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Neurology Sep 2019To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3).
OBJECTIVE
To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3).
METHODS
Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively.
RESULTS
Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA).
CONCLUSION
AP3B2 (previously named β-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.
Topics: Adaptor Protein Complex 3; Adaptor Protein Complex beta Subunits; Adult; Animals; Autoantibodies; Autoimmunity; Biomarkers; Cells, Cultured; Cerebellar Ataxia; Female; Gait Disorders, Neurologic; Humans; Immunoglobulin G; Male; Mice; Middle Aged; Rats
PubMed: 31371564
DOI: 10.1212/WNL.0000000000008061 -
Current Journal of Neurology Oct 2023Scarce data are available on the neurological presentations of coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) and COVID-19-unrelated...
Scarce data are available on the neurological presentations of coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) and COVID-19-unrelated rhino-orbito-cerebral mucormycosis (ROCM). This study aimed to compare the neurological presentations and their associated outcomes in patients with CAM and COVID-19-unrelated ROCM. In December 2021, a case-control analysis was conducted on the CAM (case group) and COVID-19-unrelated ROCM (control group) referrals of one center in Isfahan, Iran. Confirmed CAM patients from January 2020 to December 2021 constituted the case group, and patients with COVID-19-unrelated ROCM from 2016-2019 constituted the control group. Their data were then analyzed using proper (non) parametric tests and generalized linear models (GLM), therein P-value below 0.05 was considered as the criterion of statistical significance, and the SPSS software was used. After retrieving data on 177 patients with mucormycosis, 78 patients with CAM were included as the case group and 72 patients with COVID-19-unrelated ROCM were included as the control group. Neurological presentations suggestive of second, third, and eighth cranial nerve involvement were more prevalent in the CAM group (all with P < 0.05). The mortality rate in the CAM group was 1.9 times that of the controls (P = 0.01), being explained by higher extent of corticosteroid administration among them. Higher age and presentation with gait ataxia, ptosis, and mydriasis were considered to be predictive of poor prognosis in patients with CAM (all with P < 0.05). The neurological manifestations of CAM differ from COVID-19-unrelated ROCM based on the presented results, some of which are associated with poor prognosis. Further replication is warranted to confirm our retrospective analyses.
PubMed: 38425352
DOI: 10.18502/cjn.v22i4.14531 -
The Cochrane Database of Systematic... Jun 2017Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe... (Review)
Review
BACKGROUND
Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for evaluation of polyneuropathy. There is a need to gather and review emerging evidence on treatments, as the number of people affected is likely to increase in ageing populations. This is an update of a review first published in 2004 and previously updated in 2006, 2008, 2011 and 2013.
OBJECTIVES
To assess the effects of drug therapy for chronic idiopathic axonal polyneuropathy for reducing disability and ameliorating neurological symptoms and associated impairments, and to assess any adverse effects of treatment.
SEARCH METHODS
In July 2016, we searched Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews in the Cochrane Library, MEDLINE, Embase, and the Web of Science. We searched two trials registries for ongoing trials. We also handsearched the reference lists of relevant articles, reviews and textbooks identified electronically, and we would have contacted authors and other experts in the field to identify additional studies if this seemed useful.
SELECTION CRITERIA
We sought all randomised or quasi-randomised (alternate or other systematic treatment allocation) trials that examined the effects of any drug therapy in people with CIAP at least one year after the onset of treatment. People with CIAP had to fulfil the following criteria: age 40 years or older, distal sensory or sensorimotor polyneuropathy, absence of systemic or other neurological disease, chronic clinical course not reaching a nadir in less than two months, exclusion of any recognised cause of the polyneuropathy by medical history taking, clinical or laboratory investigations, and electrophysiological studies in agreement with axonal polyneuropathy, without evidence of demyelinating features. The primary outcome was the proportion of participants with a significant improvement in disability. Secondary outcomes were change in the mean disability score, change in the proportion of participants who make use of walking aids, change in the mean Medical Research Council sum score, degree of pain relief and/or reduction of other positive sensory symptoms, change in the proportion of participants with pain or other positive sensory symptoms, and frequency of adverse effects.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed the results of the literature search and extracted details of trial methodology and outcome data of all potentially relevant trials.
MAIN RESULTS
We identified 39 studies and assessed them for possible inclusion in the review, but we excluded all of them because of insufficient quality or lack of relevance. We summarised evidence from non-randomised studies in the Discussion.
AUTHORS' CONCLUSIONS
Even though CIAP has been clearly described and delineated, no adequate randomised or quasi-randomised controlled clinical treatment trials have been performed. In their absence there is no proven efficacious drug therapy.
Topics: Aged; Axons; Chronic Disease; Gait Ataxia; Humans; Leg; Polyneuropathies
PubMed: 28631805
DOI: 10.1002/14651858.CD003456.pub3 -
ELife Jul 2020Several spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait... (Comparative Study)
Comparative Study
Several spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait alterations and neuroanatomical abnormalities throughout the brain differ across mutants. We previously used the LocoMouse system to quantify specific deficits in locomotor coordination in mildly ataxic mice ( Machado et al., 2015). Here, we analyze the locomotor behavior of severely ataxic mutants and compare and contrast it with that of . Despite clearly visible gait differences, direct comparison of locomotor kinematics and linear discriminant analysis reveal a surprisingly similar pattern of impairments in multijoint, interlimb, and whole-body coordination in the two mutants. These findings capture both shared and specific signatures of gait ataxia and provide a quantitative foundation for mapping specific locomotor impairments onto distinct neuropathologies in mice.
Topics: Animals; Gait Ataxia; Locomotion; Mice; Mice, Neurologic Mutants; Models, Animal
PubMed: 32718435
DOI: 10.7554/eLife.55356 -
Frontiers in Cellular Neuroscience 2019Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing... (Review)
Review
Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing formation of long chain fatty acids. ELOVL4 is the only family member that catalyzes production of Very Long Chain Saturated Fatty Acids (VLC-SFA) and Very Long Chain Polyunsaturated Fatty Acids (VLC-PUFA) with chain lengths ≥28 carbons. ELOVL4 and its VLC-SFA and VLC-PUFA products are emerging as important regulators of synaptic signaling and neuronal survival in the central nervous system (CNS). Distinct sets of mutations in cause three different neurological diseases in humans. Heterozygous inheritance of one set of autosomal dominant mutations that leads to truncation of the ELOVL4 protein causes Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset retinal degeneration. Heterozygous inheritance of a different set of autosomal dominant mutations that leads to a full-length protein with single amino acid substitutions causes spinocerebellar ataxia 34 (SCA34), a late-onset neurodegenerative disease characterized by gait ataxia and cerebellar atrophy. Homozygous inheritance of a different set of mutations causes a more severe disease with infantile onset characterized by seizures, spasticity, intellectual disability, ichthyosis, and premature death. ELOVL4 is expressed widely in the CNS and is found primarily in neurons. ELOVL4 is expressed in cell-specific patterns within different regions of the CNS that are likely to be related to disease symptoms. In the retina, ELOVL4 is expressed exclusively in photoreceptors and produces VLC-PUFA that are incorporated into phosphatidylcholine and enriched in the light sensitive membrane disks of the photoreceptor outer segments. VLC-PUFA are enzymatically converted into "elovanoid" compounds that appear to provide paracrine signals that promote photoreceptor and neuronal survival. In the brain, the main ELOVL4 products are VLC-SFA that are incorporated into sphingolipids and enriched in synaptic vesicles, where they regulate kinetics of presynaptic neurotransmitter release. Understanding the function of ELOVL4 and its VLC-SFA and VLC-PUFA products will advance our understanding of basic mechanisms in neural signaling and has potential for developing novel therapies for seizure and neurodegenerative diseases.
PubMed: 31616255
DOI: 10.3389/fncel.2019.00428 -
International Journal of Environmental... Aug 2021Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social... (Review)
Review
Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development.
Topics: Cell Death; Cerebellar Ataxia; Cerebellum; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Humans; Pregnancy
PubMed: 34444449
DOI: 10.3390/ijerph18168678 -
American Journal of Human Genetics May 2004Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is... (Review)
Review
Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-X-associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.
