Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

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 Participants: In 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 Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio 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.</p

Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome

Purpose Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. Methods A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. Results Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). Conclusion Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis

Developing multidisciplinary clinics for neuromuscular care and research

ABSTRACT Multidisciplinary care is considered the standard of care for both adult and pediatric neuromuscular disorders and has been associated with improved quality of life, resource utilization, and health outcomes. Multidisciplinary care is delivered in multidisciplinary clinics that coordinate care across multiple specialties by reducing travel burden and streamlining care. In addition, the multidisciplinary care setting facilitates the integration of clinical research, patient advocacy, and care innovation (e.g., telehealth). Yet, multidisciplinary care requires substantial commitment of staff time and resources. We calculated personnel costs in our ALS clinic in 2015 and found an average cost per patient visit of $580, of which only 45% was covered by insurance reimbursement. In this review, we will describe classic and emerging concepts in multidisciplinary care models for adult and pediatric neuromuscular disease. We will then explore the financial impact of multidisciplinary care with emphasis on sustainability and metrics to demonstrate quality and value. Muscle Nerve 56: 848–858, 201

Understanding Relationships Between Autism, Intelligence, and Epilepsy: A Cross-Disorder Approach

Aim As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy. Method The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype. Results A total of 180 SRS questionnaires were filled out in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21y, range 4–63y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9y range 4–22y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism. Interpretation Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific for these conditions

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

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 Participants: In 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 Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio 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.