Intra-Articular Ultrasonography Probe for Minimally Invasive Upper Extremity Arthroscopic Surgery: A Phantom Study.

BACKGROUND: Upper extremity arthroscopic surgery is a highly technique-dependent procedure that requires the surgeon to assess difficult cartilage conditions and manage the risk of iatrogenic damage to nerves and vessels adjacent to the joint capsule in a confined joint space, and a device that can safely assist in this procedure has been in demand. METHODS: In this study, we developed a small intra-articular ultrasound (AUS) probe for upper extremity joint surgery, evaluated its safety using underwater sound field measurement, and tested its visualization with a phantom in which nerves and blood vessels were embedded. RESULTS: Sound field measurement experiments confirmed the biological safety of the AUS probe's output, while confirming that sufficient output power level performance was obtained as an ultrasound measurement probe. In addition, images of blood vessels and nerves were reconstructed discriminatively using A-mode imaging of the agar phantom. CONCLUSIONS: This study provides proof-of-concept of the AUS probe in upper extremity surgery. Further studies are needed to obtain approval for use in future medical devices.

Lymphocytic Infundibuloneurohypophysitis Diagnosis Owing to Positive Anti-rabphilin-3A Antibody Test Result in an 8-year-old Boy with Early-onset Central Diabetes Insipidus.

Childhood-onset lymphocytic infundibuloneurohypophysitis (LINH) has rarely been reported. Pathological evaluation via pituitary biopsy is necessary for a definitive diagnosis of LINH. However, pituitary biopsy is a highly invasive procedure. Recently, anti-rabphilin-3A antibody (RPH3A-Ab) has been reported as a promising diagnostic marker for LINH in adults; however, there are few such reports in the pediatric population. We report the case of an 8-year-old boy with central diabetes insipidus (CDI) who was clinically diagnosed with LINH based on RPH3A-Ab positivity. He was diagnosed with CDI using a water deprivation test combined with desmopressin administration. Serum and cerebrospinal fluid tumor markers were negative, and T1-weighted magnetic resonance imaging (MRI) revealed the absence of high signal intensity in the posterior pituitary gland and an enlarged pituitary stalk. Anterior pituitary function tests revealed no abnormalities. No pituitary biopsy was performed because of its invasive nature, and desmopressin treatment was initiated. Three months after CDI onset, the patient tested positive for RPH3A-Ab. MRI performed 9 months after CDI onset revealed amelioration of the pituitary stalk enlargement, and the clinical course corroborated our diagnosis of LINH. RPH3A-Ab may be useful as an early diagnostic tool for LINH in the pediatric population.

Barents-Kara sea-ice decline attributed to surface warming in the Gulf Stream.

Decline in winter sea-ice concentration (SIC) in the Barents-Kara Sea significantly impacts climate through increased heat release to the atmosphere. However, the past Barents-Kara SIC decrease rate is underestimated in the majority of Coupled Model Intercomparison Project Phase 6 (CMIP6) climate models. Here we show that climate model simulations can reproduce the Barents-Kara SIC trend for 1970-2017 when sea surface temperature (SST) variability in the Gulf Stream region is constrained by observations. The constrained warming of the Gulf Stream strengthens ocean heat transport to the Barents-Kara Sea that enhances the SIC decline. The linear trends between the SIC and SST are highly correlated in the CMIP6 ensemble, suggesting that the externally forced component of the Gulf Stream SST increase explains up to 56% of the forced Barents-Kara SIC trend. Therefore, future warming of the Gulf Stream can be an essential pacemaker of the SIC decline.

Establishment to measure oxycodone in plasma with liquid chromatography-tandem mass spectrometry.

