IgLON5 autoimmunity in a patient with Creutzfeldt-Jakob disease: case report and review of literature.

Objective: We present the case of a patient with clinical and imaging features of sporadic Creutzfeldt-Jakob disease (sCJD) and positive IgLON5 antibodies (Abs) in the serum and CSF. Case report: A 66-year-old Chinese man presented to the hospital with a stroke-like episode, followed by rapidly progressive cognitive decline, mutism, and parkinsonism. The MRI results showed a cortical ribboning sign in diffusion-weighted MRI, periodic triphasic waves with a slow background in EEG, and positive protein 14-3-3 in CSF. There were matching IgLON5 Abs in the serum and CSF. A literature review showed positive autoimmune encephalitis Abs or autoimmune inflammatory disease between 0.5 and 8.6% among patients with clinical suspicion of CJD, most commonly anti-voltage-gated potassium channel (VGKC) complex and anti-N-methyl-D-aspartate receptor (NMDAR) Abs; however, IgLON5 autoimmunity in CJD has been rarely reported. This is an intriguing association as both conditions have been associated with brain deposits of phosphorylated tau protein. Conclusion: IgLON5 Abs may be observed in patients with a diagnosis of CJD; it is unknown whether a synergistic effect of IgLON5 Abs with CJD exists, increasing neurodegenerative changes.

ADGRV1 Variants in Febrile Seizures/Epilepsy With Antecedent Febrile Seizures and Their Associations With Audio-Visual Abnormalities.

Objective: ADGRV1 gene encodes adhesion G protein-coupled receptor-V1 that is involved in synaptic function. ADGRV1 mutations are associated with audio-visual disorders. Although previous experimental studies suggested that ADGRV1 variants were associated with epilepsy, clinical evidence is limited and the phenotype spectrum is to be defined. Methods: Trio-based targeting sequencing was performed in a cohort of 101 cases with febrile seizure (FS) and epilepsy with antecedent FS. Protein modeling was used to assess the damaging effects of variants. The genotype-phenotype correlations of the ADGRV1 variants in epilepsy and audio-visual disorders were analyzed. Results: ADGRV1 variants were identified in nine unrelated cases (8.91%), including two heterozygous frameshift variants, six heterozygous missense variants, and a pair of compound heterozygous variants. These variants presented a statistically higher frequency in this cohort than that in control populations. Most missense variants were located at CalX-ß motifs and changed the hydrogen bonds. These variants were inherited from the asymptomatic parents, indicating an incomplete penetrance. We also identified SCN1A variants in 25 unrelated cases (24.75%) and SCN9A variants in 3 unrelated cases (2.97%) in this cohort. Contrary to SCN1A variant-associated epilepsy that revealed seizure was aggravated by sodium channel blockers, ADGRV1 variants were associated with mild epilepsy with favorable responses to antiepileptic drugs. The patients denied problems with audio-visual-vestibular abilities in daily life. However, audio-visual tests revealed auditory and visual impairment in the patient with compound heterozygous variants, auditory or vestibular impairment in the patients with heterozygous frameshift, or hydrogen-bond changed missense variants but no abnormalities in the patients with missense variants without hydrogen-bond changes. Previously reported ADGRV1 variants that were associated with audio-visual disorders were mostly biallelic/destructive variants, which were significantly more frequent in the severe phenotype of audio-visual disorders (Usher syndrome 2) than in other mild phenotypes. In contrast, the variants identified in epilepsy were monoallelic, missense mainly located at CalX-ß, or affected isoforms VLGR1b/1c. Significance: ADGRV1 is potentially associated with FS-related epilepsy as a susceptibility gene. The genotype, submolecular implication, isoforms, and damaging severity of the variants explained the phenotypical variations. ADGRV1 variant-associated FS/epilepsy presented favorable responses to antiepileptic drugs, implying a clinical significance.

DNA hypermethylation of NOTCH2NLC in neuronal intranuclear inclusion disease: a case-control study.

