A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.

Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.

Neuromyelitis optica preceded by hyperCKemia and a possible association with coxsackie virus group A10 infection.

We report the case of a 48-year-old woman presenting with an elevated serum creatine kinase level (hyperCKemia) associated with an initial attack of neuromyelitis optica (NMO). The patient initially showed general fatigue with fever. Laboratory findings showed hyperCKemia and subsequently she developed a slight weakness of both lower limbs and reduced vision. Autoantibodies against aquaporin 4 were found in her serum, and a retrospective examination of viral titers indicated a possible coxsackie virus group A10 infection. The present case suggests that hyperCKemia-mediated disease onset is involved in some patients with NMO, and furthermore, it may be related to muscular destruction associated with viral infection.

Steroid-responsive thalamic lesions accompanying microbleeds in a case of Hashimoto's encephalopathy with autoantibodies against α-enolase.

A 67-year-old man receiving antithrombotic therapy developed rapidly progressive amnesia. T2-weighted images of brain MRI revealed hyperintense lesions in the bilateral thalami accompanied by microbleeds. Antithyroglobulin antibodies and autoantibodies against the N-terminal of α-enolase (NAE) were identified in the patient's serum; therefore, Hashimoto's encephalopathy (HE) was suspected. Although the patient's radiological findings improved following steroid therapy, his symptoms did not improve, possibly due to increased thalamic microbleeds. Because anti-NAE antibodies are possibly associated with vasculitis, HE accompanied by anti-NAE antibodies may be exacerbated by microbleeds in patients receiving antithrombotic therapy.

Marked improvement in opsoclonus and cerebellar ataxia after the surgical removal of a squamous cell carcinoma of the thymus: a case report.

A 69-year-old man with rapidly evolving vertigo and ataxia was admitted to our hospital. He was presented with a dysarthric speech and chaotic eye movements, identified as opsoclonus. Neurological examination revealed limb and truncal ataxias and an inability to stand unless fully assisted. A chest CT scan revealed a mass at the anterior mediastinum, which suggested paraneoplastic neurological syndrome (PNS). However, an extensive search for anti-neuronal antibodies linked to cerebellar ataxia failed to find any autoantibodies, including cell surface autoantibodies. Subsequently, a total surgical removal of the thymic tumor was performed, leading to marked improvements in his signs and symptoms. The pathological findings by conventional and immunohistochemical examinations confirmed a squamous cell carcinoma of the thymus. Three months after onset his signs and symptoms improved and he was able to walk without support. In contrast to thymomas, PNS is extremely rare in patients with thymic carcinoma. Previous reports have shown that neurological symptoms, similar to opsoclonus or cerebellar ataxia, deteriorated in cases of thymic carcinoma that could not be controlled. The present report indicates that early diagnosis and total removal of the rare neoplasm may increase the possibility of neurological recovery.

Reversible distension of the subarachnoid space around the optic nerves in a case of idiopathic hypertrophic pachymeningitis.

Idiopathic hypertrophic pachymeningitis (IHP) is a chronic inflammatory disease of unknown cause. We report a case of IHP with bilateral distended subarachnoid space (SAS) of the optic nerves and unilateral visual disturbance. We observed marked amelioration of magnetic resonance (MR) imaging findings after initiation of treatment with prednisolone. This radiological finding implicates optic nerve sheath involvement that affects cerebrospinal fluid (CSF) dynamics around the optic nerve.

The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease.

Sporadic Parkinson's disease (sPD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the pathogenesis of the disease remains undetermined, phosphorylation of alpha-synuclein and its oligomer formation seem to play a key role. However, the protein kinase(s) involved in the phosphorylation in the pathogenesis of sPD has not been identified. Here, we found that G-protein-coupled receptor kinase 5 (GRK5) accumulated in Lewy bodies and colocalized with alpha-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein. Genetic association study revealed haplotypic association of the GRK5 gene with susceptibility to sPD. The haplotype contained two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bound to YY1 (Yin Yang-1) and CREB-1 (cAMP response element-binding protein 1), respectively, and increased transcriptional activity of the reporter gene. The results suggest that phosphorylation of alpha-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.

