Axonal Sensorimotor Neuropathy Research Articles

Obsessive-compulsive disorder as a first manifestation of Ataxia with Oculomotor Apraxia type 2 due to a novel mutation of SETX gene.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disorder presenting with cerebellar ataxia, sensory-motor axonal neuropathy, oculomotor apraxia, cerebellar atrophy and high alpha-fetoprotein (AFP) serum level. AOA2 is due to coding mutations of the SETX gene, mapped to chromosome 9q34. Seldom noncoding mutations affecting RNA processing have been reported too. To date psychiatric symptoms have never been reported in AOA2. A 19 years-old man came to our attention for progressive gait ataxia debuted five years earlier. His past medical history was unremarkable, while his parents were consanguineous. On neurological examination, he had bilateral horizontal gaze-evoked nystagmus with hypometric saccades and saccadic horizontal smooth pursuit, appendicular ataxia, limbs and trunk myoclonic involuntary movements with hands' dystonic postures and dance of the tendons. Psychological evaluation described intrusive and obsessive thoughts experienced by the patient, then diagnosed as obsessive-compulsive disorder. Blood tests detected an elevated AFP level. Brain MRI showed cerebellar atrophy, while electroneuromyography revealed an axonal sensory-motor polyneuropathy. In the suspicion of a pathology belonging to the autosomal recessive cerebellar ataxias (ARCA) spectrum disorder, a direct search of point mutations by whole-exome sequencing was performed revealing a novel biallelic variant in SETX gene (c.6208+2dupT), which was classified as likely pathogenic. The present case expands the genotypic and phenotypic spectrum of AOA2, reporting a novel likely pathogenic SETX mutation (c.6208+2dupT) and highlighting an early psychiatric involvement in AOA2, suggesting the need for psychiatric assessment in these neurologic patients.

Lower limb nerve ultrasound: A four-way comparison of acquired and inherited axonopathy, inherited neuronopathy and healthy controls.

In a recent study, we showed that nerve ultrasound of the upper limbs could distinguish inherited sensory neuronopathy from inherited axonopathy; surprisingly, no differences were found in the lower limb nerves. In this study, we compared lower limb nerve ultrasound measurements in inherited neuronopathy, inherited axonopathy, and acquired axonopathy. Tibial and sural nerve ultrasound cross-sectional areas (CSAs) of 34 healthy controls were retrospectively compared with those of three patient groups: 17 with cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS), 18 with Charcot-Marie-Tooth type 2 (CMT2), and 18 with acquired length-dependent sensorimotor axonal neuropathy, using ANOVA with post-hoc Tukey honestly significance difference (HSD) (significance level set at p < .05). The nerve CSAs of CANVAS and CMT2 patients were not significantly different. Both the tibial and the sural nerve CSAs were significantly smaller in CANVAS and CMT2 compared with the acquired axonal neuropathy group. Tibial nerve CSAs of CANVAS and CMT2 were significantly smaller than controls. Tibial and sural nerve CSAs of the acquired axonal neuropathy group were also significantly larger than the controls'. Ultrasound of the lower limb nerves distinguished inherited from acquired axonopathy with the nerve size respectively reduced and increased in these two groups. This has potential implication for the differential diagnosis of these diseases in clinical practice.

Vasculitis associated with psoriatic arthritis: a case report

BackgroundPsoriatic arthritis is a chronic inflammatory condition associated with psoriasis, which affects joints. The coexistence of vasculitis, an inflammation of blood vessels, with psoriatic arthritis is rare, highlighting a complex interplay between autoimmune diseases that affect both joints and vascular structures.Case presentationWe report on a 56-year-old male with a long-standing history of psoriasis and psoriatic arthritis, who presented with new-onset skin lesions and neurological symptoms. Clinical evaluations confirmed the presence of leukocytoclastic vasculitis and asymmetric sensory motor axonal neuropathy. The absence of positive results from various standard tests led to a challenging diagnostic process, ultimately pointing towards vasculitis associated with psoriatic arthritis. The patient was treated with corticosteroids and immunosuppressive therapy, leading to partial symptom improvement.ConclusionsThis case underlines the complex and often overlapping nature of autoimmune conditions, particularly the occurrence of vasculitis in patients with psoriatic arthritis, which is rare. It stresses the importance of considering vasculitis in patients with psoriatic arthritis who present with unexplained skin lesions and neurological symptoms. This case adds to the spectrum of psoriatic disease manifestations and suggests a need for further research to explore the underlying mechanisms and improve management strategies.

