires gastrostomy because of dysphagia. The clinical course of our case confirmed that p.E253K is associated with severe neurological features. Severe KIF1A deficiency could cause thermoregulatory dysfunction and may increase the risk of acute encephalopathy including HSES.

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in KIF1A have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel de novo missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, in silico structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect of the R169T variant on the KIF1A protein together with the presence of the typical clinical features indicates its causal pathogenic effect.