Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.

OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients.

BACKGROUND AND PURPOSE: The most common strategy for treating patients with acute ischemic stroke is thrombolytic therapy, though only a few patients receive benefits because of the narrow time window. Inflammation occurring in the central nervous system (CNS) in association with ischemia is caused by immune cells including monocytes and involved in lesion expansion. If the specific roles of monocyte subsets in stroke can be revealed, they may become an effective target for new treatment strategies. METHODS: We performed immunological examinations of 36 consecutive ischemic stroke patients within 2 days of onset and compared the results with 24 age-matched patients with degenerative disorders. The stroke patients were repeatedly tested for the proportions of monocyte subsets in blood, and serum levels of pro- and anti-inflammatory cytokines immediately after admission, on days 3-7 and 12-16 after stroke onset, and on the day of discharge. In addition, immunological measurements were analyzed for relationships to stroke subtypes and complications, including progressive infarction (PI) and stroke-associated infection (SAI). RESULTS: Monocyte count was significantly increased from 0-16 days after stroke as compared to the controls (p<0.05). CD14(high)CD16(-) classical and CD14(high)CD16(+) intermediate monocytes were significantly increased from 0-7 and 3-16 days after stroke, respectively (p<0.05), whereas CD14 (dim)CD16(high) non-classical monocytes were decreased from 0-7 days (p<0.05). Cardioembolic infarction was associated with a persistent increase in intermediate monocytes. Furthermore, intermediate monocytes were significantly increased in patients with PI (p<0.05), while non-classical monocytes were decreased in those with SAI (p<0.05). IL-17A levels were positively correlated with monocyte count (r=0.485, p=0.012) as well as the percentage of non-classical monocytes (r=0.423, p=0.028), and negatively with that of classical monocytes (r=-0.51, p=0.007) during days 12-16. CONCLUSIONS: Our findings suggest that CD14(high)CD16(+) intermediate monocytes have a role in CNS tissue damage during acute and subacute phases in ischemic stroke especially in relation to cardioembolism.

Novel FUS mutation in patients with sporadic amyotrophic lateral sclerosis and corticobasal degeneration.

We report a patient with sporadic amyotrophic lateral sclerosis (ALS) with a novel fusion in malignant liposarcoma (FUS) gene mutation whose neurological signs were conspicuous left-sided rigidity and apraxia. A novel heterozygous guanine (G)-to-thymine (T) transition at position 1392, c.1392G>T, leading to a methionine-to-isoleucine substitution (p.Met464Ile), was found in exon13 of FUS. Re-sequencing of the genes for superoxide dismutase 1 (SOD1) and transactive response-DNA binding protein (TARDBP) revealed no mutations. The present findings suggest that this novel FUS mutation (p.Met464Ile) is related to manifestations of ALS as well as clinical features of corticobasal degeneration.

[A case of Castleman disease with status epileptics originating from focal cortical dysplasia].

A 55-year-old man was admitted to our hospital because of prolonged consciousness disturbance after generalized convulsions. He had been afflicted with chronic inflammatory symptoms since 43 years of age, while multiple abdominal lymphadenopathy with a high level of serum IL-6 was revealed at the age of 53. FDG-PET/CT showed hypermetabolism in the left medial portion of the frontal lobe. Biopsy specimens of this lesion revealed a pathology of focal cortical dysplasia (FCD). Non-convulsive status epileptics continued despite enhanced treatment with antiepileptic drugs, while cortical T2 hyperintense lesions developed and expanded. Castleman disease was confirmed by pathological findings of abdominal lymph node biopsy specimens. The patient showed a higher level of IL-6 in cerebrospinal fluid (1,400 pg/dl) than in serum (720 pg/dl), thus indicating intrathecal production of this proinflammatory cytokine. We concluded that continuous exposure of FCD tissue to IL-6 may have augmented epileptogenesis of the originally silent congenital lesion.

[Primary neurolymphomatosis of the cervical nerve root].

