Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

A 76‐year‐old female with no apparent immunosuppressive conditions and no history of exposure to freshwater and international travel presented with headache and nausea 3 weeks before the presentation. On admission, her consciousness was E4V4V6. Cerebrospinal fluid analysis showed pleocytosis with mononuclear cell predominance, elevated protein, and decreased glucose. Despite antibiotic and antiviral therapy, her consciousness and neck stiffness gradually worsened, right eye‐movement restriction appeared, and the right direct light reflex became absent. Brain magnetic resonance imaging revealed hydrocephalus in the inferior horn of the left lateral ventricle and meningeal enhancement around the brainstem and cerebellum. Tuberculous meningitis was suspected, and pyrazinamide, ethambutol, rifampicin, isoniazid, and dexamethasone were started. In addition, endoscopic biopsy was performed from the white matter around the inferior horn of the left lateral ventricle to exclude brain tumor. A brain biopsy specimen revealed eosinophilic round cytoplasm with vacuoles around blood vessels, and we diagnosed with amoebic encephalitis. We started azithromycin, flucytosine, rifampicin, and fluconazole, but her symptoms did not improve. She died 42 days after admission. In autopsy, the brain had not retained its structure due to autolysis. Hematoxylin and eosin staining of her brain biopsy specimen showed numerous amoebic cysts in the perivascular brain tissue. Analysis of the 16S ribosomal RNA region of amoebas from brain biopsy and autopsy specimens revealed a sequence consistent with Balamuthia mandrillaris. Amoebic meningoencephalitis can present with features characteristic of tuberculous meningitis, such as cranial nerve palsies, hydrocephalus, and basal meningeal enhancement. Difficulties in diagnosing amoebic meningoencephalitis are attributed to the following factors: (1) excluding tuberculous meningitis by microbial testing is difficult, (2) amoebic meningoencephalitis has low incidence and can occur without obvious exposure history, (3) invasive brain biopsy is essential in diagnosing amoebic meningoencephalitis. We should recognize the possibility of amoebic meningoencephalitis when evidence of tuberculosis meningitis cannot be demonstrated.

An 81‐year‐old man developed axial rigidity, bradykinesia, and cognitive impairment within 6 weeks. On initial examination, he was misdiagnosed with progressive supranuclear palsy (PSP). Brain magnetic resonance imaging showed hyperintensities in the bilateral mesial temporal lobes and basal ganglia. Neuronal antibodies previously reported in autoimmune encephalitis mimicking PSP were negative. Immunohistochemical and immunocytochemical analysis revealed the autoantibodies recognized neuronal surface and intracellular antigens. The diagnostic criteria for probable autoimmune encephalitis were fulfilled. We diagnosed him with autoimmune encephalitis. Intravenous immunoglobulin and steroid therapy improved his symptoms. The presence of novel autoantibodies causing autoimmune encephalitis presenting with atypical parkinsonism was suggested.

Anti‐immunoglobulin‐like cell adhesion molecule 5 (IgLON5) disease is an autoimmune encephalitis that targets the cell adhesion molecule, IgLON5. The disease presents with various clinical features, including sleep disorders, bulbar palsy, movement disorders, cognitive dysfunction and neuromuscular manifestations. Sleep disorders are characterized by parasomnias and sleep‐disordered breathing (stridor and sleep apnea). Bulbar palsy includes dysarthria, dysphagia, vocal cord paralysis and stridor. Movement disorders include a variety of symptoms and signs, such as chorea, dystonia, rigidity, tremor, myoclonus and myorhythmia. Cognitive dysfunction includes executive dysfunction, impairment of attention, and verbal and visual memory dysfunction. Neuromuscular manifestations include fasciculations in the tongue and peripheral muscles, limb weakness, and muscle atrophy. Some patients resemble those with neurodegenerative diseases, such as progressive supranuclear palsy or amyotrophic lateral sclerosis. On video polysomnography, undifferentiated non‐rapid eye movement sleep and poorly structured N2 sleep are characteristic. Brain magnetic resonance imaging and cerebrospinal fluid studies are often normal or non‐specific. Human leukocyte antigen testing shows that HLA‐DRB1*10:01‐DQB1*05:01 is highly associated with the disease. Pathologically, neuronal deposition of both hyperphosphorylated 3‐repeat and 4‐repeat tau isoforms, neuronal loss, and gliosis in the hypothalamus, brainstem tegmentum, and upper cervical cord are observed. Some patients are responsive to immunotherapies, such as steroids, intravenous immunoglobulin, plasma exchange therapy and rituximab. Factors associated with a favorable response to immunotherapies include early initiation of treatment, cerebrospinal fluid inflammation and immunoglobulin G1 (IgG1) predominance of IgLON5 antibody compared with immunoglobulin G4 (IgG4). Anti‐IgLON5 disease should be suspected in patients with atypical movement disorders complicated by sleep disturbances.

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