Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.     

结节性硬化症多器官损害7例报告

目的探讨结节性硬化症多器官损害的临床特点以提高诊断治疗水平。方法回顾性分析7例结节性硬化症伴皮肤、大脑、肾脏、肝脏等多器官损害患者的临床资料,探讨其特征性临床表现及影像学改变。结果7例患者均有多器官损害,累及两个器官3例,3个及以上器官损害4例;皮肤损害主要为面部血管纤维瘤6例,皮肤色素脱失斑7例,鲨鱼皮斑3例,趾甲下纤维瘤1例;癫痫发作6例,智力低下4例,颅脑CT或MRI检查提示室管膜下结节4例,皮质结节2例;4例合并双侧肾脏多发错构瘤,1例合并肝脏错构瘤。结论特殊的皮肤损害、癫痫发作、智力低下,脑CT或MRI检查提示室管膜下结节或皮质结节或内脏多发性错构瘤为本病的主要临床特征,提高本病的认识有助于早期诊断和治疗。     

Arthritis in a patient with homozygous familial hypercholesterolemia

Familial hypercholesterolemia is a disorder of lipoprotein metabolism characterized by elevated cholesterol, low-density lipoprotein cholesterol, xanthomas and early onset atherosclerosis. Tendinitis and arthritis have been reported in patients with familial hypercholesterolemia. A report is presented of a 9-year-old girl with an acute arthritic attack who was diagnosed as homozygote familial hypercholesterolemia with hypercholesterolemic arthritis.     

Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis

Pulmonary lymphangioleiomyomatosis (LAM) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells (LAM cells) in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC) (TSC-LAM), a genetic disorder with autosomal dominant inheritance with various expressivity resulting from mutations of either the TSC1 or TSC2 gene. We examined mutations of both TSC genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified six unique and novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of 6 patients with TSC-LAM and TSC1 germline mutation in 1 (4.5%) of 22 sporadic LAM patients. In accordance with the tumor-suppressor model, loss of heterozygosity (LOH) was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or two identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting LAM cells can spread from one lesion to another. Our results from Japanese patients with LAM confirmed the current concept of pathogenesis of LAM: TSC-LAM has a germline mutation but sporadic LAM does not; sporadic LAM is a TSC2 disease with two somatic mutations; and a variety of TSC mutations causes LAM. However, our study indicates that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even for patients with sporadic LAM. Received: August 30, 2001 / Accepted: November 2, 2001     

Neurological prognosis correlated with variations over time in the number of subependymal nodules in tuberous sclerosis

In tuberous sclerosis (TS), brain CT reveals subependymal nodules, cortical tubers and white matter lesions. This study is a retrospective analysis of the relationship between the variations over time in the number of subependymal nodules and the clinical course in cases of tuberous sclerosis. Twenty-four children with tuberous sclerosis, who attended the National Children's Hospital as outpatients, were followed by means of brain CT examinations for 7 years and 1 month on average. Cranial MRI was also performed in 22 cases. Brain CT disclosed subependymal nodules already in early infancy. In almost all cases, the number of subependymal nodules gradually increased with age, especially around the frontal horn of the lateral ventricle. The increase stopped at around age 10. The cases with five or more subependymal nodules at the initial or subsequent CT examination (17 patients; Group A) exhibited a significantly greater number of cortical tubers than those with less than five (five patients; Group B) and had white matter lesions unlike Group B. In addition, the number of cases with either infantile spasms or mental retardation was significantly higher in Group A than Group B (P<0.005). In conclusion, the number of ventricular subependymal nodules may allow prediction of the severity of the cerebral dysfunction in TS. Our results suggest that its variation may reflect the degree of the embryologic disorder when neuronal cells grow in the early gestational period.     

Giant angiomyolipoma associated with marked pulmonary lesions suggesting lymphangioleiomyomatosis in a patient with tuberous sclerosis

The association between Tuberous Sclerosis (TS) and Angiomyolipoma (AML) is well known. A patient with TS and giant AML mimicking Renal Cell Carcinoma (RCC), measuring 29 × 18 × 11 cm, weighing 4700 gr is presented. Imaging studies revealed coexistent pulmonary lymphangioleiomyomatosis and concurrent renal and pulmonary involvement is extremely rare in patients in TS. We believe that the growth potential of this hamartomatous lesion may reach to a life threatening size. This revised version was published online in August 2006 with corrections to the Cover Date.     

6例口腔粘膜疣状黄瘤的诊断及治疗

目的:探讨疣状黄瘤的临床生物学特征、病理诊断及治疗.方法:对6例口腔粘膜疣状黄瘤的临床病理资料进行回顾性分析,并进行随访.结果:6例患者5例术前误诊,术中快速病理及术后病理确诊为疣状黄瘤,局部切除即可治愈,随访无复发、恶变病例.结论:疣状黄瘤临床上易误诊,怀疑恶性肿瘤者术中需作快速病理确诊,以避免过度治疗,局部切除后预后良好.     

Cutaneous manifestations in neuro-oncology: clinically relevant tumor and treatment associated dermatologic findings

Skin findings are a rare but important aspect of the evaluation and management of patients with tumors of the nervous system. Skin findings have the highest prevalence in genetic tumor syndromes termed neuro-genodermatoses, which include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and tuberous sclerosis. Skin changes are observed in patients with non-syndromic nervous system malignancy, often as a result of pharmacotherapy. The skin may also manifest findings in paraneoplastic conditions that affect the nervous system, providing an early indication of underlying neoplasm, including dermatomyosistis, neuropathic itch, and brachioradial pruritus. In this article, we review the major cutaneous findings in patients with tumors of the brain, spine, and peripheral nervous system focusing on (1) cutaneous manifestations of genetic and sporadic primary nervous system tumor syndromes, and (2) paraneoplastic neurological syndromes with prominent cutaneous features.     

Epilepsy associated with autism and attention deficit hyperactivity disorder: Is there a genetic link?

Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options.