BACKGROUND: GGC repeat expansions in NOTCH2NLC gene have been recently proposed to cause neuronal intranuclear inclusion disease (NIID) via prevailing gain-of-function mechanism (protein and RNA toxicity). Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of repeat-mediated disorders. METHODS: In this study, using MethylTarget sequencing, we performed a quantitative analysis of the methylation status of 68 CpG sites located around the NOTCH2NLC promoter in 25 NIID patients and 25 age- and gender-matched healthy controls. We further explored the correlation of DNA methylation (DNAm) status with disease features and performed receiver operating characteristic (ROC) analysis. RESULTS: DNAm levels of GGC repeats and adjacent CpG islands were higher in the NIID patients than in controls, independent of gender and family history. DNAm levels at 4 CpG sites (CpG_207, CpG_421, GpG_473 and CpG_523) were negatively correlated with age at onset, and DNAm levels at 7 CpG sites (CpG_25, CpG_298, CpG_336, CpG_374, CpG_411, CpG_421 and CpG_473) were positively correlated with GGC repeats. NIID patients had concomitant system symptoms besides nervous system symptoms, and negative correlations between NOTCH2NLC DNAm levels and the number of multi-systemic involvement were observed in the study. The area under the ROC curve at NOTCH2NLC DNAm level reached to 0.733 for the best cutoff point of 0.012. CONCLUSIONS: Our findings suggested the aberrant DNAm status of the NOTCH2NLC promoter in NIID, and we explored the link between DNAm levels and disease features quantitatively for the first time, which may help to further explore pathogenic mechanism.

Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype-Phenotype Correlation.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1470delC/p.R490fs494X), in seven unrelated families with PKAN. All the patients showed an eye-of-the-tiger sign on the MRI, six of seven patients had dystonia, and two of seven patients had Parkinsonism. Biallelic mutations of PANK2 decreased PANK2 protein expression and reduced mitochondrial membrane potential in human embryonic kidney (HEK) 293T cells. The biallelic mutations from patients with early-onset PKAN, a severity phenotype, showed decreased mitochondrial membrane potential more than that from late-onset patients. We systematically reviewed all the reported patients with PKAN with PANK2 mutations. The results indicated that the early-onset patients carried a significantly higher frequency of biallelic loss-of-function (LoF) mutations compared to late-onset patients. In general, patients with LoF mutations showed more severe phenotypes, including earlier onset age and loss of gait. Although there was no significant difference in the frequency of biallelic missense mutations between the early-onset and late-onset patients, we found that patients with missense mutations in the mitochondrial trafficking domain (transit peptide/mitochondrial domain) of PANK2 exhibited the earliest onset age when compared to patients with mutations in the other two domains. Taken together, this study reports three novel mutations and indicates a correlation between the phenotype and mitochondrial dysfunction. This provides new insight for evaluating the clinical severity of patients based on the degree of mitochondrial dysfunction and suggests genetic counseling not just generalized identification of mutated PANK2 in clinics.

CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia.

AIMS: CHD4 gene, encoding chromodomain helicase DNA-binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity Framework of ClinGen and an evaluating method from five clinical-genetic aspects were used to determine the association between CHD4 variants and epilepsy. RESULTS: Four novel heterozygous missense mutations in CHD4, including two de novo mutations (c.1597A>G/p.K533E and c.4936G>A/p.E1646K) and two inherited mutations with co-segregation (c.856C>G/p.P286A and c.4977C>G/p.D1659E), were identified in four unrelated families with eight individuals affected. Seven affected individuals had sinus arrhythmia. From the molecular sub-regional point of view, the missense mutations located in the central regions from SNF2-like region to DUF1087 domain were associated with multisystem developmental disorders, while idiopathic epilepsy-related mutations were outside this region. Strong evidence from ClinGen Clinical Validity Framework and evidences from four of the five clinical-genetic aspects suggested an association between CHD4 variants and epilepsy. CONCLUSIONS: CHD4 was potentially a candidate pathogenic gene of childhood idiopathic epilepsy with arrhythmia. The molecular sub-regional effect of CHD4 mutations helped explaining the mechanisms underlying phenotypic variations.

Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders.

OBJECTIVES: To describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal disorders. PATIENTS AND METHODS: The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members. RESULTS: Cerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel. CONCLUSION: We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.

[Efficacy and safety of cyclophosphamide as a sequential immunotherapy drug for anti-N-methyl-D-aspartate receptor encephalitis in children].

