Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy.

Hartnup disease cases were rare, and the genotype-phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3/5 to 4/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous SLC6A19 mutations: c.533G>A (p.Arg178Gln) and c.1379-1G>C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G>A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co-existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.

Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies.

Background: Myelin oligodendrocyte glycoprotein-antibody (MOG-ab)-associated disease (MOGAD) has highly heterogenous clinical and imaging presentations, in which encephalitis is an important phenotype. In recent years, some atypical presentations in MOG-ab-associated encephalitis (MOG-E) have been increasingly reported but have not yet been described well. The aim of the study was to describe the clinical and imaging features of patients with MOG-E in our center. Atypical phenotypes would be reported, which is expected to expand the spectrum of MOGAD. Methods: We reviewed medical records of 59 patients with MOGAD diagnosed in our center and identified cases who had ever experienced encephalitic symptoms. Three hundred ten patients with autoimmune encephalitis (AE) were also reviewed, and cases with positive MOG-ab were identified. Besides, patients with chronically progressive encephalitis were identified from 13 MOG-E and 310 AE patients. We collected demographic, clinical, laboratory, radiological, and outcome data to explore clinical and imaging characteristics in MOG-E, especially in the atypical phenotype of chronically progressive encephalitis. Results: We identified 13 patients (7 males, 6 females) with MOG-E. The median age at onset was 33 years (range 13~62 years). Most (9/13, 69.2%) of patients showed acute or subacute onset of encephalitic symptoms. Brain MRI abnormalities were observed in all patients. The most common lesion locations on MRI were cortical/subcortical (11/13, 84.6%), deep/periventricular white matter (10/13, 76.9%) and corpus callosum (4/13, 30.8%). Brain MRI patterns were categorized into four phenotypes. The most common pattern was cortical encephalitis with leptomeningeal enhancement/brain atrophy (10/13, 76.9%). Eight (8/13, 61.5%) patients had a good response to immunotherapy. Four (4/13, 30.8%) patients with chronically progressive course were identified from MOG-E cohort. They showed leukodystrophy-like pattern, multifocal hazy lesions, or cortical encephalitis on MRI. With immunotherapy, they only showed mild or no improvement. We also identified four (4/310, 1.3%) patients with chronically progressive course from AE cohort. They had better outcomes than counterparts in MOG-E. Conclusions: This study demonstrates that encephalitic presentations in MOGAD had complex clinical patterns. Chronically progressive encephalitis may be a new phenotype of MOGAD. We recommend to test MOG-ab in subacute and chronic progressive dementia with leukodystrophy-like MRI lesions.

Autophagy Suppression Accelerates Apoptosis Induced by Norcantharidin in Cholangiocarcinoma.

Norcantharidin is a cantharidin demethylated analog with antitumor effects in many tumors, including cholangiocarcinoma. Autophagy suppression is known to increase chemosensitivity in cholangiocarcinoma. This study aimed to determine whether autophagy suppression accelerates apoptosis induced by norcantharidin in human cholangiocarcinoma cells. The human cholangiocarcinoma cell line QBC939 was incubated in RPMI 1640 medium with or without norcantharidin. Autophagy was induced using HBSS media with Ca2+ and Mg2+ supported by 10 mM HEPES or suppressed by treatment with 3-MA or transfection with siRNA against Atg5. The comparison was drawn between these conditions in mitochondrial membrane potential disturbance, the levels of reactive oxygen species (ROS), apoptotic proteins, and apoptosis. Cholangiocarcinoma cell apoptosis was accelerated by norcantharidin. Autophagy suppression up-regulated norcantharidin's pro-apoptotic effect, but autophagy induction weakened it. As apoptosis was accelerated, ROS production was up-regulated. Bax protein expression, cytochrome c levels and localization, mitochondrial membrane disturbance, and the levels of caspase-9, caspase-3, and cleaved PARP were higher when autophagy was suppressed, and all of those were down-regulated when autophagy was induced. To sum up, it was found that norcantharidin induced cholangiocarcinoma cell death, and autophagy suppression enhanced the pro-apoptotic action of norcantharidin, which appears to involve the mitochondrial apoptosis pathway activation and ROS generation.

Distinct clinical, neuroimaging and genetic profiles of late-onset cobalamin C defects (cb1C): a report of 16 Chinese cases.

