Dataset Information

Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

ABSTRACT: Dominant mutations in serine palmitoyltransferase long chain base subunit 1 (SPTLC1), a known cause of hereditary sensory autonomic neuropathy type 1 (HSAN1), are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression. We present a case of SPTLC1-associated JALS followed for 30 years. She was initially evaluated at age 22 years for upper extremity weakness. She experienced gradual decline in muscle strength with development of weakness and hyperreflexia in lower extremities and diffuse fasciculations in the upper extremities at 26 years. She lost independent ambulation at age 45 years. Pulmonary function declined from a forced vital capacity of 94% predicted at 27 years to 49% predicted at 47 years, and she was hospitalized twice for respiratory failure. To our knowledge, this is the longest documented follow-up period of JALS caused by a de novo pathogenic variant in SPTLC1.

SUBMITTER: Ajjarapu A

PROVIDER: S-EPMC10368087 | biostudies-literature | 2023 Jan-Dec

REPOSITORIES: biostudies-literature

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Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

Ajjarapu Aparna A Feely Shawna M E SME Shy Michael E ME Trout Christina C Zuchner Stephan S Moore Steven A SA Mathews Katherine D KD

Case reports in neurology 20230101 1

Dominant mutations in serine palmitoyltransferase long chain base subunit 1 (SPTLC1), a known cause of hereditary sensory autonomic neuropathy type 1 (HSAN1), are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression. We present a case of SPTLC1-associated JALS followed for 30 years. She was initially evaluated at age 22 years for upper extremity weakness. She experienced gradual decline in muscle strength with development ...[more]

PMID: 37497262

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Project description:ImportanceJuvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.ObjectiveTo 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 relevanceThese data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Dataset Information

Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

Publications

Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

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