OBJECTIVE: To evaluate the efficacy and safety of cyclophosphamide as a second-line drug in the treatment of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Six children with anti-NMDAR encephalitis, who showed poor response to steroids and intravenous immunoglobulin, were given cyclophosphamide as a second-line immunotherapy. Follow-up was performed to evaluate the efficacy and safety of cyclophosphamide. RESULTS: After first-line immunotherapy for 1-4 weeks, the six patients had reduced psychiatric symptoms, seizures, and involuntary movements; three patients had an improved level of consciousness and were able to make simple conversations. However, all the patients still showed slow response, as well as cortical dysfunction symptoms such as aphasia, alexia, agraphia, acalculia, apraxia, and movement disorders. The six patients continued to receive cyclophosphamide as a sequential therapy. They were able to answer simple questions 7 days after treatment. Three school-aged patients were able to make simple calculation, had greatly improved reading and writing ability, and almost recovered self-care ability 2-3 weeks later. The cognitive function of the six patients was almost restored to the level before the onset of disease, and their living ability returned to normal 2-3 months later. During the treatment period, there were no adverse reactions or abnormal results of routine blood test and liver and kidney function tests. CONCLUSIONS: Children with anti-NMDAR encephalitis should be given appropriate immunotherapy as soon as possible. Cyclophosphamide as a sequential therapy has good efficacy and safety.

Is elevated SUA associated with a worse outcome in young Chinese patients with acute cerebral ischemic stroke?

BACKGROUND: Elevated serum uric acid (SUA) levels can enhance its antioxidant prosperities and reduce the occurrence of cerebral infarction. Significantly elevated SUA levels have been associated with a better prognosis in patients with cerebral infarction; however, the results from some studies on the relationship between SUA and the prognosis of patients with cerebral infarction remain controversial. METHODS: We analyzed the relationship between SUA and clinical prognosis of 585 young Chinese adults with acute ischemic stroke as determined by the modified Rankin Scale at discharge. Using multivariate logistic regression modeling, we explore the relationship between SUA levels and patient's clinical prognosis. RESULTS: Lower SUA levels at time of admission were observed more frequently in the lowest quintile for patients with severe stroke (P = 0.02). Patients with cerebral infarction patients caused by small-vessel blockage had higher SUA concentrations (P = 0.01) and the lower mRS scores (P < 0.01) were observed in, while the lowest SUA concentrations and the highest mRS scores were seen in patients with cardiogenic cerebral infarction patients. Logistic regression analysis adjusted for confounders confirmed the following independent predictors for young cerebral infarction: uric acid (-0.003: 95%CI 0.994 to 0.999) and platelet (0.004, 95%CI 0.993 to 0.996). CONCLUSION: Elevated SUA is an independent predictor for good clinical outcome of acute cerebral infarction among young adults.

The clinical study of POEMS syndrome in China.

OBJECTIVE: POEMS syndrome is a unique clinical entity. It was described by the presence of several typical characteristics as paraproteinemia, polyneuropathy, organomegaly, endocrinopathy, and skin changes. Few people reported characteristics of Chinese POEMS patients. PATIENTS AND METHODS: Retrospective evaluation of Chinese patients with POEMS syndrome was carried out to reveal clinical features and compare with foreign series reported previously. In addition to typical characteristics, Chinese patients often were presented with extravascular volume overload (84%), papilledema (44%), bone lesions (41%), raynaud phenomenon (31%) and Clubbing (22%). RESULTS: Clinical laboratory tests found most patients had increased erythrosedimentation rate, hyperlipidemia, liver disorder and renal involvement. 70% patients had hypothyroidism, including overt hypothyroidism (6 patients) and subclinical hypothyroidism (13 patients). High prevalence of positive antimitochondrial antibody (ANA) and positive antineutrophil cytoplasmic antibody (ANCA) was the more common phenomenon. Chinese patients with bone damage in the incidence are lower than in the West and Japanese reports. CONCLUSIONS: In summary, our study demonstrate the POEMS syndrome diagnostic criteria proposed by Dispenzieri et al is also more high applicability in the Chinese population.At the time of diagnosis, we should not pay attention on the typical characteristics of the disease, but also on the changes in thyroid, liver, kidney function and lipid metabolism.

Analysis of SCA2 and SCA3/MJD repeats in Parkinson's disease in mainland China: genetic, clinical, and positron emission tomography findings.

To investigate the prevalence and clinical feature(s) of Parkinson's disease (PD) patients with expanded (ATXN2 and MJD1) genes of spinocerebellar ataxia type 2 and 3 (SCA2 and SCA3/MJD) in a mainland Chinese population, CAG triplet repeat expansions of (SCA2 and SCA3/MJD) genes (ATXN2 and MJD1) were analyzed in a cohort of 452 PD patients, including 386 sporadic and 66 familial forms. Striatal dopamine transporter was evaluated in two SCA2 and two SCA3/MJD-positive family members, an idiopathic PD patient and a healthy control using carbon (C11) [(11)C]-radiolabeled-CFT positron emission tomography (PET). We found two patients in one familial PD (FPD) family (1.5%) and two sporadic PD patients (0.5%) with expanded CAG repeats in the ATXN2 locus, four patients in two FPD families (3%) and another three sporadic PD patients (0.8%) in the MJD1 locus. [(11)C]-CFT PET in detected members in SCA2 and SCA3/MJD families showed decrements of (11)C-CFT uptake. These findings suggest that a mutation in SCA2 or SCA3/MJD may be one of the genetic causes of PD.

