Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

G protein-coupled receptors related to autoimmunity in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is characterized by exaggerated orthostatic tachycardia in the absence of orthostatic hypotension. The pathophysiology of POTS may involve hypovolemia, autonomic neuropathy, a hyperadrenergic state, and cardiovascular deconditioning, any of which can co-occur in the same patient. Furthermore, there is growing evidence of the role of autoimmunity in a subset of POTS cases. In recent years, investigators have described an increased rate of autoimmune comorbidities as evidenced by the finding of several types of neural receptor autoantibody and non-specific autoimmune marker in patients with POTS. In particular, the association of the disease with several types of anti-G protein-coupled receptor (GPCR) antibodies and POTS has frequently been noted. A previous study reported that autoantibodies to muscarinic AChRs may play an important role in POTS with persistent, gastrointestinal symptoms. To date, POTS is recognized as one of the sequelae of coronavirus disease 2019 (COVID-19) and its frequency and pathogenesis are still largely unknown. Multiple autoantibody types occur in COVID-related, autonomic disorders, suggesting the presence of autoimmune pathology in these disorders. Herein, we review the association of anti-GPCR autoantibodies with disorders of the autonomic nervous system, in particular POTS, and provide a new perspective for understanding POTS-related autoimmunity.

[A case of non-fluent/agrammatic variant of primary progressive aphasia with logoclonia].

We report a case of non-fluent/agrammatic variant of primary progressive aphasia in a 79-year-old right-handed man who was admitted with a 5-year history of non-fluent speech and apraxia of speech. He also presented with agrammatism and logoclonia (the meaningless repetition of the middle or final syllable of a word). Furthermore, brain MRI revealed atrophy of the bilateral frontal and temporal lobes, while N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography (SPECT) revealed relative hypoperfusion in the right basal ganglia. In addition, dopamine transporter SPECT revealed a decrease in specific binding ratio values, indicating neural dopamine dysfunction, which led to his diagnosis of progressive non-fluent aphasia with logoclonia. Logoclonia is a severe linguistic dysfunction usually observed in the advanced stages of Alzheimer's disease. However, based on the clinical course and cerebrospinal fluid evaluation results, our patient did not show any features of Alzheimer's disease. Thus, logoclonia might be associated with lesions involving the basal ganglia, right hemisphere, and left frontotemporal lobe.

Acute Reversible Encephalopathy with Neuronal Intranuclear Inclusion Disease Diagnosed by a Brain Biopsy: Inferring the Mechanism of Encephalopathy from Radiological and Histological Findings.

A 75-year-old man presented with headache and disturbance of consciousness. Magnetic resonance imaging revealed edema localized mainly in the cortex and linear contrast enhancement. A brain biopsy revealed numerous astrocytes with inclusion, and genetic testing demonstrated prolonged GGC repeats in NOTCH2NLC. The present case provided two novel insights into the mechanism underlying encephalopathy associated with neuronal intranuclear inclusion disease. First, the histological findings at a site with contrast enhancement on magnetic resonance imaging did not demonstrate any organic association, such as the presence of inflammation or ischemic changes. Second, the imaging and cerebrospinal fluid findings demonstrated increased cerebral blood flow and opening of the blood-brain barrier, indicating the cause of the cerebral swelling.

Case report: MRI-negative myelitis following COVID-19 with SEP abnormalities: a case series and literature review.

Coronavirus Disease 2019 (COVID-19) is known to have various, neurological manifestations. We herein report three patients with MRI-negative myelitis following COVID-19 with abnormal somatosensory evoked potentials (SEPs). Decreased amplitude of the cortical potential and prolonged latency in the SEPs contributed to diagnosing myelitis in the present patients. The SEP findings improved as the neurological symptoms improved. Despite a delay in initiating immunosuppressive treatment after myelitis onset, all the patients improved clinically. In the light of recent progress in COVID-19 research, several hypotheses can be made to explain the pathophysiology underlying MRI-negative myelitis, including antibody-binding and microglial synapse elimination.

Association of autoantibodies to muscarinic acetylcholine receptors with gastrointestinal symptoms and disease severity in patients with postural orthostatic tachycardia syndrome.

