Jingyao Liu

Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family

Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. TTR amyloidosis is linked to a vast number of mutations with varying phenotype and tissue distribution. Several Chinese kindred with FAP type 1 have been reported in Beijing, Hong Kong, Taiwan, and elsewhere. Here, histopathological features and TTR gene polymorphism were analyzed by using autopsy and blood specimens from a Chinese proband of a family with FAP. This proband is a 34-year old man with FAP type 1 who developed motor, sensory and autonomic impairments with neuropathy, gastrointestinal dysfunction, and orthostatic hypotension. Genetic findings of TTR revealed a T to C transition in codon 30 causing the mutation TTR Ala30. This patient died of respiratory and circulatory failure 7 years after onset. Autopsy showed heavy amyloid deposition in the peripheral nerves, liver, testes, thyroid, pancreas and muscles. There was moderate deposition in the heart, kidneys, bladder, gastrointestinal tract, tongue, lung, blood vessels, and gall bladder. The spleen showed only slight deposition, and none was observed in the central nervous system. TTR amyloidosis was confirmed by immunochemical staining with a specific TTR antibody. These results indicate that the distribution of amyloid deposition, (i.e., heavy in the liver, testes and slight in the spleen), is a characteristic feature and reflects the severity of FAP with TTR Val30Ala.

The impact of V30A mutation on transthyretin protein structural stability and cytotoxicity against neuroblastoma cells

Single point mutations in the transthyretin (TTR) gene may cause a hereditary neurodegenerative disease termed familial amyloidotic polyneuropathy (FAP) due to accelerated deposition of amyloid fibrils, resulting in peripheral and autonomic nervous system dysfunction. Recently, we found a Chinese FAP family involving a TTR V30A mutation. To understand the pathogenic mechanisms of this V30A TTR, we investigated the effects of this mutation on TTR quaternary and tertiary structural stabilities and cytotoxicities against neuroblastoma cells along with the most common variant V30M TTR and the wild-type (WT) TTR. Our results showed that the V30A mutation impaired the thermodynamic and kinetic stabilities of the TTR protein by increasing the extent and rate of tetramer dissociation and unfolded monomer and amyloid fibril formation, even to a greater extent than the V30M mutation under several experimental conditions. Further, an obviously cytotoxic effect of the V30A TTR on the human neuroblastoma cell line, IMR-32, was observed. The V30A TTR induced apoptosis and autophagy concomitant with the accumulation of reactive oxygen species (ROS) and DNA double-strand breaks, reflected in the induction of phosphor-H2A.X. These results suggest that the V30A mutation in the TTR gene promotes the formation of unfolded monomers and amyloid fibrils, which potentially contribute to the increased neurotoxicity and the pathology associated with this FAP family.

Familial Cerebral Cavernous Angiomas: Clinical and Genetic Features in a Chinese Family with a Frame-Shift Mutation in the CCM1 Gene (krit1)

A few cases of cerebral cavernous malformation (CCM) have been reported in Chinese families with different mutations during the past decade. Herein, we report a case of CCM in a proband in a Chinese family, for whom the mutation type of the CCM remains to be identified. The proband of the family presented a range of clinical symptoms and features that included paralysis, aphasia, multiple lesions in the brain, and cutaneous capillary–venous malformations. PCR was performed to amplify all of the coding exons of the three CCM genes (CCM1, CCM2, and CCM3) in the proband and revealed a heterozygous T deletion in exon 15 (c.1542delT) of CCM1 gene. Targeted mutation analysis in family members demonstrated that this mutation segregated with the disease in the family. This is the first report of a heterozygous CCM1 deletion mutation. Our findings provide a new CCM gene mutation profile in a Chinese family which will be of significance in genetic counseling for CCM.

