Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Spatial rotational orientation ability in standing children with cerebral palsy.

This study quantified perception and reorientation ability after passive horizontal rotations in thirteen children with cerebral palsy (CP). They stood barefoot on a platform in front of a fixed reference point (static posture task, SPT) and were then blindfolded and passively rotated with six velocity profiles (maximum angular velocity: 57°/s; rotation amplitudes: ±90°, ±180° and ±360°). After the perturbation, the blindfolded children were asked to point to the fixed reference point with their preferred hand (pointing task, PT) and to step back to the initial position on the stationary platform (reorientation task, RT). In order to gain further insight into rotational attitude, the results were comparatively examined with body segment rotations determined using standardized gait analysis (gait task, GT). The kinematic evaluations were conducted using an optoelectronic system: for SPT, PT and RT we confined the analysis, in the horizontal plane, to the head and upper pointing arm of the subject and to the platform; for GT a full body analysis was performed. When CP children were passively rotated towards their more affected side, they overestimated the imposed angle in PT but under-reproduced it in RT. A higher variability emerged in left-hemiplegic children, confirming that the spatial disorganization is predominantly related to right brain lesion. Patients tended to rotate in GT towards the more affected side while in RT they showed an opposite trend.