Previous studies have reported a relationship between postural orthostatic tachycardia syndrome (POTS) and positivity for serum autoantibodies against G-protein-coupled receptors (GPCRs). However, the role of these autoantibodies in POTS is unclear. The present retrospective study analyzed the autoimmune etiology of POTS in 24 patients using a head-up tilt test to assess for any correlation between the clinical features of POTS and serum levels of autoantibodies against diverse GPCRs. In total, ten assessment items, including autonomic function tests, were analyzed. Of these, persistent, gastrointestinal symptoms and disease severity showed a significant association with the serum level of anti-muscarinic acetylcholine receptor (mAChRs) antibodies (gastrointestinal symptoms, M1, M2, M5; disease severity, M1, M3, M4, M5) [P <0.05]), while no significant association was found between the clinical features and autoantibodies against adrenergic receptors (α1, α2, ß1, ß2), angiotensin receptor 1, or endothelin receptor A. The patients were further divided into two groups based on the presence or absence of persistent gastrointestinal symptoms and then were characterized by the ten assessment items and neuropsychological tests, including the Wechsler Adult Intelligence Scale score and Self-Rating Depression Scale score. The results demonstrated a clear difference between the two groups in terms of disease severity, age at onset (older or younger than 20 years), and processing speed index (P <0.05), which were highly consistent with the association between these clinical features and the levels of serum anti-mAChR antibodies, particularly the anti-M5 receptor antibody. These findings suggested that anti-mAChR antibodies may play an important role in a subgroup of POTS patients with persistent gastrointestinal symptoms.

[Case Report: Broca's Aphasia in a Left-Handed Patient with a Right Brain Infarction and Early Stage Aphonia].

We report a case of Broca's aphasia in a left-handed patient with a right brain infarction. The patient's speech is consistent with a particular type of aphemia, that is, without vocalization except for a few phonemes or words. The patient presented with aphonia in an early stage. The lack of speech could be due to the impairment of the phonological-speech process or speech initialization. This type of aphemia has been reported to involve the right inferior precentral gyrus or right middle and inferior frontal gyri. Our patient had both lesions. The symptom and the lesion of this type of aphemia could differ from those of another type of aphemia corresponding to apraxia of speech, and the speech of Broca's aphasia could have multiple mechanisms. Our case shows Alexander's anomalous type with atypical lateralization and distribution of the lesion. Verbal intrahemispheric dissociation apraxia was suspected in our patient. The coexistence of aphasia, anosodiaphoria of hemiplegia is a dual symptom in which bilateral hemispheric functions exist in a unilateral hemisphere. (Received 1 December, 2021; Accepted 1 February, 2022; Published 1 April, 2022).

Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T > C mutation in mitochondrial DNA.

We present a Japanese family suffering from mitochondrial encephalomyopathy associated with a T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 3291. Clinical manifestations of the patients include cerebellar ataxia with myopathy, recurrent headache, and myoclonus and epilepsy. The phenotypic variation among the affected members of a single family and the mutational analysis showing maternal inheritance in a heteroplasmic fashion are consistent with well-recognized phenomena associated with many pathogenic point mutations of mtDNA tRNA genes. The 3291 mutation is a rare mtDNA mutation whose clinical presentation had only been reported in three sporadic cases. This is the first report of a family segregating the 3291 mutation with multigenerational matrilinear recurrence of mitochondrial encephalopathy. Our findings provide conclusive evidence for the pathogenicity of the 3291T > C mutation in mtDNA and its characteristic clinical heterogeneity.

[A case of chronic postural tachycardia syndrome with positive anti-ganglionic acetylcholine receptor (gAChR) antibody].