Topics: Chromosomes, Human, X; DNA Repeat Expansion; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Mental Disorders; Nerve Tissue Proteins; RNA-Binding Proteins
PubMed: 15052536
DOI: 10.1086/386296 -
Cerebellum (London, England) Dec 2020Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it... (Review)
Review
Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it within the context of these diseases. Here, we compare the clinical and postmortem features of ET with other cerebellar degenerations, thereby placing it within the broader context of these diseases. Action tremor is the hallmark feature of ET. Although often underreported in the spinocerebellar ataxias (SCAs), action tremors occur, and it is noteworthy that in SCA12 and 15, they are highly prevalent, often severe, and can be the earliest disease manifestation, resulting in an initial diagnosis of ET in many cases. Intention tremor, sometimes referred to as "cerebellar tremor," is a common feature of ET and many SCAs. Other features of cerebellar dysfunction, gait ataxia and eye motion abnormalities, are seen to a mild degree in ET and more markedly in SCAs. Several SCAs (e.g., SCA5, 6, 14, and 15), like ET, follow a milder and more protracted disease course. In ET, numerous postmortem changes have been localized to the cerebellum and are largely confined to the cerebellar cortex, preserving the cerebellar nuclei. Purkinje cell loss is modest. Similarly, in SCA3, 12, and 15, Purkinje cell loss is limited, and in SCA12 and 15, there is preservation of cerebellar nuclei and relative sparing of other central nervous system regions. Both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration.
Topics: Cerebellar Diseases; Cerebellum; Essential Tremor; Humans
PubMed: 32666285
DOI: 10.1007/s12311-020-01160-4 -
Neurology May 2023To describe the clinical, micronutrient, and electrophysiologic spectra and prognosis in patients with acute nutritional axonal neuropathy (ANAN).
BACKGROUND AND OBJECTIVES
To describe the clinical, micronutrient, and electrophysiologic spectra and prognosis in patients with acute nutritional axonal neuropathy (ANAN).
METHODS
Patients with ANAN were identified between 1999 and 2020 by a retrospective review of our EMG database and electronic health records and categorized on clinical and electrodiagnostic grounds, as pure sensory, sensorimotor, or pure motor; and by risk factor (alcohol use disorder, bariatric surgery, or anorexia). Laboratory abnormalities were recorded including thiamine, vitamin B, B, and E, folate, and copper. Ambulatory and neuropathic pain status at last follow-up were recorded.
RESULTS
Of 40 patients with ANAN, 21 had alcohol use disorder, 10 were anorexic, and 9 had recently undergone bariatric surgery. Their neuropathy was pure sensory in 14 (7 with low thiamine), sensorimotor in 23 (8 with low thiamine), and pure motor in 3 (1 with low thiamine). Vitamin B was most commonly low (85%), followed by vitamin B (77%) and folate (50%). The risk factor and neuropathy type were not associated with a particular micronutrient deficiency. Of the 37 patients who were seen in follow-up, only 13 (35%) were walking independently, and only 8 (22%) were pain free at the last follow-up visit at a mean of 22 months (range 2-88 months) from onset.
DISCUSSION
The spectrum of ANAN is wide, ranging from: (1) a pure sensory neuropathy with areflexia, limb and gait ataxia, neuropathic pain, and unevocable sensory responses to (2) a motor axonal neuropathy with low-amplitude motor responses without conduction slowing, block, or dispersion, and (3) a mixed sensorimotor axonal polyneuropathy. Specific micronutrient deficiencies or risk factors do not predict neuropathy subtype. The subgroup of patients with ANAN with documented thiamine deficiency also range from pure sensory to pure motor, and only a minority have Wernicke encephalopathy. We do not know whether coexistent micronutrient deficiencies may help explain the wide clinical spectrum of thiamine-deficient ANAN. The prognosis of ANAN is guarded due to residual neuropathic pain and slow recovery of independent ambulation. Therefore, early recognition of patients at risk is important.
Topics: Humans; Alcoholism; Thiamine; Folic Acid; Prognosis; Vitamins; Neuralgia; Micronutrients
PubMed: 36973043
DOI: 10.1212/WNL.0000000000207215