A 74-year-old woman was admitted with muscle weakness and sharp pain in her upper limbs. On (18)FDG-PET, abnormal accumulation was noted on both sides of the brachial plexus at the cervical spinal cord. A diagnosis of primary peripheral nerve neurolymphomatosis was made based on biopsy of the third cervical nerve. Following R-CHOP therapy, the abnormal accumulation of (18)FDG-PET scan disappeared. However, disturbance of consciousness occurred 6 months later and recurrence as multiple brain tumors was detected. Although salvage chemotherapy was performed, the patient died of overwhelming sepsis. Primary peripheral nerve neurolymphomatosis is extremely rare. Early distinct diagnosis using (18)FDG-PET and combination chemotherapy of rituximab and high dose methotrexate may improve the outcome for such patients.

Moyamoya disease presenting with an acute confusional state in an elderly patient.

Moyamoya disease is the angiographic diagnosis of a clinical syndrome showing bilateral stenosis or occlusion of the distal internal carotid arteries and their major branches with extensive parenchymal, leptomeningeal, or transdural anastomoses. The clinical features normally present as reversible ischemic neurologic deficits, sensory-motor attacks with acute hemiplegia, and motor convulsion. An acute confusional state (ACS) among hospitalized patients is a frequent and serious problem. It is characterized by an acute neurologic deficit with a fluctuating course of impaired attention span, unorganized thinking, and altered levels of consciousness. We report a case of 66-year-old woman who presented with an ACS in the emergency department. The subsequent workups including a neuroradiological examination revealed a rare case of moyamoya disease with bifrontal ischemic infarction. The recognition of an ACS as a manifestation of moyamoya disease should therefore be included in the differential diagnosis of elderly patients who present with an acutely altered neuropsychiatric state. A prompt diagnosis may help to select the most appropriate therapy for this rare disorder especially in elderly patients.

Primary skeletal muscle involvement in chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a hereditary disease characterized by involuntary movements and amyotrophy with elevation of serum creatine kinase. Although skeletal muscle involvement in ChAc has been suggested, the mechanism remains unclear. To investigate chorein abnormalities of the skeletal muscles of ChAc patients with an apparently heterozygous VPS13A mutation compared with those of other hereditary choreic diseases, we performed histological and immunohistochemical studies of the skeletal muscles from 3 ChAc, 1 Huntington's disease (HD), 1 McLeod syndrome (MLS), and 1 normal control (NC) with 2 originally generated anti-chorein antibodies. Chorein immunoreactivities in HD, MLS, and NC were found linearly along the sarcolemma and appeared as speckles in the sarcoplasma, but those in ChAc were uneven and discontinuous along the sarcolemmas and increased in the sarcoplasma especially in type I fibers. This histological observation suggests chorein abnormalities of skeletal muscles might be associated with primary involvement of skeletal muscles in this disorder.

Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD.

OBJECTIVE: Cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy studies of patients with idiopathic Parkinson's disease (PD) found decreased uptake. Whether this decrease is associated with clinical severity as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the phenotypes of PD has not been determined. METHODS: Cardiac MIBG scintigraphy was performed on 34 patients with PD, 7 with multiple system atrophy (MSA), 4 with dementia with Lewy bodies (DLB), and 11 normal controls (NCs). Early and delayed MIBG heart/mediastinum (H/M) ratios were evaluated. PD severity was assessed by the Hoehn and Yahr (H-Y) stage and UPDRS. Patients were grouped in two phenotypes, tremor and postural instability gait difficulty (PIGD)-dominant groups based on UPDRS components. Associations between MIBG uptake and age at onset, UPDRS, and disease phenotype were analyzed in each group. RESULTS: The early H/M ratio was significantly lower in patients with PD (1.45+/-0.207) than in the NCs (2.08+/-0.231), and in those with MSA (1.99+/-0.284), but not in those with DLB (1.29+/-0.0435). The delayed H/M ratio for PD (1.33+/-0.276) also was significantly decreased as compared to the ratios for NCs (2.17+/-0.286) and MSA (2.16+/-0.414) but not DLB (1.16+/-0.0949). The early H/M ratio was significantly correlated with both UPDRS score and age at onset, whereas the delayed H/M ratio only was significantly correlated with age at onset. The PIGD-dominant group had significantly higher UPDRS scores and lower H/M ratios than the tremor-dominant group. CONCLUSION: Cardiac MIBG scintigraphy can be used to differentiate PD from MSA and NC, and to determine the disease severity and phenotypes of PD.