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18 . All affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

Accelerated neuropathy among chronic kidney disease patients undergoing hemodialysis: Analysis of an institutional cluster.

Accelerated neuropathy is a rare syndrome of rapidly worsening peripheral neuropathy, typically described in end-stage kidney disease (ESKD) patients undergoing dialysis. In our center, we encountered a surge in the occurrence of accelerated neuropathy among ESKD patients undergoing hemodialysis, which prompted systematic research. In this case-control study, we present the clinical features, electrophysiologic findings, and outcome of a series of patients who developed accelerated neuropathy after commencing hemodialysis for ESKD. Those who initiated hemodialysis and did not develop accelerated neuropathy were included as controls. We used logistic regression to identify predictors of accelerated neuropathy. Among 436 ESKD patients who initiated hemodialysis over 4 years, 17 were diagnosed with accelerated neuropathy. The median-time (interquartile range) from hemodialysis initiation to presentation with accelerated neuropathy was 3 weeks (2-6). It typically presented as acute onset of unsteadiness of gait necessitating assistance for ambulation. Electrophysiology revealed length-dependent symmetric sensorimotor axonal neuropathy. Diabetes mellitus (odds ratio [OR] 4.1, 95% CI 1.2-13.9, p = 0.02), pre-existing peripheral neuropathy (OR 9.25, 95% CI 2.79-30.6, p < 0.001), and serum alkaline phosphatase (OR 1.2 for every 10 U increase, 95% CI 1.00-1.52, p = 0.04) significantly predicted accelerated neuropathy. With continued dialysis and supportive care, neurologic status improved, total-neuropathy score (summary score of peripheral nerve dysfunction incorporating clinical and electrophysiological parameters) declined from 26.5 to 18.4 (p < 0.001) and most regained unassisted ambulation. This study presents the largest series of patients with accelerated neuropathy and has identified predictors. However, in view of the unusually high incidence of accelerated neuropathy we speculate that other unidentified factor(s) could be underlying its pathogenesis.

Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.

Understanding Neuropathy Features in the Context of Nitrous Oxide Abuse: A Combined Electrophysiological and Metabolic Approach.

The incidence of neurological complications associated with nitrous oxide (N2O) abuse, including N2O-induced myelopathy and neuropathy, has risen in the past decade. N2O-induced neuropathy often presents as a subacute axonal pathology; however, demyelinating patterns mimicking Guillain-Barré syndrome have also been observed. This study explores the metabolic pathophysiology of N2O-induced neuropathy, focusing on the alteration in metabolism to provide a deeper understanding of the biochemical pathways influencing the diverse electrophysiological patterns observed. We conducted a combined metabolic and electrophysiological exploration of 35 patients who underwent electromyographic exams at our referral center over a three-year period for sensorimotor symptoms linked to recreational N2O use. We collected demographic, clinical, radiological, electrophysiological, and biological data. Patients were categorized into axonal or demyelinating groups based on their electrophysiological patterns, and metabolic parameters were compared. Our cohort predominantly exhibited a length-dependent sensorimotor axonal symmetrical neuropathy affecting the lower limbs. Among the patients, 40% met the demyelinating criteria, with four patients exhibiting conduction blocks. The demyelinating group had a significantly higher peripheral neuropathy disability (PND) score at diagnosis. Elevated homocysteine and methylmalonic acid (MMA) levels were noted in all patients, but these were lower in the demyelinating group. This study highlights the diverse electrophysiological manifestations of N2O-induced neuropathy and underscores the potential role of metabolic parameters as biomarkers to understand its pathophysiology. Lower hyperhomocysteinemia and MMA levels were observed in demyelinating patterns. In this study, we did not observe further improvement, but it is well-known that demyelinating features have a better prognosis related to the further remyelination. These findings contribute to a better understanding of N2O-related neuropathic damage and could guide future therapeutic interventions based on biochemical-neurophysiological stratifications.

Nerve conduction study findings in females with systemic lupus erythematosus

Aim of the workTo investigate the frequency, characteristics, and associated factors of systemic lupus erythematosus-related peripheral neuropathy (SLE-PN) using nerve conduction study (NCS). Patients and methodsA retrospective chart review was conducted at the Rheumatology clinics of King Abdulaziz University Hospital, Jeddah, Saudi Arabia from 2016 to 2020. Eligibility included systemic lupus erythematosus (SLE) diagnosed patients with at least one NCS result in their clinical records. Demographic, clinical, and biological characteristics were collected. ResultsAmong 101 female SLE patients, abnormal NCS findings were observed in 11 (10.9%) patients. Of those with abnormal NCS, 27.3% showed mixed axonal and demyelinated motor neuropathy, 18.2% had sensory-motor axonal neuropathy, another 18.2% presented with axonal left common peroneal neuropathy, and the same percentage was observed for axonal sensory neuropathy. Comparisons between abnormal and normal NCS groups in a study population revealed that the abnormal NCS group had significantly higher proportions of non-Saudi nationality, lupus nephritis, seizures, and high SLICC DI. Furthermore, this group was associated with higher ANA titers and exhibited a non-significant trend towards increased positive anti-DNA frequency. Multivariate analysis identified non-Saudi nationality and the presence of end-organ damage as two significant predictors of SLE-related PN. ConclusionPeripheral neuropathy in SLE patients in Saudi Arabia is not uncommon, specifically those with heightened disease activity, organ damage, or disadvantaged socioeconomic backgrounds. Predominantly, the condition presents as axonopathy impacting sensory nerves, with possible motor involvement. The critical role of electrophysiological studies in early detection and improved patient management is high lightened.

Prevalence of Peripheral Neuropathy (PN) Among Patients with Asymptomatic Monoclonal Gammopathies: A Clinical & Electrophysiological Study

Introduction: Asymptomatic monoclonal gammopathies (MGUS, SMM or aWM) are common among adults &amp;gt;50y. Peripheral neuropathy (PN) refers to any disorder of the peripheral nervous system including mononeuropathies, and symmetrical or asymmetrical polyneuropathy. PN is also common among individuals &amp;gt;50y. Common risk factors include diabetes, vitamin deficiencies, alcohol, renal insufficiency, hypothyroidism, autoimmune diseases and exposure to neurotoxic medication. Epidemiological studies have shown an association between monoclonal gammopathies and PN but a mechanistic link has been established only for some (anti-MAG IgM-related PN, amyloidosis, POEMS syndrome etc). However, the true prevalence of PN among patients (pts) with monoclonal gammopathies is unknown and remains challenging to associate monoclonal gammopathy with PN. The aim of our study is to establish the prevalence of PN in a large cohort of pts with asymptomatic monoclonal gammopathy and identify potential determinants. Methods: This is an ongoing prospective, non-invasive study aiming to screen ~1500 pts with asymptomatic monoclonal gammopathies for PN. Pts under regular follow-up at the Department of Therapeutics, University of Athens, Greece are screened for neuropathic symptoms using the Michigan Neuropathy Screening Instrument (MNSI), a validated screening tool for the presence of PN that consists of 15 yes/no items. A cut off ≥ 4 has been proposed as a screening cut off in diabetic PN. All pts scoring ≥4 on MNSI and pts scoring &amp;lt;4 but without risk factors for PN were assessed clinically and electrophysiologically (EDX) with standard nerve conduction studies (NCS), sympathetic skin response (SSR) test and - if needed - electromyography (EMG) by a specialist. NCS protocol includes assessment of the median nerve (motor and sensory), superficial radial nerve (sensory), tibial nerve (motor) and sural nerve (sensory) conduction studies. Axonal PN was diagnosed when the sural to radial ratio (SRAR) is below 0.25 and/or the sural nerve action potential is below 6μV, demyelinating PN if the EAN/PNS criteria for demyelination are fulfilled and sympathetic dysfunction when the SSR amplitude was &amp;lt;500 uV. Results: As of to date, 320 pts (42.8% males, median 67y) with asymptomatic monoclonal gammopathy have been screened; 64.3% had a diagnosis of MGUS (72.3% IgG, 14.1% IgA, 6.3% IgM, 7.3% light chain only), 23.9% had SMM and 11.8% had aWM. Among enrolled pts, 217 (68%) had no common risk factors for PN and 82 pts (25.6%) had an MNSI score ≥4; the commonest symptoms were cramps (48.4%), weakness (26.9%) and pain when walking (26.3%). Among pts without risk factors for PN, 42 (19.4%) had an MNSI score ≥ 4 and the commonest symptoms were cramps (44.7%), pain when walking (22.1%) and weakness (21.7%) (Table 1). There was no difference in the prevalence of MNSI score ≥4 among pts with different paraprotein types. To date, 105 pts (41.9% males, median 66y) had EDX evaluation, of which 77 (73%) had no common risk factors for PN. Among the EDX evaluated pts, 23 (21.9%) had large fiber PN, 42 (40%) had sudomotor dysfunction and 53 (50.5%) had large fiber PN and/or sudomotor dysfunction. Among the cohort of pts without risk factors for PN, 13 (16.9%) had large fiber PN, 25 (32.5%) had sudomotor dysfunction and 34 (44.2%) had large fiber PN and/or sudomotor dysfunction. Nineteen pts that went through EDX were asymptomatic (MNSI=0), of those 4 (21.1%) had large fiber PN, 4 (21.1%) had sudomotor dysfunction and 7 (33.3%) had large fiber PN and/or sudomotor dysfunction. Only one patient, without other risk factors, had a demyelinating neuropathy while all other pts had a length-dependent axonal sensory or sensorimotor neuropathy. Pts with large fiber PN were older (73.7±11.4 vs 63±9.4, p&amp;lt;0.001) but no significant differences were found regarding sex, or paraprotein or light chain type. Pts with sudomotor dysfunction were more likely to have a non-IgM monoclonal gammopathy (90.2% vs 72.6 %, p=0.029). Conclusion: Peripheral neuropathy is common in pts with monocloncal gammopathies affecting ~20% of those without any other risk factors for PN. Although most pts with PN describe mild symptoms, both large fiber PN and sudomotor dysfunction may remain completely asymptomatic. This data provides a new insight into the prevalence of PN in pts with monoclonal gammopathies with implications for future research. The study is ongoing and updated results will be presented.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.

Small fiber neuropathy associated with ANCA positivity: a case series and brief literature review.

Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN. This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA. Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients. This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association.

Symptomatic Copper Deficiency Masquerading as Paraneoplastic Syndrome (P9-4.005)

<h3>Objective:</h3> To describe an unusual case of symptomatic copper deficiency initially suspected to be paraneoplastic syndrome. <h3>Background:</h3> Copper deficiency is exceedingly rare, especially in developed nations, and is usually the result of genetic deficit. It often presents with neuropathy, weakness and encephalopathy. In this case, we describe a case of copper deficiency presenting with weakness, hallucinations and encephalopathy initially mistaken for paraneoplastic syndrome in a patient recently diagnosed with breast cancer. <h3>Design/Methods:</h3> NA <h3>Results:</h3> Our patient is a 58 year old female with a history of recently diagnosed breast cancer who presented with new-onset lower extremity weakness and confusion. She was initially admitted to the medical-oncology service for management of her malignancy. During her hospitalization, she developed frank hallucinations and worsening encephalopathy. Neurologic workup including MRI brain, C and T-Spine, EEG, lumbar puncture with basic studies and autoimmune panel were negative. She got 3 days of IVIG and 5 days of PLEX with no improvement. The patient’s sister revealed for 8 weeks she had only been eating vegetables grown in her own garden. EMG revealed axonal sensorimotor neuropathy. Serum vitamins were checked and revealed a copper level of 30 ug/dL (80–120 ug/dL). She was started on IV copper replacement and slowly improved; she was seen in the clinic six months later with marked improvement of her mentation, but persistent lower extremity paraparesis. <h3>Conclusions:</h3> While vitamin deficiency—especially copper deficiency—is rare, it should be considered in cases where patients with weakness and neuropsychiatric symptoms have a benign neurologic workup and fail to respond to conventional immunologic therapies. <b>Disclosure:</b> Dr. Welsh has nothing to disclose. Dr. Hoskin has nothing to disclose.

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.

Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy.

Variant Transthyretin Amyloidosis (ATTRv) neuropathy is an adult-onset, autosomal dominant, lethal, multisystemic disease due to the deposition of mutated transthyretin (TTR) in various organs, commonly involving the peripheral nerves and the heart. Circulating TTR tetramers are unstable due to the presence of mutated TTR and dissociate into monomers, which misfold and form amyloid fibrils. Although there are more than 140 mutations in the TTR gene, the p.Val50Met mutation is by far the commonest. In the typical, early-onset cases, it presents with a small sensory fibre and autonomic, length-dependent, axonal neuropathy, while in late-onset cases, it presents with a lengthdependent sensorimotor axonal neuropathy involving all fibre sizes. Treatment is now available and includes TTR stabilizers, TTR amyloid removal as well as gene silencing, while gene editing therapies are on the way. Its timely diagnosis is of paramount importance for a better prognosis.

STUDY OF NERVE CONDUCTION ABNORMALITIES IN ASYMPTOMATIC TYPE II DIABETIC INDIVIDUALS

Diabetic neuropathy occurs in 50% of individuals with long standing diabetes mellitus. It is the most dreadful microvascular complication of poorly controlled long standing diabetes mellitus, ending up in amputation in worst cases. It is signicantly associated with age, duration of diabetes, smoking and HbA1c. Neuropathy can cause sensory decit, neurological disorder, limb ulcers, osteomyelitis and lead to amputation. Nearly 50% of diabetic peripheral neuropathy is asymptomatic. Methods: 80 cases who were diabetic and without any symptoms of neuropathy were taken into the study and both motor and sensory nerve conduction studies were performed. Results:In this study, patterns of nerve conduction velocities show abnormal conduction patterns in 65% of individuals. Of these demyelinating axonal sensorimotor neuropathy is predominant (20%), followed by demyelinating sensorimotor (15%), axonal sensory (10%), demyelinating sensory (10%), demyelinating motor (5%), axonal sensorimotor (2.5%) and axonal motor (2.5%). Conclusions: Nerve conduction studies even in asymptomatic cases may prove to be valuable indices of progression to full blown diabetic neuropathy in due course and help initiate prophylactic measures to retard its progress

Electrophysiology of ataxia-telangiectasia-like disorder 1.

Ataxia-telangiectasia-like disorder-1 (ATLD1, OMIM # 604391) is a very rare clinical condition, characterized by slowly progressive ataxia with onset in childhood, associated with oculomotor apraxia and dysarthria. Laboratory findings reveal increased susceptibility to radiation, with a defect in DNA repair. Patients with ATLD1 show no telangiectasia, have no immunodeficiency, and also have preserved cognition. Reflexes might be initially brisk and later becomes reduced associated with axonal sensorimotor neuropathy. Brain magnetic resonance imaging (MRI) detects cerebellar atrophy. The condition is caused by mutations in the meiotic recombination 11 (MRE11A) gene. The present study reports on the neurophysiologic finding in eight Saudi patients, belonging to three Saudi families, who have genetically confirmed ATLD1. All investigated patients had cerebellar atrophy on brain MRI (5/5). Electrophysiologic studies showed normal motor conduction velocity (MCV) of the median (8/8) and tibial (2/2) nerves, while 5/6 (83%) had normal peroneal nerve MCV. The distal motor latency (DML) for median, tibial, and peroneal nerves was within the normal range in all examined patients. The amplitude of compound muscle action potential (CMAP) of median and tibial nerves was also normal, while that of the peroneal nerve was normal in 3/6 (50%). Two of seven (29%) patients had reduced amplitude of median nerve sensory nerve action potential (SNAP) while 3/8 (38%) had a reduction in the amplitude of sural nerve SNAP. These findings favour an axonal type of neuropathy predominately affecting the sensory fibres (axonal sensorimotor neuropathy). The present study constitutes the largest cohort of ATLD1 patients worldwide who had electrophysiologic tests.

Phaeohyphomycotic cyst.

Phaeohyphomycosis is a term used for a rare opportunistic infection caused by a group of dematiaceous fungi which contains melanin in their cell walls. In 1974, the term phaeohyphomycosis was first coined by Ajello for an entity caused by pigmented fungi.1 Four clinical forms of phaeohyphomycosis exist: i) cutaneous, ii) subcutaneous, iii) systemic, and iv) cerebral. Among these, the subcutaneous form (phaeohyphomycotic cyst) is the most common subtype which usually presents as nodular swelling mainly over the distal extremities, which may be misdiagnosed as epidermal inclusion cyst, ganglion or lipoma. These fungi are present in the soil, where they infect mostly farmers and persons working in fields and farms. It was also highlighted that these infections are seen mostly in immunocompromised individuals and are byproducts of antimicrobial, steroid, and immunosuppressive therapy for various illnesses, including cancer, autoimmune diseases, and transplant cases.1 The pigment giving the characteristic brownish-black appearance to the fungi is melanin, which prevents phagocytosis and hence acts as a virulence factor.2 This group has more than 120 species and 70 genera.3 They have a broad spectrum of clinical manifestations, including superficial and deep fungal infections, sinus involvement, and disseminated forms, including lung and brain abscesses. The incidence ranges from 1-3.1 per 100,000 patients.4 The gold standard method for diagnosis is histopathological examination and culture. Fontana-Masson stain is of immense help in identifying these dematiaceous fungi in tissue as it highlights the melanin pigment in the cell walls. Figure 1 refers to a 59-year-old farmer man who presented with nodular swelling over the dorsum of the left hand for the last 9 months. Initially, the swelling was of peanut size, which gradually progressed to the present size of 5x3x2cm. The lesion was painless, well-defined, and freely mobile. The joint was not affected. He is on medication for type II diabetes mellitus and hypertension. He underwent Whipple's surgery for periampullary carcinoma. He was treated for proximal sensory-motor axonal neuropathy and tuberculosis three years back. Because of isoniazid-induced hepatitis, the patient received a modified anti-tuberculous regime for 9 months, after which he developed gastric ulceration with hematemesis and melena. On endoscopic biopsy, he was found to have chronic active gastritis with Helicobacter pylori infection. In addition, the patient had severe iron deficiency and hypoalbuminemia due to malabsorption. After treatment, he completely recovered at the time of hospital discharge. Figure 1 Phaeohyphomycotic cyst. A - A well-encapsulated and unilocular cyst measuring 4.5x2.2x1.8cm in size (scale bar = 2.5cm); The cyst lumen contains homogenous and translucent gelatinous soft material; B - Multinucleated giant cells showing fungal profile with septate, branching and globose swelling (H&E; x200); C - Periodic Acid-Schiff stain showing bright magenta positivity (PAS stain; x200); D - Fontana Masson stain giving brownish black color due to melanin in the fungal cell walls (x200).: Thus, the nodular swelling was wholly excised and sent for histopathological examination. Grossly, a well-encapsulated mass measuring 4.5x2.2x1.8 cm was submitted for histological analysis (Figure 1A). The external aspect appeared intact, yellowish-white, and congested. A unilocular cyst was identified on serial slicing with a capsular thickness of 0.1-0.2cm. The cut surface was soft in consistency with homogenous and gelatinous translucent material within the lumen. On light microscopy, an outer thick fibrous capsule layer was identified. Just beneath this capsular layer was the vascularized granulation tissue, proliferating fibroblasts, numerous multinucleated foreign and Langhan’s giant cells, and variable lymphoplasmacytic cell infiltrate. Also, abundant basophilic mucoid material with a background of many degenerated cells. These giant cells engulfed pigmented fungal profiles that depicted branching, septate and globose swelling (Figure 1B). Periodic Schiff-Acid stain gave bright magenta color to these fungi (Figure 1C), whereas Fontana Masson stain gave brownish black color due to melanin in the fungal cell walls (Figure 1D). Given the morphology, a diagnosis of a phaeohyphomycotic cyst was rendered. On follow-up, the patient is doing well, and has not received any antifungal agent. The leading treatment choice in non-invasive subcutaneous phaeohyphomycosis is local excision.

Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits.

A Metabolic Signature of Hereditary Transthyretin Amyloidosis: A Pilot Study.

Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv amyloidosis can present as a progressive, axonal sensory autonomic and motor neuropathy or as an infiltrative cardiomyopathy. The definition of biomarkers for the early diagnosis of ATTRv is particularly important in the current era of emerging treatments. In this sense, metabolomics could be an instrument able to provide metabolic profiles with their related metabolic pathways, and we would propose them as possible fluid biomarkers. The aim of this study is to identify altered metabolites (free fatty acids and amino acids) in subjects with a confirmed pathogenic TTR variant. Out of the studied total free fatty acids and amino acids, the serum values of palmitic acid are significantly lower in the ATTRv patients compared to the recruited healthy subjects. The metabolic remodeling identified in this neurogenetic disorder could be the manifestation of pathophysiological processes of the disease, such as mitochondrial dysfunction and neuroinflammation, and contribute to explaining some of its clinical manifestations.

Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability

Biallelic rare variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes ranging from severe neurodegenerative disorders to isolated mitochondrial myopathy or deafness. To date, only a small number of patients with NARS2 variants have been reported, and possible genotype-phenotype correlations are still lacking. Here, we present three siblings who had an early-onset hearing loss, while one developed severe symptoms in adulthood associated with early intellectual impairment, refractory seizures, moderate axonal sensorimotor neuropathy, and atypical psychiatric symptoms. Biochemical analysis revealed impairment of the activity and assembly of the respiratory chain complexes in this patient's muscle and fibroblasts. Whole Exome Sequencing allowed identification of a heterozygous variant NM_024678.5(NARS2):c.822G > C (p.Gln274His) that is known to be pathogenic and to affect splicing of the NARS2 gene, but was unable to detect a second variant in this gene. Coverage analysis and Sanger sequencing led to identification of a novel intronic deletion NM_024678.5(NARS2):c.922-21_922-19del in the three siblings in trans with the c.822G > C. Functional analysis by RT-PCR showed that this deletion was causing aberrant splicing and led to exon 9 skipping in NARS2 mRNA in patient fibroblasts. Our work expands the phenotype and genotype spectrum of NARS2-related disorders. We provide evidence of the pathogenic effect of a novel intronic deletion in the NARS2 gene and report on additional adult patients with a large intrafamilial variability associated with splice variants in this gene. More specifically, we detail the phenotype of the oldest living patient to date with NARS2 variants and, for the first time, we report the psychiatric symptoms associated with this gene. Our work confirms the complexity of genotype-phenotype correlation in patients with pathogenic NARS2 variants.