RARE DISEASE
Hereditary sensory and autonomic neuropathy type 1
Hereditary sensory and autonomic neuropathy type 1
Hereditary sensory and autonomic neuropathy type 1
Synonyms: HSAN1, Hereditary sensory and autonomic neuropathy type I
Synonyms: HSAN1, Hereditary sensory and autonomic neuropathy type I
Synonyms: HSAN1, Hereditary sensory and autonomic neuropathy type I
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1) is a rare autosomal dominant disorder characterized by progressive sensory loss (pain, temperature, and pressure) predominantly in the distal extremities, autonomic dysfunction (e.g., anhidrosis), and variable motor involvement. Symptoms typically emerge in adolescence/adulthood, with complications including painless injuries, chronic ulcers, osteomyelitis, and limb amputations. Mutations in SPTLC1, SPTLC2, ATL1, ATL3, or DNMT1 (HSAN1E subtype) drive sphingolipid metabolism defects, leading to toxic lipid accumulation and neurodegeneration [1][5][12][14].
Therapies
Supportive care: Foot ulcer prevention (diabetic foot protocols), infection management, and protective footwear [1][5][9].
L-serine supplementation: Reduces toxic deoxysphingolipids; clinical trials show slowed progression (400 mg/kg/day) [3][7].
Genetic counseling: Critical for family planning due to 50% inheritance risk [1][5].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
64 drug discovery papers about Hereditary sensory and autonomic neuropathy type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
64 drug discovery papers about Hereditary sensory and autonomic neuropathy type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-03 | Health Equality and Socioeconomic Impact of Hereditary Sensory Neuropathy Type 1 (HSN1) in the UK.
Hereditary Sensory Neuropathy Type 1 (HSN1) is a rare autosomal dominant neuropathy caused by variants in the SPTLC1 and SPTLC2 genes, resulting in sensory loss, motor weakness, chronic ulceration, and risk of limb amputation. Whilst the clinical manifestations are well characterised, the socioeconomic and psychosocial impact remains under-researched and poorly understood. This pilot study aimed to assess the health equality and socioeconomic impact of HSN1 on affected individuals in the UK. A novel 28-item anonymised questionnaire focusing on employment, healthcare access, finance, mobility, and wellbeing was distributed to 50 genetically confirmed HSN1 patients from an UK cohort. Responses were collected electronically. Quantitative and qualitative data were analysed descriptively. A total of 37 participants (74%) responded. Of these, only 24% were in full-time work, with 24% taking early medical retirement. Nearly half (46%) felt the disease negatively impacted career progression. Although 49% requested workplace adjustments, responses were mixed, with some reporting inadequate or denied support. Healthcare access was inconsistent due to long wait times, restrictive referral criteria, and poor awareness of HSN1 outside specialist centres. Financial strain was common; 41% reported income loss, and 21% spent over £1000 annually on disease-related costs. Driving ability was affected in 48%, and over half reported reduced participation in social activities. Nearly half believed healthcare professionals lacked sufficient understanding of the disease. HSN1 imposes a substantial burden beyond physical symptoms, affecting employment, finances, independence, and mental health. These results highlight the need for better patient-centred care and improved education for non-specialist healthcare professionals. This is particularly timely in the context of emerging disease-modifying therapies such as L-serine and future gene therapy trials. SENSE trial NCT06113055.
