Influence of Spinal Sagittal Alignment in Sitting Posture on the Swallowing Speed of Older Adult Women: A Cross-Sectional Study.

Thoracolumbar kyphosis in sitting posture is associated with forward head posture and may adversely affect swallowing function. However, few studies have investigated the effect of spinal alignment in the sitting posture on the swallowing function of older adults. This cross-sectional study aimed to investigate whether spinal alignment in the sitting posture influences the swallowing function of older adult women. Overall, 18 older adult women (mean age, 69.78 ± 3.66 years) without dysphagia were enrolled. Participants were positioned in two sitting postures, namely, comfortable sitting (CS) and thoracic upright sitting (TUS). In each sitting posture, the kyphosis index (using a flexicurve), sagittal angles (head, cervical, shoulder, and pelvic angles; using a digital camera), and cervical range of motion (ROM) were evaluated. Swallowing speed (100-mL water swallowing test), maximum tongue pressure (MTP), and oral diadochokinesis (ODK) were also evaluated. Compared with TUS, CS showed a greater kyphosis index, anterior head translation, and posterior pelvic tilt. CS had greater flexion (p < 0.001) and less extension (p < 0.001) of cervical ROM than TUS. Swallowing speed was significantly decreased in CS compared with TUS (p = 0.008). MTP and ODK were not significantly different between CS and TUS. Thus, changes in sitting posture with spinal alignment may affect swallowing speed. Consequently, adjustments to reduce sitting postural kyphosis in older adult women may improve swallowing speed.

A study on the reliability and validity of the Japanese version of the Scenario Test for people with chronic stroke-induced aphasia: A cross-sectional study.

BACKGROUND: The Scenario Test is recognised for its effectiveness in assessing the interactive aspects of functional communication in people with post-stroke aphasia (PWA). AIMS: To develop a Japanese version of the Scenario Test (Scenario Test-JP) and assess its reliability and validity. METHODS & PROCEDURES: Among 66 participants, we selected 61 individuals: 34 PWA and 27 healthy controls (HCs). We modified the Scenario Test-JP based on the UK version and subsequently evaluated its reliability (internal consistency, test-retest and intra-rater and inter-rater reliabilities) and validity (convergent and discriminant) by comparing PWA and HCs. OUTCOMES & RESULTS: The Scenario Test-JP showed strong reliability with a Cronbach's α of 0.93, test-retest reliability with an intraclass correlation coefficient (ICC) of 0.97, intra-rater reliability with an ICC of 0.95-1.00, and inter-rater reliability with an ICC of 0.96. The validity of the test was confirmed with concurrent scores ranging from ρ = 0.37 to 0.76 (p < 0.05) and known-groups validity (p < 0.001, r = -0.56). CONCLUSIONS & IMPLICATIONS: The reliability and validity of the Scenario Test-JP align with those of the original Dutch version and the UK and Greek versions. Additionally, the assessment can now include extended alternative communication methods, such as digital devices, indicating the potential of the Scenario Test-JP for modern Japanese speech-language therapy. WHAT THIS PAPER ADDS: What is already known on the subject Interactive communication is a facet of functional communication and is crucial for evaluating engagement and participation of people with aphasia (PWA) in speech-language therapy. The Scenario Test provides valuable information for planning speech-language treatment strategies by assessing dialogic communication. What this study adds This study describes the development of the Scenario Test-JP for use with Japanese speakers and Japanese PWA, which is adapted from the Scenario Test UK version. This study evaluated the reliability and validity of this assessment tool and provided supporting evidence. What are the clinical implications of this work? The reliability and validity of the Scenario Test-JP were consistent with those of the Dutch, UK and Greek versions. The Scenario Test-JP contributes to speech-language therapy in Japan, where high-quality support for the activities and participation of PWA is required. PRACTITIONER POINTS: Insights from the Scenario Test The Scenario Test plays a crucial role in evaluating the functional communication skills of people with post-stroke aphasia (PWA). Enhancing functional communication has been linked to improved social engagement among PWA, which in turn influences their overall quality of life (QOL). Issues addressed by the Scenario Test The Scenario Test aids in delineating rehabilitation objectives for activities and participation among PWA, particularly concerning functional communication. The test facilitates tailored support for PWAs' interactive communication and forms the foundation for appropriate speech-language therapy interventions. Transformation of speech-language therapy (SLT) in Japan through the introduction of the Scenario Test-JP The integration of the Scenario Test-JP could enhance the SLT services provided to PWA in Japan. With Japan experiencing an unprecedented ageing population, the prevalence of social isolation and diminished QOL resulting from communication disorders like stroke-induced aphasia is expected to rise. Consequently, the SLT rehabilitation sector in Japan is actively seeking effective interventions to support functional communication among PWA. Hence, the adoption of the Scenario Test-JP is anticipated to streamline the evaluation of functional communication, facilitating the judicious selection and timely provision of assistance to PWA in SLT, including guidance on communication partner support and communication skill training.

