Inflammatory sensory neuronopathies.

Inflammatory sensory neuronopathies are rare disorders mediated by dysimmune mechanisms targeting sensory neurons in the dorsal root ganglia. They constitute a heterogeneous group of disorders with acute, subacute, or chronic courses, and occur with cancer, systemic autoimmune diseases, notably Sjögren syndrome, and viral infections but a noticeable proportion of them remains isolated. Identifying inflammatory sensory neuronopathies is crucial because they have the potential to be stabilized or even to improve with immunomodulatory or immunosuppressant treatments provided that the treatment is applied at an early stage of the disease, before a definitive degeneration of neurons. Biomarkers, and notably antibodies, are crucial for this early identification, which is the first step to develop therapeutic trials.

Neuromuscular ultrasound as a marker for inherited sensory neuronopathy.

A review and detailed analysis of the literature over the past two decades has revealed a unique ultrasound feature of pathologically "small" nerves in inherited sensory neuronopathies. Although sample sizes were limited, due to the rarity of these diseases, this characteristic ultrasound finding has been consistently reported across a variety of inherited diseases that affect the dorsal root ganglia. Direct comparisons with both acquired and inherited diseases that primarily affect the axons in the peripheral nerves showed that the ultrasound finding of abnormally "small" cross-sectional areas (CSAs) in mixed nerves of the upper limbs has a high diagnostic accuracy for inherited sensory neuronopathy. Based on this review, ultrasound CSA of the mixed upper limb nerves can be proposed as a marker for inherited sensory neuronopathy.

CANVAS, a sensory neuronopathy to look for in ataxia.

Sensory neuronopathies name the degeneration of peripheral sensory neurons in dorsal root ganglia. Among the genetic causes, CANVAS could be the most frequent. CANVAS is a clinical entity associating cerebellar ataxia, sensory neuronopathy and vestibular areflexia due to biallelic expansions in RFC1. This study reports the 18 individuals with sensory neuronopathy tested for RFC1 expansion in our center. The clinical picture showed that chronic cough was a frequent sign beginning before the onset of other symptoms. CANVAS is an underestimated cause of late-onset sensory and cerebellar ataxia that needs to be tested for widely now that the molecular cause is known.

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxia.

DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which was thought to be pathogenic. This case describes the latest known symptomatic onset of DMN1L-related disease described in literature. We highlight our approach to a challenging diagnostic workup and interpretation of a specific variant that has not been previously reported. Furthermore, the case highlights the diagnostic importance of utilizing genomic sequencing and research studies for patients with rare disease.

Conformation-stabilizing ELISA and cell-based assays reveal patient subgroups targeting three different epitopes of AGO1 antibodies.

Autoantibodies (Abs) are biomarkers for many disease conditions and are increasingly used to facilitate diagnosis and treatment decisions. To guarantee high sensitivity and specificity, the choice of their detection method is crucial. Via cell-based assays, we recently found 21 patients with neurological diseases positive for antibodies against argonaute (AGO), 10 of which having a neuropathy (NP). Here, we established a simple and conformation-sensitive ELISA with the aim to distinguish between AGO1 Abs against conformational epitopes and non-conformational epitopes and to reveal further characteristics of AGO1 antibodies in NP and autoimmune disease (AID). In a retrospective multicenter case/control and observational study, we tested 434 patients with NP, 274 disease controls with AID, and 116 healthy controls (HC) for AGO1 Abs via conformation-stabilizing ELISA. Seropositive patients were also tested for conformation-specificity via comparative denaturing/stabilizing ELISA (CODES-ELISA), CBA positivity, AGO1 titers and IgG subclasses, and AGO2 reactivity. These parameters were statistically compared among different epitope-specific patient groups. We found Abs in 44 patients, including 28/434 (6.5%) NP, 16/274 (5.8%) AID, and 0/116 (0%) HC. Serum reactivity was consistently higher for AGO1 than AGO2. Globally among the 44 AGO1 Abs-positive patients, 42 were also tested in CBA for AGO1 Abs positivity and 15 (35.7%) were positive. Furthermore, 43 were tested for conformation-specificity and 32 (74.4%) bound a conformational epitope. Among the subgroups of highly positive patients (ELISA z-score >14) with sera binding conformational epitopes (n=23), 14 patient sera were also CBA positive and 9 bound a second conformational but CBA-inaccessible epitope. A third, non-conformational epitope was bound by 11/43 (15.6%). Among the epitope-specific patient subgroups, we found significant differences regarding the Abs titers, IgG subclass, and AGO2 reactivity. When comparing AGO1 Abs-positive NP versus AID patients, we found the conformation-specific and CBA inaccessible epitope significantly more frequently in AID patients. We conclude that 1) conformational ELISA was more sensitive than CBA in detecting AGO1 Abs, 2) serum reactivity is higher for AGO1 than for AGO2 at least for NP patients, 3) AGO1 Abs might be a marker-of-interest in 6.5% of NP patients, 4) distinguishing epitopes might help finding different patient subgroups.

Anti-disialosyl-immunoglobulin M chronic autoimmune neuropathies: a nationwide multicenter retrospective study.

BACKGROUND AND PURPOSE: In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with anti-disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA). RESULTS: Fifty-five patients with a polyneuropathy evolving for more than 2 months and with at least one anti-disialosyl ganglioside IgM antibody, that is, anti-GD1b, -GT1b, -GQ1b, -GT1a, -GD2 and -GD3, were identified. Seventy-eight percent of patients were male, mean age at disease onset was 55 years (30-76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty-five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti-GD1b antibodies were found in 78% of cases, whilst other anti-disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty-six percent of CNDA patients were intravenous immunoglobulins-responsive, and rituximab was successfully used as second-line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years. CONCLUSION: Chronic neuropathies with anti-disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins-responsive and present with a good outcome in a majority of cases.

Subacute sensory neuronopathy associated with Merkel cell carcinoma with unknown primary: a case report with literature review.

Paraneoplastic neurologic syndromes (PNSs) are a wide spectrum of neurologic diseases characterized by different clinical features, associated with a neoplasia, and triggered by an immune-mediated process. In most cases, it is possible to detect specific neuronal antibodies and the Hu protein is one of the most frequently recognized intracellular antigens in patients with PNSs. Small-cell lung cancer is the most common cancer associated with PNSs, followed by urological, gynecological and hematological malignancies. Otherwise, extra-pulmonary small-cell carcinomas, including Merkel cell carcinoma (MCC), have been rarely described as related to PNSs. In this article we report, for the first time in the published literature, a case of anti-Hu antibody-related subacute sensory neuronopathy in association with MCC.

Distal symmetric polyneuropathy phenotype in patients with sensory neuronopathy at the time of electrodiagnosis.

INTRODUCTION/AIMS: It is unknown how often patients with sensory neuronopathy (SNN) present with a distal symmetric polyneuropathy (DSP) phenotype. In these cases, electrodiagnostic testing may discriminate SNN with a DSP phenotype from DSP. METHODS: We reviewed the records of patients who met SNN diagnostic criteria between January 2000 and February 2021 and identified patients with a DSP phenotype at the time of electrodiagnosis. RESULTS: Sixty-two patients fulfilled SNN diagnostic criteria. At symptom onset, 20 (32.2%) patients presented with distal symmetric sensory symptoms limited to the feet. However, most progressed rapidly over 6 months or developed asymmetric symptoms. At the time of electrodiagnosis, only seven (11.3%) patients had a DSP phenotype. Of these seven patients, four had cerebellar ataxia with neuropathy and vestibular areflexia syndrome, one had vitamin B6 deficiency, one was thought to be alcohol-induced, and one was idiopathic. DISCUSSION: Patients with SNN rarely present with a DSP phenotype at the time of electrodiagnosis. The finding that one third of cases resemble DSP at onset highlights the importance of clinical monitoring. In patients with a DSP phenotype, the presence of ataxia at onset or significant progression within 6 months may suggest the possibility of SNN and should prompt additional investigations, such as electrodiagnosis.

Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy.

INTRODUCTION/AIMS: Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X-linked spinal and bulbar muscular atrophy (SBMA). We investigated the hypothesis that nerves of SBMA patients show the same morphological changes on ultrasound as other inherited sensory neuronopathies and that these changes are distinct from those in axonal neuropathy. METHODS: We compared the ultrasound cross-sectional areas (CSAs) of median, ulnar, sural, and tibial nerves of prospectively recruited SBMA patients with those of patients with acquired axonal neuropathy and healthy controls. We also compared the individual nerve CSAs of SBMA and neuropathy patients with our laboratory reference values. RESULTS: There were 7 SBMA patients, 18 neuropathy patients, and 42 healthy controls. The nerve CSAs of the SBMA patients were significantly smaller than those of patients in the other two groups. The changes were most prominent in the upper limbs (p < .001), with the nerves of the SBMA patients being on average approximately half the size of the controls and a third the size of the neuropathy patients. On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one SBMA patient. DISCUSSION: These ultrasound changes are similar to those reported in other inherited sensory neuronopathies and clearly different from the ultrasound findings in axonal neuropathy. Smaller nerves are possibly a distinctive finding in SBMA that may distinguish it from other motor neuron syndromes. Further studies are warranted to confirm this and determine the optimal sonographic protocol.

Motor neuron pathology in CANVAS due to RFC1 expansions.

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (P < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy.

Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A>G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient's fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients' fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.

Sensory neuronopathies: A case series and literature review.

Sensory neuronopathies are heterogeneous disorders of dorsal root ganglia. The clinical and laboratory features in a single-centre series, including response to treatment and outcome have been described. They retrospectively included 54 patients meeting Camdessanché et al (2009) criteria for sensory neuronopathy. The patients were classified according to their likely aetiology and analysed their demographic, clinical, neurophysiological, histological and spinal MRI features. The outcome with the modified Rankin Scale (mRS) was evaluated, and the response to treatment was assessed. About 54 patients were included (18 male; median age 54.5 years). The most common initial symptoms were hypoaesthesia, paraesthesia, ataxia and pain. Half of patients had a slow onset, greater than 12 months before seeing a neurologist. The aetiology as possibly inflammatory (meaning nonspecific laboratory evidence of immune abnormality) in 18 patients (33%), paraneoplastic 8 (15%), autoimmune 7 (13%) and idiopathic 6 (11%) was classified. About 31 patients received immune therapy of which 11 (35%) improved or stabilised. Corticosteroids were the most used treatment (24 patients) and cyclophosphamide had the highest response rate (3/6, 50%). At the final follow up (median 24 months) 67% had mRS ≥3 and 46% mRS ≥4, including 15% who died. Worse outcome was associated with generalised areflexia and pseudoathetosis by logistic regression, and with motor involvement and raised CSF protein by univariate analysis. Sensory neuronopathies caused severe disability, especially in patients with generalised areflexia and pseudoathetosis. Of those without an obvious cause, most had some evidence of dysimmunity. Some patients had a positive response to immunotherapy, but rarely enough to improve disability much.

Immune-Mediated Neuropathies.

The immune-mediated neuropathies are a broad category of diseases differentiated by time course, affected nerve fibers, and disease associations. This article spans the common, well-defined inflammatory demyelinating polyradiculoneuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy) to the rarer, acquired demyelinating neuropathy variants (Miller-Fisher syndrome and multifocal motor neuropathy), vasculitic neuropathies, and sensory neuronopathies (dorsal root ganglionopathies). These case studies illustrate the characteristic clinical patterns of the immune-mediated neuropathies encountered in neurologic practice. Recommendations for diagnostic evaluation and treatment approach accompany each case. Prompt recognition of these disorders is imperative; delays in treatment may result in prolonged morbidity and permanent disability.

Sensory neuronopathy is a specific and disabling neurological manifestation of autoimmune hepatitis.

BACKGROUND AND PURPOSE: Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. METHODS: Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. RESULTS: Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P = 0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. CONCLUSION: Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

[A case of paraneoplastic sensory neuronopathy with anti-Hu antibody associated with large cell neuroendocrine carcinoma of the endometrium].

An 81-year-old woman was admitted to our hospital due to paresthesia of the extremities and difficulty in walking for three months. She underwent a total hysterectomy and bilateral salpingo-oophorectomy for large cell neuroendocrine carcinoma (LCNEC) of the endometrium seven months before the admission. The serum levels of neuron specific enolase (NSE) reduced after the surgery. She showed numbness of her limbs, disturbance of vibration, areflexia and autonomic dysfunction. Nerve conduction studies showed sensory dominant sensory neuronopathy. CT scan of her abdomen and pelvis revealed the recurrence of LCNEC of the endometrium. The serum levels of NSE was elevated and anti-Hu antibody was also positive. Other laboratory test, including autoantibodies were unremarkable. We diagnosed her as paraneoplastic sensory neuronopathy associated with postoperative recurrence of LCNEC of the endometrium. Here we show a clinical picture of anti-Hu positive paraneoplastic neurological syndrome with LCNEC of the endometrium.

Contributions to the study of spinocerebellar ataxia type 38 (SCA38).

OBJECTIVE: To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38). PATIENTS AND METHODS: Five family members spanning two generations developed gait ataxia and intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found. RESULTS: Whole-exome sequencing demonstrated a heterozygous variant in ELOVL5, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel-shin slide item scores. CONCLUSION: The mentioned ELOVL5 variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.

Sensory neuronopathy as a major clinical feature of mitochondrial trifunctional protein deficiency in adults.

INTRODUCTION: Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. OBJECTIVES: To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. RESULTS: Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy ("ganglionopathy"). All patients harbored at least one c.1528G>C mutation. DISCUSSION: We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.