2026-04-03 | Sphingolipid remodelling in SPT-related neuropathies
Abstract Sphingolipid homeostasis is critical for neuronal structural and functional integrity in the central and peripheral nervous systems. The rate-limiting enzyme of this pathway, serine-palmitoyltransferase (SPT), establishes the metabolic entry point into sphingolipid biosynthesis. Mutations in the SPT subunits, SPTLC1 and SPTLC2 lead to contrasting disease phenotypes in patients, including amyotrophic lateral sclerosis (ALS) and hereditary sensory neuropathy (HSAN1). A third mixed sensory-motor phenotype is attributed to distinct mutation sets in SPTLC1 and SPTLC2. However, a direct comparison of the metabolic consequences of mutations spanning these disease conditions has not been performed. Here, we demonstrate that SPTLC1- and SPTLC2-ALS variants contribute to enhanced sphingolipid flux while the ceramide-mediated homeostatic control is impaired. In contrast, HSAN1-associated variants display altered substrate selectivity, shifting flux towards non-canonical 1-deoxysphingolipid (1-deoxySL) production but decreasing canonical synthesis. The variant associated with a mixed sensory-motor phenotype exhibit a third metabolic state with elevated 1-deoxySL formation and, in contrast to HSAN1-variants, increased canonical sphingolipid synthesis. Sphingolipid profiling reveals that ALS variants are characterized by preferential accumulation of dihydro- and intermediate chain sphingolipid species. Notably, the separation of lipid species between ALS and HSAN1 is robust, with canonical sphingolipids enriched in ALS variants, while long-chain 1-deoxySL dominate in HSAN1. The SPT-variants associated with mixed sensory and motor symptoms are associated with elevated levels of both types. The data support the view that segregated shifts in sphingolipid flux underlie divergence of clinical phenotypes in SPT-variants and offer guidance for therapeutic interventions. Importantly, therapeutic strategies must account for these metabolic configurations, as L-serine supplementation may benefit HSAN1 but exacerbate pathology in ALS and sensory-motor disease conditions.
2025-05-16 | Very long chain fatty acids drive 1-deoxy-Sphingolipid toxicity
Abstract 1-deoxy-sphingolipids (1-deoxySLs) are atypical sphingolipids synthesized by the serine palmitoyltransferase (SPT) when L-alanine is used instead of its canonical substrate L-serine. Increased 1-deoxySLs are associated with sensory neuropathies such as Hereditary Sensory and Autonomic Neuropathy type 1 (HSAN1) and diabetic polyneuropathy (DPN). Despite their known cellular, mitochondrial, and neurotoxic effects, the mechanisms underlying their toxicity remain poorly understood. Using a CRISPR interference (CRISPRi) screening approach, we identified CERS2, ELOVL1, ACACA, HSD17B12, and PTPLB as key mediators of 1-deoxySL-induced toxicity. All genes are integral to the biosynthesis of very long-chain (VLC) fatty acids and VLC-ceramides. We validated these findings through genetic knockdown experiments, cytotoxicity assays, and stable isotope-resolved lipidomics via LC-MS/MS. Pharmacological inhibition of ELOVL1 using a preclinical tested compound alleviated the cellular, mitochondrial, and neuronal toxicity induced by 1-deoxySLs. Supplementation experiments combining 1-deoxySLs with various VLC fatty acids revealed that 1-deoxyDHceramide conjugated to nervonic acid (m18:0/24:1) is the principal toxic specie. Further mechanistic studies showed that m18:0/24:1 induces apoptosis through the mitochondrial permeability transition pore (mPTP) formation. Inhibition of BAX or blocking mPTP formation with cyclosporin A effectively prevented toxicity. In conclusion, our findings demonstrate that 1-deoxyDHCeramides conjugated to nervonic acid are the primary mediators of 1-deoxySL toxicity, acting through mitochondrial dysfunction and BAX-dependent apoptosis.
2025-04-10 | Ultrasound-guided femoral nerve block combined with lateral femoral cutaneous nerve block in a patient with congenital insensitivity to pain and anhidrosis: a case report.