[Clinical manifestations and detection of pantothenate kinase 2 gene mutation in a patient with Hallervorden-Spatz syndrome].

OBJECTIVE: To investigate the clinical features and detection of pantothenate kinase 2 (PANK2) gene mutation in a Chinese patient with Hallervorden-Spatz syndrome (HSS). METHODS: The clinical features were analyzed in one HSS patient. PANK2 gene mutations were detected by polymerase chain reaction (PCR) and DNA sequence analysis in this patient, her parents and 50 unrelated healthy persons. RESULTS: The main symptoms of this patient were involuntary movements, dysarthria and progressive course. MRI scans showed hypointensity with a central region of hyperintensity in medial globus pallidus on T2 and T2-weighted fluid attenuated inversion recovery (FLAIR) images, i.e. "eye-of-the-tiger" sign. Novel compound heterozygous PANK2 gene mutations, G115T and A803G, were found in this patient, leading to substitution of a glutamic acid for a premature stop codon at amino acid 39 (E39X) and an aspartic acid for glycine codon at amino acid 268 (D268G) respectively. The father was a heterozygote for G115T mutation and the mother a heterozygote for A803G mutation. CONCLUSION: PANK2 gene mutations are present in Chinese HSS patients. And A803G mutation of PANK2 gene is probably a hot spot.

[Study on the single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene in Chinese patients with spinocerebellar ataxia].

OBJECTIVE: To study the single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene in spinocerebellar ataxia (SCA) patients in China. METHODS: The single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene was detected by PCR, digested with EcoN I, separated on 8% polyacrylamide gel in 68 probands of autosomal dominant SCA families and 119 sporadic SCA patients, who had been excluded CAG/CAA repeat expansion at the SCA1, 2, 3, 6, 7, 17 and dentatorubral-pallidolluysian atrophy (DRPLA) loci. The results were confirmed in four patients by direct sequencing. RESULTS: The single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene was not identified in authors' cohort. CONCLUSION: The mutation of c.-16C to T of the PURATROPHIN-1 gene might be rare in SCA patients in China.

[Studies on the CTA/CTG trinucleotide repeats of ATXN8OS gene in Chinese Hans].

OBJECTIVE: To study the normal range of (CTA/CTG)n repeats of ATXN8OS gene in Chinese Hans, and the frequency of ATXN8OS (CTA/CTG)n repeat expansion in spinocerebellar ataxia(SCA) patients in Mainland China. METHODS: The (CTA/CTG)n repeats of ATXN8OS gene were detected using fluorescence-PCR, 8% denaturing polyacrylamide gel and capillary electrophoresis technique in 132 SCA patients in whom CAG expansion at the SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17 and dentatorubral-pallidoluysian atrophy(DRPLA) loci has been excluded, and 261 healthy controls. RESULTS: There were no obvious abnormal changes of the (CTA/CTG)n repeats of ATXN8OS gene in the 132 SCA patients. Thirty-five SCA patients were homozygotes (26.5%), and the range of CTA/CTG repeat number was 17 to 47 (24.20+/-4.57), among which 18 repeats appeared most frequently. In 261 normal controls, 70 were homozygotes (26.8%), and the range of the CTA/CTG repeat number was from 12 to 43 (24.04+/-4.53), among which 18 repeats was the most frequent. CONCLUSION: SCA8 is a rare subtype of SCA in Mainland China. The low prevalence of SCA8 seems to be correlated with the low frequency of large (CTA/CTG)n copy number alleles in Chinese population.

[Frequency of different subtypes of spinocerebellar ataxia in the Han nationality of Hunan province in China].