Oxycodone (OXY) is classified as a "strong opioid" in the World Health Organization system of cancer pain treatment. However, OXY also causes severe adverse reactions, such as respiratory depression. Thus, in order to adjust the dosage of OXY for well-managed pain relief with less toxicity, we tried establishing and validating a system for measuring plasma concentrations of OXY using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human pooled plasma samples containing OXY diluted with 0.1% formic acid solution and internal standard (papaverine) were used for solid-phase extraction. The eluents were injected into LC-MS/MS with Unison UK-Silica column (100 × 2 mm, 3 µm, Imtakt). Mobile phase was a mixture of 1 mM ammonium formate solution and acetonitrile containing 0.1% formic acid (50:50). OXY in plasma could be measurable with good linearity in a concentration range of 2-100 ng/ml by using 100 µl of plasma within 4 min. Relative standard deviations of all validation results were within ±15%. These results suggest that our established method using LC-MS/MS to measure OXY in plasma would be useful to adjust the dosage of OXY in order to obtain its efficacy and to avoid its adverse reactions.

Hyperosmolar hyperglycemic syndrome induced by diazoxide and furosemide in a 5-year-old girl.

Hyperglycemia and hyperosmolar hyperglycemic syndrome (HHS) are the rare adverse effects of diazoxide. Furosemide has been reported to worsen glucose tolerance and cause HHS. A 5-yr-old girl presented to the emergency department with complaints of tachycardia, polyuria, and lethargy for 1 wk prior to hospitalization. She was treated with two diuretics for aortic valve reflux disease and diazoxide for congenital hyperinsulinemia. She was diagnosed with HHS based on her serum glucose level of 529 mg/dL and serum osmotic pressure of 357 mOsm/kg. There were no findings suggestive of new-onset diabetes mellitus. She had fever on admission and, was diagnosed with a urinary tract infection. The blood diazoxide level at the time of hospitalization was 25 µg/dL. Diazoxide use, even in patients with low diazoxide levels, may cause hyperglycemia. Patients on diuretics and diazoxide must be carefully monitored, considering the risk of developing HHS.

Transient Pseudohypoaldosteronism Secondary to Group B Streptococcus Pyelonephritis.

Secondary pseudohypoaldosteronism is a condition characterized by aldosterone resistance in renal tubules. It is highly associated with urinary tract infection and urinary tract malformations. Only a few cases of pseudohypoaldosteronism secondary to group B Streptococcus pyelonephritis have been reported to date. A four-month-old boy developed poor sucking and weight loss, and his laboratory test results revealed hyponatremia, hyperkalemia, renal dysfunction, high anion gap metabolic acidosis, pyuria, and hydronephrosis. Laboratory tests including urinalysis confirmed the diagnosis of pseudohypoaldosteronism secondary to group B Streptococcus. He was treated with intravenous normal saline and antimicrobial therapy. Electrolyte disorders were addressed and he was discharged on the 10th day of hospitalization without any sequelae. Voiding cystourethrography performed after discharge showed bilateral grade 5 vesicoureteral reflux and intrarenal reflux in the right kidney. Transient pseudohypoaldosteronism is an important consideration in the differential diagnosis in infants with hyponatremia and hyperkalemia. A thorough evaluation for urinary tract malformations should be performed, including early abdominal ultrasonography and systemic management.

Calcium ions in the aquatic environment drive planarians to food.

BACKGROUND: Even subtle changes in environmental factors can exert behavioral effects on creatures, which may alter interspecific interactions and eventually affect the ecosystem. However, how changes in environmental factors impact complex behaviors regulated by neural processes is largely unknown. The freshwater planarian Dugesia japonica, a free-living flatworm, displays distinct behavioral traits mediated by sensitive perception of environmental cues. Planarians are thus useful organisms for examining interactions between environmental changes and specific behaviors of animals. RESULTS: Here we found that feeding behavior was suppressed when the concentration of ions in the breeding water was low, while other behaviors were unaffected, resulting in differences in population size. Notably, the decline in feeding behavior was reversed in an ion-concentration-dependent manner soon after the planarians were moved to ion-containing water, which suggests that ions in environmental water rapidly promote feeding behavior in planarians. Moreover, the concentration of ions in the environmental water affected the feeding behavior by modulating the sensitivity of the response to foods. Finally, we found that calcium ions in the aquatic environment were required for the feeding behavior, and exposure to higher levels of calcium ions enhanced the feeding behavior, showing that there was a good correlation between the concentration of calcium ions and the responsiveness of planarians to foods. CONCLUSIONS: Environmental calcium ions are indispensable for and potentiate the activity level of the feeding behavior of planarians. Our findings suggest that the ions in the aquatic environment profoundly impact the growth and survival of aquatic animals via modulating their neural activities and behaviors.

A simple method for sequencing the whole human mitochondrial genome directly from samples and its application to genetic testing.

Next-generation sequencing (NGS) is a revolutionary sequencing technology for analyzing genomes. However, preprocessing methods for mitochondrial DNA (mtDNA) sequencing remain complex, and it is required to develop an authenticated preprocessing method. Here, we developed a simple and easy preprocessing method based on isothermal rolling circle mtDNA amplification using commercially available reagents. Isothermal amplification of mtDNA was successfully performed using both nanoliter quantities of plasma directly and 25 ng of total DNA extracted from blood or tissue samples. Prior to mtDNA amplification, it was necessary to treat the extracted total DNA with Exonuclease V, but it was not required to treat plasma. The NGS libraries generated from the amplified mtDNA provided sequencing coverage of the entire human mitochondrial genome. Furthermore, the sequencing results successfully detected heteroplasmy in patient samples, with called mutations and variants matching those from previous, independent, Sanger sequencing analysis. Additionally, a novel single nucleotide variant was detected in a healthy volunteer. The successful analysis of mtDNA using very small samples from patients is likely to be valuable in clinical medicine, as it could reduce patient discomfort by reducing sampling-associated damage to tissues. Overall, the simple and convenient preprocessing method described herein may facilitate the future development of NGS-based clinical and forensic mtDNA tests.

A case of severe Alexander disease with de novo c. 239 T > C, p.(F80S), in GFAP.

Alexander disease (AxD) is a progressive neurodegenerative disease caused by a mutation in the glial fibrillary acid protein (GFAP) gene. A 4-year-old boy presented several times with hemiclonic seizures with eye deviation for a few minutes at 28 days after birth. Electroencephalogram showed independent sharp waves in the right and left temporal area. Magnetic resonance imaging showed high intensity T1-weighted images in the white matter of the frontal lobe and basal ganglia. He showed no head control at 4 years of age, and his weight gain was insufficient. He did not show macrocephaly. At 4 years of age, he died of bacterial pneumonia and septic shock. He was diagnosed with AxD, and direct sequencing revealed a de novo known mutation, c. 239 T > C, p.(F80S), in GFAP. Hela and U2-OS cells transfected with GFAP cDNA with c. 239 T > C showed dot-like cytoplasmic aggregation, similar to R239C, a common mutation found in severe infantile AxD. Aggregation in the cytoplasm caused by a GFAP mutation is a hallmark of AxD. Although there is only one previous report of a patient with an F80S mutation, our data support that F80S can cause the severe, infantile form of AxD.

Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients.

Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities.

Cell-contact-dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts.

OBJECTIVE: To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4+ T cells. METHODS: Naïve CD4+ T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4+ T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4+ T cells, CD161+ or CD161- naïve CD4+ T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. RESULTS: SF enhanced naïve CD4+ T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4+ T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161+ naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CONCLUSION: CD4+ T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

The protection mechanism of proline from D-galactosamine hepatitis involves the early activation of ROS-eliminating pathway in the liver.

The oral pre-administration of proline, one on the non-essential amino acids, has been shown to effectively protect the liver from D-galactosamine (GalN)-induced liver injury and dramatically improve the survival rate. In the previous study, we reported that protective effect of proline involves the early activation of IL-6/STAT-3 pathway, an anti-inflammatory and regenerative signaling in the liver. Reactive oxygen species (ROS) are mediator of cellular injury and play an important role in hepatic damage during GalN-induced hepatitis. The aim of this study is to investigate the effect of proline on ROS-eliminating system. The activities of major ROS-detoxifying enzymes, i.e., glutathione peroxidase (GP), glutathione reductase (GR), catalase, and the level of glutathione in the liver were determined. Catalase activity was significantly upregulated in proline group from 0 to 3 h after GalN-injection, although GP and GR were downregulated during this period, compared with control group. From 6 to 12 h, the level of reduced glutathione (GSH) was significantly higher and the ratio of GSH/oxidized glutathione (GSSG) tended to be higher in proline group. Consistently with this, at 6 h, the GR activity in the proline group was significantly higher, followed with the higher tendency of GP activity at 12 h. Catalase activity was also significantly higher at 12 h. Taken together, catalase was activated at the beginning, followed with the significant activation of glutathione redox system around 6 to 12 h in proline group. These results suggest that the elimination of ROS in the liver was accelerated in proline group compared with control group at the very early stage of GalN-induced hepatitis.

Periodontitis and Porphyromonas gingivalis in preclinical stage of arthritis patients.

PURPOSE: To determine whether the presence of periodontitis (PD) and Porphyromonas gingivalis (Pg) in the subgingival biofilm associates with the development of rheumatoid arthritis (RA) in treatment naïve preclinical stage of arthritis patients. METHODS: We conducted a prospective cohort study of 72 consecutive patients with arthralgia who had never been treated with any anti-rheumatic drugs or glucocorticoids. Periodontal status at baseline was assessed by dentists. PD was defined stringently by the maximal probing depth≧4 mm, or by the classification by the 5th European Workshop in Periodontology (EWP) in 2005 using attachment loss. Up to eight plaque samples were obtained from each patient and the presence of Pg was determined by Taqman PCR. The patients were followed up for 2 years and introduction rate of methotrexate (MTX) treatment on the diagnosis of RA was compared in patients with or without PD or Pg. RESULTS: Patients with PD (probing depth≧4mm) had higher arthritis activity (p = 0.02) and higher risk for future introduction of MTX treatment on the diagnosis of RA during the follow up than patients without PD (Hazard ratio 2.68, p = 0.03). Arthritis activity and risk for MTX introduction increased with the severity of PD assessed by EWP, although not statistically significant. On the other hand, presence of Pg was not associated with arthritis activity (p = 0.72) or the risk for MTX introduction (p = 0.45). CONCLUSION: In treatment naïve arthralgia patients, PD, but not the presence of Pg, associates with arthritis activity and future requirement of MTX treatment on the diagnosis of RA.

The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis.

BACKGROUND: Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. METHODS: We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. RESULTS: The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. CONCLUSIONS: GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.

New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders.

OBJECTIVE: Mitochondrial respiratory chain disorder (MRCD) is an intractable disease of infants with variable clinical symptoms. Our goal was to identify the causative mutations in MRCD patients. METHODS: The subjects were 90 children diagnosed with MRCD by enzyme assay. We analyzed whole mitochondrial DNA (mtDNA) sequences. A cybrid study was performed in two patients. Whole exome sequencing was performed for one of these two patients whose mtDNA variant was confirmed as non-pathogenic. RESULTS: Whole mtDNA sequences identified 29 mtDNA variants in 29 patients (13 were previously reported, the other 13 variants and three deletions were novel). The remaining 61 patients had no pathogenic mutations in their mtDNA. Of the 13 patients harboring unreported mtDNA variants, we excluded seven variants by manual curation. Of the remaining six variants, we selected two Leigh syndrome patients whose mitochondrial enzyme activity was decreased in their fibroblasts and performed a cybrid study. We confirmed that m.14439G>A (MT-ND6) was pathogenic, while m.1356A>G (mitochondrial 12S rRNA) was shown to be a non-pathogenic polymorphism. Exome sequencing and a complementation study of the latter patient identified a novel c.55C>T hemizygous missense mutation in the nuclear-encoded gene NDUFA1. INTERPRETATION: Our results demonstrate that it is important to perform whole mtDNA sequencing rather than only typing reported mutations. Cybrid assays are also useful to diagnose the pathogenicity of mtDNA variants, and whole exome sequencing is a powerful tool to diagnose nuclear gene mutations as molecular diagnosis can provide a lead to appropriate genetic counseling.

Increase of hemoglobin levels by anti-IL-6 receptor antibody (tocilizumab) in rheumatoid arthritis.

OBJECTIVE: To compare the effect of tocilizumab (TCZ) with other biologic therapies in improving anemia of rheumatoid arthritis (RA) patients. METHODS: We compared the change of hemoglobin (Hb) levels in a cohort of 147 consecutive RA patients who were treated with biologics for more than 12 weeks. Twenty eight patients were treated with TCZ, and 119 patients were treated with biologics other than TCZ (87 with TNF inhibitors and 32 with abatacept). The change of Hb levels from baseline to week 12 was compared between the TCZ and the non-TCZ groups. We performed univariate and multivariate analyses with adjustment of potential confounders such as baseline characteristics, concomitant treatment, and the clinical response to treatment. RESULTS: Hb levels generally increased after biologic therapies both in the TCZ and the non-TCZ groups. The increase of Hb levels was greater in the TCZ group than in the non-TCZ groups (1.1 g/dL in the TCZ group vs 0.3 g/dL in the non-TCZ group, p = 0.009). Univariate analysis revealed that increase of Hb levels was also significantly associated with lower Hb, higher Low Hemoglobin Density, and higher CRP levels at baseline and greater reduction in the clinical disease activity index. TCZ therapy was significantly associated with the increase of Hb levels even after adjustment for these factors by multivariate analysis (p<0.001, effect size 0.08-0.12). CONCLUSION: TCZ therapy is an independent factor associated with the increase of Hb level after biologic therapies in RA patients. It will help in selecting appropriate biologics for RA patients with anemia.

Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome.

BACKGROUND: Although mitochondrial respiratory chain disorders (MRCD) are one of the most common congenital metabolic diseases, there is no cumulative data on enzymatic diagnosis and clinical manifestation for MRCD in Japan and Asia. METHODS: We evaluated 675 Japanese patients having profound lactic acidemia, or patients having symptoms or signs of multiple-organ origin simultaneously without lactic acidemia on respiratory chain enzyme activity assay and blue native polyacrylamide gel electrophoresis. Quantitative polymerase chain reaction was used to diagnose mitochondrial DNA depletion syndrome (MTDPS). Mutation analysis of several genes responsible for MTDPS was also performed. RESULTS: A total of 232 patients were diagnosed with a probable or definite MRCD. MRCD are common, afflicting one in every several thousand people in Japan. More than one in 10 of the patients diagnosed lacked lactic acidemia. A subsequent analysis of the causative genes of MTDPS identified novel mutations in six of the patients. A 335 bp deletion in deoxyguanosine kinase (DGUOK; g.11692_12026del335 (p.A48fsX90)) was noted in two unrelated families, and may therefore be a common mutation in Japanese people. The proportion of all patients with MTDPS, and particularly those with recessive DNA polymerase γ (POLG) mutations, appears to be lower in Japan than in other studies. This is most likely due to the relatively high prevalence of ancient European POLG mutations in Caucasian populations. No other significant differences were identified in a comparison of the enzymatic diagnoses, disease classifications or prognoses in Japanese and Caucasian patients with MRCD. CONCLUSION: MTDPS and other MRCD are common, but serious, diseases that occur across all races.

Leigh syndrome with Fukuyama congenital muscular dystrophy: a case report.

We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17 months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I+II deficiency has rarely been reported, suggesting a nuclear gene mutation.