Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review

The management of inherited neuropathies relies mostly on the treatment of symptoms. In recent years, a better understanding of the pathogenic mechanisms that underlie neuropathies has allowed for the development of disease-modifying therapies. Here, we systematically review the therapies that have emerged in this field over the last five years. An updated list of diseases with peripheral neuropathy as a clinical feature was created based on panels of genes used clinically to diagnose inherited neuropathy. This list was extended by an analysis of published data by the authors and verified by two experts. A comprehensive search for studies of human patients suffering from one of the diseases in our list yielded 28 studies that assessed neuropathy as a primary or secondary outcome. Although the use of various scales and scoring systems made comparisons difficult, this analysis identified diseases associated with neuropathy for which approved therapies exist. An important finding is that the symptoms and/or biomarkers of neuropathies were assessed only in a minority of cases. Therefore, further investigation of treatment efficacy on neuropathies in future trials must employ objective, consistent methods such as wearable technologies, motor unit indexes, MRI or sonography imaging, or the use of blood biomarkers associated with consistent nerve conduction studies.


Introduction
Hereditary neuropathies are a broad range of diseases that differ in terms of inheritance (dominant, recessive, X-linked, or mitochondrial), electrophysiological features (demyelinating, axonal, or intermediate), and clinical properties. Indeed, neuropathy may be the primary feature of a disease, such as in Charcot-Marie-Tooth disease (CMT), hereditary sensory and autonomic neuropathies (HSAN), or hereditary motor neuropathies (HMN), in which patients may present different levels of muscle atrophy and weakness, sensory and autonomic disturbances, and/or skeletal deformities. On the other hand, neuropathy may be part of a more complex systemic disease, as in peroxisomal, lysosomal, or mitochondrial diseases, for which neuropathy can be the first symptom but can also remain subclinical, making diagnosis more challenging [1][2][3]. The global prevalence of inherited neuropathies is unknown, but CMT has an estimated prevalence of 1/2500, making it the most common inherited disorder of the peripheral nervous system. The management of inherited neuropathies relies mostly on symptomatic treatments such as physiotherapy, analgesics, or surgery [4]. In recent years, a better understanding of the pathological mechanisms underlying some of these diseases has allowed the development of disease-modifying therapies or diets, although these treatments have been validated for a very small subset of

Literature and Clinical Trial Database Searches
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and flow diagram were followed for the design and reporting of this work, as detailed below. Two independent authors (MH and A-MS) conducted a systematic search of Ovid Medline [15] on 24 February 2023 for original, full-text articles published in English after 1 January 2018. The studies that were included described the assessment of treatments in any of the inherited neuropathies identified (Appendix A) with a clinical, biological, or electrophysiological outcome. Non-pharmacological interventions such as physiotherapy, genetic counselling, or surgery were excluded. Retrospective observational studies were not included. A search was also carried out using the Clinicaltrial.gov [16] database on 24 February 2023. Database-specific filters were applied to ensure that only interventional studies completed with results published after 1 January 2018 were included and that studies describing diseases such as cancer, carpal tunnel, amyloid cardiomyopathy, Xlinked cerebral adrenoleukodystrophy, and bone assessment in Gaucher disease were not included. Finally, relevant articles were extracted from the reference sections of systematic or expert reviews and meta-analyses. The search strategy is shown schematically in Figure 1.
A table displaying information about the diseases for which clinical trials were identified is presented in Appendix B.

Selection of Studies
Two researchers (MH and A-MS) independently screened titles and abstracts and then full texts for eligibility. To be included, studies had to meet the following criteria: (1) the study was performed on human patients, (2) patients had been diagnosed with one of the diseases included in our list (Appendix A), (3) a pharmacological treatment or diet was evaluated, and (4) the results were presented. No restriction was applied regarding gender, age at onset, severity, ethnicity, or phenotypic features. The two reviewers compared their findings and potential disagreements were resolved by consensus.

Data Extraction and Analysis
For each study that fulfilled our criteria, information was collected on the study (authors, year of publication, type, duration), the population (sample, specific characteristics where applicable), the treatment (drug/dietary supplement name, dosing and administration, mechanism), and the outcome (clinical, biological, or electrophysiological). Clinical and biological outcomes that were related to symptoms other than neuropathies were not extracted. All biomarkers were included as they were considered a way of attesting to the disease-modifying aspect of treatments. Only the most recent updates on pilot projects were considered. Eligible papers were assessed for risk of bias using the Jadad score (score ranging from 0 to 5 according to whether the study was described as randomized and double-blinded and including a thorough description of withdrawals) [17] (Appendix C).

Selection of Studies
Two researchers (MH and A-MS) independently screened titles and abstracts and then full texts for eligibility. To be included, studies had to meet the following criteria: (1) the study was performed on human patients, (2) patients had been diagnosed with one of the diseases included in our list (Appendix A), (3) a pharmacological treatment or diet was evaluated, and (4) the results were presented. No restriction was applied regarding gender, age at onset, severity, ethnicity, or phenotypic features. The two reviewers compared their findings and potential disagreements were resolved by consensus.

