IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURESDe novo variants present only in the index case and not in unaffected family members. RESULTSTrio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

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This study aims to explore the potential impairment of Theory of Mind (ToM; i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration. Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioral, and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT), and Eyes Task (ET). ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances, and “Mental Health” scores among QoL items. Our results suggest that not only “cognitive” but also “affective” subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients’ “Mental Health.”

Objective. The Montreal Cognitive Assessment (MoCA) is a screening test widely used in clinical practice and suited for detection of Mild Cognitive Impairment. Alternate forms of the MoCA were developed to avoid "learning effect" in serial assessments, and the present study aimed at investigating inter-form parallelism and at providing normative values for the Italian versions of MoCA 2 and 3. Method. Three separate convenience samples were recruited: the first (n= 78) completed three alternate MoCA versions for ascertaining inter-form parallelism; the second (n= 302) and the third (n= 413) samples were administered MoCA 2 or 3 to compute normative data. Results. A three-step procedure complemented by confirmatory factor analysis and a mixed factorial ANOVA suggested that the three MoCA versions are not strictly parallel. Multiple linear regression analysis revealed that age and education significantly influenced MoCA 2 and 3 total scores. No significant effect of sex was found. From the derived linear equation, correction grids for MoCA 2 and 3 raw scores were built and equivalent scores computed. Inferential cutoff for adjusted scores, estimated using a non-parametric technique, were 17.49 for MoCA 2 and 18.34 for MoCA 3. Correlation analysis showed strong correlations of MoCA 2 (r= 0.69, p< .001) and MoCA 3 (r= 0.61, p< .001) adjusted total scores with MMSE adjusted scores. Conclusion. The three MoCA forms are not strictly parallel. Specifically developed normative data must be adopted for using MoCA in serial cognitive assessments for clinical and research studies.

Objective. Advanced neuroimaging techniques may offer the potential to monitor disease progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative, multisystem disease that still lacks therapeutic outcome measures. We aim to investigate longitudinal functional and structural magnetic resonance imaging (MRI) changes in a cohort of patients with ALS monitored for one year after diagnosis. Methods. Resting state functional MRI, diffusion tensor imaging (DTI), and voxel-based morphometry analyses were performed in 22 patients with ALS examined by six-monthly MRI scans over one year. Results. During the follow-up period, patients with ALS showed reduced functional connectivity only in some extramotor areas, such as the middle temporal gyrus in the left frontoparietal network after six months and in the left middle frontal gyrus in the default mode network after one year without showing longitudinal changes of cognitive functions. Moreover, after six months, we reported in the ALS group a decreased fractional anisotropy (P = .003, Bonferroni corrected) in the right uncinate fasciculus. Conversely, we did not reveal significant longitudinal changes of functional connectivity in the sensorimotor network, as well as of gray matter (GM) atrophy or of DTI metrics in motor areas, although clinical measures of motor disability showed significant decline throughout the three time points. Conclusion. Our findings highlighted that progressive impairment of extramotor frontotemporal networks may precede the appearance of executive and language dysfunctions and GM changes in ALS. Functional connectivity changes in cognitive resting state networks might represent candidate radiological markers of disease progression.