Clinical Features and Neuroimaging Findings of Neuropil Antibody-Positive Idiopathic Sporadic Ataxia of Unknown Etiology.

Idiopathic sporadic ataxia (ISA) is the clinical term for nonfamilial ataxia with adult-onset and a slowly progressive course. However, immune-mediated cerebellar ataxia cannot be completely excluded from ISA. The current study investigated the neuropil antibodies against cell-surface antigens and clarified the clinical features and neuroimaging findings of patients with these antibodies. Using tissue-based immunofluorescence assays (TBAs), we examined antibodies against the cerebellum in serum samples from 67 patients who met the ISA diagnostic criteria, including 30 patients with multiple system atrophy with predominant cerebellar features (MSA-C) and 20 patients with hereditary ataxia (HA), and 18 healthy control subjects. According to the TBA results, we divided subjects into three groups: subjects positive for neuropil antibodies, subjects positive for intracellular antibodies only, and subjects negative for antibodies. We compared clinical features and neuroimaging findings in ISA patients among these three groups. The prevalence of neuropil antibodies in ISA (17.9%) was significantly higher than that in MSA-C (3.3%), HA (0%), or healthy subjects (0%). The neuropil antibody-positive ISA patients showed pure cerebellar ataxia more frequently than the other ISA patients. Two neuropil antibody-positive patients showed significant improvement of cerebellar ataxia after immunotherapy. We detected neuropil antibodies in 17.9% of ISA patients. Characteristic clinical features of neuropil antibody-positive ISA patients were pure cerebellar ataxia. Some cases of neuropil antibody-positive ISA responded to immunotherapy.

Effect of Spinal Sagittal Alignment in Sitting Posture on Swallowing Function in Healthy Adult Women: A Cross-Sectional Study.

Swallowing function is both directly and indirectly related to postures, such as head and cervical angle and body position. However, the effects of different sitting postures on oropharyngeal swallowing have not been investigated. This study aimed to investigate whether the change in thoracolumbar alignment affected the oropharyngeal swallowing. A total of 58 healthy adult women (mean age 22.2 ± 1.67 years) without dysphagia were enrolled in this cross-sectional study. Participants were positioned in three sitting postures: comfortable sitting (CS), thoracic upright sitting (TUS), and slump sitting (SS). In each sitting posture, the kyphosis index (using a flexicurve), head and cervical angles (using a digital camera), swallowing speed (100-ml water swallowing test), and oral and articulatory function [by maximum tongue pressure (MTP) and oral diadochokinesis (ODK)] were evaluated. SS showed the largest kyphosis index and was associated with a greater anterior translation of the head. Swallowing speed was significantly decreased in SS compared with CS (p = 0.002) and TUS (p = 0.020) and ODK was significantly decreased in SS compared with other postures, for both /ta/ (p = 0.004) and /ka/ (p < 0.001) syllables. Further, MTP tended to decrease in SS compared with TUS (p = 0.064). Our results suggest that changes in sitting posture with different thoracolumbar alignments affect swallowing speed and oral and articulatory function. Consequently, adjustments to reduce sitting postural kyphosis may improve swallowing speed and oral and articulatory function.

Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis.

Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.

Carotenoid Production in Oleaginous Yeasts.

Oleaginous yeasts, Yarrowia lipolytica and Lipomyces starkeyi, can synthesize more than 20% of lipids per dry cell weight from a wide variety of substrates. This feature is attractive for cost-efficient production of industrial biodiesel fuel. These yeasts are also very promising hosts for the efficient production of more value-added lipophilic compound carotenoids, e.g., lycopene and astaxanthin, although they cannot naturally biosynthesize carotenoids. Here, we review recent progress in researches on carotenoid production by oleaginous yeasts, which include red yeasts that naturally produce carotenoids, e.g., Rhodotorula glutinis and Xanthophyllomyces dendrorhous. Our new results on pathway engineering of L. starkeyi for lycopene production are also revealed in the present review.

Effects of Tongue-Strengthening Self-Exercises in Healthy Older Adults: A Non-Randomized Controlled Trial.

Tongue-strengthening exercises (TSE) using a device have been proposed as an intervention for improving tongue strength and endurance. However, devices for TSE have been expensive and difficult to manipulate and are not commonly used in home or clinical settings. This study therefore aimed to investigate whether tongue-strengthening self-exercises (TSsE) using a tongue-strengthening self-exercise tool at home can improve tongue strength in healthy older adults. This study included 27 participants (exercise group, η = 16, 7 men, 9 women, median age 84.5 years; control group, n = 11, 2 men, 9 women, median age 79.0 years). Exercises in the exercise group consisted of pushing the anterior tongue against the hard palate 30 times, 3 times a day, 5 days a week, for 8 weeks using a tongue-strengthening self-exercise tool. This tool is available in five levels of hardness. The most suitable hardness of the tool for each participant was calculated based on 60% of maximum tongue pressure (MTP) during the first 2 weeks of the training period and 80% of MTP for the remainder of the training period, as assessed using a tongue pressure-measuring device. The exercise group showed a significant improvement of 4.1 kPa in MTP (an 11.53% increase) and 4.53 s in endurance of tongue pressure (ETP) (a 99.86% increase). Furthermore, adherence in the exercise group was 99.2%. In conclusion, performing TSsE for 8 weeks was effective for increasing MTP and ETP in healthy older adults. This indicates that TSsE may be useful in older individuals at home to prevent age-related tongue muscle weakness.

Brain-derived neurotrophic factor/tropomyosin-related kinase B signaling pathway contributes to the aggressive behavior of lung squamous cell carcinoma.

The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P<0.001), and advanced stage (P=0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression (P=0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.

Inter-generational instability of inserted repeats during transmission in spinocerebellar ataxia type 31.

The causative mutation for spinocerebellar ataxia type 31 (SCA31) is an intronic insertion containing pathogenic pentanucleotide repeats, (TGGAA)n. We examined to what degree the inserted repeats were unstable during transmission. In 14 parent-child pairs, the average change of onset age was -6.4±7.3 years (mean±s.d.) in the child generation when compared with the parent generation. Of the 11 pairs analyzed, six showed expansion of inserted repeat length during transmission, and five showed contraction. On average, the inserted repeats expanded by 12.2±32.7 bp during transmission, but their mean length (with a 95% confidence interval) was not significantly different between parent and child generations. We consider that the length of the inserted repeats in SCA31 is changeable during transmission, but inter-generational instability is not marked, as far as the current sizing method can determine.

Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients.

Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.

Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study.

Spinocerebellar ataxia type 31 (SCA31) is known as a late-onset, relatively pure cerebellar form of ataxia, but a longitudinal prospective study on the natural history of SCA31 has not been done yet. In this prospective cohort study, we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan. Patients were evaluated every year for 4 years using the Scale for the Assessment and Rating of Ataxia (SARA) and the Barthel Index (BI). Of the 176 follow-up visits (91.5%), 161 were completed in this study. Five patients (11.4%) died during the follow-up period, and two patients (4.5%) were lost to follow-up. The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year (mean ± standard error). Shorter disease duration at baseline was associated with faster progression of the SARA score. Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years. Our prospective dataset provides important information for clinical trials of forthcoming disease-modifying therapies for cerebellar ataxia. It also represents a useful resource for SCA31 patients and their family members in genetic counseling sessions.

