Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes.

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

[A case of intravascular large B-cell lymphoma that presented with recurrent multiple cerebral infarctions and followed an indolent course].

A 66-year-old woman presented with vertigo and deafness. Diffusion-weighted magnetic resonance imaging of the head showed multiple cerebral infarctions involving several blood vessel regions. A diagnosis of cardiogenic embolism was made, and anticoagulation therapy was begun. The woman had no additional symptoms until suddenly developing left hemiparesis one year later. She was again found to have multiple cerebral infarctions. The hemiparesis gradually improved, but ataxic gait and apraxia appeared and progressed over two weeks. Holter ECG, carotid ultrasound, and transthoracic/transesophageal echocardiography revealed no evidence of cardiogenic embolism. However, serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL2R) levels were elevated (LDH, 782 IU/l; sIL2R, 1,396 IU/ml), which suggested malignant lymphoma. Contrast chest/abdominal CT scan and gallium-67 scintigraphy revealed no evident lesions; however, random skin biopsy and open brain biopsy showed that blood vessels were infiltrated by CD20-positive atypical lymphocytes. These findings were consistent with intravascular large B-cell lymphoma. This type of lymphoma is known as a rapidly progressive disease with poor prognosis, but this case followed an indolent course, with a one-year interruption in disease progression.

Factors contributing to the overall survival in patients with hepatocellular carcinoma treated by sorafenib.

BACKGROUND/AIMS: In both SHARP and Asia-Pacific Study, sorafenib was proved to improve the overall survival of the patients with hepatocellular carcinoma. However, factors contributing to the improvement of overall survival of the patients treated by sorafenib have not been fully evaluated. In this study, patient-derived, background liver disease-derived and tumor-derived factors before treatment were evaluated whether they have contributed to the improvement of the overall survival. METHODOLOGY: Forty-seven cases with HCC treated by sorafenib between Sept 2009 and Feb 2011 were included in this analysis. The survival of these cases was analyzed by Kaplan-Meier Method. Factors used for univariate analysis were two patient-derived parameters, two background liver disease-derived, five tumor-derived. Factors related to the over-all survival were analyzed by multivariate analysis using Cox regression model. RESULTS: In the multivariate analysis, only background liver disease-derived parameter Child-Pugh class A vs. B, (p=0.007, HR=0.21 (0.07-0.65)) was significant. No other parameters including tumor-derived factors were statistically significant by multivariate analysis. CONCLUSIONS: We undertook the statistical analysis on the three categories. Surprisingly, no tumor derived parameter contributed to the overall survival. Background liver disease-derived parameter rather than tumor-derived parameter was found to define the prognosis of patients with advanced HCC treated by sorafenib.

Efficacy of autologous peripheral blood stem cell transplantation in POEMS syndrome with polyneuropathy.

POEMS syndrome (POEMS) is a rare multi-system disease which is typically associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. We report herein a case of POEMS with progressive polyneuropathy resistant to high-dose intravenous immunoglobulin therapy who experienced improvement in polyneuropathy after the administration of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. Improvements in polyneuropathy remain despite recognition of monoclonal gammopathy by immunofixation as of 1 year after treatment. We demonstrated that autologous peripheral blood stem cell transplantation can improve clinical symptoms and signs due to polyneuropathy in POEMS even without achieving complete remission.

[Cluster like headache in a patient with the Maffucci's syndrome].

Maffucci's syndrome is a rare congenital, nonhereditary mesodermal dysplasia characterized by soft tissue hemangiomas and multiple enchondromas. A 52 years old man was diagnosised as Maffucci's syndrome in his childhood. He complained of mild paraesthesia which gradually progressed to intolerable pain lasting one to two houres with rhinorrhea (cluster like headache). Magnetic resonance imaging showed a pituitary adenoma which invaded into right cavernous sinus. Serum hormone level was almost normal, therefore we diagnosed nonfunctional pituitary adenoma. The pharmacological preventive treatments for headache, such as loxoprofen, sumatriptan, lomerizine had no effect. On the other hand, verapamil showed moderate improvement of his headache, then the symptons was gradually getting better and finally he felt no pain. This case demonstrated occurence mechanism of cluster headache and preventive effect of verapamil associated with cavernous sinus.