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathies (HSAN I-V), is an exceptionally rare autosomal recessive disorder. The pathogenesis of CIPA remains not fully elucidated. Clinical manifestations primarily include the absence of pain perception, painless injuries to the extremities, oral mutilation, anhidrosis accompanied by hyperthermia, and delayed intellectual development. Given the autonomic dysfunction in CIPA patients, previous reports on anesthetic management for this rare disorder have predominantly depended on general anesthesia or neuraxial anesthesia, both of which pose significant challenges. This case report presents a unique approach to anesthetic management in a child with CIPA, who successfully underwent hollow nail internal fixation for femoral neck fracture under orthopedic navigation using ultrasound-guided femoral nerve block combined with lateral femoral cutaneous nerve block. The patient was sedated with dexmedetomidine and did not require any opioids during the procedure. Her vital signs remained stable throughout the surgery, and her recovery was uneventful, with discharge occurring 5 days post-operation. This case contributes to the medical literature by demonstrating a safe and effective anesthetic strategy in a pediatric CIPA patient, highlighting the potential of regional anesthesia techniques as a viable alternative to general anesthesia or neuraxial anesthesia in such high-risk cases.
2024-06-27 | Functional and Molecular Characterization of New SPTLC1 Missense Variants in Patients with Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1).
Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 "gain-of-function" variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.
oligonucleotides
2025-10-22 | Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model.
Hereditary sensory neuropathy type IA (HSN1A) is a rare neurodegenerative condition caused by dominant mutations in the Serine Palmitoyl Transferase Long Chain base subunit 1 (SPTLC1) gene. There is no treatment available. Allele-specific silencing by antisense oligonucleotides (ASOs) to preferentially silence the mutant transcripts has shown therapeutic promise for dominant gain-of-function genetic disorders. In this study, we validated an allele-specific ASO therapy to selectively silence mutant SPTLC1 (p.S331F) in a disease mouse model carrying a heterozygous p.S331F mutation (S331F mice). Gapmer ASOs, targeting the S331F variant in either 2'-O-methyl (2'-OMe), locked nucleic acid (LNA) or 2'-O-methoxy ethyl (MOE) chemistries, were first studied in cultured mouse skin fibroblasts. The candidate ASOs in LNA or MOE were further evaluated in vivo. Single subcutaneous injection of ASOs into neonatal or adult S331F mice achieved over 90% mutant transcript silencing in liver and dorsal root ganglia (DRG). Weekly subcutaneous injections of LNA-ASOs, either unconjugated or conjugated with N-acetylgalactosamine (GalNAc), into S331F mice showed GalNAc-LNA-ASOs to be more efficient than unconjugated LNA-ASOs at reducing mutant transcripts in liver, DRG and sciatic nerve, without affecting wild-type transcripts. GalNAc-LNA-ASOs also resulted in significantly reduced blood levels of 1-deoxysphingoid bases (1-deoxySL), neurotoxic metabolites used as biomarkers in HSN1A patients. Transcriptomic studies in DRG demonstrated mitochondrial pathway involvement in the pathological changes observed in S331F mice. Quantitative RT-PCR confirmed the differentially expressed genes between S331F and wild-type mice. Furthermore, these aberrantly expressed genes in S331F mice were reversed by GalNAc-LNA-ASO treatment. Our data provide necessary in vivo evidence as proof of concept for ASO-mediated mutant-allele-specific silencing as a therapeutic approach for SPTLC1-related HSN1.
2022-04-27 | Towards personalized medicine for amyotrophic lateral sclerosis.
Mohassel et al. provide unprecedented dichotomy of consequences on sphingolipid biosynthesis between pathogenic variants in the SPTLC1 gene, responsible for either amyotrophic lateral sclerosis (ALS) or hereditary sensory and autonomic neuropathy type 1 (HSAN1). Normalization of sphingolipid levels by siRNA selectively targeting the ALS mutant allele mRNA sheds light on new therapeutic approaches.
2005-06-13 | Hereditary peripheral neuropathies of childhood.