OBJECTIVE: To determine the frequency of different subtypes of spinocerebellar ataxias (SCAs) in the Han nationality of Hunan province in China. METHODS: The mutations of SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and dentatorulral-pallidoluysian (DRPLA) were detected with the polymerase chain reaction (PCR), denaturing polyacrylamide gel and DNA sequencing techniques in 139 autosomal dominant SCA families and 61 sporadic SCA patients. RESULTS: Of the 139 families, 11 (7.9%) were positive for SCA1, 9(6.5%) were positive for SCA2, 71 (51.1%) were positive for SCA3, 4 (2.9%) were positive for SCA6, 2 (1.4%) were positive for SCA7, and none was positive for SCA17 and DRPLA. There was 1 SCA2 patient, 3 SCA3 patients, 1 SCA6 patient in the 61 sporadic SCA patients. CONCLUSION: The frequency of SCA3 is substantially higher than that of SCA1 and SCA2 in the autosomal dominant SCA patients in the Han nationality of Hunan province. SCA6 and SCA7 are rare subtypes.

[Clinical characteristics and molecular biology of hereditary spinocerebellar ataxia type 7: study of 3 Chinese families].

OBJECTIVE: To study the clinical characteristics and molecular biology of hereditary spinocerebellar ataxia type 7 (SCA7). METHODS: Peripheral blood samples were collected from 245 with autosomal dominant SCA from 184 families and 71 sporadic SCA patients. Polymerase chain reaction, polyacrylamide gel electrophoresis, and capillary electrophoresis technique were used to detect the SCA7 (CAG) n trinucleotide repeat mutations. 163 healthy persons were used as controls. The abnormal allele fragments were sequenced by ABI 377 DNA sequencing machine. RESULTS: Three SCA families with 15 patients were identified with a positive rate of 1.6%. DNA sequencing showed that the abnormal SCA7 alleles with CAG repeat were expanded to 38 to 71 repeats, and the normal SCA7 alleles were carried from 6 to 15 CAG repeats. Analysis of parent-child couples demonstrated the existence of marked anticipation in 2 families, especially in paternal transmission. Linkage analysis found a maximum two-point LOD score of 2.82 in the microsatellite D3S1300 at recombination fraction (theta = 0.00). CONCLUSION: CAG expansion is the pathogenic cause of SCA7, a rare subtype of SCA. The 38 CAG is the minimum pathological expansion in mainland China.

Acute dystonia induced by lamivudine.

Lamivudine is the most widely prescribed drug of choice for chronic hepatitis B infection, which is a common health problem in China. Generally, the administration of lamivudine has been well tolerated. The authors report two cases of acute dystonic reactions (ADRs) as a side effect of lamivudine. ADR induced by drug treatment can be a side effect of treatment with antipsychotic drugs and other drugs; however, there have been no reports of lamivudine-induced ADR in the English literature. The authors think that although lamivudine is widely used and well tolerated, it can cause ADRs, which are reversible after drug withdrawal.

[Clinical features and treatment of giant cell arteritis in Chinese, a prospective study].

OBJECTIVE: To investigate the clinical features of giant cell (temporal) arteritis (GCA) in China. METHODS: The clinical manifestations, temporal artery biopsy, response to steroid therapy, and follow-up data of sixteen patients with the diagnosis of GCA from July 1999 to March 2001 were analyzed. The American College of Rheumatology (ACR) criteria for classification of GCA were used as reference. RESULTS: Twenty-one patients who sought medical advice in the Second Hospital Affiliated to Xiangya Medical College were suspected of GCA. A definite diagnosis of GCA was made among sixteen patients. The diagnosis among 13 of them fulfilled the 1990 American College of Rheumatology criteria for the classification of GCA. The mean age at disease onset was 43.13 years (range 28 approximately 60 years) and 81.25% of the patients were under the age of 50 when they came down with the disease. The ratio between male and female cases was 15:1. The commonest initial clinical manifestations included newly occurring headache, temporal artery abnormality, visual symptoms, fever, and raised erythrocyte sedimentation rate. Jaw claudication, fatigue, syncope, and hemiparesis could be found in some patients. All the 16 patients underwent temporal artery biopsy. Light and electron microscopy showed inflammatory cell infiltration in arterial wall in 11 cases, fragmented internal elastica in 16 cases, fibrinoid necrosis in 3 cases, smooth muscle cell changes in 10 cases, and thrombosis in the lumen in 5 cases. The mean time from symptom onset to suspicion of GCA or biopsy was 5.52 months (range 0.25 approximately 24.33 months). The misdiagnosis rate during first visit was 87.50%. CONCLUSION: GCA may not be a rare disorder in China. In comparison with the cases abroad, the Chinese GCA patients come down with disease at the earlier age, and most Chinese GCA patients are male. This disease is not understood by many clinicians in China. Misdiagnosis is common.