Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

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.

Ascaris lumbricoides Discharge from the Mouth.

A 68-year-old Japanese man presented with Ascaris lumbricoides discharge from his mouth. The infection was suspected to have occurred while the patient was in the Philippines. This A. lumbricoides migration occurred because a proton pump inhibitor was used and Billroth I resection had been performed, which reduced gastric acid secretion and increased gastric pH. In addition, the pylorus had been removed during Billroth I resection, enabling easy access to the stomach. The number of imported foods, of infected migrants and refugees, and of overseas travels is increasing, and these factors may lead to an increase in A. lumbricoides infection even in countries with a typically low incidence of such infections. Clinicians should bear in mind that parasitic infections may occur in nonendemic areas.

Recurrent Painful Ophthalmoplegic Neuropathy with Residual Mydriasis in an Adult: Should it Be Classified as Ophthalmoplegic Migraine?

Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare condition that manifests as headache and ophthalmoplegia. It typically occurs in children. Although migraine or neuropathy have been suggested as etiologies, the precise etiology remains unclear. In the International Classification of Headache Disorders 3rd edition-beta version (ICHD3ß) (code 13.9), RPON was categorized into painful cranial neuropathies and other facial pains. We encountered a 48-year-old woman who had diplopia and right ptosis. The administration of prednisolone led to the immediate improvement of her oculomotor palsy, but residual mydriasis remained. Based on this case, the pathophysiology of RPON may involve temporary nerve inflammation with migraine. Repeated and severe migraine attacks may cause irreversible nerve damage. Thus, medication for migraine prophylaxis might be needed to prevent RPON.

A clinical and neuropathological study of an unusual case of sporadic tauopathy. A variant of corticobasal degeneration?

We report a sporadic case of tauopathy with unusual clinical and neuropathological features. The patient presented with progressive symmetric rigid-akinetic parkinsonism and dementia of the subcortical type. Magnetic resonance imaging of the brain revealed atrophy resembling multiple system atrophy. The level of cerebrospinal fluid tau protein phosphorylated at serine 199 was markedly elevated. The autopsy revealed more glial than neuronal tauopathy, with much heavier involvement of subcortical white matter and the brainstem than of the cerebral cortex. Analysis of dephosphorylated tau revealed that hyperphosphorylated four-repeat tau isoforms were deposited in the brain of the patient. Despite morphological and biochemical resemblance to a certain form of familial fronto-temporal dementia, no mutation of the tau gene including exon 10 could be found. Our findings, taken together with those in previous similar case reports, indicate that the case represents an atypical form of corticobasal degeneration or a new variant of sporadic tauopathy.

[A case of Guillain-Barré syndrome starting from severe upper back pain].

Examination of a 58-year-old woman who had developed severe upper back pain showed left peripheral type of facial nerve palsy, sensory disturbance of limbs and body trunk (Th7-9), cerebellar ataxia and generalized hyporeflexia. Upper back pain increased at night and was resistant to NSAIDs, antianxiety agents, opioids, and corticosteroids. Concentrations of serum CK and cerebrospinal fluid total protein were elevated. Electromyography (EMG) of perivertebral muscles (Th7-10) showed reduced recruitment and polyphasic potential. Several days later, our patient developed weakness of limbs and respiratory failure, and required mechanical ventilation. From these findings, we diagnosed her as having Guillain-Barré syndrome (GBS) and began treatment with intravenous immunoglobulin therapy. All symptoms including upper back pain improved gradually, and she had recovered almost completely by the 40th hospitalization day. Pain, especially lower back and leg pain, have attracted attention as common symptoms in GBS. However, only one GBS patient with initial severe upper back pain has been reported. Although the precise mechanism of pain in GBS remains unclear, EMG findings lead us to surmise our patient's pain originated from the nerve roots. Limb and back pain should therefore be taken into account for the diagnosis and treatment of GBS patients.