The purpose of this review is to assist neurologists, paediatricians and other interested readers in following the expanding volume of information relating to the hereditary peripheral neuropathies of childhood. During the last year, an exciting new potential therapy for hereditary sensory and motor neuropathy has been reported, and there has been a rapid expansion in our understanding of the genetic basis of a number of dominantly and recessively inherited neuropathies of childhood, most particularly in forms with pure motor or sensory and autonomic involvement. Advances in our understanding of the molecular basis of the inherited neuropathies of childhood may provide greater insight into the pathogenesis of these disorders, hopefully identifying new therapeutic strategies for these lifelong conditions.
gene therapies
2025-05-01 | A Brief Review of Inherited Neuropathies: A Perspective from Saudi Arabia.
Inherited neuropathies are a heterogeneous group of disorders that affect the peripheral nervous system, leading to motor, sensory, and autonomic dysfunction. These disorders are classified into various subgroups, including hereditary sensory and motor neuropathies, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, and more complex forms. Advances in genetic testing, particularly next-generation sequencing (NGS), have significantly improved the identification of these disorders. Emerging therapies, such as gene therapy, small molecule therapies, and antisense oligonucleotides, offer promising treatment options. However, current treatments remain limited, and their clinical benefits in humans are not yet fully established. This review provides a comprehensive overview of recent developments and evolving therapeutic options for hereditary neuropathies, focusing on gene therapy, small molecule therapies, and antisense oligonucleotides. It also highlights the current state of inherited neuropathies in Saudi Arabia, emphasizing the need for national guidelines, patient registries, and collaborative research efforts. By integrating advanced genomic technologies and fostering international collaboration, we can improve the diagnosis, management, and treatment outcomes for patients with inherited neuropathies.
2020-05-11 | Hereditary Sensory and Autonomic Neuropathies: Adding More to the Classification.
Hereditary sensory and autonomic neuropathies (HSANs) are a clinically heterogeneous group of inherited neuropathies featuring prominent sensory and autonomic involvement. Classification of HSAN is based on mode of inheritance, genetic mutation, and phenotype. In this review, we discuss the recent additions to this classification and the important updates on management with a special focus on the recently investigated disease-modifying agents. In this past decade, three more HSAN types were added to the classification creating even more diversity in the genotype-phenotype. Clinical trials are underway for disease-modifying and symptomatic therapeutics, targeting mainly HSAN type III. Obtaining genetic testing leads to accurate diagnosis and guides focused management in the setting of such a diverse and continuously growing phenotype. It also increases the wealth of knowledge on HSAN pathophysiologies which paves the way toward development of targeted genetic treatments in the era of precision medicine.
2016-12-13 | Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies.
Hereditary sensory and autonomic neuropathies (HSANs) represent a group of heritable peripheral nerve disorders usually taking a severe clinical course. HSAN-affected patients manifest with deep, poorly-healing ulcerations of the feet and hands. To date no definitive cure for HSANs has been developed and the molecular pathology of these disorders is complex. The aim of this review is therefore to present recent findings in terms of HSAN molecular pathogenesis. So far, mutations in 12 genes coding for different proteins have been reported in association with HSAN and the molecular pathogenesis has been elucidated in HSAN1a, HSAN4 and HSAN5. The genes involved in molecular pathogenesis of HSAN code for a wide spectrum of proteins from enzymes to specific nerve growth factors. As far as HSAN1a is concerned, the enhanced understanding has given rise to achievements in experimental therapy particularly in respect to disease models. Despite a rapid progress in studies on the molecular background of HSAN, numerous loci and genes remain still to be discovered.