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance characterized by symptoms such as lightheadedness, fainting, and brain fog that occur with a rapid elevation in heart rate when standing up from a reclining position. The etiology of POTS has yet to be established. However, a growing body of evidence suggests that POTS may be an autoimmune disorder such as autoimmune autonomic ganglionopathy, an acquired, immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (gAChRs) in the autonomic ganglia. Herein, we describe a 39-year-old female patient with an eight-year history of orthostatic intolerance. POTS was diagnosed based on the findings of a head-up tilt test, in which a rapid increase in the patient's heart rate from 58 bpm in the lying position to 117 bpm in the upright position without orthostatic hypotension was observed. The POTS symptoms were refractory to various medications except for pyridostigmine bromide, which resulted in a partial resolution of her symptoms. Her serum was found to be strongly positive for anti-gAChR (ß4 subunit) autoantibody (2.162 A.I., normal range: below 1.0). Based on these findings, a limited form of autoimmune POTS was diagnosed. After obtaining written informed consent, she was treated with intravenous immunoglobulin (IVIg) 400 mg/kg/day for five days, which led to clinical improvement by reducing her heart rate increase in the upright position. She was able to return to work with IVIg treatment at regular intervals. Our case provides further evidence of a potential autoimmune pathogenesis for POTS. Aggressive immunotherapy may be effective for POTS even in chronic cases.

Coexistence of Hereditary Spastic Paraplegia Type 4 and Narcolepsy: A Case Report.

Spastic paraplegia type 4 (SPG4) is the most common type of hereditary spastic paraplegia (HSP) caused by the mutations in the SPAST gene, which encodes a microtubule-severing protein named spastin. Spastin regulates the number and mobility of microtubules and is essential for axonal outgrowth and neuronal morphogenesis. Herein, we report a patient with SPG4 harboring a novel donor splice site mutation in the SPAST gene (c.1616+1dupG). Although SPG4 usually manifests itself as a pure form of HSP, this patient exhibited a slow progressive cognitive decline and also developed narcolepsy type 2 (narcolepsy without cataplexy) prior to the onset of SPG4. Recently, cognitive decline has attracted attention as a main non-motor symptom of SPG4. However, this is the first reported case of a patient developing both SPG4 and narcolepsy, although it remains unclear whether the manifestation of the two diseases is a coincidence or an association. In this report, we describe the clinical symptoms and genetic background of the patient.

[Progressive supranuclear palsy-Richardson syndrome with visual attention disturbance (Holmes and Horrax) and ataxie optique (Garcin): a case report].

[Background] Supranuclear extraorbital muscle palsy is the core feature of progressive supranuclear palsy (PSP), and ordinarily presents as spontaneous vertical gaze constriction. However, higher visual function associated with visuospatial cognition in PSP patients was not previously considered. [Case presentation] We present a 72-year old right-handed man with PSP- Richardson syndrome (PSP-RS) and abnormal higher visual function. His symptoms began 2 years previously and included the use of small steps while walking, forgetfulness, and postural instability. Neurological examination revealed supranuclear vertical gaze limitation, akinesia, and lead-pipe rigidity without laterality. Neuro-ophthalmological examination showed abnormal ocular movement consistent with PSP, and no visual abnormality was observed. General cognitive functions, including attention and prominent visuospatial orientation and visual attention disturbances, were assessed using neuropsychological tests and concomitant spatial agraphia and impaired configuration using figure copying. Although he presented with mildly decreased and monotonous speech with palilalia, he showed no apparent aphasia, apraxia, visual object agnosia, or Bálint's 'optische Ataxie' i.e. visual ataxia under fixation. Brain MRI revealed atrophy of the mesencephalic tegmentum, bilateral frontal lobe, and bilateral hippocampus. N-isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography revealed decreased cerebral blood flow in the bilateral frontal lobe, lateral temporal lobe, and basal ganglia. Dopamine transporter single photon emission CT revealed uptake attenuation in the bilateral striatum. 123I-metaiodobenzyl-guanidine myocardium scintigraphy results were normal. [Discussion] The patient's symptoms indicated classical PSP-RS accompanied with a combination of disturbances in spatial orientation and visual attention as noted by Holmes and Horrax and 'ataxie optique' by Garcin. Thus, as observed in this patient, many clinically diagnosed PSP patients with undiagnosed higher visual dysfunction, masked by limited eye movement may exist. These symptoms may further our understanding about posterior cortical atrophy and tauopathy including not only PSP but also corticobasal syndrome and Alzheimer disease.