OBJECTIVE: The importance of late-onset cobalamin C (cblC) disorder is underestimated in adults. Improved awareness on its clinical and neuroimaging features helps timely diagnosis and appropriate treatment. METHODS: Totally 16 late-onset cblC cases were diagnosed based on clinical, biochemical findings and MMAHC gene mutation analysis. Clinical presentations, neuroimaging features and mutational spectrum were reviewed. RESULTS: The case series included 10 males and 6 females, with average age of 22 (range 13-40) years. All the 16 patients displayed bilateral pyramidal tract signs, and most of the cases (13) had cognitive impairment. Other symptoms included psychiatric symptoms (6), epilepsy (6), peripheral nerve damage (5), ocular symptoms (4) and lower-limb thrombosis (1). The neuroimaging findings were dominated by cerebral atrophy (11/16), followed by white matter lesions (4), cerebellar lesions/atrophy (2) and spinal cord lesions (1). There were also 2 patients with normal imaging. All the MMACHC mutations were compound heterozygous, of which the most and second frequent was c.482G > A (p.R161Q; 15/16 case; allele frequency: 46.88%) and c.609G > A(p.W203X; 6/16 case; allele frequency: 18.75%). In addition, patients carrying frameshift mutations (deletion/duplication) presented more frequently with psychiatric symptoms (57.1%) and optic nerve damages (42.9%) than those carrying point mutations (22.2 and 11.1%, respectively). In contrast, peripheral nerve (44.4%) and white matter lesions (33.3%) were more frequently identified in point mutation- carriers. However, the differences did not achieve statistical significance (all p > 0.05). CONCLUSION: Compared to the early-onset form, late-onset cblC displayed some clinical, neuroimaging and mutational profiles, which warrants particular attention in adult neurologic practice. These findings not only broaden our insights into the genotypes and phenotypes of the disease, but highlight the importance of early diagnosis and initiation of appropriate treatments.

Comparison Study of Polysomnographic Features in Multiple System Atrophy-cerebellar Types Combined with and without Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: The brain stem is found to be impaired in multiple system atrophy-cerebellar types (MSA-C). Rapid eye movement (REM) sleep behavior disorder (RBD) is reported as a marker of progressive brain stem dysfunction. Few systematic studies about the sleep disturbances in MSA-C patients combined with or without RBD were reported. This study aimed to explore the polysomnographic (PSG) features of sleep disturbances between MSA-C patients with and without RBD. METHODS: Totally, 46 MSA-C patients (23 with RBD, and 23 without RBD) were enrolled in this study. All patients underwent a structured interview for their demographic data, history of sleep pattern, and movement disorders; and then, overnight video-PSG was performed in each patient. All the records were evaluated by specialists at the Sleep Medicine Clinic for RBD and the Movement Disorder Clinic for MSA-C. The Student's t-test, Mann-Whitney U-test for continuous variables, and the Chi-square test for categorical variables were used in this study. RESULTS: MSA-C patients with RBD had younger visiting age (52.6 ± 7.4 vs. 56.7 ± 6.0 years, P = 0.046) and shorter duration of the disease (12.0 [12.0, 24.0] vs. 24.0 [14.0, 36.0] months, P = 0.009) than MSA-C patients without RBD. MSA-C with RBD had shorter REM sleep latency (111.7 ± 48.2 vs. 157.0 ± 68.8 min, P = 0.042), higher percentage of REM sleep (14.9% ±4.0% vs. 10.0% ± 3.2%, P = 0.019), and lower Stage I (9.5% ±7.2% vs. 15.9% ±8.0%, P = 0.027) than MSA-C without RBD. Moreover, MSA-C patients with RBD had more decreased sleep efficiency (52.4% ±12.6% vs. 65.8% ±15.9%, P = 0.029) than that without RBD. CONCLUSIONS: In addition to the RBD, MSA-C patients with RBD had other more severe sleep disturbances than those without RBD. The sleep disorders of MSA patients might be associated with the progress of the disease.

[To evaluate the cervical spine curvature and growth rate for studying the pathogenesis of Hirayama disease in adolescents].

OBJECTIVE: To explore the pathogenesis of Hirayama disease from juvenile cervical curvature and growth rate. METHODS: Totally 60 patients diagnosed with Hirayama disease (HD) from 2009 to 2011 in our hospital were included in the present study. Patient's height and growth rate 1-2 years prior to the onset of disease were recalled by patients and family members. Lateral cervical X-ray was examined, and cervical curvature was measured by Borden's method. RESULTS: All the patients were adolescents with onset age at 12-25 (17.0 ± 2.4) years old and peak age of onset at 15-18 [45 cases (75.0%)]. Fifty-seven cases were male and 3 cases were female. Cervical MRI examination of the 60 cases showed that the spinal cord atrophy involving C4-C8 vertebral level. The C line values for cervical curvature by Borden's method of the patients was 2.6 (1.2, 4.2) mm. Among 60 patients, 57 of them were with abnormal cervical curvature. The average height growth rate 1 year prior to the onset was (7.1 ± 1.8) cm. CONCLUSIONS: The clinical manifestations that featured in overgrowth in the first two years and abnormal cervical vertebra curvature are possible related with pathogenesis of HD. HD is possibly a cervical spinal cord compression disease, which is associated with cervical spinal dysplasia during juvenile growth.