Analysis of Mitochondrial Haplogroups Associated With TTR Val30Ala Familial Amyloidotic Polyneuropathy in Chinese Patients

ABSTRACT Extracellular deposition of abnormal transthyretin (TTR) amyloid fibrils leads to familial amyloidotic polyneuropathy (FAP), an inherited autsomal dominant disease. A large number of protein variants, each caused by a different point mutation in the TTR gene have been identified, including TTR Val30Ala. Since the age of onset, organ involvement, and disease progression are highly variable in FAP, even among individuals with the same TTR genetic variation. it is likely that other genetic and environmental factors influence FAP disease phenotype. One study has found a relationship between mitochondrial haplogroups and age of onset of FAP. In this study, we wondered whether certain mitochondrial haplogroups were associated with the cases of TTR Val30Ala FAP in a Chinese population. Mitochondrial haplogroup analysis was performed on a group of patients and their relatives and on a group of healthy controls. All FAP probands were unrelated in their maternal lineages. The chi-squared test for independence found no difference in mitochondrial haplogroup distribution between FAP and control groups. This is the first study reporting frequency and distribution of different haplogroups in FAP in a Chinese population. Although the study group was small, TTR Val30Ala FAP in China seems unrelated to mitochondrial haplogroup.

Evaluate the Efficacy and Safety of Anti-epileptic Medications for Partial Seizures of Epilepsy: A Network Meta-analysis†

Epilepsy is a brain and neurological disorder with high prevalence. It was reported that more than 70% of epileptic seizures were controlled by anti‐epileptic medications, whereas the lack of evidence with respect to head‐to‐head comparisons motivated researchers to seek alternative approaches that are able to provide deep insights into the profile of anti‐epileptic medications. In this study, we performed a network meta‐analysis (NMA) to evaluate the efficacy and safety of anti‐epileptic medications for partial seizures of epilepsy. Publications were retrieved from PubMed, Embase, and Cochrane Library. Then, studies were screened and selected based on the inclusion criteria. Data were extracted and a NMA was performed to combine both direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) was obtained for ranking purposes. Consistency between direct and indirect evidence was assessed by using the node‐splitting method. Seventeen anti‐epileptic medications from 90 publications were enrolled. Fifty percent responder and state of seizure freedom were studied as outcomes for efficacy; treatment emergent adverse effect (TEAE), including dizziness, somnolence, headache, fatigue, and nausea were evaluated as safety outcomes. Topiramate, levetiracetam, pregabalin, and oxcarbazepine were recommended for their relatively high efficacy and low‐risk of adverse events for partial seizures. Rufinamide was the least preferable medication due to its low efficacy and high‐risk of adverse effects. J. Cell. Biochem. 118: 2850–2864, 2017.

Higher frequency of brain abnormalities in neuromyelitis optica spectrum disorder patients without primary Sjögren's syndrome

Neuromyelitis optica spectrum disorder often co-exists with primary Sjögren′s syndrome. We compared the clinical features of 16 neuromyelitis optica spectrum disorder patients with (n = 6) or without primary Sjögren′s syndrome (n = 10). All patients underwent extensive clinical, laboratory, and MRI evaluations. There were no statistical differences in demographics or first neurological involvement at onset between neuromyelitis optica spectrum disorder patients with and without primary Sjögren′s syndrome. The laboratory findings of cerebrospinal fluid oligoclonal banding, serum C-reactive protein, antinuclear autoantibody, anti-Sjögren′s-syndrome-related antigen A antibodies, anti-Sjögren′s-syndrome-related antigen B antibodies, and anti-Sm antibodies were significantly higher in patients with primary Sjögren′s syndrome than those without. Anti-aquaporin 4 antibodies were detectable in 67% (4/6) of patients with primary Sjögren′s syndrome and in 60% (6/10) of patients without primary Sjögren′s syndrome. More brain abnormalities were observed in patients without primary Sjögren′s syndrome than in those with primary Sjögren′s syndrome. Segments lesions (> 3 centrum) were noted in 50% (5/10) of patients without primary Sjögren′s syndrome and in 67% (4/6) of patients with primary Sjögren′s syndrome. These findings indicate that the clinical characteristics of neuromyelitis optica spectrum disorder patients with and without primary Sjögren′s syndrome are similar. However, neuromyelitis optica spectrum disorder patients without primary Sjögren′s syndrome have a high frequency of brain abnormalities.