The effects of anesthetic agents on pupillary function during general anesthesia using the automated infrared quantitative pupillometer.

Pupil reactivity can be used to evaluate central nervous system function and can be measured using a quantitative pupillometer. However, whether anesthetic agents affect the accuracy of the technique remains unclear. We examined the effects of anesthetic agents on pupillary reactivity. Thirty-five patients scheduled for breast or thyroid surgery were enrolled in the study. Patients were divided into four groups based on the technique used to maintain anesthesia: a sevoflurane-remifentanil (SEV/REM) group, a sevoflurane (SEV) group, a desflurane-remifentanil (DES/REM) group, and a propofol-remifentanil (PRO/REM) group. We measured maximum resting pupil size (MAX), reduction pupil size ratio (%CH), latency duration (LAT) and neurological pupil index (NPi). A marked reduction in MAX and %CH compared with baseline was observed in all groups, but LAT was unchanged during surgery. NPi reduced within the first hour of surgery in the SEV/REM, SEV, and DES/REM groups, but was not significantly different in the PRO/REM group. Compared with the PRO/REM group, mean %CH and NPi in patients anesthetized with SEV/REM, SEV or DES/REM were markedly lower at 1 h after surgery had commenced. There was no correlation between NPi and bispectral index. Fentanyl given alone decreased pupil size and %CH in light reflex, but did not change the NPi. NPi was decreased by inhalational anesthesia not but intravenous anesthesia. The difference in pupil reactivity between inhalational anesthetic and propofol may indicate differences in the alteration of midbrain reflexs in patients under inhalational or intravenous anesthesia.

Outcomes of cervical end-to-side triangulating esophagogastric anastomosis with minimally invasive esophagectomy.

BACKGROUND: Esophagogastric anastomosis after esophagectomy has been performed with a variety of techniques during the past decade. However, anastomotic leakage and stricture are still important clinical problems after esophagogastric anastomosis, causing burdensome symptoms and poor quality of life. Herein, we describe a novel cervical end-to-side triangulating esophagogastric anastomoasis using linear stapler. METHODS: A total of 90 patients (85 % male; mean age 63 years) with thoracic esophageal cancer who underwent cervical end-to-side esophagogastric triangular anastomosis using a linear stapler after minimally invasive esophagectomy between November 2006 and April 2013 were retrospectively reviewed. RESULTS: The median operation time was 602 min (range 424-936 min). The volume of blood loss during the entire operative procedure was 127 ml (range 0-700 ml). There were no cases of anastomotic leakage in this study, although four patients (4.4 %) developed dysphagia associated with benign anastomotic stricture formation. All patients with a benign anastomotic stricture underwent balloon dilation, which resulted in improvement in their symptoms. CONCLUSIONS: Considering the absence of anastomotic leakage and low rate of anastomotic stricture formation in this study, our modified triangular esophagogastric anastomosis technique appears promising and may contribute to reduced morbidity and mortality rates following esophagectomy.

[Mediastinal Hemangioma with Literature Review;Report of a Case].

A 58-year-old woman visited a local physician for evaluation of collagen disease and screening computed tomography (CT) showed a posterior mediastinal tumor. After referral to our hospital, CT and magnetic resonance imaging (MRI) showed a mass, approximately 2 cm in diameter, located on the right of the 1st thoracic vertebra. Since a neurogenic tumor was suspected, thoracoscopic excision was performed. Surgical findings revealed a tumor between the 1st and 2nd ribs in the close vicinity of the right brachiocephalic vein. We severed blood vessels flowing into the tumor and removed it. The tumor, 25 mm in maximal diameter, was diagnosed as hemangioma by histological examinations. The prevalence of a hemangioma is less than 0.5% of all mediastinal tumors. Since it lacks specific imaging findings, its preoperative diagnosis is quite difficult to establish. Although a hemangioma in the mediastinum is quite rare, it should be included in the differential diagnoses of mediastinal tumors.