[Clinicopathological study of non-Langerhans cell histiocytosis in central nervous system].

OBJECTIVE: To explore the clinicopathological features and imaging characteristics of non-Langerhans cell histiocytosis in central nerve system, thus to facilitate the diagnosis and differential diagnosis. METHODS: A total of ten cases were enrolled in the study, with seven cases of Rosai-Dorfman disease (RDD) and three cases of xanthoma disseminatum (XD). Data on the clinicopathological features, imaging, immunophenotype and prognosis were collected and analyzed. RESULTS: Seven patients with RDD, 5 males and 2 females with the mean age of 46.7 years old, all presented as dural-based or intraparenchymal hypo- to isointense lesions on T1 and T2 with post-contrast enhancement. The polymorphous admixture of histiocytes, lymphocytes and plasma cells was observed in a fibrous stroma, with emperipolesis of some histiocytes. The immunohistostaining of CD11c, CD68, MAC387 and S-100 was positive in the histiocytes, while the staining of CD1α was negative. Five patients recovered after the operation, while one patient died of the disease. All the 3 XD patients were female, with the median age of 20.7 years old. All XD patients presented as multiple intraparenchymal hypointense lesions on T1 and hyperintense lesions on T2 with post-contrast enhancement. The infiltration of foam-like histiocytes, a few Touton giant cells, lymphocytes and eosnophils was observed in all XD patients. The immunohistostaining of CD68 and CD11c was positive in the histiocytes and that of MAC387 partly positive, while the staining of S-100 and CD1α was negative. One XD patient survived well, while another one died of the disease. CONCLUSIONS: The diagnosis of RDD and XD should be based on their typical morphology and immunophenotype and should be differentiated from Langerhans cell histiocytosis and other non-Langerhans cell histiocytosis. Non-Langerhans cell histiocytosis in central nerve system often presents untypical clinical presentation and imaging features, thus the communication and cooperation between clinician and pathologist is needed.

[The clinical and imaging study of thalamic venous infarction].

OBJECTIVE: To explore the clinical and radiological features of bilateral thalamus venous infarction. METHODS: The cases definitely diagnosed as thalamus venous infarction were collected and the corresponding clinical and radiological data were retrospectively analyzed. RESULTS: Four cases confirmed as thalamus venous infarction by digital substraction angiography (DSA) were collected. Bilateral thalamus lesions were detected in all cases by brain MRI scans which mainly presented as thalamus edema with high T1 and T2 signals with partial enhancement. Mild hemorrage was also shown in one case. Acute or subacute onset with clinical manifestations of headache, hypomnesia and hypersomnia were reported in all cases. The neurological examination showed conscious disturbance, memory impairment and positive Babinski sign. The venous thrombi were formed mainly in the transverse and the straight sinuses in 3 cases with the deep cerebral venous involved in 2 cases. All patients were improved after the anticoagulation therapy. Dural arteriovenous fistula was found in the other case drained by the Rosenthal's vein, and the symptoms were ameliorated after the embolotherapy. CONCLUSIONS: As the thalamus is drained by the thalamostriate vein and the lateral thalamic vein towards the internal cerebral vein with the caudate portion drained particularly by the Rosenthal's vein, venous thrombosis or fistula drainage into these veins would probably disturb the normal drainage of the thalamus and result in further edema and infarction. Thus, the venous infarction should be taken into consideration whenever bilateral thalamus lesions are encountered in clinical practice and DSA is necessary to confirm the diagnosis.

The COX-2 rs20417 polymorphism and risk of coronary artery disease: evidence from 17,621 subjects.