Data Extraction and Analysis
For each study that fulfilled our criteria, information was collected on the study (authors, year of publication, type, duration), the population (sample, specific characteristics where applicable), the treatment (drug/dietary supplement name, dosing and administration, mechanism), and the outcome (clinical, biological, or electrophysiological). Clinical and biological outcomes that were related to symptoms other than neuropathies were not extracted. All biomarkers were included as they were considered a way of attesting to the disease-modifying aspect of treatments. Only the most recent updates on pilot projects were considered. Eligible papers were assessed for risk of bias using the Jadad score (score ranging from 0 to 5 according to whether the study was described as randomized and double-blinded and including a thorough description of withdrawals) [17] (Appendix C).
Data extraction was carried out by MH, reviewed by A-MS, and then reviewed by LS. Due to differences in clinical and biological outcomes, meta-analysis was precluded.

Identification of Studies That Assessed Treatments for Inherited Neuropathies
We first compiled a list of genes associated with neuropathies. Based on a literature and clinical trials database search for studies of pharmacological treatments or dietary interventions in patients diagnosed with one of the diseases identified in our list (Appendix A), we identified 271 studies, from which 26 duplicates were removed. Of the remaining studies, 119 were excluded based on titles and abstracts. The remaining 126 studies were read in full by two assessors, resulting in the exclusion of 61 studies. Three additional relevant studies were captured from the reference sections of systematic or expert reviews and meta-analyses. In the end, 68 studies met our criteria ( Figure 1). Among these, only 28 assessed neuropathy as a primary or secondary outcome. These studies assessed 14 different drugs in nine inherited neuropathies (Table 1).
Moreover, 40 articles that assessed biomarkers or neurological clinical aspects potentially related to neuropathy were identified ( Table 2). Changes in disease-related biomarkers or the modification of neurological features such as balance, gait, strength, or dexterity can be indicative of therapeutic efficacy, even if neuropathy was not assessed as a primary or secondary outcome. The inclusion of biomarkers or neurological clinical aspects potentially related to neuropathy allowed us to capture early-phase, proof-of-concept studies.
Appendix B lists modes of inheritance, clinical presentation, and standards of care for each disease for which a relevant clinical trial was identified.

Familial Dysautonomia
A randomized, placebo-controlled, crossover phase 2 study of the effect of DOPA decarboxylase inhibitor carbidopa was conducted in 22 patients with familial dysautonomia [41]. At the end of the three 4-week treatment periods, the two co-primary endpoints, reduction in systolic blood pressure variability and systolic blood pressure peaks, were met. Although this is a symptomatic treatment, this could improve quality of life.

Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)
A randomized, placebo-controlled, phase 1/2 study of L-serine with an open-label extension (OLE) was conducted on 18 patients with HSAN1 [42]. The total duration of the trial was 2 years. This study showed a non-significant improvement in the Charcot-Marie-Tooth Neuropathy Score (CMTNS) compared to placebo, a significant reduction in the neurotoxic deoxysphinganine levels, and evidence of reinnervation at 1 year from distal biopsies. No significant electrophysiological differences were detected in the tested nerves after 1 year; however, there was a paucity of recordable responses at baseline, and the statistical power of the study was limited by the small sample size. Further studies are needed to determine the efficacy of this potentially disease-modifying treatment.
After a favourable phase 2 trial [94], a randomized, double-blind, placebo-controlled phase 3 study was conducted to evaluate the efficacy and safety of a high-and lowdose combination of baclofen, naltrexone, and sorbitol (PTX3003) in 323 CMT1A patients over 15 months. Although crystal formation in the high-dose formulation led to early discontinuation, significant clinical improvements were observed in this group compared to the placebo. In the ongoing open-label continuation study, participants are being treated with twice the volume of the low-dose formulation instead of the high dose to limit this stability issue [43].  [95], and around 10 years of clinical follow-up [18]. Tafamidis was approved in Europe in 2011 and subsequently in several other countries for the treatment of stage 1 ATTRv-PN. This drug has not been approved in the USA for this condition due to a lack of robust efficacy in clinical trials [21].
Tolcapone is another TTR stabilizer approved for clinical use in the treatment of Parkinson's disease. It is currently under development to treat ATTRv-PN and other forms of ATTR, including leptomeningeal amyloidosis, due to its ability to cross the blood-brain barrier [56]. It was shown to have efficacy in a phase 2 study of subjects with ATTRv-PN [55].
Acoramidis (AG10) is an orally bioavailable, selective TTR stabilizer that is currently being assessed for effects on mortality and hospitalization for cardiovascular causes in subjects with transthyretin amyloid cardiomyopathy in an ongoing phase 3 trial, with topline data expected in mid-2023. The phase 3 study in ATTRv-PN patients was terminated by the sponsor after a review of the currently available treatments [53,96,97].
Gene silencers: Inotersen, which is an antisense oligonucleotide that targets TTR mRNA for degradation, proved its efficacy in a 15-month, randomized, placebo-controlled, doubleblind phase 3 trial conducted on 172 adult patients with stage 1 or 2 ATTRv-PN [31][32][33][34]. Glomerulonephritis occurred in three patients and thrombocytopenia occurred in three patients treated with inotersen, with one death associated with grade 4 thrombocytopenia [31]. In the OLE, an update at 3 years showed a sustained efficacy compared with natural history, regardless of the mutation, prior treatment, or stage of the disease (except in the group treated first with the placebo and then inotersen in stage 2). In the OLE, no cases of acute glomerulonephritis were reported, but approximately 50% of patients in both the group treated first with the placebo and then with inotersen and the group continuously treated with inotersen experienced thrombocytopenia (<100 × 10 9 /L), although none had a grade 4 platelet count decrease [36]. Narayanan et al. [98] reported that patients with grade 4 thrombocytopenia in the phase 3 trial had higher levels of proinflammatory cytokines at baseline, which suggests a predisposition to immune-mediated thrombocytopenia via antiplatelet IgG antibodies. A post hoc analysis demonstrated that the higher health-related quality of life of patients treated with inotersen compared to placebo-treated subjects during the pivotal study was sustained through week 104 of the OLE study, highlighting the importance of early treatment [37].
Eplontersen is an antisense oligonucleotide targeting TTR mRNA that is conjugated to N-acetylgalactosamine, a ligand for a receptor expressed on hepatocytes, which improves distribution to these liver cells compared to unconjugated oligonucleotides. Two randomized, double-blind, placebo-controlled phase 1 studies showed greater TTR reduction compared to inotersen (88% at 45 mg q4w relative to inotersen 74% at 300 mg weekly) [51]. The efficacy and safety of eplontersen are currently being investigated in phase 3 trials.
Patisiran is a small interfering RNA (siRNA) that targets TTR mRNA for degradation through the endogenous RNA interference pathway to reduce the expression of TTR [22]. The efficacy and safety of patisiran were assessed in an 18-month randomized, placebocontrolled, double-blind phase 3 trial in 225 adult patients with a polyneuropathy disability score of IIIb or lower. Positive effects were seen across all subgroups, irrespective of age, sex, race, body weight, mutation, prior use of tafamidis, and mild/moderate renal or hepatic involvement [24]. Most of the adverse events were mild or moderate and the rate of serious adverse events was similar between the patisiran-treated and placebo groups [22]. Another 24-month phase 2 OLE study confirmed this favourable safety and efficacy profile, with concomitant tafamidis or diflunisal use [25]. A phase 3b open-label trial proved efficacy and tolerability in subjects with ATTRv-PN after liver transplantation, and no apparent drug interactions were observed between patisiran and immunosuppressive treatments [27].
Vutrisiran is another siRNA that reduces the synthesis of variant and wild-type transthyretin. Unlike patisiran, it is given subcutaneously and hence does not require premedication. In a phase 3 open-label study, vutrisiran reduced TTR levels to an extent similar to patisiran and was more efficacious than patisiran in multiple assessments. Vutrisiran was well tolerated and most adverse events were consistent with an expected ATTRv natural history progression [29]. A randomized treatment extension period is currently ongoing in which patients receive vutrisiran injections once every 6 months or once every 3 months.
Gene editing: NTLA-2001 is a gene-editing therapy based on CRISPR-Cas9. The two active components of this therapeutic are the mRNA encoding the Cas9 endonuclease and a single guide RNA complementary to the gene encoding TTR. These components are encapsulated in a lipid nanoparticle that enables targeted delivery to hepatocytes. The interim results of an ongoing phase 1 study (NCT04601051) in six patients with ATTRv-PN showed a reduction in TTR concentration in a dose-dependent manner after a single intravenous dose. In terms of safety, all the adverse events occurring during or after treatment were mild in severity. Increased D-dimer levels were noticed 4 to 24 h after infusion in five of the six patients but values returned to baseline after 7 days [54,97].
Comparison of approved ATTRv-PN treatments: No head-to-head comparisons of the therapeutics approved for the treatment of ATTRv-PN have been made. Indirect comparisons based on available data suggest that patisiran has a greater effect on neuropathy and quality of life than inotersen or tafamidis [99,100]. The choice of treatment should be based on the physician's expertise, considering the disease's stage and phenotype and country-specific recommendations. Further questions that need to be addressed include the optimal timing of treatment initiation or whether combinations of treatments might be more efficacious than single agents.

Metachromatic Leukodystrophy (MLD)
Enzyme replacement therapy (ERT) with recombinant human arylsulfatase A (rhASA) has been tested in two phase 1/2 open-label trials in subjects with MLD, one with intravenous (IV) delivery and one with intrathecal (IT) delivery [44,45]. The study assessing the IV delivery of ERT was conducted in a cohort of 13 children. The trial lasted 52 weeks, and there was an additional 24-month extension period. The study with the IT delivery of ERT, on the other hand, enrolled 24 children and lasted for 38 weeks. The ongoing extension study should be completed by December 2024 (NCT01887938). Both ERT dosing routes resulted in a reduction in cerebrospinal fluid (CSF) sulfatide levels and no serious drug-related adverse events, but a clinical improvement was not demonstrated and electrophysiological parameters did not change compared to baseline. The IV study was terminated after 24 months due to a lack of efficacy, suggesting that the recombinant protein may not cross the blood-brain barrier in therapeutic quantities. In the study evaluating the IT delivery of ERT, 10 patients developed anti-rhASA antibodies in serum, with seven having an in vitro neutralizing status, but no correlation was found with the occurrence of adverse events. Anti-rhASA antibodies were also detected in CSF in some patients but a neutralizing status has not been determined.
A gene therapy, atidarsagene autotemcel (arsa-cel), has also been tested in subjects with MLD. The therapeutic is an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding ASA. This novel approach was evaluated in a phase 1/2 study conducted on 29 children with pre-symptomatic or earlysymptomatic early-onset MLD compared to a natural history cohort [46]. Promising results were obtained, such as increased ARSA activity and considerable clinical improvement. Some patients were found to have gross motor development similar to healthy children. There were significant differences in nerve conduction velocities between treated patients with late-infantile MLD and the natural history cohort. In terms of safety, arsa-cel was well tolerated with busulfan conditioning. Four patients developed anti-ARSA antibodies but this did not affect clinical outcomes.

Spinal and Bulbar Muscular Atrophy (SBMA or Kennedy Disease)
Patients with SBMA may experience myotonia-like symptoms under cold exposure. It has been hypothesized that this is linked to sodium channel dysfunction in skeletal muscles [101]. Yamada et al. [49] conducted an observational study on 51 SBMA patients and noticed that ulnar nerve distal latency was prolonged under cold exposure compared to healthy controls (p < 0.001), and this was correlated with grip strength. They then conducted a randomized, placebo-controlled, double-blind study on 20 subjects over 4 weeks to evaluate mexiletine hydrochloride. Statistically significant improvements in some clinical parameters were observed, although there was not a significant change in nerve conduction velocity. No serious adverse events were reported. Further trials are warranted to evaluate the symptomatic effect of mexiletine hydrochloride on motor function.
Insulin-like growth factor 1 (IGF-1) stimulates Akt-mediated phosphorylation of the androgen receptor, which promotes its clearance. BVS857 is a pegylated IGF-1 mimetic with a longer half-life than endogenous IGF-1. The safety and efficacy of BVS857 were evaluated in a randomized, placebo-controlled trial in 27 adults that lasted 12 weeks. The subcutaneous delivery of BVS857 resulted in erythema at the injection site and low and variable exposure. Thus, IV delivery was employed in phase B of the study. Five participants developed neutralizing antibodies to endogenous IGF-1, but this did not have a clinical or pharmacokinetic impact. The half-life of BVS857 was less than theorized, barely 24 h. Nevertheless, a significant increase was observed in thigh muscle volume over the short period of the study, although this was not correlated with the improvement of any of the motor functional measures [90].

Adult Polyglucosan Body Disease (APBD)
Polyglucosan bodies were detected in the astrocytes of a patient with confirmed glycogen branching enzyme (GBE) deficiency [102]. Therefore, it is believed that the accumulation of abnormal glycogen in astrocytes leads to a lack of energy substrates for neurons and is responsible for certain symptoms of APBD. Due to its anaplerotic properties, triheptanoin was tested in a randomized, cross-over, placebo-controlled trial on 23 participants with APBD over 1 year (6 months on treatment and 6 months on placebo), followed by a 4-year OLE. Neither the 6 min walk test (6MWT) nor the secondary endpoints were met at the end of the study. However, two patients who were mildly disabled at baseline remained clinically stable after treatment discontinuation, as assessed by the 6MWT and Expanded Disability Status Scale (EDSS), and this was associated with stable nerve conduction studies under treatment. This study confirmed the safety profile of triheptanoin, but further investigations are needed to evaluate its effect on peripheral nerve deficits [50].

Fabry Disease (FB)
The mechanisms underlying the neuropathy experienced by FB patients are not fully understood, but globotriaosylceramide (Gb-3) has been demonstrated to accumulate in dorsal root ganglia [103,104], myelinated axons [105], and microvascular endothelial cells, which can result in ischemic axonal degeneration [106]. These data suggest that Gb3 drives peripheral neuron dysfunction. Two approved ERTs (agalsidase alfa and beta) have shown favourable effects on peripheral neuropathies and reduce Gb3 and globotriaosylsphingosine (lyso-Gb3), especially when initiated soon after the onset of symptoms [107][108][109]. Lower dose regimens of agalsidase beta were tested in a paediatric cohort by Ramaswami et al., but it did not show consistent benefit, and the approved dose of 1 mg/kg/2-weekly was supported by this trial [62]. More recently, a new agalsidase beta (ISU303) with an almost identical structure to Fabrazyme was developed by ISU Abxis. This alternative agalsidase beta is of lower cost, but close monitoring is required to ensure its quality, safety, and efficacy [63]. A PEGylated ERT, pegunigalsidase alfa, was developed with the aim of increasing plasma half-life and reducing immunogenicity. A 1-year, dose-ranging, open-label, phase 1/2 trial (NCT01981720) of the PEGylated compound was conducted on 18 adult FB patients [64]. One patient was withdrawn from the study due to bronchospasm after the first infusion, and three patients developed treatment-induced antibodies, but this did not influence the efficacy or safety. The results of the 60-month extension study were recently published on clinicaltrial.gov, but no peer-review publications were available at the time of this review.
Migalastat is an approved orally administered chaperone that enhances the activity of endogenous patients' alpha-galactosidase-A. It is only suitable for selected patients with certain mutations, as determined by an in vitro assay [110]. Results from the ATTRACT trial, an 18-month randomized, open-label, active-controlled trial and its 12-month OLE showed a relatively safe profile among adult FB patients after a switch from an ERT to migalastat. Migalastat had comparable or superior effects on renal function, reducing cardiac mass and FB-related clinical events, compared to the ERT. The effect on neuropathy was not monitored in this trial. Interestingly, plasma lyso-Gb3 levels remained low from baseline to month 30 in migalastat-treated subjects. White blood cell alpha-galactosidase-A activity in male patients increased in the group treated with migalastat during the randomized period but remained stable in the group treated with the ERT [58,59]. The efficacy of migalastat in males with classic phenotypes was confirmed in the phase 3 FACETS trial and its extension study, but, again, the impact on neuropathy was not assessed [60].
Venglustat, a substrate reduction therapy, was assessed in a 26-week open-label phase 2 study and its 130-week extension study in 11 ERT-naïve adult male patients with classic FB phenotypes. Biomarkers all decreased upon treatment with venglustat, but the effect on pain was not significantly sustained at the end of the study and specific neuropathy endpoints were not assessed [61]. Phase 3 trials are ongoing.

Acute Intermittent Porphyria (AIP)
A siRNA that silences the expression of the gene encoding ALAS1 has been approved for the treatment of AIP [111]. The siRNA, givosiran, prevents the accumulation of delta-aminolevulinic (ALA) and porphobilinogen (PBG), which are intermediates in heme synthesis. In the ENVISION trial, givosiran treatment resulted in sustained reductions in hepatic ALAS1 mRNA and urinary ALA and PBG levels and annualized attack rate compared to placebo [74,76]. Givosiran had an acceptable safety profile, although two patients discontinued the study because of increased homocysteine levels and one because of alanine aminotransferase levels greater than eight times the upper limit of normal. Small decreases in eGFR observed early in therapy stabilized over months 12 to 24, and no patients discontinued givosiran due to renal events during the extension period [75]. By lowering the annualized attack rate, givosiran reduces the probability that patients will develop acute motor neuropathy during an attack or more chronic neuropathies that appear in subjects not treated promptly or with recurrent attacks [112].

Spinocerebellar Ataxia Type 38 (SCA 38)
It has been shown that mutations in ELOVL5 are responsible for a reduction in serum docosahexanoic acid (DHA) in patients with SCA 38 [113]. Oral DHA given to nine patients in a 2-year OLE study showed clear clinical benefits and nerve conduction velocities were stable during the treatment period [40]. To determine whether DHA has an effect on neuropathy, additional information, such as analyses of compound muscle action potential and sensory nerve action potential, which are relevant considering the predominantly axonal nature of the polyneuropathy experienced by SCA 38 patients [114], and a longer follow-up are needed.

Spinocerebellar Ataxia Type 2 (SCA2)
Two randomized, placebo-controlled, double-blind studies were recently conducted in SCA2 cohorts. The first assessed the safety and efficacy of riluzole, which had previously shown benefits in inherited ataxias [115]. The study was conducted over one year in 45 moderately affected adult patients; riluzole treatment did not result in any improvement compared to placebo [65]. The second study enrolled 34 mildly or moderately affected Cuban adult patients to test the efficacy and safety of nasally administered human recombinant erythropoietin (EPO). Supporting the utility of this treatment, endogenous EPO is abnormally low in the cerebrospinal fluid (CSF) of SCA2 patients [116], and EPO has been shown to have an additional neurotrophic role [117]. The proportion of high responders in the spinocerebellar ataxia functional index (SCAFI ≥ 0.75), which is a composite score of motor performances, was slightly higher among the EPO-treated patients than those given a placebo despite a considerable placebo effect. Moreover, the drug was relatively well tolerated including in terms of erythropoiesis activity [66]. Further studies are warranted to evaluate the effect of EPO on neuropathy.

Ataxia-Telangiectasia (A-T)
The efficacy of low-dose betamethasone was studied in a 2-year open-label study of patients with A-T. Although transient efficacy was observed after 6 months, sustained benefits were not observed at the end of the trial [87]. Although it was not used in this specific trial, the encapsulation of steroids within autologous erythrocytes (EryDex) allows a slow release for up to 1 month. This novel encapsulation approach was used with dexamethasone sodium phosphate in a phase 3, randomized-controlled, double-blind trial (ATTeST) in A-T patients and showed clear clinical benefits after 6 months [88].

X-Linked Adrenoleukodystrophy (X-ALD)
Redox imbalance plays an important role in the pathogenesis of X-ALD, and this is the reason why a combination of antioxidants (α-tocopherol, N-acetylcysteine, and α-lipoic acid) was evaluated in a pilot open-label phase 2 study in 13 subjects [48]. In patients with X-ALD, there is a negative correlation between the levels of the chemokine MCP1 and the pro-inflammatory metabolite 15-hydroxyeicosatetraenoic with 6MWT, hence these oxidative damage markers are considered predictors of disease progression. Treatment with the combination of antioxidants resulted in a considerable decrease in all oxidative damage markers and pro-inflammatory markers and significant clinical improvements. Nerve conduction velocities were stable after 1 year in treated patients, whereas the conduction time of motor-evoked potential decreased, suggesting an improvement in upper motor neuron function. Laser-evoked potentials increased in two-thirds of treated patients. Although these positive effects do not seem to be linked to an impact on neuropathy, further testing of antioxidants is warranted.
ADVANCE was a randomized, double-blind, phase 2/3 study evaluating the safety and efficacy of oral leriglitazone in 116 men with X-ALD who had adrenomyeloneuropathy for a total of 96 weeks [89]. A change from baseline in the 6MWT, the primary outcome measure, was not observed. Therefore, the hierarchical testing of all secondary endpoints was not performed. Moreover, adverse effects, including weight gain and peripheral oedema, were observed. In post hoc subgroup analyses, patients with early-stage disease who were treated with leriglitazone had less decline in the 6MWT and in EDSS scores relative to those treated with a placebo at week 96. Finally, no leriglitazone-treated patients developed cerebral adrenoleukodystrophy (CALD), demonstrating that the drug may slow the progression of CALD. An OLE is ongoing (NCT03231878).

Friedreich Ataxia (FRDA)
Multiple trials have been conducted in subjects with FRDA in recent years, and our search yielded seven publications since 2018, assessing six different drugs. Most trials used the Friedreich Ataxia Rating Scale (FARS) or modified FARS (mFARS), 9-hole peg test (9HPT), and 25 or 8 min walk tests to assess the efficacies of the drugs. However, none of these tests are specific to neuropathy progression. For example, the mFARS omits the peripheral nervous system subscore section of the FARS. Three drugs, luvadaxistat [81], (+)-epicatechin [80], and IFN-γ1b [78] did not demonstrate efficacy in terms of neurological outcomes. EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort and also showed clinically meaningful improvement in the FARS-neuro at 6 months [79]. RT001 improved peak workload relative to baseline in a double-blind phase 1/2 study, and there was not a significant difference in FARS-neuro scores between the drug and comparator over a short period of 28 days [84]. Omaveloxolone statistically improved mFARS over placebo in a 12-week, dose-ranging study and in an international, doubleblind, randomized, placebo-controlled, phase 2 trial conducted on 103 patients with a daily dose of 150 mg [82,83]. This drug has been approved by the FDA in 2023 but its efficacy on neuropathy is unknown.

Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS)
An open-label phase 2 trial was conducted on 10 FXTAS patients to assess the safety and efficacy of citicoline on motor and cognitive functions over a 1-year treatment period. There were no significant changes in FXTAS rating scale scores in treated subjects, although worsening was expected in this population. Moreover, most of the secondary outcome measures remained stable, and citicoline was well tolerated [93]. These findings suggest that citicoline may stabilize disease progression, but a larger study will be necessary to confirm these results.

Treatments for Conditions
Where Neuropathy Is Inconsistent and/or Subclinical 3.5.1. Acid Sphingomyelinase Deficiency (ASMD) ASMD, also known as Niemann-Pick disease, is a lysosomal storage disease. Olipudase alfa is a human recombinant acid sphingomyelinase. IV administration is used in non-central nervous system manifestations as it does not cross the blood-brain barrier. Two open-label studies assessed this therapy in ASMD patients. In one study, five adults were treated for 30 months [92], and the other enrolled 20 paediatric patients with chronic ASMD [91]. Both studies showed a reduction in biomarkers and benefits in non-neurological parameters; however, neuropathy was not assessed. No adult patients developed antidrug antibodies, but antidrug antibodies were detected in eight paediatric patients. None tested positive for neutralizing antibodies that would interfere with enzyme uptake into cells, although one tested transiently positive for the inhibition of enzyme catalytic activity. One of the patients had an anaphylactic reaction but continued with treatment after desensitization. Further studies are required to evaluate the effects of olipudase alfa on neuropathy.

Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)
Three peer-reviewed publications were found that describe the testing of amino acids Larginine [67], taurine [69], and glutamine [68] in subjects with MELAS. None of these studies assessed neuropathy as a primary or secondary endpoint. Neither of the two open-label phase 3 studies conducted in Japan that evaluated taurine and L-arginine demonstrated improvement in treated subjects based on the Japanese Mitochondrial Disorder Rating Scale, but the frequencies of stroke-like episodes were decreased by treatment, and both amino acids had good safety profiles. In a study of the effects of glutamine, Guerrero-Moline et al. [68] showed that high-dose oral supplementation resulted in a decrease in CSF glutamate levels and an increase in glutamine levels in subjects with MELAS. Thus, L-arginine, taurine, and glutamine have potential and should be further evaluated.

Gaucher Disease Type 1 (GD1)
Although GD1 is usually considered to be non-neuronopathic, there is growing evidence that peripheral nervous system manifestations are part of the clinical spectrum of this disease [14,118]. However, the aetiology of polyneuropathy associated with GD1 is unclear. It is not known if the imbalance in calcium homeostasis seen in the central nervous system of certain patients with GD1 [119] is also to blame for peripheral nerve injuries. Therefore, no biomarkers of peripheral nervous system involvement in GD1 have been validated.
Several therapies have been approved for the treatment of GD1. Three are ERTs: the recombinant β-glucocerebrosidases imiglucerase, velaglucerase alfa, and taliglucerase alfa. Another approach is substrate reduction therapy with glucosylceramide synthase inhibitors miglustat and eliglustat [120]. None of the identified trials assessed neuropathy as an outcome. In the phase 3 placebo-controlled, double-blind ENGAGE trial, eliglustat led to a reduction in several biomarkers, including median chitotriosidase, glucosylceramide (the primary sphingolipid that accumulates in GD1), glucosylsphingosine (a sphingolipid that is a highly specific validated biomarker of GD1), 4-monosialodihexosylganglioside (GM3, a precursor for more complex gangliosides), and macrophage inflammatory protein MIP-1β, which is a marker of metabolic inflammation [70]. Similar findings were reported after 8 years in previously untreated adults with GD1 who completed an open-label, phase 2 trial of eliglustat [71]. Further trials are required to test the efficacy of these drugs on neuropathy. It will be important to determine whether there is a correlation between neuropathy and any of the biomarkers, as this could help reveal the underlying mechanism of peripheral nervous system involvement in GD1.

Bile Acid Synthesis Disorder (BASD)
Cholic acid and chenodeoxycholic acid, depending on the subtype of BASD, downregulate bile acid synthesis and are used clinically to treat BASD. The efficacy of cholic acid was demonstrated in a phase 3 open-label continuation study on 53 paediatric patients [85]. This study confirmed that cholic acid downregulates the production of atypical bile acids and improves liver biochemistries and growth in patients with BASD. Interestingly, one patient discontinued the study because of peripheral neuropathy that was reported as a treatment-emergent adverse event. It is possible that this neuropathy was a natural history progression. Further studies are warranted to evaluate the potential benefit of cholic acid on neuropathy in BASD.

Limitations of This Analysis
Our search was limited to studies with results published after 1 January 2018. For this reason, several clinically validated therapies for inherited neuropathies (e.g., vitamin E for AVED, riboflavin for Brown-Vialetto-Van-Laere, diet to limit pristanic acid for Refsum disease, etc.) were not captured in our search (but are well described by Fernandez-Eulate et al. [2]), nor were unsuccessful trials prior to 2018 (e.g., ascorbic acid, progesterone antagonists/modulators in CMT1A) [8]. Similarly, suspended studies (e.g., the gene therapy scAAV1.tMCK.NTF3 for CMT1A; NCT03520751) were not considered. Finally, we did not include preclinical studies or recruiting trials, thereby missing potential future therapeutic approaches (e.g., gene therapies for Charcot-Marie-Tooth type 4J and X, AT007 for sorbitol dehydrogenase deficiency patients).

