Neuralgic amyotrophy and hepatitis E virus infection.
ABSTRACT: OBJECTIVE: To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from patients without an associated HEV infection. METHODS: HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011-2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004-2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR). RESULTS: Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome. CONCLUSIONS: Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms.
Project description:Neuralgic amyotrophy is a distinct clinical syndrome with acute severe pain and patchy paresis in the shoulder and arm region. The clinical phenotype was recently found to be more comprehensive and the long-term prognosis less optimistic than usually assumed for many patients. The disorder can be idiopathic or hereditary in an autosomal dominant fashion, with only few phenotypical variations between the two. This article provides a practical overview of current knowledge on the clinical presentation, diagnosis, pathogenesis and the treatment of pain and complications.
Project description:We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.
Project description:OBJECTIVE:Neuralgic amyotrophy is considered a rare peripheral nervous system disorder but in practice seems grossly under recognized, which negatively affects care for these patients. In this study we prospectively counted the one-year incidence rate of classic neuralgic amyotrophy in a primary care setting. METHODS:In a prospective cohort study during the year 2012 we registered all new cases of neck, shoulder or arm complaints from two large primary care centers serving a population of 14,118. Prior to study, general practitioners received a short training on how to diagnose classic neuralgic amyotrophy. Neuralgic amyotrophy was defined according to published criteria irrespective of family history. Only patients with a classic phenotype were counted as definite cases. After inclusion, patients with suspected neuralgic amyotrophy who had not yet seen a neurologist were offered neurologic evaluation for diagnostic confirmation. RESULTS:Of the 492 patients identified with new onset neck, shoulder or arm complaints, 34 were suspected of having neuralgic amyotrophy. After neurologic evaluation the diagnosis was confirmed in 14 patients. This amounts to a one-year incidence rate for classic neuralgic amyotrophy of 1 per 1000. CONCLUSIONS:Our findings suggest that neuralgic amyotrophy is 30-50 times more common than previously thought. Unawareness of the disorder and its clinical presentation seems the most likely explanation for this difference. An incidence rate of 1 per 1000 and the long-term sequelae many patients suffer warrant more vigilance in diagnosing the disorder, to pave the way for timely treatment and prevent complications.
Project description:Hereditary neuralgic amyotrophy is a rare disorder characterized by the sudden onset of recurrent episodes of painful brachial plexus neuropathies, followed by atrophy within a few weeks. The authors present the case of a 5-year-old boy who developed hereditary neuralgic amyotrophy in the right upper limb after a gastroenteritis illness. He made a full and rapid recovery with the use of intravenous immunoglobulin. A subsequent episode in the left upper limb during the course of intravenous immunoglobulin was significantly attenuated. A de novo c.262C>T mutation in exon 2 of the SEPT9 gene was identified. To our knowledge, he is the first pediatric patient with SEPT9 hereditary neuralgic amyotrophy to be treated with intravenous immunoglobulin. The authors hypothesize that the c.262C>T mutation in exon 2 of the SEPT9 gene generates pathology via the numerous isoforms under specific conditions and that intravenous immunoglobulin can play a role at the epigenetic level of improving dysfunctional SEPT9 expression.
Project description:BACKGROUND:Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder that manifests as recurrent, episodic, painful brachial neuropathies. A gene for HNA maps to chromosome 17q25.3 where mutations in SEPT9, encoding the septin-9 protein, have been identified. OBJECTIVE:To determine the frequency and type of mutations in the SEPT9 gene in a new cohort of 42 unrelated HNA pedigrees. METHODS:DNA sequencing of all exons and intron-exon boundaries for SEPT9 was carried out in an affected individual in each pedigree from our HNA cohort. Genotyping using microsatellite markers spanning the SEPT9 gene was also used to identify pedigrees with a previously reported founder haplotype. RESULTS:Two missense mutations were found: c.262C>T (p.Arg88Trp) in seven HNA pedigrees and c.278C>T (p.Ser93Phe) in one HNA pedigree. Sequencing of other known exons in SEPT9 detected no additional disease-associated mutations. A founder haplotype, without defined mutations in SEPT9, was present in seven pedigrees. CONCLUSIONS:We provide further evidence that mutation of the SEPT9 gene is the molecular basis of some cases of hereditary neuralgic amyotrophy (HNA). DNA sequencing of SEPT9 demonstrates a restricted set of mutations in this cohort of HNA pedigrees. Nonetheless, sequence analysis will have an important role in mutation detection in HNA. Additional techniques will be required to find SEPT9 mutations in an HNA founder haplotype and other pedigrees.