BACKGROUND: The Cyclooxygenase-2 (COX-2) rs20417 polymorphism has been implicated in coronary artery disease (CAD) risk, but individually published studies have shown inconsistent results. The aim of this study was to clarify the effects of COX-2 rs20417 polymorphism on CAD risk. METHODS: A systematic literature search up to October 27, 2013 was carried out in PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases, and the references of retrieved articles were screened. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were analysed for co-dominant model (CC vs. GG), additive model (C vs. G), dominant model (CC+GC vs. GG), and recessive model (CC vs. GG+GC) to assess the association using fixed- or random-effect model. RESULTS: We identified nine articles (10 case-control studies) that included 3,439 cases and 14,182 controls for the present meta-analysis. Significant association between COX-2 rs20417 polymorphism and risk of CAD was observed in co-dominant model (OR=0.64, 95% CI=0.43-0.95, p=0.026) and recessive model (OR=0.77, 95% CI=0.61-0.97, p=0.025). Moreover, in the subgroup analysis stratified by ethnicity, significant associations were observed in Asians (OR=0.28, 95% CI=0.13-0.61, p=0.001 for CC vs. GC+GG; OR=0.24, 95% CI=0.11-0.51, p<0.001 for CC vs. GG) but not in Caucasians. CONCLUSIONS: These results suggest that COX-2 rs20417 polymorphism may contribute to CAD development, especially in Asians.

MRI findings and early diagnosis of general paresis of the insane.

The objective of this study was to improve the knowledge of the clinical and MRI presentation of general paresis of the insane (GPI) and achieve its early diagnosis. Fifteen patients with GPI were gathered. Their clinical data and brain MRI information were analyzed. The age range was 33-62 years (mean: 48·8 years). The disease lasted 34 days-28 months (mean: 10·87 months). Treponema pallidum hemagglutination assays (TPHAs) on the cerebrospinal fluid (CSF) and sera were positive. All patients were human immunodeficiency virus (HIV) negative and primarily showed progressive cognitive impairment, mostly accompanied with emotional disturbance and psychosis. The accompanying symptoms included epilepsy (n  =  7), ataxia (n  =  5), cerebral vascular disease (n  =  3), and limbs tremor (n  =  2). Typical Argyll Robertson's pupil was observed in two cases. A CSF examination showed elevated white blood cell (WBC) and protein level. Purely cerebral atrophy was found in three cases. Abnormal high signals were found in nine cases in different brain area, mainly in bilateral temporal, insular, and frontal lobes and hippocampus in T2-weighted and fluid-attenuated inversion recovery (FLAIR), which was accompanied by cerebral and/or hippocampus atrophy. Purely atrophy of bilateral or unilateral hippocampus was found in two cases. Cerebral infarction lesions were found in three cases. Contrary to the previous reports, the hippocampal atrophy and bilateral abnormal signals of hippocampus and temporal lobe in brain MRI were more common in cases with GPI. Abnormal signals were probably related to proliferation of glial cells rather than cytotoxic edema. The pathogenesis of the abnormal signals needs to be further explored. General paresis of the insane has a wide variety of central nervous system manifestations, either clinically or neuroradiologically. Identification of these presentations could be important for early diagnosis.

A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China.

BACKGROUND: Combined methylmalonic aciduria and homocystinuria, cblC type (cblC disease), is the most common inborn disorder of cobalamin metabolism. This disorder is caused by MMACHC gene mutations, and it is usually diagnosed in the early neonatal period. Late-onset cblC is rare and difficult to recognize due to a wide diversity of symptoms. METHODS: Three cases with late-onset combined methylmalonic aciduria and homocystinuria, cblC type, are reported; patients' clinical presentation, imaging and MMACHC gene mutations were analyzed. RESULTS: The age of onset in the three patients was 22 years, 40 years and 7 years of age. Two of the patients had MMACHC gene mutations heterozygous for c.609G>A and c.482G>A (case 1 and case 3). The other patient (case 2) presented with gene mutations heterozygous for c.609G>A and c.1A>G. The three patients presented with a heterogeneous clinical picture, including cognitive impairment, epilepsy, ataxia, pyramidal and peripheral nerve symptoms. Cerebral atrophy and bilateral hyperintensity in the deep white matter were visible in MRI scans of the patients' brains; those were significant findings in the three patients with late-onset cblC disease. In contrast with previous reports, bilateral cerebellar cortex abnormalities were also found in one patient (case 2). CONCLUSION: Although its occurrence is rare, late-onset combined methylmalonic aciduria and homocystinuria, cblC type, should be considered in making a differential diagnosis in patients who present with neurological symptoms that are not consistent with common neurological diseases, especially when cognition, the pyramidal tract and peripheral nerves are involved.

Atypical clinical and pathological findings in a patient with isolated cortical vein thrombosis.