Added Value of This Analysis
Inherited neuropathies are challenging to diagnose and treat. Here, we provided an up-to-date list of conditions that may have neuropathy as a clinical feature, highlighting those that are treatable or for which treatment could soon be available.
The list of genes causative of neuropathy continues to grow, and whilst it is established that certain conditions (e.g., Friedreich ataxia) are associated with neuropathy, the latter can be a very minor and inconstant aspect of an inherited condition, making it difficult to confirm the association of neuropathy with a particular disease, especially in small cohorts of patients. This review identified neuropathies by beginning with gene panels used for the diagnosis of inherited neuropathies in the UK, France, and the USA; this list was extended by the authors and through searches of published data [1][2][3]14] and revised by two experts. Although it may not be exhaustive, the list provided here includes genes not described in recent publications and highlights the inconsistencies among published data and the different gene panels used for this analysis. Indeed, only a few genes were consistently found in all three panels, and some genes mentioned in the literature were not found in any of these three panels (Appendix A).
In addition to providing an updated list of conditions associated with inherited neuropathies, this review summarized data from clinical trials conducted in the last 5 years, evaluating therapies for these specific conditions. This analysis allowed us to identify 28 studies evaluating the effects of drugs or dietary interventions on neuropathy. Among these, 14 different drugs were assessed in nine inherited neuropathies. Nine additional therapies were identified that were not included in the systematic review published by Jennings et al. in 2021 [7], attesting to the increased interest in this field over recent years. Our search yielded several disease-modifying drugs, including small molecules, nucleic acid-based drugs, and gene therapy, especially in patients with ATTRv-PN and MLD. Some trials looked promising (e.g., L-serine for HSAN1 and PTX3003 for CMT1A) and will require close monitoring in the future, whereas others showed relatively stable nerve conduction studies upon treatment (e.g., DHA for SCA 38, rhASA for MLD) and warrant longer follow-ups and/or comparisons to natural history cohorts to assess the effects on neuropathy. Finally, some treatments of symptoms were beneficial (e.g., carbidopa in familial dysautonomia).
Although not designed to evaluate neuropathy as an endpoint, several therapeutics were demonstrated to cause changes in biomarkers thought to be causal of neuropathies (i.e., NTLA-2001 and eplontersen for ATTRv-PN, givosiran for AIP, and ERT, EET, and SRT for Fabry disease). These therapeutics should be tested with a focus on neuropathy in further trials. Other therapeutics caused changes in biomarkers but the association with neuropathy is unknown (i.e., taurine and glutamine for MELAS, SRT and ERT for Gaucher disease, several trials in FRDA, cholic acid in BASD, leriglitazone in X-ALD, and olipudase alfa in ASMD). Finally, improvements in neurological assessments were observed for patients with FRDA treated with EPI-743 and omaveloxolone and for patients with X-ALD treated with leriglitazone, but further investigations are needed in terms of efficacy on neuropathy, especially since omaveloxolone has recently been approved by the FDA.
In addition, this research highlighted two general findings. Firstly, most clinical trials have been conducted with subjects diagnosed with complex disorders with a possible neuropathology component rather than pure hereditary neuropathies. As neuropathy is only one of a number of symptoms that can be experienced by these subjects, fewer than 50% of studies monitored nerve conduction or employed specific neuropathy scales to assess treatment efficacy. Secondly, among clinical trials with neuropathy as an outcome measure, various clinical scales or scoring systems were used, which prevented comparisons between studies. Moreover, some scoring systems, although validated for use in the evaluation of the progression of neuropathy, may not be appropriate in all circumstances. For example, heart rate to deep breathing from the modified Neuropathy Impairment Score +7 scale, which is validated for use in neuropathies involving autonomic dysfunction [121], was not performed in the NEURO-TTR trial evaluating inotersen, because most ATTRv-PN patients included in this trial had active pacing or atrial fibrillation. Therefore, other endpoints must be used to assess autonomic dysfunction in such subjects. Additional limitations are that the scoring systems are subjective and cannot reliably detect subtle motor changes, especially in small cohorts.
Therefore, it will be important to assess neuropathy as an outcome in further trials, aiming to support an association of various complex conditions with neuropathies amongst larger cohorts. In addition, it will be critical to develop objective and reliable methods for this analysis. Research is ongoing to evaluate disease progression in subjects with peripheral neuropathies, including the use of wearable technologies [122,123], nerve sonography [124], intramuscular fat accumulation demonstrated by MRI imaging of the lower limbs [125], elevated plasma neurofilaments light chain concentration [126], and changes in the motor unit index (MUNIX) (NCT03715283). Associated with systematic nerve conduction studies, this could allow a better characterization of the type of neuropathy, their prevalence, and their potential correlation with readily monitored biomarkers to lead to a better understanding of the underlying physiopathological mechanisms of neuropathy and more effective treatment.  Acid ceramidase deficiency, also known as Farber disease ASAH1 [131] Multiple sulfatase deficiency, also known as Austin disease SUMF1 [132] Glucocerebrosidase deficiency, also known as Gaucher disease GBA [14,118] Galactosialidosis CTSA [1,14]     Familial dysautonomia ELP-1 AR Defect in baroreceptor neurons in cranial nerves IX and X [137].
Variability in blood pressure among other dysautonomia symptoms [137].

SPTLC1 and SPTLC2 AD
Mutation reduces the affinity of the serine palmitoyltransferase enzyme for its normal substrate, serine and increases affinity for alanine and glycine, leading to the production of abnormal neurotoxic 1-deoxysphingolipids [138].
Small-fibre and sensory axonal neuropathy [139] -Symptomatic. -Allogeneic haematopoietic stem-cell transplantation has been reported to slow disease progression in some patients, especially in late-onset presymptomatic phenotype [145,146].

X-linked
Mutation in protein involved in the transmembrane transport of very-long-chain fatty acids leads to accumulation of these fatty acids in different tissues [147].
Very broad spectrum. Symptoms range from adrenocortical insufficiency only to cerebral adrenoleukodystrophy to adrenomyeloneuropathy (AMN). Most adult patients present with AMN, which involves myelopathy, neuropathy, and possible cerebral involvement [147].
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease Expansion of CAG repeat in the AR gene

X-linked
Mutation of the receptor for androgen results in degeneration of lower motor neurons and skeletal muscles [148].
Muscle weakness, atrophy, fasciculations, occasionally androgen insensitivity [1,148].  Mutation of GBE1 results in glycogen branching enzyme deficiency, which causes polyglucosan body accumulation in various tissues including peripheral nerves and cerebral white matter [149].
Fabry disease (FD) GLA X-linked Mutation of GLA results in α-galactosidase A activity deficiency, leading to accumulation of globotriaosylceramide (Gb3) and its deacylated form globotriaosylsphingosine (lyso-Gb3) in plasma and different cell types.
The severity of phenotype depends on the level of galactosidase A activity [150].
Acid sphingomyelinase deficiency (ASMD) SMPD1 AR Mutation results in lysosomal enzyme acid sphingomyelinase activity deficiency, leading to sphingomyelin accumulation in various tissues, including the macrophage-monocyte system [152].
Phenotypic spectrum ranges from severe infantile presentation with early death to subacute/chronic neurovisceral forms. Patients present with hepatosplenomegaly, thrombocytopenia, and interstitial lung disease [152].
Subclinical polyneuropathy, predominantly sensory axonal [1,154] -Symptomatic (anticonvulsivant drugs).  Deficiency or lack of activity in enzymes that catalyse the conversion of cholesterol to bile acids (i.e., single enzyme defects) or defects in oxidation and shortening of the cholesterol side chain caused by generalized peroxisomal dysfunction (Zellweger spectrum disorder) [162].