2016-09-30 | The CRISPR/Cas9 system for gene editing and its potential application in pain research
The CRISPR/Cas9 system is a research hotspot in genome editing and regulation. Currently, it is used in genomic silencing and knock-in experiments as well as transcriptional activation and repression. This versatile system consists of two components: a guide RNA (gRNA) and a Cas9 nuclease. Recognition of a genomic DNA target is mediated through base pairing with a 20-base gRNA. The latter further recruits the Cas9 endonuclease protein to the target site and creates double-stranded breaks in the target DNA. Compared with traditional genome editing directed by DNA-binding protein domains, this short RNA-directed Cas9 endonuclease system is simple and easily programmable. Although this system may have off-target effects and in vivo delivery and immune challenges, researchers have employed this system in vivo to establish disease models, study specific gene functions under certain disease conditions, and correct genomic information for disease treatment. In regards to pain research, the CRISPR/Cas9 system may act as a novel tool in gene correction therapy for pain-associated hereditary diseases and may be a new approach for RNA-guided transcriptional activation or repression of pain-related genes. In addition, this system is also applied to loss-of-function mutations in pain-related genes and knockin of reporter genes or loxP tags at pain-related genomic loci. The CRISPR/Cas9 system will likely be carried out widely in both bench work and clinical settings in the pain field.
small molecules
2026-06-03 | Health Equality and Socioeconomic Impact of Hereditary Sensory Neuropathy Type 1 (HSN1) in the UK.
Hereditary Sensory Neuropathy Type 1 (HSN1) is a rare autosomal dominant neuropathy caused by variants in the SPTLC1 and SPTLC2 genes, resulting in sensory loss, motor weakness, chronic ulceration, and risk of limb amputation. Whilst the clinical manifestations are well characterised, the socioeconomic and psychosocial impact remains under-researched and poorly understood. This pilot study aimed to assess the health equality and socioeconomic impact of HSN1 on affected individuals in the UK. A novel 28-item anonymised questionnaire focusing on employment, healthcare access, finance, mobility, and wellbeing was distributed to 50 genetically confirmed HSN1 patients from an UK cohort. Responses were collected electronically. Quantitative and qualitative data were analysed descriptively. A total of 37 participants (74%) responded. Of these, only 24% were in full-time work, with 24% taking early medical retirement. Nearly half (46%) felt the disease negatively impacted career progression. Although 49% requested workplace adjustments, responses were mixed, with some reporting inadequate or denied support. Healthcare access was inconsistent due to long wait times, restrictive referral criteria, and poor awareness of HSN1 outside specialist centres. Financial strain was common; 41% reported income loss, and 21% spent over £1000 annually on disease-related costs. Driving ability was affected in 48%, and over half reported reduced participation in social activities. Nearly half believed healthcare professionals lacked sufficient understanding of the disease. HSN1 imposes a substantial burden beyond physical symptoms, affecting employment, finances, independence, and mental health. These results highlight the need for better patient-centred care and improved education for non-specialist healthcare professionals. This is particularly timely in the context of emerging disease-modifying therapies such as L-serine and future gene therapy trials. SENSE trial NCT06113055.
2026-04-03 | Sphingolipid remodelling in SPT-related neuropathies
Abstract Sphingolipid homeostasis is critical for neuronal structural and functional integrity in the central and peripheral nervous systems. The rate-limiting enzyme of this pathway, serine-palmitoyltransferase (SPT), establishes the metabolic entry point into sphingolipid biosynthesis. Mutations in the SPT subunits, SPTLC1 and SPTLC2 lead to contrasting disease phenotypes in patients, including amyotrophic lateral sclerosis (ALS) and hereditary sensory neuropathy (HSAN1). A third mixed sensory-motor phenotype is attributed to distinct mutation sets in SPTLC1 and SPTLC2. However, a direct comparison of the metabolic consequences of mutations spanning these disease conditions has not been performed. Here, we demonstrate that SPTLC1- and SPTLC2-ALS variants contribute to enhanced sphingolipid flux while the ceramide-mediated homeostatic control is impaired. In contrast, HSAN1-associated variants display altered substrate selectivity, shifting flux towards non-canonical 1-deoxysphingolipid (1-deoxySL) production but decreasing canonical synthesis. The variant associated with a mixed sensory-motor phenotype exhibit a third metabolic state with elevated 1-deoxySL formation and, in contrast to HSAN1-variants, increased canonical sphingolipid synthesis. Sphingolipid profiling reveals that ALS variants are characterized by preferential accumulation of dihydro- and intermediate chain sphingolipid species. Notably, the separation of lipid species between ALS and HSAN1 is robust, with canonical sphingolipids enriched in ALS variants, while long-chain 1-deoxySL dominate in HSAN1. The SPT-variants associated with mixed sensory and motor symptoms are associated with elevated levels of both types. The data support the view that segregated shifts in sphingolipid flux underlie divergence of clinical phenotypes in SPT-variants and offer guidance for therapeutic interventions. Importantly, therapeutic strategies must account for these metabolic configurations, as L-serine supplementation may benefit HSAN1 but exacerbate pathology in ALS and sensory-motor disease conditions.
