A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder

BackgroundCUL3 encodes cullin-3, a core component of a ubiquitin E3 ligase. CUL3 mutations have recently been associated with autism spectrum disorder (ASD); however, the detailed clinical courses have been described in only a limited number of patients with CUL3 mutations and neurodevelopmental diseases, including ASD.Case reportA 21-month-old Japanese girl presented with febrile status epilepticus and thereafter exhibited developmental regression, including loss of her verbal ability, eye contact, and skills in activities of daily living. Trio-based exome sequencing identified a de novo two-base insertion in CUL3, c.1758_1759insTG, p.(Thr587*).ConclusionWe report a case of a patient with ASD and a stop-gain CUL3 variant. Screening of CUL3 variants is worth considering for patients with ASD, especially those with Rett-like developmental regression.     

Analysis of daily energy,protein, fat,and carbohydrate intake in citrin-deficient patients: Towards prevention of adult-onset type II citrullinemia

Patients with citrin deficiency during the adaptation/compensation period exhibit diverse clinical features and have characteristic diet of high protein, high fat, and low carbohydrate. Japanese cuisine typically contains high carbohydrate but evaluation of diet of citrin-deficient patients in 2008 showed a low energy intake and a protein:fat:carbohydrate (PFC) ratio of 19:44:37, which indicates low carbohydrate consumption rate. These findings prompted the need for diet intervention to prevent the adult onset of type II citrullinemia (CTLN2). Since the publication of the report about 10 years ago, patients are generally advised to eat what they wish under active dietary consultation and intervention. In this study, citrin-deficient patients and control subjects living in the same household provided answers to a questionnaire, filled-up a maximum 6-day food diary, and supplied physical data and information on medications if any. To study the effects of the current diet, the survey collected data from 62 patients and 45 controls comparing daily intakes of energy, protein, fat, and carbohydrate. Food analysis showed that patient's energy intake was 115% compared to the Japanese standard. The confidence interval of the PFC ratio of patients was 20–22:47–51:28–32, indicating higher protein, higher fat and lower carbohydrate relative to previous reports. The mean PFC ratio of female patients (22:53:25) was significantly different from that of male patients (20:46:34), which may explain the lower frequency of CTLN2 in females. Comparison of the present data to those published 10 years ago, energy, protein, and fat intakes were significantly higher but the amount of carbohydrate consumption remained the same. Regardless of age, most patients (except for adolescents) consumed 100–200 g/day of carbohydrates, which met the estimated average requirement of 100 g/day for healthy individuals. Finally, patients were generally not overweight and some CTLN2 patients were underweight although their energy intake was higher compared with the control subjects. We speculate that high-energy of a low carbohydrate diet under dietary intervention may help citrin-deficient patients attain normal growth and prevent the onset of CTLN2.     

Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase but inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210(bcr/abl), is a unique chromosomal abnormality in the chronic phase, additional chromosomal abnormalities are frequently detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p53 plays a role in the evolution of CML, we crossmated p210(bcr/abl)-transgenic (BCR/ABL(tg/-)) mice with p53-heterozygous (p53(+/-)) mice and generated p210(bcr/abl)-transgenic, p53-heterozygous (BCR/ABL(tg/-)p53(+/-)) mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. The BCR/ABL(tg/-)p53(+/-) mice died in a short period compared with their wild-type (BCR/ABL(-/-)p53(+/+)), p53 heterozygous (BCR/ABL(-/-)p53(+/-)), and p210(bcr/abl) transgenic (BCR/ABL(tg/-)p53(+/+)) litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML. The blast cells were clonal in origin and expressed p210(bcr/abl) with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, implying that a certain mechanism facilitating the loss of p53 allele exists in p210(bcr/abl)-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210(bcr/abl)-expressing hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML. (Blood. 2000;95:1144-1150)     

Cicatricial Pemphigoid of the Oropharynx after Allogeneic Stem Cell Transplantation for Relapsed Follicular Lymphoma