Isolated cortical vein thrombosis often produces a focal lesion. Because of the rapid development of collateral circulation, increased intracranial pressure has never been reported in a patient with isolated cortical vein thrombosis. The diagnosis of isolated cortical vein thrombosis is based mainly on MRI, catheter digital subtraction angiography, and histological findings, but may be challenging. We report a patient who presented with intermittent seizures and left-sided limb weakness. Her symptoms gradually progressed, and she eventually developed signs of increased intracranial pressure. Imaging studies showed a space-occupying lesion in the right frontal lobe of the brain. As we could not diagnose isolated cortical vein thrombosis based on the preoperative findings, surgical excision of the lesion was performed under general anesthesia. Histological examination showed destruction of the brain parenchyma with infiltration of macrophages, proliferation of reactive astrocytes and small vessels, and foci of hemorrhage. Further examination found that a number of small vessels in both the subarachnoid space and brain parenchyma were filled with thrombus, some of which was organized. Elastic fiber staining showed that the obstructed vessels were veins. We diagnosed isolated cortical vein thrombosis with atypical clinical features.

[The clinical and magnetic resonance imaging studies of brain damages in neuromyelitis optica].

OBJECTIVE: To investigate the feature brain damage and clinical manifestations in neuromyelitis optica (NMO) patients; To investigate the relationship between serum NMO-IgG antibody and NMO brain damage. METHODS: Clinical data of 37 NMO patients and their head and spinal cord MRI by 1.5T superconducting MR scanner, were analyzed; serum NMO-IgG antibody were measured by immunofluorescence. RESULTS: 17 cases were found to have abnormal signals on MRI, which were mainly in the white matter, pons, medulla, ventricle, aqueduct, and around the corpus callosum; According to pathological changes, brain damage can be divided into scattered irregularity (13 cases), fusion (3 cases), multiple sclerosis-like (1 case), with scattered irregularity more common, 5 cases had clinical manifestations of brain damage: somnolence, vomiting, diplopia, visual rotation, 11 cases patients with brainstem damage show positive serum NMO-IgG antibodies. CONCLUSIONS: Brain damage can be seen in half of NMO patients, they often located in the high expression area of AQP4: brain white matter, periventricular, brainstem and so on. Clinical symptoms has nothing to do with the size of lesions but the location, they often occur when brainstem was involved. Serum NMO-IgG is helpful in differentiating NMO with brain damage and MS.

[The early diagnosis of juvenile germinoma originating from the basal ganglia and thalamus].

OBJECTIVE: To explore the early diagnosis of germinoma originating from the basal ganglia (BG) and thalamus during juveniles. METHODS: Retrospective analysis was done with the clinical cases of germinomas in BG and thalamus from 2000 to 2009. The symptoms, signs, neuroimaging, cerebrospinal fluid (CSF) findings were analyzed and related literature were reviewed. RESULTS: Eight patents were collected. The main symptoms were hemiplegia, associated with aphasia and/or impaired cognition. Brain CT showed high density and calcification. Abnormal T1 and T2 signal were found in brain MRI frequently associated with ipsilateral hemisphere atrophy. MRS showed increased choline and decreased N-acetylaspartate level. Elevated CSF human chorionic gonadotrophin level were found in two of them. CONCLUSIONS: Germinoma in BG and thalamus predominates in a boy. The neuroimaging features are very informative for early diagnosis.

[Comparison of three anti-aquaporin 4 antibody detection methods in neuromyelitis optical].

OBJECTIVE: To evaluate three methods of detecting anti-aquaporin 4(AQP4) antibody in neuromyelitis optical(NMO), including indirect immunofluorescence assay organization (IIF), cell immunofluorescence method (CBA) and ELISA. METHODS: The patients were divided into NMO group (n = 29), multiple sclerosis (MS) group (n = 23), and healthy controls group (n = 50). IIF, CBA and ELISA were used in 3 groups to detect serum anti-AQP4 antibody. The sensitivity and specificity as well as the consistency of positive results were compared. RESULTS: In the aspect of the sensitivity of the three anti-AQP4 antibody to diagnosis NMO, CBA (72.4%) > IIF (62.1%) > ELISA (51.7%); in the aspect of specificity, CBA (100.0%) > ELISA (98.6%) > IIF (97.3%). Kappa testing and evaluation method showed that the three detection methods were all in good consistency, particular in CBA and ELISA (P < 0.01). CONCLUSIONS: CBA method showed a highest specificity and sensitivity in all these three anti-AQP4 antibody detection methods. CBA and ELISA are in better consistency of positive results.