Ataxic Neuropathy Research Articles

Ultrarare Cause of Childhood Chorea: Celiac Disease.

Chorea, a movement disorder that commonly affects children, may be caused by various diseases with metabolic, structural, pharmacologic, or autoimmune origins. Celiac disease is an autoimmune enteropathy that may rarely cause neurologic symptoms in children, primarily ataxia and peripheral neuropathy, even in the absence of gastrointestinal symptoms. A 9-year-old male patient diagnosed with Sydenham chorea was admitted to our clinic because of valproic acid resistance. He had involuntary, brief, random, and irregular movements in his arms over the past 2 weeks. A low-dose, high-potency dopamine-2 receptor-blocking agent was added to the patient's treatment regimen. After 2 weeks, he had maculopapular rashes on their hands and arms, as well as arthritis in his left hand. Oral prednisone was prescribed, and the patient's arthritis and rashes were completely resolved. Although movement disorder symptoms persisted in the distal left upper extremity, the chorea in the right upper extremity was recovered. Extensive investigations were conducted to rule out possible metabolic, autoimmune, inflammatory, infectious, and paraneoplastic diseases, all of which yielded normal results. Brain magnetic resonance imaging (MRI) results were normal, and genetic analysis results for chorea were negative. The patient's tissue glutaminase IgG levels exceeded 200 U/mL (normal range: 0-10 U/mL) and IgA levels at 24 U/mL (normal range: 0--10 U/mL), leading to a diagnosis of celiac disease. His duodenal biopsies showed changes consistent with gluten-sensitive enteropathy. After the diagnosis of celiac disease, the patient began a gluten-free diet and remained free of chorea at the 6-month follow-up. Chorea is a rare neurologic celiac disease manifestation that can be reversible. The celiac disease should be considered in the diagnostic workup of chorea for all ages, particularly in the treatment-resistant population, even in the absence of gastrointestinal symptoms. This report presents the first known case of chorea caused by celiac disease in a pediatric patient.

Novel AIFM1 Variant in 2 Siblings With Sensorineural Hearing Loss and Cerebellar Ataxia.

Apoptosis-inducing factor mitochondria-associated 1 (AIFM1) gene encodes a mitochondrial flavoprotein that mediates caspase-independent programmed cell death. We report a novel AIFM1 variant in 2 siblings with early-onset hearing loss and progressive cerebellar ataxia. We evaluated the clinical features, brain MRI scans, EMG studies, and whole genome sequencing (WGS). Sibling A is a 19-year-old man with auditory neuropathy at age 15 years, who subsequently developed optic atrophy, progressive gait and limb ataxia, peripheral neuropathy, and ambulation with cane by age 17 years. Brain MRI was normal. Sibling B is a 13-year-old boy with auditory neuropathy diagnosed at 7 and gait instability at 13, with rapid development of peripheral neuropathy, cerebellar ataxia, muscle weakness and atrophy needing wheelchair for mobility, and neuromuscular respiratory failure requiring noninvasive ventilation. Brain MRI showed mild cerebellar atrophy. Initial EMGs showed axonal neuropathy in both and diffuse chronic and active anterior horn cell disorder later in Sibling B. WGS revealed an X-linked, maternally inherited novel AIFM1 variant (c.1299C>G p. Ile433Met). AIFM1 variants should be considered in patients with hereditary cerebellar ataxia and auditory neuropathy. We highlight a novel AIFM1 variant and its phenotypic intrafamilial variability expanding the knowledge of the genetic spectrum of AIFM1-related diseases.

CANVAS For A Diagnosis: Can You Hear The Hooves Of Zebras?