[FEMALE SURGEONS SHOULD BE AWARE OF THE IMPORTANCE OF A CLEAR VISION FOR THEIR CAREER AND LIFE PLANS TO ACHIEVE THEIR CAREER DEVELOPMENT.: A SURVEY OF 20 FEMALE SURGEONS AT THE DEPARTMENT OF SURGERY AND ONCOLOGY, KYUSHU UNIVERSITY].

A shortage of surgeons has been a serious problem in recent years. There is an urgent need to utilize female surgeons who tend to resign because of bearing and raising of children. To examine possible measures to deal with the issue, we performed questionnaire survey about work-life balance and career planning on 20 female surgeons in the Department of Surgery and Oncology, Kyushu University. The response rate was 80.0%. In the 16 respondents, seven were unmarried and nine were married. A large fraction of the respondents recognized the importance of work-life-balance. Female surgeons have many difficulties to continue working with good work-life balance; therefore, understanding and cooperation of both their spouses and coworkers is considered to be necessary. Married female surgeons considered that improvement of the working environment and sufficient family support were more important for good work-life balance compared to those who were unmarried. Female surgeons should recognize the importance of improvement of their environment, including the workplace and the family to continue working with good work-life balance in youth and should have the prospects about their career plan of their own.

Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation.

BACKGROUND: Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy. METHODS: This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample. RESULTS: We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency. CONCLUSIONS: We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

Solitary fibrous tumor of the thyroid gland.

Solitary fibrous tumor is a spindle cell neoplasm rarely arising in the thyroid gland. We present a 78-year-old man with the diagnosis of solitary fibrous tumor of the thyroid gland resected by subtotal thyroidectomy. Fine needle aspiration cytology via ultrasound guidance demonstrated a hypocellular aspirate that revealed follicular epithelial cells with mild nuclear atypia and scattered spindle cells with bland nuclei. Histologically, the patternless proliferation of spindle cells was seen among collagenous bundles, accompanied by hemangiopericytomatous vessels, and variously dilated follicles with mild atypical cells having slightly enlarged nuclei, indicating adenomatous goiter. The neoplastic spindle cells showed diffuse immunoreactivity to CD34, bcl-2, CD99 and vimentin, but were negative for cytokeratins, calcitonin, TTF-1 and CD5. Although solitary fibrous tumor arising in thyroid gland is rare, this tumor should be included in the differential diagnosis of thyroid spindle cell tumors and also that of adenomatous.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study.

BACKGROUND: Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. METHODS: We retrospectively evaluated the medical records of 202 consecutive participants. RESULTS: A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4-36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of -1.2 mg/dL/year. CONCLUSIONS: Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Auditory Neuropathy Spectrum Disorder Progressing with Motor and Sensory Neuropathy Caused by an ATP1A1 Variant.

We encountered a 27-year-old Japanese woman with sensorineural deafness progressing to motor and sensory neuropathy. At 16 years old, she had developed weakness in her lower extremities and hearing impairment, which gradually deteriorated. At 22 years old, combined audiological, electrophysiological, and radiological examination results were consistent with auditory neuropathy spectrum disorder (ANSD). Genetic analyses identified a previously reported missense variant in the ATP1A1 gene (NM_000701.8:c.1799C>G, p.Pro600Arg). Although sensorineural deafness has been reported as a clinical manifestation of ATP1A1-related disorders, our case suggested that ANSD may underlie the pathogenesis of deafness in ATP1A1-related disorders. This case report broadens the genotype-phenotype spectrum of ATP1A1-related disorders.

Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 (beta-1,4-N-acetylgalactosaminyltransferase 1) gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N-acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM_001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activation-induced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted 10 novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku medical megabank organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP.