Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I

Dawkins, Jennifer L.; Hulme, D.J.; Brahmbhatt, Sonal; Auer‐Grumbach, Michaela; Nicholson, Garth A.

doi:10.1038/85879

Cited by 399 publications

(294 citation statements)

References 17 publications

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“…Emerging evidence indicates that aberrant Cer and GSL metabolism has an important role in the pathogenesis of a number of neuromuscular diseases including HSP, HSN1, and non-5q SMA (14)(15)(16)(17)28). Here, we show that alterations in GSLs are also a feature of ALS and provide evidence to suggest that these changes likely influence the rate of disease progression.…”

Section: Discussionsupporting

confidence: 57%

“…For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine palmitoyltransferase long chain base subunit-1 (SPTLC1), the rate-limiting enzyme in Cer synthesis. Notably, certain mutations in SPTLC1 associated with HSNT1 result in elevated levels of Cer and GlcCer (14). In addition, mutations in acid ceramidase (ASHA1), an enzyme that mediates the hydrolysis of Cer, are linked to forms of spinal muscular atrophy that are not caused by the more frequent mutations in the survival motor neuron 1 gene (non-5q SMA) (15).…”

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confidence: 99%

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Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

141

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Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1 G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1 G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2-9)-all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine...

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Section: Discussionsupporting

confidence: 57%

mentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

141

View full text Add to dashboard Cite

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“…On the basis of the clinical data and the electrophysiological results of the nerve conduction studies, our family could have been classified as having a sensorimotor axonal form of CMT with autonomic dysfunction. In this respect, the serine palmitoyltransferase long chain base subunit-1 gene was recently associated with an autosomal dominant form of hereditary sensory and autonomic neuropathy (Bejaoui et al, 2001;Dawkins et al, 2001), which does not however, share the electrophysiological features of the affected individuals of our family, who had significantly reduced motor conduction velocities. Indeed, several CMT families carrying an MPZ gene mutation and showing an axonal phenotype with late onset have been described (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;De Jonghe et al, 1999;Misu et al, 2000).…”

Section: Discussionmentioning

confidence: 86%

Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

Stojkovic

Seze

Dubourg³

et al. 2003

Clinical Neurophysiology

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Objective: To report the clinical and electrophysiological characteristics of a family presenting Charcot -Marie-Tooth disease (CMT) associated with autonomic nervous system disturbances.Methods: We studied nerve conduction values, postural adaptation, sympathetic skin reflex, the variation in heart rate by the Valsalva ratio and pupillometry in 7 members of a French family in which CMT due to a Thr124Met mutation in the myelin protein zero (MPZ) gene was diagnosed.Results: Clinical and laboratory evidence of autonomic nervous system disturbances were found in the affected individuals. The clinical phenotype was characterized by sensorimotor peripheral neuropathy, defined as axonal type by electrophysiological studies, and was associated with severe pain, bladder dysfunction, sudorimotor disturbances and abolished pupillary reflex to light. Moreover, two patients had severe restrictive respiratory insufficiency requiring noninvasive mechanical ventilation.Conclusions: Our study demonstrates that autonomic disturbances may be one of the major clinical signs associated with CMT secondary to MPZ gene mutation in codon 124. Testing of pupillary reflex allows the discrimination of affected and unaffected subjects in our family. However, involvement of the autonomic nervous system in this type of neuropathy is unclear and further studies are required to elucidate the role of the MPZ gene in the autonomic nervous system.

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“…Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, only three human diseases are associated with mutations in enzymes involved in de novo GSL synthesis and patients are extremely rare. 15,19,20 The identification of the p.Arg288* mutation in a Amish pedigree is the only example of a GM3 synthase deficiency reported in the literature but without any reference to a mitochondrial dysfunction. 15 Contrary to our family, no reference to deafness was reported by Simpson et al 15 Nevertheless, mice lacking GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti demonstrating that GM3 is essential for acquisition and maintenance of hearing.…”

Section: Discussionmentioning

confidence: 99%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

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Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I

Cited by 399 publications

References 17 publications

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

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