To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals.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.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.The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.
We herein report a case of corticobasal syndrome (CBS) due to asymmetric degeneration of the motor cortex and substantia nigra with transactivation response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy, associated with Alzheimer's disease (AD) pathology. An 85‐year‐old man initially noticed that he had difficulty in walking and had trouble in moving his right hand and lower limb one year later. His gait disturbance was aggravated, and at the age of 87 years, his neurological examination revealed parkinsonism and positive frontal lobe signs. Brain magnetic resonance imaging (MRI) revealed atrophy of the left frontotemporal lobe and cerebral peduncle, and cerebral blood flow scintigraphy revealed hypoperfusion of the left frontotemporal lobe, leading to a possible diagnosis of CBS. At the age of 89 years, he was bedridden, and rarely spoke. He died of aspiration pneumonia five years after the onset of initial symptoms. At the autopsy, the brain weighed 1280 g and showed left‐sided hemiatrophy of the cerebrum and cerebral peduncle. Neuropathological examination revealed AD pathology (Braak AT8 stage V, Braak stage C, CERAD B, Thal classification 5). Phosphorylated TDP‐43 (p‐TDP‐43) immunohistochemistry revealed widespread deposits of dystrophic neurites (DNs), glial cytoplasmic inclusions (GCIs), and neuronal cytoplasmic inclusions (NCIs), which were most remarkable in layers II/III of the motor cortex and predominant on the left hemisphere of the frontal cortex, these neuropathology being consistent with frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) type A. Interestingly, neuronal loss in the substantia nigra was more severe on the left than the right side, with a few phosphorylated tau (p‐tau) and p‐TDP‐43 deposits. It is highly likely that asymmetric TDP‐43 pathology rather than symmetric tau pathology contributed to the laterality of degeneration of the cerebral cortex, substantia nigra, and pyramidal tract, which led us to suggest that TDP‐43 proteinopathy might be a primary cause.
A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.
A 41-year-old man presented with gradually progressing proximal-dominant lower limb atrophy and weakness. His brother, mother and maternal aunt had the same symptoms. A physical examination and muscle imaging (CT and ultrasound) showed selective muscle involvement of the bilateral paraspinal, gluteus and posterior groups of lower limb muscles. Based on the characteristic muscle involvement pattern, the clinical findings and the muscle biopsy results, we made a straightforward diagnosis of limb-girdle muscular dystrophy (LGMD) due to a DNAJB6 Phe93Leu mutation based on a targeted gene analysis. In the differential diagnosis of adult-onset LGMD syndromes, in addition to investigating the family history, it is important to perform an extensive physical examination to determine the pattern of muscle involvement, and to perform a muscle biopsy. Our case suggests that posterior-dominant lower limb muscle impairment with gluteus and truncal muscle involvement and the detection of rimmed vacuoles on a muscle biopsy could be clues for the diagnosis of LGMD due to DNAJB6 mutations.
Summary objective Antithyroid drugs are effective in some patients with Graves’ disease but not in others. The factors responsible for this difference are still unknown. We examined the relationship between the nature of anti‐TSH receptor (TSH‐R) antibodies and responsiveness to drugs in Graves’ disease. patients Twenty‐eight untreated patients with Graves’ disease were treated with thiamazole and followed for up to 13 years. measurement Antithyroid microsomal antibodies (MCHAs) and antithyroglobulin antibodies (TGHAs) were measured by the passive haemagglutination method. Anti‐TSH‐R antibodies were measured by a radioreceptor assay (TBII), and thyroid‐stimulating antibodies (TSAbs) and TSH‐stimulation blocking antibodies (TSBAbs) were measured by bioassays using FRTL‐5 cells. Blocking antibodies were also measured by the conversion assay. In order to confirm the usefulness of the conversion assay, in vitro experiments using mixtures of TSAb serum and TSBAb serum were performed. results In in vitro conversion experiments, the conversion assay sensitively detected coexisting blocking antibodies. TSBAb was found in seven patients and a positive conversion ratio was found in four patients, and, of these, three patients had both antibodies. Finally, eight patients (28·6%) had blocking antibodies and 25 of 28 patients (89·3%) had stimulating antibodies. These patients with blocking antibodies (Group A) responded well initially to antithyroid drugs and showed earlier normalization of the serum T4 level (3·0 ± 1·2 weeks) than patients without blocking antibodies (Group B, 10·7 ± 8·5, P < 0·001). Unexpectedly, remission of Graves’ thyrotoxicosis was earlier in Group B (5·1 ± 4·4 years) than in Group A (8·0 ± 4·3 years, P < 0·05). Other parameters, including serum T4, goitre size, ophthalmopathy, TBII, TSAb, TGHA and MCHA, were not different between the two groups. conclusions Graves’ patients with coexisting blocking antibodies initially respond well to thiamazole but are relatively slow to achieve remission. Measurement of blocking antibodies may be useful for selection of treatment options in Graves’ disease.
Mutations of the early growth response 2 ( EGR2 ) gene have been reported in a variety of severe demyelinating neuropathies such as autosomal recessive congenital hypomyelinating neuropathy, autosomal dominant child‐onset Dejerine‐Sottas neuropathy, and autosomal dominant adult‐onset Charcot‐Marie‐Tooth disease (CMT). Here, we report on a heterozygous mutation in EGR2 (c.1160C>A), which results in threonine at position 387 being changed to asparagine, in a family with a mild demyelinating form of adult‐onset CMT. Of note, both the proband and her asymptomatic son exhibited neither pes cavus nor champagne‐bottle leg atrophy, suggesting that the heterozygous T387N mutation may result in a relatively mild phenotype of demyelinating CMT.
Objectives Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. Methods Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. Results Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (> 60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n= 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. Conclusions This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.