A 44-year-old woman with refractory follicular lymphoma underwent allogeneic stem cell transplantation (SCT) and achieved complete remission. Grade III acute graft-versus-host disease (GVHD) developed on day 23, but no chronic GVHD occurred. The patient developed severe erosion with bullous lesions in the oral cavity 18 months after SCT. At that time, the lymphoma remained in complete remission, and she had no clinical or laboratory findings suggesting chronic GVHD. A biopsy of the oral mucosa showed moderate lymphoplasmacytic infiltration and subepidermal bullae, and direct immunofluorescence staining demonstrated linear deposition of C3 at the dermo-epidermal junction. An immunoblotting assay using human epidermal extracts confirmed the presence in her serum of an antibody against the 230-kd bullous pemphigoid antigen 1 (BPAG1). A diagnosis of cicatricial pemphigoid (CP) was made, and complete resolution of the CP was achieved with pred-nisolone therapy. The occurrence of autoimmune blistering diseases is rare after allogeneic SCT.     

Weight loss may be a better approach for managing musculoskeletal conditions than increasing muscle mass and strength

To prevent or remedy musculoskeletal conditions, the relationship between obesity and the characteristics of muscle mass and strength need to be clarified. [Subjects and Methods] A total of 259 Japanese males aged 30–64 years were classified into 4 groups according to the Japanese obesity criteria. Body composition was evaluated, and handgrip strength and knee extensor strength were measured for the upper and lower extremities, respectively. Physical performance was evaluated with a jump test. [Results] Obesity was positively correlated with skeletal muscle mass index, percentage of whole-body fat, and leg muscle strength and negatively correlated with the percentage of muscle mass index, body weight-normalized handgrip strength, and knee extensor strength, and the jump test results. [Conclusion] Weight loss may be a better approach than increasing muscle mass and strength to improve musculoskeletal conditions in obese adult males.Key words: Obesity, Muscle mass, Muscle strength     

Usefulness of a 50-meter round walking test for fall prediction in the elderly requiring long-term care

[Purpose] This study aimed to verify the usefulness of a 50-m round walking test developed as an assessment method for walking ability in the elderly. [Subjects] The subjects were 166 elderly requiring long-term care individuals (mean age, 80.5 years). [Methods] In order to evaluate the factors that had affected falls in the subjects in the previous year, we performed the 50-m round walking test, functional reach test, one-leg standing test, and 5-m walking test and measured grip strength and quadriceps strength. [Results] The 50-m round walking test was selected as a variable indicating fall risk based on the results of multiple logistic regression analysis. The cutoff value of the 50-m round walking test for determining fall risk was 0.66 m/sec. The area under the receiver operating characteristic curve was 0.64. The sensitivity of the cutoff value was 65.7%, the specificity was 63.6%, the positive predictive value was 55.0%, the negative predictive value was 73.3%, and the accuracy was 64.5%. [Conclusion] These results suggest that the 50-m round walking test is a potentially useful parameter for the determination of fall risk in the elderly requiring long-term care.Key words: 50-meter round walk test, Local elderly individuals, Falls     

Hepatic subcapsular hematoma after extracorporeal shock wave lithotripsy (ESWL) for pancreatic stones

We present a patient with complication of huge hepatic subcapsular hematoma after extracorporeal shock wave lithotripsy (ESWL) for pancreatic lithotripsy. The hematoma measured 78–110 mm. Angiography showed a subcapsular hematoma, rather than a hematoma in the liver. In the arterial phase, the distal end of the small vessel showed spotty opacification similar to microaneurysma, suggesting that it was an injury caused by separation of the liver and its capsule, caused by the shock waves. The portal vein and hepatic vein were normal. After 8 weeks of conservative therapy, the hematoma was gradually absorbed and the patient was discharged. Eight months after the accident, the hematoma had decreased to 40 mm in size. After 20 months, it was completely absorbed. The reported rate of renal subcapsular hematoma after ESWL for renal or ureter stones is 0.1%–0.7%. To date, however, only five cases of hepatic subcapsular hematoma after right renal stone disintegration have been reported. This is the first report of hepatic subcapsular hematoma after ESWL for pancreatic stones. Received: September 11, 1998 / Accepted: April 16, 1999