Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve. To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease). In this prospective multicenter study, 3D-T1-weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters. The pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7. Evaluation of the pons-to-superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI-ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society.

SPG30 is a newly categorized type of HSP caused by variants in the kinesin family member 1A gene (KIF1A). Advances in next-generation sequencing have resulted in a limited number of studies describing the clinical, electrophysiological, and radiological features of HSP, with variable manifestations. Most known pathogenic KIF1A variants affect the motor domain, although some rare pathogenic variants have been identified that affect the non-motor domain. Here, we report a Korean family with a rare homozygous autosomal-recessive form of SPG30. A 59-year-old man and his father presented with an uncomplicated, mild SPG30 phenotype, characterized by a progressive, spastic gait. Familial co-segregation analysis revealed a pathogenic c.2751_2753delGGA KIF1A variant that affects the non-motor domain. Our case broadens the genetic and clinical variability of SPG30, warranting similar studies to consolidate the pathogenicity of SPG30.

PNS and CNS myelin contain large amounts of galactocerebroside and sulfatide with 2-hydroxylated fatty acids. The underlying hydroxylation reaction is catalyzed by fatty acid 2-hydroxylase (FA2H). Deficiency in this enzyme causes a complicated hereditary spastic paraplegia, SPG35, which is associated with leukodystrophy. Mass spectrometry-based proteomics of purified myelin isolated from sciatic nerves of Fa2h-deficient (Fa2h-/-) mice revealed an increase in the concentration of the three proteins Cadm4, Mpp6 (Pals2), and protein band 4.1G (Epb41l2) in 17-month-old, but not in young (4 to 6-month-old), Fa2h-/- mice. These proteins are known to form a complex, together with the protein Lin7, in Schmidt-Lanterman incisures (SLIs). Accordingly, the number of SLIs was significantly increased in 17-month-old but not 4-month-old Fa2h-/- mice compared to age-matched wild-type mice. On the other hand, the relative increase in the SLI frequency was less pronounced than expected from Cadm4, Lin7, Mpp6 (Pals2), and band 4.1G (Epb41l2) protein levels. This suggests that the latter not only reflect the higher SLI frequency but that the concentration of the Cadm4 containing complex itself is increased in the SLIs or compact myelin of Fa2h-/- mice and may potentially play a role in the pathogenesis of the disease. The proteome data are available via ProteomeXchange with identifier PXD030244.

Haploinsufficiency is widely accepted as the pathogenic mechanism of spastic paraplegia type 4 (SPG4). However, there are some cases that cannot be explained by reduced function of the spastin protein encoded by SPAST. To identify the causative gene of autosomal dominant hereditary spastic paraplegia in three large Chinese families and explore the pathological mechanism of a spastin variant. Three large Chinese hereditary spastic paraplegia families with a total of 247 individuals (67 patients) were investigated, of whom 59 members were recruited to the study. Genetic testing was performed to identify the causative gene. Western blotting and immunofluorescence were used to analyze the effects of the mutant proteins in vitro. In the three hereditary spastic paraplegia families, of whom three index cases were misdiagnosed as other types of neurological diseases, a novel c.985dupA (p.Met329Asnfs*3) variant in SPAST was identified and was shown to cosegregate with the phenotype in the three families. The c.985dupA mutation produced two truncated mutants (mutant M1 and M87 isoforms) that accumulated to a higher level than their wild-type counterparts. Furthermore, the mutant M1 isoform heavily decorated the microtubules and rendered them resistant to depolymerization. In contrast, the mutant M87 isoform was diffusely localized in both the nucleus and the cytoplasm, could not decorate microtubules, and was not able to promote microtubule disassembly. SPAST mutations leading to premature stop codons do not always act through haploinsufficiency. The truncated spastin may damage the corticospinal tracts through an isoform-specific toxic effect.

Uniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a complex neurodevelopmental disorder was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed. A combination of clinical, molecular, and imaging data and functional studies in patient-derived fibroblasts. We report a 4-year-old female with a blended, complex phenotype of Silver-Russell syndrome (SRS) and hereditary spastic paraplegia type 50 (SPG50) caused by total maternal isodisomy of chromosome 7 (UPiD(7)mat) and a loss-of-function variant in AP4M1 (NM_00472.3: c.59-1G>C, IVS1-1G>C). Functional studies in patient-derived fibroblasts confirmed the loss of adaptor protein complex 4 function. Distinctive facial features, intrauterine growth restriction, short stature, feeding difficulties, and severe gastroesophageal reflux were consistent with SRS. Features associated with SPG50 included early-onset epilepsy, episodes of stereotypical laughter, and thinning of the corpus callosum and ventriculomegaly on brain MRI. Symptoms shared by both syndromes such as developmental delay, short stature, and axial and appendicular hypotonia were also present. Notably, other common manifestations of SPG50 such as microcephaly or spasticity had not developed yet. This case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity.