Objective To explore the clinical and genetic features in the pedigree of Cb1X type X-linked methylmalonic aciduria. Methods Clinical data of one child with X-linked methylmalonic aciduria diagnosed by blood and urine analysis were analyzed retrospectively. Targeted next-generation sequencing has been performed to detect the mutation of methylmalonic aciduria-related genes. Results The boy started presenting with seizures and severe mental retardation at 2 months of age. At 5 months of age, he had the manifestations of seizures, severe mental retardation, increased methylmalonic acid in urinary, increased propionylcarnitine in blood and increased plasma homocysteine, and met the requirements for the diagnosis of methylmalonic aciduria complicated with hyperhomocysteinemia. No mutation was detected in his MMA-related autosomal genes. However, a hemizygote mutation c.344C?>?T (p.Ala115Val) was identiifed in exon 3 of HCFC1 in X chromosome, which conifrmed the CblX type methylmalonic aciduria. His parents were healthy. His elder brother also manifested severe psychomotor retardation with intractable epilepsy, and died at 6 months of age with unknown cause. His mother carried the same mutation and had slightly elevated urine methylmalonic acid and plasma total homocysteine. His father did not carry the mutation. Conclusion A pedigree of a rare Cb1X type X-linked methylmalonic acidemia is ifrstly diagnosed in China by the new generation sequencing technology.

Objective To investigate the clinical,biochemical and genetic findings in patients with isolated methylmalonic aciduria. Methods From January 2001 to December 2014,a total of 126 patients with isolated methyl-malonic aciduria from Peking University First Hospital were enrolled in this study. In 60 patients,gene analysis was per-formed. The clinical characteristics,laboratory findings,treatment and outcomes were retrospectively analyzed. Results Among the 126 patients,only 3 cases(2. 4% )were detected through newborn screening and treated with dietary in-tervention,cobalamin and L - camitine. The age at onset of 123 cases(97. 6% )varied from a few hours after birth to 7 years and 11 months old. The common presentations were recurrent vomiting,mental retardation,poor feeding,lethargy, respiratory distress,coma,seizures,cutaneous lesion and jaundice with 11 patients(8. 73% )dead. Abnormal family his-tory was found in 27(21. 4% )patients. Metabolic acidosis and anemia were frequent laboratory findings. Basal ganglia damage and white matter changes were observed in most patients. Sixty patients got genetic analysis,and 58 cases of them had MUT gene mutations. One case had MMAA defect. One case had MMAB defect. In MUT gene,12 novel muta-tions were identified. After treatment,mild to severe psychomotor retardation was observed in 112 patients with isolated methylmalonic aciduria. Conclusions The clinical manifestation of patients with isolated methylmalonic aciduria is complex,and prone to appear metabolic crisis. MUT defect is the main cause. Early metabolic investigation is very im-portant to reach diagnosis. Newborn screening,early diagnosis and adequate therapy are key points to reduce the morta-lity and handicap.

Objective To explore the clinical characteristics of elderly patients with tuberculous meningitis (TBM) and analyze the causes of misdiagnosis.Methods The clinical data of patients aged 60 years and over with TBM in Beijing Chest Hospital Affiliated to Capital Medical University from January 2011 to January 2017 were retrospectively analyzed.The clinical characteristics of the elderly patients with TBM were analyzed and compared between misdiagnosis and non-misdiagnosis groups.Results Among 60 elderly patients with TBM,32 cases (53.3%) were misdiagnosed before hospitalization.Among 32 misdiagnosed cases,11 (34.4%) were misdiagnosed as pulmonary infection,6 (18.8%) as infectious diseases with unspecified site,4(12.5%) as upper respiratory tract infections and 3 (9.4%) as cerebral vascular diseases,and so on.The onset time of TBM,fever prevalence and CSF glucose levels were 42.5 (20.3,60.0) d,96.9% (31 cases),1.5(1.1,2.3)mmol/L in misdiagnosis group respectively,and 15.0 (10.0,20.0) d,75.0%(21 cases),2.3(1.4,3.2)mmol/L in non-misdiagnosis group respectively,which was statistically significantly different between the two groups (all P< 0.05).There were no statistically significant differences in age,gender,occupation,residence,complications,comorbidities,radiographic signs between the two groups (all P> 0.05).Conclusions Elderly patients with TBM have atypical clinical manifestations,many comorbidities,and less specific imaging,and especially,the cerebrospinal fluid pathogen sensitivity is low,which may result in higher misdiagnosis rate.

Objective To explore the clinical, therapeutic and genetic features of IVD gene in late-onset non-classical isovaleric aciduria. Methods One boy and two girls presented with intractable vomiting were admitted. Urine organic acids and blood acylcarnitines proifles were analyzed. Isovaleric aciduria was diagnosed and conifrmed by IVD gene analysis. The patients were treated with leucine-restricted diet and the supplements of L-carnitine and glycine. Results Three patients had recurrent vomiting, drowsiness, odor of sweaty feet and metabolic acidosis from the age of 1 to 2 years. All of them had normal intelligence and leukopenia. One had oligocythemia. The blood isovalerylcarnitines (4.6 to 8.2μmol/L) and urine isovalerylglycines (36.1 to 1783.56 mmol/mmol creatinine) were elevated. Six mutations were found in their IVD gene. Four mutations (c.157C>T, c.214G>A, c.1183C>G and c.1208A>G) were reported. Two (c.1039G>A and c.1076A>G) were novel. The patients completely recovered after treatment with protein-restricted diet and the supplements of L-carnitine and glycine. Currently, they were aged 19 months to 14 years with normal physical and psychomotor development. Conclusions The clinical features of late-onset non-classical isovaleric aciduria are complex. It is onset in infants and young children and characteristic of recurrent vomiting and metabolic acidosis, which can be diagnosed by the blood acylcarnitine spectrum, urine organic acid analysis, and conifrmed by genetic analysis. L-carnitine supplement and diet intervention has signiifcant effects.

Objective:To analyze the MRI characteristics of surgical resected renal angiomyolipoma (AML) smaller than 4 cm.Methods:A total of 112 patients with surgical pathology confirmed renal AML of which the maximum diameter was smaller than 4 cm were analyzed retrospectively in the First Medical Centre, Chinese PLA General Hospital from January 2014 to November 2020, 5 of which were epithelioid angiomyolipoma (EAML) patients. According to the presence or absence of visible fat in lesions on MRI, the lesions were divided into AML with fat group and AML without visible fat (AML wovf) group. The MRI features were evaluated, including maximum diameter, location, growth pattern, shape, beak sign, angular interface with renal parenchyma, pseudo-capsule, hemorrhage, cystic degeneration, coagulative necrosis, flowing void in the tumor, signal intensity and homogeneity on T 2WI and diffusion weighter imaging (DWI), the peak enhanced phase. The differences of maximum diameter of AML with fat and AML wovf were analyzed using Mann-Whitney U test, and the differences of MRI features were analyzed using χ 2 test or Fisher′s exact probability test. Results:There were 123 lesions found in 112 patients, and 96 lesions contained fat and 27 lesions were AML wovf. 82 lesions showed round and round-like shapes, 112 lesions showed exophytic growth pattern, 71 lesions with peak enhancement in corticomedullary phase. And the numbers of lesions with angular interface with renal parenchyma, beak sign, cystic degeneration, pseudo-capsule, hemorrhage were 30, 49, 1, 1, 1, respectively. There was no coagulative necrosis in all lesions. Compared with AML with fat, AML wovf was single lesion. The diameters of AML with fat and AML wovf were 2.5 (1.7, 3.5) and 1.8 (1.4, 2.3) cm respectively, with statistically significant difference ( Z=-2.80, P=0.005). In the AML with fat and AML wovf, 65 and 12 cases were heterogeneous in T 2WI, 44 and 5 lesions showed beak sign, 26 and 4 lesions showed angular interface with renal parenchyma, 57 and 10 cases were heterogeneous in DWI. And there were 5 and 6 lesions showed the endophytic, 44 and 8 lesions showed partly exophytic, 47 and 13 lesions showed exophytic in patterns of tumor growth respectively. The beak sign, homogeneous in T 2WI and DWI, patterns of tumor growth showed statistical differences in AML with fat and AML wovf (all P<0.05), and there was no significant difference in other features ( P>0.05). A total of 5 EAML patients were with 8 lesions. One patient had 4 lesions with fat, other patients had single lesion in which 2 lesions with fat, 2 lesions without visible fat. One lesion without visible fat showed hemorrhage. Conclusions:Surgical resected AML smaller than 4 cm is often exophytic round and round-like, enhanced in corticomedullary phase, showing angular interface with renal parenchyma and beak sign, with rare cystic degeneration, pseudo-capsule, hemorrhage and improbable coagulation necrosis. AML wovf is single smaller lesion which often shows endophytic growth pattern, and beak sign is infrequent. EAML seems to be present in two modes, multiple lesions with fat and AML wovf with hemorrhage.

OBJECTIVEArgininemia is a rare disorder of urea cycle defect. The clinical manifestations of this disorder are similar to those of cerebral palsy so that the diagnosis is usually much delayed. This study aimed to investigate the phenotypes and genotypes of seven Chinese patients suffering from argininemia.

METHODThree boys and four girls with spastic tetraplegia were diagnosed as argininemia by blood aminoacids analysis and ARG1 gene study. Patients were given a protein-restricted diet, citrulline, sodium benzoate, and other treatment intervention. The mother of Patient 5 and 6 accepted genetic counseling and underwent prenatal diagnosis by amniocentesis.

RESULTSeven patients presented with progressive spastic tetraplegia and poor physical growth from the age of 1 month to 4 years. Argininemia was found at the age of 1 year and 10 months to 12 years. Five patients had mental retardations. Three had seizures. Their blood arginine elevated (86.66 to 349.83 µmol/L, normal controls 5 to 25 µmol/L). Liver dysfunction was found in six patients. Five patients had elevated blood ammonia levels. In four patients, cerebral atrophy was observed by cranial magnetic resonance imaging. Nine mutations in the ARG1 gene were identified from 7 patients. Only two mutations, c.703G > A in exon 7 and c.32T > C in exon 1 had been reported. c.34G > T, c.53G > A, c.67delG, c.232dupG, c.374C > T, c.539G > C and c.646-649delCTCA, were novel mutations of ARG1. A homozygous mutation c.703G > A was found in the amniocytes of Patient 5's mother, indicating that the fetus was affected by argininemia. Induced abortion was performed. c.53G > A from Patient 6 was not found in the amniocytes of her mother, indicating that the fetus was not affected by hepatocyte arginase deficiency. The result was confirmed by postnatal mutation analysis of cord blood and the normal blood arginine of the newborn.

CONCLUSIONArgininemia is one of the few treatable causes of pediatric spastic paralysis. In this study, seven Chinese patients with spastic tetraplegia were detected by blood aminoacids analysis and confirmed by molecular analysis. Seven novel mutations on ARG1 gene were identified. Prenatal diagnosis of the fetus of a family was performed by amniocytes ARG1 gene analysis.

Abortion, Induced ; Amniocentesis ; Arginase ; Arginine ; blood ; Asian Continental Ancestry Group ; Child ; Child, Preschool ; DNA Mutational Analysis ; Diet, Protein-Restricted ; Exons ; Female ; Fetus ; Genotype ; Homozygote ; Humans ; Hyperammonemia ; diagnosis ; Hyperargininemia ; diagnosis ; physiopathology ; Infant ; Infant, Newborn ; Male ; Mutation ; Phenotype ; Pregnancy ; Prenatal Diagnosis ; Quadriplegia ; diagnosis ; physiopathology ; Seizures

PIM (proviral integration site for moloney murine leukemia virus) kinase plays a key role as an oncogene in various cancers including myeloma, leukemia, prostate and breast cancers. The aberrant expression and/or activation of PIM kinases in various cancers follow an isoform-specific pattern. While PIM1 is predominantly expressed in hematological and solid tumors, PIM2 and PIM3 are largely expressed in leukemia and solid tumors, respectively. All of PIM kinases cause transcriptional activation of genes involved in cell survival and cell cycle progression in cancer. A variety of pro-tumorigenic signaling molecules, such as MYC, p21(Cip1/Waf1)/p27(kip1), CDC25, Notch1 and BAD have been identified as the downstream targets of PIM kinases. So far, three kinds of adenosine triphosphate-competitive PIM inhibitors, SGI-1776, AZD1208, and LGH447 have been in clinical trials for the treatment of acute myelogenous leukemia, prostate cancer, lymphoma, or multiple myeloma. This review sheds light on the signaling pathways involved in the PIM kinase regulation and current status of developing PIM kinase inhibitors as clinical success in combating human cancer.
Adenosine ; Breast ; Cell Cycle ; Cell Survival ; Humans ; Leukemia ; Leukemia, Myeloid, Acute ; Lymphoma ; Multiple Myeloma ; Oncogenes ; Phosphotransferases ; Prostate ; Prostatic Neoplasms ; Transcriptional Activation

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQ-containing regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients. Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM. Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups. Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Objective:To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency.Methods:This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively.Results:The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders.Conclusions:Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Objective: To analyz the current situation of the diagnosis, treatment and prevention of methylmalonic acidemia, the phenotypes, biochemical features and genotypes of the patients in the mainland of China, were investigated. Methods: Tottally 1 003 patients of methylmalonic acidemia from 26 provinces and municipalities of the mainland of China were enrolled. The clinical data, biochemical features and gene mutations were studied. Blood aminoacids and acylcarnitines, urine organic acids, and plasma total homocysteine were determined for the biochemical diagnosis. Gene analyses were performed for the genetic study of 661 patients. The patients were treated with individual intervention and long-term follow up. Prenatal diagnoses were carried out for 165 fetuses of the families. Results: Among 1 003 patients (580 boys and 423 girls), 296 cases (29.5%) had isolated methylmalonic acidemia; 707 cases (70.5%) had combined homocysteinemia; 59 patients (5.9%) were detected by newborn screening; 944 patients (94.1%) had the onset at the ages from several minutes after birth to 25 years and diagnosed at 3 days to 25 years of age. The main clinical presentations were psychomotor retardation and metabolic crisis. Multi-organ damage, including hematological abnormalities, pulmonary hypertension, kidney damage, were found. MMACHC, MUT, MMAA, MMAB, HCFC1, SUCLG1, SUCLA2 mutations were found in 631 patients (96.6%) out of 661 patients who accepted gene analysis. MMACHC mutations were detected in 460 patients (94.7%) out of 486 cases of methylmalonic acidemia combined with homocysteinemia. MUT mutations were found in 158 (90.3%) out of 169 cases of isolated methylmalonic acidemia. The development of 59 patients detected by newborn screening were normal; 918 cases (97.2%) were diagnosed after onset accepted the treatment. Forty-five of them completely recovered with normal development. Twenty-six patients (2.7%) died; 873 (92.5%) patients had mild to severe psychomotor retardation. Methylmalonic acidemia were found in 35 out of 165 fetuses by metabolites assay of amniotic fluid and amniocytes gene analysis. Conclusion Combined methylmalonic acidemia and homocysteinemia is the common type of methylmalonic acidemia in the mainland of China. CblC defect due to MMACHC mutations is the most common type of methylmalonic acidemia combined with homocysteinemia. MUT gene mutations are frequent in the patients with isolated methylmalonic acidemia. Newborn screening is key for the early diagnosis and the better outcome. Combined diagnosis of biochemical assays and gene analysis are reliable for the prenatal diagnosis of methylmalonic acidemia.