Spasticity represents a core clinical feature of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) patients. Nonetheless, its pathophysiological substrate is poorly investigated. We assessed the microstructural integrity of the corticospinal tract (CST) using diffusion MRI (dMRI) via profilometry analysis to understand its possible role in the development of spasticity in ARSACS. In this multi-center prospective study, data of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years) and 29 controls (M/F = 13/16; 42.1 ± 17.2 years) acquired within the PROSPAX consortium were collected from January 2021 to October 2022 and analyzed. Differences in terms of global CST microstructural integrity were probed, as well as a possible spatial distribution of the damage along the tract via profilometry analysis. Possible correlations between clinical severity, including the Spastic Paraplegia Rating Scale (SPRS), were also tested. A significant global involvement of the CST was found in ARSACS compared to controls (all tests with p < 0.001), with a spatially defined pattern of more pronounced microstructural integrity loss occurring right below and above the pons, a structure that was also confirmed to be thickened in these patients (p < 0.001). A bilateral negative correlation emerged between the microstructural integrity of the CST and clinical indices of spasticity expressed via SPRS (p = 0.02 for both CSTs). A clinically meaningful microstructural involvement of CST is present in ARSACS patients, with a spatially defined pattern of damage occurring right below and above a thickened pons. An evaluation of the microstructure of this bundle might serve as a possible biomarker in this condition.

Spastic ataxic syndrome is a combination of cerebellar ataxia with spasticity and other pyramidal features. Common causes of spastic ataxic syndrome include spinocerebellar ataxia (SCA) 1, SCA2, autosomal recessive ataxia of Charlevoix-Saguenay, Friedreich ataxia, and hereditary spastic paraplegia type-7. We report a 32-year-old female who presented with unsteadiness of gait, incoordination, and tremulousness of both hands for 10 years with microphthalmia, microdontia, dental caries, and syndactyly. Magnetic resonance imaging of the brain showed T2 fluid-attenuated inversion recovery hyper intensities in periventricular and lobar white matter and internal capsule. Thus, we report a genetically confirmed oculodentodigital dysplasia (ODDD), an autosomal dominant disorder, in an Indian patient who presented with spastic ataxic syndrome, a rarity that has not been reported so far.

Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST. Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder. We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4. Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.

Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

Intracellular transport is essential for neuronal function and survival. The most effective plus-end-directed neuronal transporter is the kinesin-3 KIF1C, which transports large secretory vesicles and endosomes.1-4 Mutations in KIF1C cause hereditary spastic paraplegia and cerebellar dysfunction in human patients.5-8 In contrast to other kinesin-3s, KIF1C is a stable dimer and a highly processive motor in its native state.9,10 Here, we establish a baseline for the single-molecule mechanics of Kif1C. We show that full-length KIF1C molecules can processively step against the load of an optical trap and reach average stall forces of 3.7 pN. Compared with kinesin-1, KIF1C has a higher propensity to slip backward under load, which results in a lower maximal single-molecule force. However, KIF1C remains attached to the microtubule while slipping backward and re-engages quickly, consistent with its super processivity. Two pathogenic mutations, P176L and R169W, that cause hereditary spastic paraplegia in humans7,8 maintain fast, processive single-molecule motility in vitro but with decreased run length and slightly increased unloaded velocity compared with the wild-type motor. Under load in an optical trap, force generation by these mutants is severely reduced. In cells, the same mutants are impaired in producing sufficient force to efficiently relocate organelles. Our results show how its mechanics supports KIF1C's role as an intracellular transporter and explain how pathogenic mutations at the microtubule-binding interface of KIF1C impair the cellular function of these long-distance transporters and result in neuronal disease.