2025-05-16 | Very long chain fatty acids drive 1-deoxy-Sphingolipid toxicity
Abstract 1-deoxy-sphingolipids (1-deoxySLs) are atypical sphingolipids synthesized by the serine palmitoyltransferase (SPT) when L-alanine is used instead of its canonical substrate L-serine. Increased 1-deoxySLs are associated with sensory neuropathies such as Hereditary Sensory and Autonomic Neuropathy type 1 (HSAN1) and diabetic polyneuropathy (DPN). Despite their known cellular, mitochondrial, and neurotoxic effects, the mechanisms underlying their toxicity remain poorly understood. Using a CRISPR interference (CRISPRi) screening approach, we identified CERS2, ELOVL1, ACACA, HSD17B12, and PTPLB as key mediators of 1-deoxySL-induced toxicity. All genes are integral to the biosynthesis of very long-chain (VLC) fatty acids and VLC-ceramides. We validated these findings through genetic knockdown experiments, cytotoxicity assays, and stable isotope-resolved lipidomics via LC-MS/MS. Pharmacological inhibition of ELOVL1 using a preclinical tested compound alleviated the cellular, mitochondrial, and neuronal toxicity induced by 1-deoxySLs. Supplementation experiments combining 1-deoxySLs with various VLC fatty acids revealed that 1-deoxyDHceramide conjugated to nervonic acid (m18:0/24:1) is the principal toxic specie. Further mechanistic studies showed that m18:0/24:1 induces apoptosis through the mitochondrial permeability transition pore (mPTP) formation. Inhibition of BAX or blocking mPTP formation with cyclosporin A effectively prevented toxicity. In conclusion, our findings demonstrate that 1-deoxyDHCeramides conjugated to nervonic acid are the primary mediators of 1-deoxySL toxicity, acting through mitochondrial dysfunction and BAX-dependent apoptosis.
2025-04-10 | Ultrasound-guided femoral nerve block combined with lateral femoral cutaneous nerve block in a patient with congenital insensitivity to pain and anhidrosis: a case report.
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathies (HSAN I-V), is an exceptionally rare autosomal recessive disorder. The pathogenesis of CIPA remains not fully elucidated. Clinical manifestations primarily include the absence of pain perception, painless injuries to the extremities, oral mutilation, anhidrosis accompanied by hyperthermia, and delayed intellectual development. Given the autonomic dysfunction in CIPA patients, previous reports on anesthetic management for this rare disorder have predominantly depended on general anesthesia or neuraxial anesthesia, both of which pose significant challenges. This case report presents a unique approach to anesthetic management in a child with CIPA, who successfully underwent hollow nail internal fixation for femoral neck fracture under orthopedic navigation using ultrasound-guided femoral nerve block combined with lateral femoral cutaneous nerve block. The patient was sedated with dexmedetomidine and did not require any opioids during the procedure. Her vital signs remained stable throughout the surgery, and her recovery was uneventful, with discharge occurring 5 days post-operation. This case contributes to the medical literature by demonstrating a safe and effective anesthetic strategy in a pediatric CIPA patient, highlighting the potential of regional anesthesia techniques as a viable alternative to general anesthesia or neuraxial anesthesia in such high-risk cases.
2024-06-27 | Functional and Molecular Characterization of New SPTLC1 Missense Variants in Patients with Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1).
Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 "gain-of-function" variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.
oligonucleotides
2025-10-22 | Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model.
Hereditary sensory neuropathy type IA (HSN1A) is a rare neurodegenerative condition caused by dominant mutations in the Serine Palmitoyl Transferase Long Chain base subunit 1 (SPTLC1) gene. There is no treatment available. Allele-specific silencing by antisense oligonucleotides (ASOs) to preferentially silence the mutant transcripts has shown therapeutic promise for dominant gain-of-function genetic disorders. In this study, we validated an allele-specific ASO therapy to selectively silence mutant SPTLC1 (p.S331F) in a disease mouse model carrying a heterozygous p.S331F mutation (S331F mice). Gapmer ASOs, targeting the S331F variant in either 2'-O-methyl (2'-OMe), locked nucleic acid (LNA) or 2'-O-methoxy ethyl (MOE) chemistries, were first studied in cultured mouse skin fibroblasts. The candidate ASOs in LNA or MOE were further evaluated in vivo. Single subcutaneous injection of ASOs into neonatal or adult S331F mice achieved over 90% mutant transcript silencing in liver and dorsal root ganglia (DRG). Weekly subcutaneous injections of LNA-ASOs, either unconjugated or conjugated with N-acetylgalactosamine (GalNAc), into S331F mice showed GalNAc-LNA-ASOs to be more efficient than unconjugated LNA-ASOs at reducing mutant transcripts in liver, DRG and sciatic nerve, without affecting wild-type transcripts. GalNAc-LNA-ASOs also resulted in significantly reduced blood levels of 1-deoxysphingoid bases (1-deoxySL), neurotoxic metabolites used as biomarkers in HSN1A patients. Transcriptomic studies in DRG demonstrated mitochondrial pathway involvement in the pathological changes observed in S331F mice. Quantitative RT-PCR confirmed the differentially expressed genes between S331F and wild-type mice. Furthermore, these aberrantly expressed genes in S331F mice were reversed by GalNAc-LNA-ASO treatment. Our data provide necessary in vivo evidence as proof of concept for ASO-mediated mutant-allele-specific silencing as a therapeutic approach for SPTLC1-related HSN1.
2022-04-27 | Towards personalized medicine for amyotrophic lateral sclerosis.
Mohassel et al. provide unprecedented dichotomy of consequences on sphingolipid biosynthesis between pathogenic variants in the SPTLC1 gene, responsible for either amyotrophic lateral sclerosis (ALS) or hereditary sensory and autonomic neuropathy type 1 (HSAN1). Normalization of sphingolipid levels by siRNA selectively targeting the ALS mutant allele mRNA sheds light on new therapeutic approaches.
2005-06-13 | Hereditary peripheral neuropathies of childhood.
The purpose of this review is to assist neurologists, paediatricians and other interested readers in following the expanding volume of information relating to the hereditary peripheral neuropathies of childhood. During the last year, an exciting new potential therapy for hereditary sensory and motor neuropathy has been reported, and there has been a rapid expansion in our understanding of the genetic basis of a number of dominantly and recessively inherited neuropathies of childhood, most particularly in forms with pure motor or sensory and autonomic involvement. Advances in our understanding of the molecular basis of the inherited neuropathies of childhood may provide greater insight into the pathogenesis of these disorders, hopefully identifying new therapeutic strategies for these lifelong conditions.
gene therapies
2025-05-01 | A Brief Review of Inherited Neuropathies: A Perspective from Saudi Arabia.
