Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)

Houlden, Henry; King, R. H. M.; Blake, Julian; Groves, Mike; Love, Seth; Woodward, Cathy E.; Hammans, Simon; Nicoll, James; Lennox, Graham; O’Donovan, Dominic G; Gabriel, Carolyn; Thomas, P K; Reilly, Mary M.

doi:10.1093/brain/awh712

Cited by 129 publications

(137 citation statements)

References 24 publications

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“…HSN-1 is the most common HSN subtype resulting in the progressive degeneration and dying back of neurons in the dorsal root ganglia. Despite its initial characterisation over 50 years ago [7] and the identification of critical mutations in the SPTLC1 gene, the molecular mechanisms underlying disease development and progression still remain poorly understood [8,9].…”

Section: Introductionmentioning

confidence: 99%

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

et al. 2014

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Hereditary sensory neuropathy type 1 (HSN-1) is an autosomal dominant neurodegenerative disease caused by missense mutations in the SPTLC1 gene. The SPTLC1 protein is part of the SPT enzyme which is a ubiquitously expressed, critical and thus highly regulated endoplasmic reticulum bound membrane enzyme that maintains sphingolipid concentrations and thus contributes to lipid metabolism, signalling, and membrane structural functions. Lipid droplets are dynamic organelles containing sphingolipids and membrane bound proteins surrounding a core of neutral lipids, and thus mediate the intracellular transport of these specific molecules. Current literature suggests that there are increased numbers of lipid droplets and alterations of lipid metabolism in a variety of other autosomal dominant neurodegenerative diseases, including Alzheimer's and Parkinson's disease. This study establishes for the first time, a significant increase in the presence of lipid droplets in HSN-1 patient-derived lymphoblasts, indicating a potential connection between lipid droplets and the pathomechanism of HSN-1. However, the expression of adipophilin (ADFP), which has been implicated in the regulation of lipid metabolism, was not altered in lipid droplets from the HSN-1 patient-derived lymphoblasts. This appears to be the first report of increased lipid body accumulation in a peripheral neuropathy, suggesting a fundamental molecular linkage between a number of neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

et al. 2014

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“…Sensory loss occurred in a glove and stocking distribution; pinprick perception was affected to a greater extent than vibration perception, similar to patients with SPTLC1 mutations. 16 Patient III-2 had painful tingling in the hands whereas IV-2 had no history of pain. Sensory complications including ulcers and accidental burns occurred in both patients, and severe wasting and weakness were present (figure e-2).…”

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confidence: 99%

“…Although this was predominantly an axonal neuropathy, motor conduction velocities in the upper limbs were slow (,38 m/s), even in patient III-2 who had reasonable upper limb motor amplitudes, a finding that we have previously documented in our HSANI families with SPTLC1 mutations. 16 Plasma sphingoid and deoxysphingoid base levels. Total sphinganine (SA) or sphingosine (SO) levels showed no difference between SPTLC2-A182P patients and healthy controls, whereas the 1-deoxySL levels were elevated in the plasma of the two A182P carriers.…”

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confidence: 99%

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Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2

Murphy

Ernst

et al. 2013

Neurology

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Objective: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. Methods:We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays.Results: A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. Conclusion:This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI. Hereditary sensory and autonomic neuropathy type 1 (HSANI) is an autosomal dominant (AD) sensory neuropathy complicated by ulcerations and amputations, with variable autonomic and motor involvement.1 To date, mutations in 5 genes have been reported to cause AD HSANI. 2-7Mutations in the enzyme serine palmitoyltransferase (SPT) cause HSANI. 2,3 SPT is a heteromeric enzyme composed of 3 subunits (SPTLC1-3) located at the outer membrane of the endoplasmic reticulum. 8,9 It catalyzes the first and rate-limiting step in de novo sphingolipid synthesis: the condensation of L-serine and palmitoyl-coenzyme A. Mutations in SPTLC1 account for 12% of patients with HSAN. 10 More recently, mutations in SPTLC2 were found to cause HSANI with a similar phenotype.4 SPTLC1 and SPTLC2 mutations generally cause a shift in the substrate specificity of SPT leading to the alternative use of L-alanine and L-glycine over its canonical substrate L-serine. 11,12 This forms an atypical category of 1-deoxysphingolipids (1-deoxySLs) lacking the C1 hydroxyl group, which impedes their conversion into complex sphingolipids but also their canonical degradation. Elevated 1-deoxySLs were found in the plasma and lymphoblasts of patients with HSANI 11 and plasma and tissues of transgenic HSANI *Joint first authors. These authors contributed equally to this work. ‡Joint senior authors.From the

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“…In HSN type 1, there is a wide variability of electrophysiological abnormalities. Sensory potentials are usually absent in the lower limbs but can be normal in the upper limbs 4 . Previous reports illustrated clinical and genetic heterogeneity of HSN 1.…”

Section: Introductionmentioning

confidence: 99%

Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux

Barros

Morais

Santos

et al. 2014

Arq. Neuro-Psiquiatr.

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In 2002, Spring et al reported a family with an autosomal dominant form of hereditary sensory neuropathy; patients also presented adult onset of gastroesophageal reflux and cough. Since then, no further families have been described. Objective: To study a new Portuguese family with these characteristics. Method: To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. Results: Three of five siblings presented a similar history of paroxysmal cough (5 th decade). About a decade later they experienced numbness and paraesthesia in the feets and in all cases there was evidence of an axonal sensory neuropathy. A history of gastroesophageal reflux of variable severity and age of onset was also present. Discussion: Molecular genetic studies have demonstrated genetic heterogeneity between the hereditary sensory neuropathy type 1 subtypes. The identification of these families is of major importance because further work is required to identify the underlying genetic defect.

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Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)

Cited by 129 publications

References 24 publications

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2

Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux

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