Abstract Background A 75year old male presented to a Movement Disorder Service with complex multimorbidity including: chronic pain, type 2 diabetes mellitus, hypoventilatory obesity syndrome, biliary calculus, moderate aortic stenosis, marked orthostatic hypotension, pulmonary hypertension, coronary artery bypass grafting, permanent pacemaker for complete atrioventricular block, carpal tunnel release bilaterally, polypharmacy and bilateral cataracts. History elucidated a distal to proximal sensory loss over 20years and neuropathic pain without nerve conduction confirmation; and progressively ataxic gait over several years. He also complained of hypophonia, bruxism, excessive daytime somnolence, passages, transitions, visual agnosia, textural illusion, oscillopsia, irritability, inflexibility, hoarding, impulsivity, disorganisation, inattention, apathy, depression and aspontaneity. He was intolerant of nocturnal continuous positive airway pressure device. Epworth score was 21. Methods Examination demonstrated: marked orthostatic hypotension, preserved cognition, hypersomnolence, dyspraxic dysgraphia, palmar and antecubital agraphaesthesia, downbeat horizontal nystagmus at eccentric gaze positions, square wave jerks, bidirectionally impaired head impulse test, dysmetric saccades, asymmetric cerebellar signs in upper and lower limbs, rightward Pisa syndrome, kinesigenic dystonic axial posturing, rightward laterocollis and equivocal Babinski/Oppenheim reflexes. Gait assessment demonstrated sensory and cerebellar ataxic features with marked apraxia. No pes cavus. Results Computed tomography of brain had Fazekas 1 small vessel disease, Medial temporal atrophy score 1, Koedam 1 and age-commensurate cerebral and cerebellar atrophy. RFC1 gene testing confirmed biallelic intronic AAGGG repeat expansion disorder. Conclusion Cerebellar Ataxia Neuropathy and Vestibular Areflexia Syndrome (CANVAS) should be considered in patients with presentations from mid-life of progressive sensory ataxic neuropathy, altered vestibular ocular reflex, gaze evoked nystagmus and prominent dysautonomia. CANVAS is a rare autosomal recessive genetic disorder with a protean presentation. Referral to Genetics Services should be undertaken for family counselling. Keeping an open mind in complex, multimorbid patients to a potentially unifying diagnosis is important to guide prognostication. The rumble of hooves in the distance is not always that of horses.

Antibodies in Autoimmune Neuropathies: What to Test, How to Test, Why to Test.

Autoimmune neuropathies are a heterogeneous group of immune-mediated disorders of the peripheral nerves. Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are the archetypal acute and chronic forms. Over the past few decades, pathogenic antibodies targeting antigens of the peripheral nervous system and driving peripheral nerve damage in selected patients have been described. Moreover, the detection of these antibodies has diagnostic and therapeutic implications that have prompted a modification of the GBS and CIDP diagnostic algorithms. GBS diagnosis is based in clinical criteria, and systematic testing of anti-ganglioside antibodies is not required. Nonetheless, a positive anti-ganglioside antibody test may support the clinical suspicion when diagnosis of GBS (GM1 IgG), Miller Fisher (GQ1b IgG), or acute sensory-ataxic (GD1b IgG) syndromes is uncertain. Anti-myelin-associated glycoprotein (MAG) IgM and anti-disialosyl IgM antibodies are key in the diagnosis of anti-MAG neuropathy and chronic ataxic neuropathy, ophthalmoplegia, M-protein, cold agglutinins, and disialosyl antibodies spectrum neuropathies, respectively, and help differentiating these conditions from CIDP. Recently, the field has been boosted by the discovery of pathogenic antibodies targeting proteins of the node of Ranvier contactin-1, contactin-associated protein 1, and nodal and paranodal isoforms of neurofascin (NF140, NF186, or NF155). These antibodies define subgroups of patients with specific clinical (most importantly poor or partial response to conventional therapies and excellent response to anti-CD20 therapy) and pathologic (node of Ranvier disruption in the absence of inflammation) features that led to the definition of the "autoimmune nodopathy" diagnostic category and to the incorporation of nodal/paranodal antibodies to clinical routine testing. The purpose of this review was to provide a practical vision for the general neurologist of the use of antibodies in the clinical assessment of autoimmune neuropathies.

Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.

DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.

Extra-digestive manifestations of celiac disease.

Celiac disease (CD) is a chronic autoimmune disorder triggered by gluten ingestion in genetically predisposed individuals, presenting with a diverse range of symptoms that extend beyond the gastrointestinal tract. The condition's systemic nature is evidenced by its extra-digestive manifestations, which can affect various organs including the skin, joints, liver, and nervous system. This descriptive, retrospective study was conducted at a tertiary care center, focusing on adult patients diagnosed with CD who exhibited extra-digestive symptoms. Data were extracted from medical records of patients admitted between January 1, 2010 and June 30, 2024. Variables included demographic information, primary diagnosis, and associated extra-digestive manifestations. Descriptive statistical methods were employed for data analysis. The sample included 108 patients with CD, the mean age was 43.21 years, with a predominance of females (76.85%). Iron deficiency anemia was the most common extra-digestive manifestation, affecting 20.37% of patients, followed by hypoproteinemia (18.52%) and Hashimoto's thyroiditis (14.81%). Co-occurrence analysis revealed frequent combinations of conditions, such as anemia with cardiovascular diseases and depressive disorders. Notable associations with neurological conditions like gluten ataxia and peripheral neuropathy were also observed. This study highlights the extensive extra-digestive manifestations of celiac disease, underscoring its systemic impact. The high prevalence of autoimmune conditions such as Hashimoto's thyroiditis and rheumatoid polyarthritis among CD patients reflects the need for holistic management strategies. Discrepancies between our findings and existing literature, particularly regarding skin and neurological conditions, emphasize the need for further research to better understand these associations and the long-term effects of a gluten-free diet.

Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 (beta-1,4-N-acetylgalactosaminyltransferase 1) gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N-acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM_001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activation-induced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted 10 novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku medical megabank organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP.

The spectrum of anti-GQ1B antibody syndrome: beyond Miller Fisher syndrome and Bickerstaff brainstem encephalitis.

Since the initial identification of Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE),significant milestones have been achieved in understanding these diseases.Discoveries of common serum antibodies (IgG anti-GQ1b), antecedent infections, neurophysiological data, andneuroimaging suggested a shared autoimmune pathogenetic mechanism rather than distinct pathogenesis, leadingto the hypothesis that both diseases are part of a unified syndrome, termed "Fisher-Bickerstaff syndrome". The subsequent identification of atypical anti-GQ1b-positive forms expanded the classification to a broader condition known as "Anti-GQ1b-Antibody syndrome". An exhaustive literature review was conducted, analyzing a substantial body of research spanning from the initialdescriptions of the syndrome's components to recent developments in diagnostic classification and researchperspectives. Anti-GQ1b syndrome encompasses a continuous spectrum of conditions defined by a common serological profilewith varying degrees of peripheral (PNS) and central nervous system (CNS) involvement. MFS and BBE represent theopposite ends of this spectrum, with MFS primarily affecting the PNS and BBE predominantly involving the CNS.Recently identified atypical forms, such as acute ophthalmoparesis, acute ataxic neuropathy withoutophthalmoparesis, Guillain-Barré syndrome (GBS) with ophthalmoparesis, MFS-GBS and BBE-GBS overlap syndromes,have broadened this spectrum. This work aims to provide an extensive, detailed, and updated overview of all aspects of the anti-GQ1b syndromewith the intention of serving as a stepping stone for further shaping thereof. Special attention was given to therecently identified atypical forms, underscoring their significance in redefining the boundaries of the syndrome.

Bilateral mydriasis as the first manifestation of Miller Fisher syndrome

Miller Fisher Syndrome (MFS) is a rare variant of Guillain-Barré Syndrome (GBS), characterised by a unique clinical triad of ophthalmoplegia, ataxia, and areflexia. MFS, which was first described in 1956 by Charles Miller Fisher , is frequently preceded by an infection, usually respiratory or gastrointestinal, and is believed to be triggered by an autoimmune reaction targeting peripheral nervous system components. However the MFS is further categorised into incomplete forms which can be present without the classical triad, such as acute ophthalmoparesis, acute ataxic neuropathy, acute ptosis and acute mydriasis. We report a case of a 50-year-old man presenting with dilated and unresponsive pupils, which progressed rapidly to ophthalmoplegia, ataxia, and areflexia. Given the clinical history supported by the cyto-protein dissociation in cerebrospinal fluid, the patient was diagnosed to have MFS and successfully treated with intravenous immunoglobulin. This case underscores the importance of recognising atypical features of MFS, such as primary mydriasis, and highlights the variable clinical spectrum within the syndrome. Clinicians should maintain a high index of suspicion for MFS, particularly when faced with unusual neurological presentations, to ensure timely intervention and optimal patient outcomes.

Cerebellar Ataxia, Parkinsonism and Peripheral Neuropathy in an Indian Family with MME Mutation

Cerebellar Ataxia, Parkinsonism and Peripheral Neuropathy in an Indian Family with MME Mutation

Peripheral Nerve and Muscle Disorders Associated with Sjögren's Syndrome

Sjögren's syndrome is often accompanied by various neurological complications, among which peripheral neuropathy is the most common. A variety of clinical phenotypes of peripheral neuropathy, including axonal polyneuropathy and sensory ataxic neuropathy are reported in the literature. We present an overview of the pathophysiology and differential diagnosis of each phenotype. Immunotherapy using corticosteroids and high-dose intravenous immunoglobulin therapy tends to elicit varied therapeutic responses depending on the peripheral neuropathy phenotype. We also discuss myositis, a possible complication of Sjögren's syndrome.

Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy

Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.

Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009 to 2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome sequencing and WGS and, latterly, WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. In summary, 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100 000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment, leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre and has benefitted from the use of WGS, particularly access to the raw data. However, almost one-quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

AbstractParaproteinemia‐associated neuropathy (PAN) develops with paraproteinemia and is mainly caused by the monoclonal proliferation of mature B cells, especially monoclonal gammopathy of undetermined significance (MGUS). PAN tends to increase with age, and in a super‐aging society, its frequency is expected to increase. Among paraproteinemias, the immunoglobulin (Ig)G type is most common, but the frequency of PAN is reported to be higher for the IgM type. IgG/IgA‐type PAN includes MGUS, plasma cell myeloma, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome. IgM‐type PAN includes anti‐myelin‐associated glycoprotein antibody‐associated neuropathy, chronic ataxic neuropathy with IgM antibody that recognizes disialosyl ganglioside and IgM‐type PAN without anti‐nerve antibodies. Light chain‐type PAN includes immunoglobulin‐related amyloidosis. PAN has the characteristics of a blood disease, as well as an immune‐mediated disease, and is treated by immunotherapy. As an example, anti‐myelin‐associated glycoprotein antibody‐associated neuropathy is treated with rituximab, plasmapheresis and intravenous immunoglobulin therapy, but their effectiveness has not been established. As novel treatments, lenalidomide, Bruton tyrosine kinase inhibitors, B‐cell lymphoma 2 inhibitors and mimetic human natural killer‐1 epitope polymers have been investigated. By analyzing the human natural killer‐1‐related sugar chain structure as an antigen, the selective removal of pathological antibodies might be a new therapeutic target.

Instrumented assessment of gait disturbance in PMM2-CDG adults: a feasibility analysis

BackgroundCongenital disorders of glycosylation (CDG) are genetic diseases caused by impaired synthesis of glycan moieties linked to glycoconjugates. Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent CDG, is characterized by prominent neurological involvement. Gait disturbance is a major cause of functional disability in patients with PMM2-CDG. However, no specific gait assessment for PMM2-CDG is available. This study analyses gait-related parameters in PMM2-CDG patients using a standardized clinical assessment and instrumented gait analysis (IGA).ResultsSeven adult patients with a molecular diagnosis of PMM2-CDG were followed-up from February 2021 to December 2022 and compared to a group of healthy control (HC) subjects, matched for age and sex. Standardized assessment of disease severity including ataxia and peripheral neuropathy along with isometric muscle strength and echo-biometry measurements at lower limbs were performed. IGA spatiotemporal parameters were obtained by means of a wearable sensor in basal conditions. PMM2-CDG patients displayed lower gait speed, stride length, cadence and symmetry index, compared to HC. Significant correlations were found among the used clinical scales and between disease severity (NCRS) scores and the gait speed measured by IGA. Variable reduction of knee extension strength and a significant decrease of lower limb muscle thickness with conserved echo intensity were found in PMM2-CDG compared to HC.ConclusionsThe study elucidates different components of gait disturbance in PMM2-CDG patients and shows advantages of using wearable sensor-based IGA in this frame. IGA parameters may potentially serve as quantitative measures for follow-up or outcome quantification in PMM2-CDG.

Influence of celiac disease on balance control and bone mineral density in adult women

AbstractBackground and PurposeCeliac Disease (CD) is a chronic form of autoimmune enteropathy caused by gluten and related prolamin consumption. CD presents as a neurological, rheumatological, and musculoskeletal disorder, with ataxia and peripheral neuropathy being the most common. These symptoms could affect balance control and consequently the daily activities and decreased bone mass of these individuals. Although balance disorders are increasingly common, and the diagnosis of celiac diseases is growing worldwide, there is no consensus on the influence of a gluten‐free diet (GFD) on balance control and bone mineral density (BMD). This study aimed to analyze the influence of celiac disease on balance control and BMD in adult women.MethodsA total of 52 adult women aged 18–56 years participated in the study and were divided into two groups: with (26 patients) and without celiac disease (26 patients). The outcome variables were obtained by anthropometry and sociodemographic data. The Celiac Dietary Adherence Test questionnaire was used to assess adherence to the GFD, Neurocom ™ Smart Equitest® to determine balance control, and GE® Lunar Prodigy Advance DXA Bone densitometer for evaluation of BMD. The displacement of the center of pressure in the anteroposterior and mediolateral directions was evaluated under six conditions of the sensory organization test through a routine test performed in MATLAB.ResultsAdult women with CD who adhered to a GFD had vestibular system deficits and normal BMD.DiscussionAdult women with CD presented less balance control when they required greater activation of the vestibular system, suggesting that adherence to a GFD leads to normal bone mass.

Not So Rare: Diseases Based on Mutant Proteins Controlling Endoplasmic Reticulum-Mitochondria Contact (MERC) Tethering.

Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options.

Neuropathy in ARSACS is demyelinating but without typical nerve enlargement in nerve ultrasound.

To specify peripheral nerve affection in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) by correlating high-resolution nerve ultrasound and nerve conduction studies. We assessed a cohort of 11 ARSACS patients with standardized nerve conduction studies and high-resolution ultrasound of peripheral nerves and compared nerve ultrasound findings to a healthy control group matched for age, sex, size and weight. Mean age of patients was 39.0 (± 14.1) years and disease duration at assessment 30.6 (± 12.5) years. All patients presented with a spasticity, ataxia and peripheral neuropathy. Neuropathy appeared to be primarily demyelinating in 9/11 cases and was not classifiable in 2/11 cases due to not evocable potentials. Nerve ultrasound revealed a normal ultrasound pattern sum score (UPSS) in each ARSACS patient and no significant nerve enlargement compared to the control group. Peripheral neuropathy in ARSACS showed primarily demyelinating rather than axonal characteristics and presented without nerve enlargement. As demyelinating neuropathies do commonly present enlarged nerves we recommend further genetic testing of the SACS gene in patients who present with this combination of demyelinating neuropathy without nerve enlargement. ARSACS cases that initially presented only with neuropathy without spasticity or ataxia and therefore were misdiagnosed as Charcot-Marie-Tooth disease are supporting this suggestion.

Evaluating yield and utilization of ganglioside antibody testing in clinical practice

Background and objectivesGanglioside antibodies can help diagnose distinct acute and chronic inflammatory neuropathies including axonal variants of Guillain-Barre syndrome, Miller-Fisher syndrome (MFS), multifocal motor neuropathy, and chronic sensory ataxic neuropathies. Because ganglioside antibody testing may be routinely ordered in patients with suspected inflammatory neuropathy, we sought to evaluate its yield and utilization in clinical practice. MethodsWe performed a retrospective chart review of all patients at London Health Sciences Centre who underwent ganglioside antibody testing between April 2019 and August 2023. The disease phenotype was determined for each patient, and the proportion of all tests that yielded a true-positive result was calculated. Ganglioside antibody positivity was classified as a true-positive result if the disease phenotype was robustly associated with the detected ganglioside antibody and there was no other more likely diagnosis. ResultsWe identified 92 patients who underwent ganglioside antibody testing. One patient (1%) was classified as having a true-positive result; this patient had GQ1b-IgG positivity with MFS. Among 92 patients tested, 20 patients (22%) had a disease phenotype that was considered to be robustly associated with ganglioside antibody positivity. ConclusionsThe yield of ganglioside antibody testing in clinical practice is low. We found that this testing is frequently ordered in patients with disease phenotypes that are not robustly associated with ganglioside antibody positivity, indicating that suboptimal test utilization is a primary contributor to its low yield. Restricting ganglioside antibody testing to patients with characteristic disease phenotypes would be valuable to improving yield and utilization of this testing.

Optical Genome Mapping Enables Detection and Accurate Sizing of RFC1 Repeat Expansions.

A recessive Short Tandem Repeat expansion in RFC1 has been found to be associated with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), and to be a frequent cause of late onset ataxia and sensory neuropathy. The usual procedure for sizing these expansions is based on Southern Blotting (SB), a time-consuming and a relatively imprecise technique. In this paper, we compare SB with Optical Genome Mapping (OGM), a method for detecting Structural Variants (SVs) based on the measurement of distances between fluorescently labelled probes, for the diagnosis of RFC1 CANVAS and disease spectrum. The two methods are applied to 17 CANVAS patients' blood samples and resulting sizes compared, showing a good agreement. Further, long-read sequencing is used for two patients to investigate the agreement of sizes with either SB or OGM. Our study concludes that OGM represents a viable alternative to SB, allowing for a simpler technique, a more precise sizing of the expansion and ability to expand analysis of SV in the entire genome as opposed to SB which is a locus specific method.