Inherited neuropathies are a heterogeneous group of disorders that affect the peripheral nervous system, leading to motor, sensory, and autonomic dysfunction. These disorders are classified into various subgroups, including hereditary sensory and motor neuropathies, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, and more complex forms. Advances in genetic testing, particularly next-generation sequencing (NGS), have significantly improved the identification of these disorders. Emerging therapies, such as gene therapy, small molecule therapies, and antisense oligonucleotides, offer promising treatment options. However, current treatments remain limited, and their clinical benefits in humans are not yet fully established. This review provides a comprehensive overview of recent developments and evolving therapeutic options for hereditary neuropathies, focusing on gene therapy, small molecule therapies, and antisense oligonucleotides. It also highlights the current state of inherited neuropathies in Saudi Arabia, emphasizing the need for national guidelines, patient registries, and collaborative research efforts. By integrating advanced genomic technologies and fostering international collaboration, we can improve the diagnosis, management, and treatment outcomes for patients with inherited neuropathies.
2020-05-11 | Hereditary Sensory and Autonomic Neuropathies: Adding More to the Classification.
Hereditary sensory and autonomic neuropathies (HSANs) are a clinically heterogeneous group of inherited neuropathies featuring prominent sensory and autonomic involvement. Classification of HSAN is based on mode of inheritance, genetic mutation, and phenotype. In this review, we discuss the recent additions to this classification and the important updates on management with a special focus on the recently investigated disease-modifying agents. In this past decade, three more HSAN types were added to the classification creating even more diversity in the genotype-phenotype. Clinical trials are underway for disease-modifying and symptomatic therapeutics, targeting mainly HSAN type III. Obtaining genetic testing leads to accurate diagnosis and guides focused management in the setting of such a diverse and continuously growing phenotype. It also increases the wealth of knowledge on HSAN pathophysiologies which paves the way toward development of targeted genetic treatments in the era of precision medicine.
2016-12-13 | Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies.
Hereditary sensory and autonomic neuropathies (HSANs) represent a group of heritable peripheral nerve disorders usually taking a severe clinical course. HSAN-affected patients manifest with deep, poorly-healing ulcerations of the feet and hands. To date no definitive cure for HSANs has been developed and the molecular pathology of these disorders is complex. The aim of this review is therefore to present recent findings in terms of HSAN molecular pathogenesis. So far, mutations in 12 genes coding for different proteins have been reported in association with HSAN and the molecular pathogenesis has been elucidated in HSAN1a, HSAN4 and HSAN5. The genes involved in molecular pathogenesis of HSAN code for a wide spectrum of proteins from enzymes to specific nerve growth factors. As far as HSAN1a is concerned, the enhanced understanding has given rise to achievements in experimental therapy particularly in respect to disease models. Despite a rapid progress in studies on the molecular background of HSAN, numerous loci and genes remain still to be discovered.
2016-09-30 | The CRISPR/Cas9 system for gene editing and its potential application in pain research
The CRISPR/Cas9 system is a research hotspot in genome editing and regulation. Currently, it is used in genomic silencing and knock-in experiments as well as transcriptional activation and repression. This versatile system consists of two components: a guide RNA (gRNA) and a Cas9 nuclease. Recognition of a genomic DNA target is mediated through base pairing with a 20-base gRNA. The latter further recruits the Cas9 endonuclease protein to the target site and creates double-stranded breaks in the target DNA. Compared with traditional genome editing directed by DNA-binding protein domains, this short RNA-directed Cas9 endonuclease system is simple and easily programmable. Although this system may have off-target effects and in vivo delivery and immune challenges, researchers have employed this system in vivo to establish disease models, study specific gene functions under certain disease conditions, and correct genomic information for disease treatment. In regards to pain research, the CRISPR/Cas9 system may act as a novel tool in gene correction therapy for pain-associated hereditary diseases and may be a new approach for RNA-guided transcriptional activation or repression of pain-related genes. In addition, this system is also applied to loss-of-function mutations in pain-related genes and knockin of reporter genes or loxP tags at pain-related genomic loci. The CRISPR/Cas9 system will likely be carried out widely in both bench work and clinical settings in the pain field.
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