Autosomal dominant spastic paraplegia type 4 (SPG4, SPAST gene) is commonly described as a pure phenotype, with progressive spastic weakness of the lower limbs. Some cognitive disorders have been reported but remain difficult to characterize. Brain flurodesoxyglucose (18F-FDG) PET is a sensitive biomarker of glycolytic metabolism and shows loss of neuronal activity. Our objective was to describe the cognitive impairment of SPG4 patients, supported by brain 18F-FDG PET, to characterize the cognitive pattern and its localization. Twenty subjects from the Grand Est region, with a pathogenic variant in the SPAST gene, were included. Each patient had to undergo a neuropsychological assessment, a brain 18F-FDG PET scan, and a SPATAX-EuroSpa clinical assessment, including the Spastic Paraplegia Rating Scale (SPRS). Brain 18F-FDG PET was analyzed semiquantitatively after comparison with age and sex-matched control subjects. The study population was 65% (13/20) female, with an average age of 50 years (19-75 years). The median SPRS was 15/52 (12-45). Forty-six percent (7/15) of patients had a deficient Montreal Cognitive Assessment (MoCA) score (score <26) without any severe impairment (score <10). Assessments with a pathological score of <1.65 standard deviations or at the 5th percentile included verbal episodic memory in 16-item Free and Cued Recall Test (16-FCRT; 63%, 10/16), facial emotion recognition (56%, 9/16), and executive functions (Trail Making Test A and B; 47%, 7/15; the Stroop; 47%, 7/15; digit span of Weschler Adult Intelligence Scale 4; 38%, 6/16). Compared with those of control subjects, 18-FDG PET images of the brains of SPG4 subjects revealed frontotemporal and precuneus hypometabolism, principally in the prefrontal cortex, which was mainly mesial (P voxel value <0.001, corrected for the size of the familywise error (FWE) cluster, k = 1464). Frontal hypometabolism was correlated with age at onset (k = -0.475, P = 0.046) and the time to perform the Trail Making Test B test (k = -0.597, P = 0.019). Here, we describe a mild cognitive disorder clinically in SPG4 patients, associated with an hypometabolism on 18F-FDG PET imaging, which mainly corresponded to frontotemporal localization. Mild cognitive dysfunction should be screened in SPG4, as it can have a significant impact on socioprofessional life. Brain 18F-FDG PET, combined with neuropsychological assessment appears to be a good screening and follow-up examination for cognitive disorders.

Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns. With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome. This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome. Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.

With treatment trials on the horizon, this study aimed to identify candidate digital-motor gait outcomes for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), capturable by wearable sensors with multicenter validity, and ideally also ecological validity during free walking outside laboratory settings. Cross-sectional multicenter study (four centers), with gait assessments in 36 subjects (18 ARSACS patients; 18 controls) using three body-worn sensors (Opal, APDM) in laboratory settings and free walking in public spaces. Sensor gait measures were analyzed for discriminative validity from controls, and for convergent (ie, clinical and patient relevance) validity by correlations with SPRSmobility (primary outcome) and Scale for the Assessment and Rating of Ataxia (SARA), Spastic Paraplegia Rating Scale (SPRS), and activities of daily living subscore of the Friedreich Ataxia Rating Scale (FARS-ADL) (exploratory outcomes). Of 30 hypothesis-based digital gait measures, 14 measures discriminated ARSACS patients from controls with large effect sizes (|Cliff's δ| > 0.8) in laboratory settings, with strongest discrimination by measures of spatiotemporal variability Lateral Step Deviation (δ = 0.98), SPcmp (δ = 0.94), and Swing CV (δ = 0.93). Large correlations with the SPRSmobility were observed for Swing CV (Spearman's ρ = 0.84), Speed (ρ = -0.63), and Harmonic Ratio V (ρ = -0.62). During supervised free walking in a public space, 11/30 gait measures discriminated ARSACS from controls with large effect sizes. Large correlations with SPRSmobility were here observed for Swing CV (ρ = 0.78) and Speed (ρ = -0.69), without reductions in effect sizes compared with laboratory settings. We identified a promising set of digital-motor candidate gait outcomes for ARSACS, applicable in multicenter settings, correlating with patient-relevant health aspects, and with high validity also outside laboratory settings, thus simulating real-life walking with higher ecological validity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics. UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts. Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia. Spastic paraplegia 15 (SPG15), typically an early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction. While onset of spasticity is typically in mid- to late childhood or adolescence (i.e., between ages 5 and 18 years), other manifestations, such as developmental delay or learning disability, may be present earlier, often preceding motor involvement. Individuals with adult onset have also been reported. The diagnosis of SPG15 is established in a proband with suggestive findings and biallelic pathogenic variants in ZFYVE26 identified by molecular genetic testing. Findings suggestive of SP15 on brain MRI may include thinning of the corpus callosum and characteristic signal changes in the periventricular white matter, known as the "ears of the lynx" sign. Treatment of manifestations: At present, no treatment prevents, halts, or reverses neuronal degeneration in SPG15. Treatment is directed at reducing symptoms and preventing secondary complications. Multidisciplinary care involving a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, speech and language pathologist, and feeding and nutrition team is recommended. Surveillance: Affected individuals should be evaluated periodically (i.e., every 6-12 months) by an interdisciplinary team to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations. SPG15 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a ZFYVE26 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ZFYVE26 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.