[Successful treatment of epilepsy and circadian rhythm disturbance with levetiracetam in a patient with dentatorubral-pallidoluysian atrophy (DRPLA)].

We report a 21-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA) showing progressive myoclonus epilepsy (PME), who responded to levetiracetam (LEV) at an initial dose of 1,000 mg/day. The patient developed epilepsy at the age of 10 years, and also showed intellectual regression. Various antiepileptic drugs showed no effects on generalized tonic seizures, tonic-clonic seizures, and myoclonus. Addition of LEV (1,000 mg/day) led to the reduction of myoclonus and tonic-clonic seizures, and improved the EEG and sleep-wake rhythm. He had a better appetite and gain weight. It is suggested that LEV may improve quality of life in patients with DRPLA, in addition to reducing the frequency of epileptic seizures.

Comparison of water balance among healthy young and old adults and handicapped adults.

The body's water balance is changed by food and beverage intake, metabolism, and excretion. In this study, we performed a cross-sectional study that investigated the changes of water intake and water output in healthy Japanese young and elderly people and handicapped adults. Water balance was assessed by water intake from foods and beverages, metabolic water production, non-renal water losses (NRWL), and urine volume. Most of the parameters did not change with aging in healthy adults. Estimated total water intake (ml/kg/day) increased with aging. In the healthy men, healthy women, and handicapped adults, daily water intake (median [interquartile range]) accounted for 49.4 (41.4-59.9) ml/kg, 42.9 (38.7-51.8) ml/kg, and 50.9 (43.8-74.0) ml/kg, respectively. Water loss from the kidney accounted for 19.2 (16.2-29.2) ml/kg, 22.0 (16.2-26.6) ml/kg, and 27.5 (22.7-47.2) ml/kg, respectively. NRWL accounted for 26.6 (18.5-35.2) ml/kg, 22.4 (16.2-28.8) ml/kg, and 23.5 (19.8-28.5) ml/kg, respectively. Our findings suggest that a daily total water intake of more than 50-55 ml/kg is required to prevent dehydration in healthy and handicapped adults. J. Med. Invest. 70 : 195-199, February, 2023.

Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation.

Investigations of chromosomal rearrangements in patients with mental retardation (MR) are particularly informative in the search for genes involved in MR. Here we report a family with concomitant duplications of methyl CpG binding protein 2 (MECP2) at Xq28 and ATRX (the causative gene for X-linked alpha thalassemia/mental retardation) at Xq21.1 detected by array-comparative genomic hybridization. The alterations were observed in a 25-year-old man who inherited them from his mother, who showed a normal phenotype and completely skewed X-chromosome inactivation, and also in his cousin, a 32-year-old man. The proband and his cousin showed severe MR, muscular hypotonia, recurrent respiratory infections and various other features characteristic of MECP2 duplication syndrome. However, the proband also had cerebellar atrophy never reported before in MECP2 duplication syndrome, suggesting that his phenotypes were modified through the ATRX duplication in an additive or epistatic manner.

Cut-off values for skeletal muscle strength and physical functions in Japanese elderly with walking difficulty.

Age-related changes in muscle strength and physical functions, and the association between vitamin D status and skeletal muscle functions were investigated in 36 men (21-90 years old) and 52 women (21-104 years old). Significant ageing-related decreases in several skeletal muscle functions and serum 25-hydroxyvitamin D [25(OH)D] levels were observed in both men and women. Cut-off values for the Timed up and go (TUG) test, walking speed, handgrip strength and Barthel Index (BI) detecting walking difficulties in the receiver operating characteristic (ROC) analysis were 11.1 sec, 0.60 m / sec, 17.0 kg, and 90.0 in males, and 28.6 sec, 0.43 m / sec, 13.9 kg, and 67.5 in females, respectively. By comparing personal present data of muscle strength with these cut-off values, people can easily understand their process to walking difficulty. Therefore, these results are important and useful to avoid or to delay a handicapped and dependent status by improving the vitamin D level, rehabilitation and nursing care. J. Med. Invest. 68 : 48-52, February, 2021.

Relationship between age-related decreases in serum 25-hydroxyvitamin D levels and skeletal muscle mass in Japanese women.

A clearer understanding of skeletal muscle mass (SMM) in middle-aged and elderly individuals is important for maintaining functionality. In the present study, age-related changes in SMM, the threshold of SMM with walking difficulty, intestinal nutrient absorption rate, and various serum factors were examined in Japanese populations of different ages. We used 24-h creatinine excretion as a measure of total body SMM. Age-related decreases in SMM, intestinal nutrient absorption rates, and serum 25-hydroxyvitamin D [25(OH)D] concentrations were significantly higher in women than in men. The cut-off values for SMM (kg), its percentage of total body weight (BW), the SMM index [SMMI] (Kg / m2), and creatinine height index (CHI) (%) in elderly individuals with walking difficulty were approximately 8-10 kg, 17-20% of BW, 3.9-4.6 kg / m2, and 44%, respectively. Serum 25(OH)D concentrations were closely associated with SMM (kg, % of BW, kg / m2) and CHI (%) as well as the intestinal absorption rates of nitrogen (%) and phosphorus (%) in women, but not in men. The present results demonstrate that vitamin D is an important metabolic factor in skeletal muscle, and contributes to the optimal management of skeletal muscle and the prevention of sarcopenia. J. Med. Invest. 67 : 151-157, February, 2020.

A study of oxidative stress and the newer antiepileptic drugs in epilepsy associated with severe motor and intellectual disabilities.

BACKGROUND: Patients with severe motor and intellectual disabilities (SMID) are those who have both severe intellectual disabilities and severe physical disabilities. Intractable epilepsy is often associated with SMID. The purpose of this study was to elucidate the relationship between epilepsy associated with SMID and oxidative stress, and to clarify the safety and efficacy of the newer antiepileptic drugs (newer AEDs), lamotrigine and levetiracetam. METHODS: This study was conducted in 27 SMID patients with epilepsy who were treated with the newer AEDs. The patient characteristics and the safety and efficacy of the newer AEDs were investigated. The reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP) levels were measured as indicators of the degree of oxidative stress. The relationship between the investigation results (the patient characteristics, and the safety and efficacy of the newer AEDs) and the results of measurements of the d-ROMs/BAP were analyzed. RESULTS: All the patients who discontinued the newer AEDs had abnormal plasma d-ROM levels. In addition, all the patients who developed adverse events also had abnormal d-ROM levels. Furthermore, there was a trend toward a lower response rate in patients with higher plasma d-ROM levels. CONCLUSION: The results of this study suggested that d-ROM levels are useful for predicting the safety and efficacy of the newer AEDs (lamotrigine, levetiracetam) in SMID patients with intractable epilepsy. Therefore, d-ROMs could be important biomarkers for determining the safety and efficacy of drug therapy in SMID patients with epilepsy.

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.

BACKGROUND: Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented. CASE PRESENTATION: Here, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs + isoUPD implicated in chromosomal disorders. CONCLUSIONS: To the best of our knowledge, this is the first case of CGRs + isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings.

Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities.

BACKGROUND: The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. METHODS: Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. RESULTS: The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d-ROMs ratio were noted. CONCLUSIONS: These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID.

A FRMD7 variant in a Japanese family causes congenital nystagmus.

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.