Project description:BACKGROUND:Neuralgic amyotrophy (NA) is a distinct peripheral neurological disorder of the brachial plexus with a yearly incidence of 1/1000, which is characterised by acute severe upper extremity pain. Weakness of the stabilising shoulder muscles in the acute phase leads to compensatory strategies and abnormal motor control of the shoulder - scapular dyskinesia. Despite peripheral nerve recovery, scapular dyskinesia often persists, leading to debilitating residual complaints including pain and fatigue. Evidence suggests that persistent scapular dyskinesia in NA may result from maladaptive cerebral neuroplasticity, altering motor planning. Currently there is no proven effective causative treatment for the residual symptoms in NA. Moreover, the role of cerebral mechanisms in persistent scapular dyskinesia remains unclear. METHODS:NA-CONTROL is a single-centre, randomised controlled trial comparing specific rehabilitation to usual care in NA. The rehabilitation programme combines relearning of motor control, targeting cerebral mechanisms, with self-management strategies. Fifty patients will be included. Patients are recruited through the Radboud university medical center Nijmegen, the Netherlands. Patients with a (suspected) diagnosis of NA, with lateralized symptoms and scapular dyskinesia in the right upper extremity, who are 18?years or older and not in the acute phase can be included. The primary outcome is the Shoulder Rating Questionnaire score, which measures functional capability of the upper extremity. Secondary clinical outcomes include measures of pain, fatigue, participation, reachable workspace, muscle strength and quality of life. In addition, motor planning is assessed with first-person motor imagery and functional magnetic resonance imaging. In a sub-study the patients are compared to 25 healthy participants, to determine the involvement of cerebral mechanisms. This will enable interpretation of cerebral changes associated with the rehabilitation programme and functional impairments in NA. DISCUSSION:NA-CONTROL is the first randomised trial to investigate the effect of specific rehabilitation on residual complaints in NA. It also is the first study into the cerebral mechanisms that might underlie persistent scapular dyskinesia in NA. It thus may aid the further development of mechanism-based interventions for disturbed motor control in NA and in other peripheral neurological disorders. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03441347 . Registered on 20 February 2018.
Project description:Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of ?-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of ?-tubulin, enabling septin–septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA.
Project description:Hepatitis E virus (HEV) is a serious public health problem. The commonly used tests that are specific for current HEV infection diagnosis include the detection of anti-HEV IgM and HEV RNA. Here, we report an improved enzyme-linked immunosorbent assay (ELISA) method for HEV antigen detection with a linear range equivalent to 6.3 × 10(3) to 9.2 × 10(5) RNA copies per ml. The monoclonal antibody (MAb) 12F12, a high-ability MAb that binds HEV virus, was selected as the capture antibody from a panel of 95 MAbs. The positive period of HEV antigenemia in infected monkeys using this test was, on average, 3 weeks longer than previously reported and covered the majority of the acute phase. The positive detection rates of IgM, RNA, and new antigen from the first serum samples collected from 16 confirmed acute hepatitis E patients were 81% (13/16), 81% (13/16), and 100% (16/16), respectively. In three patients, the initial serum specimens that tested negative for IgM, despite the presence of symptoms of acute hepatitis and elevated alanine aminotransferase (ALT) levels, were positive for HEV antigen and HEV RNA. In contrast, the serum samples of the three RNA-negative patients were antigen positive (and IgM positive), possibly due to the degradation of HEV nucleic acids. Our results suggest that this new antigen detection method has acceptable concordance with RNA detection and could serve as an important tool for diagnosing acute hepatitis E.
Project description:To investigate the genetic characteristics and pathogenicity of hepatitis E virus (HEV) and assess the potential risk factors for sporadic hepatitis E.Sixty-two serum samples from the patients with acute hepatitis E were collected, including 23 cases coinfected with hepatitis B virus. Anti-HEV detection and partial HEV RNA amplification were performed by enzyme immunoassays and reverse transcription-nested polymerase chain reaction (RT-nPCR) method, respectively, and PCR products were sequenced. The isolated human HEV sequences were analyzed phylogenetically.The positive rate of serum HEV RNA were 21.0% (13/62), including 5 cases of liver failure. All the 13 isolates shared a 82.1%-98.0% nucleotide homology with each other and had identities of 74.7%-81.0%, 75.3%-78.6%, 75.3%-80.0% and 82.1%-96.1% with the corresponding regions of HEV genotypes 1-4, respectively. The human HEV strain GS-NJ-12 shared a 100% nucleotide identity with the swine HEV strain swIM6-43 isolated from Inner Mongolia, China.Swine may be a principal risk factor for occurrence of sporadic hepatitis E in eastern China, and genotype 4 HEV can induce acute liver failure.
Project description:Background:Patients with chronic hepatitis B virus (HBV) may experience spontaneous biochemical flares of liver disease activity. This study aimed to determine (i) the prevalence of prior and possible acute hepatitis E virus (HEV) infection among persons with chronic HBV and (ii) whether HEV infection is associated with liver disease flares among persons with chronic HBV. Methods:Serum from a random sample of 600 adults in the Hepatitis B Research Network Cohort Study was tested for HEV RNA and anti-HEV IgM and IgG. Logistic regression models were used to estimate crude and adjusted odds ratios of anti-HEV prevalence for participant characteristics. Results:Anti-HEV IgG and IgM seroprevalence was 28.5% and 1.7%, respectively. No participants had detectable HEV RNA. Of the 10 anti-HEV IgM+ participants, only 1 had elevated serum ALT at seroconversion. The odds of anti-HEV seropositivity (IgG+ or IgM+) were higher in older participants, males, Asians, less educated people, and those born outside the United States and Canada. Conclusions:Acute HEV infection is a rare cause of serum ALT flares among persons with chronic HBV. The high seroprevalence of anti-HEV IgG among the chronic HBV patients is strongly associated with various demographic factors in this largely Asian American cohort.