[Clinical, neuroimaging and electroencephalographic findings of encephalopathy occuring after the ingestion of "sugihiratake" (Pleurocybella porrigens), an autumn mashroom: a report of two cases].

We report a 54-year-old man (case 1) and a 79-year-old woman (case 2) who presented with encephalopathy of unknown cause. Both patients were on hemodyalysis and took an autumn mashroom, "sugihiratake" (Pleurocybella porrigens), two to three weeks prior to the onset of neurological alterations. The clinical syndrome of those patients was characterized by weakness and involuntary movements of the extremities (cases 1 and 2) or dysarthria (case 1) at the onset of the disease and subsequent intractable focal motor seizures, resulting in generalized status epilepticus or comatose state, six (case 1) or three (case 2) days after the disease onset. Epileptic seizures were gradually improved in both cases. On brain MRI of case 1, no relevant lesions were detectable at the onset day, but, 6 days after onset, T2-high intensity lesions were noted in the subcortical white matter of the insular cortex, claustrum, external capsule, putamen and globus pallidus on both sides. On brain CT scan of case 2, there were no apparent lesions at the onset day, but, 4 days after onset, low density areas were noted bilaterally in the subcortical white matter of the insular cortex. Electroencephalography of the two patients taken on a day of comatose state showed periodic synchronous discharge (PSD), which disappeared when their consciousness levels were improved. As far as we have examined, there was no findings to suggest the cause of the encephalopathy in routine laboratory examinations and various viral antibody studies of the blood and cerebrospinal fluid. The reported patients could constitute a newly recognized disease entity, "sugihiratake" encephalopathy. Our observations suggest that it can be an encephalopathy with subacute progression and affect mainly the basal ganglia. Neuroimaging study and electroencephalographic findings may help the diagnosis, although they may remain unremarkable for several days after onset of the neurological alterations.

[An outbreak of encephalopathy after eating autumn mushroom (Sugihiratake; Pleurocybella porrigens) in patients with renal failure: a clinical analysis of ten cases in Yamagata, Japan].

In September and October, 2004, an outbreak of encephalopathy of unknown etiology occurred in certain areas of Japan including Yamagata, Akita, and Niigata prefectures. These patients had a history of chronic renal failure, most of them had undergone hemodialysis, and also had a history of eating Sugihiratake (Pleurocybella porrigens), an autumn mushroom without known toxicity. Since clinical details of this type of encephalopathy remain unknown, we analyzed the clinical, radiological and electroencephalographic (EEG) features of ten cases of this encephalopathy in Yamagata prefecture. The summary of the present study is as follows: 1. Ten patients had chronic renal failure, and seven underwent hemodialysis. 2. Each patient had a history of eating Sugihiratake within 2-3 weeks of the onset of neurological symptoms. 3. The onset was subacute; the initial symptoms were tremor, dysarthria, and/or weakness of the extremities, which lasted an average of 4.5 days (ranging from 2 to 11 days), followed by severe consciousness disturbance and intractable seizures, resulting in status epilepticus in 5 patients. Myoclonus was also seen in 4 patients and Babinski reflex in 3. 4. Brain CT and MRI examinations were unremarkable in the early stages of the disease. Three to eight days after onset, however, conspicuous lesions appeared in the areas of the insula and basal ganglia in 6 patients. On MRI, these brain lesions were hyperintense on T2-weighted and FLAIR images, and hypointense on T1-weighted images. 5. EEG examination was performed in 6 patients, all of whom showed abnormal EEG findings. Periodic synchronous discharge (PSD) was seen in 2 patients, spike and wave complex in one patient, and non-specific slow waves in 3. 6. Prognosis was different from case to case. Three patients died at 13, 14, and 29 days after onset. Two patients still showed persistent disturbance of consciousness one month after onset. One patient showed parkinsonism after recovering from consciousness disturbance. Four patients recovered nearly completely around one month after onset In 3 of the 4 recovered patients, renal failure was not severe and they did not need to undergo hemodialysis. This suggests that the degree of renal failure is a key for the prognosis of this type of encephalopathy. The present study suggests that this endemic disease is a newly recognized clinical entity of encephalopathy.