SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.

[A case of superficial siderosis with repeated episodes of epilepsy].

We report a patient with superficial siderosis that repeated episodes of epilepsy. The patient was a 62-year-old male, and underwent an operation for the tumor of the spinal cord at 22 years of age. He had become deaf at 50 years of age, and repeated loss of consciousness at 59 years of age and later. Neurological examination revealed cerebellar ataxia and bilateral sensorineural deafness in addition to paraplegia, which was caused by the spinal cord tumor. Brain MRI showed low intensity rim around the brain stem, cerebellar hemisphere, and inferior aspects of the temporal and frontal lobes, being consistent with superficial siderosis. Hemosiderin deposition for an extended period was considered to contribute to the pathogenesis of epilepsy.

[A case of multifocal acquired demyelinating sensory and motor neuropathy with whole body alopecia].

A 42 years-old male noticed alopecia in 2006. Three years later, he had loss of hair in the whole body and weakness in the left upper limb. Prednisolone treatment failed to alleviate these symptoms. In 2011, he was diagnosed multifocal acquired demyelinating sensory and motor neuropathy and treated by intravenous immunoglobulin (IVIg), which improved muscle strength eventually. Three years later, he had remitting weakness of the limbs, and thus underwent again IVIg with amelioration of both alopecia and weakness in the limbs. Association of multifocal acquired demyelinating sensory and motor neuropathy and alopecia, and their improvement by immunomodulatory treatment strongly suggest a role of immunological pathomechanism.

[Spastic paraplegia caused by a novel mutation in the spastin gene (1207C-->G, P361R)--clinical features of a patient without family history].

A 52-year-old man with no apparent family history of neurodegenerative diseases developed gait disturbance at age 47. Neurological examination at aged 52 revealed spastic paraplegia, generalized hyperreflexia, decreased of vibration sense in the lower limbs, and pollakisuria. Ocular symptoms, deafness, cerebellar ataxia, extrapyramidal signs, mental deterioration, dementia, peripheral neuropathy, retinal pigment degeneration, ichthyosis and syndactyly were absent. MRI of the brain was normal. A pure form of hereditary spastic paraplegia was diagnosed. Genetic analysis revealed a novel missense mutation in the spastin gene (1207C --> G, P361R). The clinical features of this patient were consistent with those of patient with the pure form of SPG4. Gene analysis should be considered for patients with spastic paraplegia even in the absence of any family history.

Four mutations of the spastin gene in Japanese families with spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A-->G, 1207C-->G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.