Objective:To analyze the gene mutation type and clinical phenotype of patients with PRRT2 mutation, and explore their relations with prognosis. Methods:A total of 18 patients with PRRT2 gene mutation (1 patient with novel mutation in PRRT2 gene, and 17 probands in 17 families with PRRT2 gene mutation) were enrolled in Department of Neurology, First Affiliated Hospital of Air Force Medical University from January 2018 to July 2023. Serum of the patients was collected for whole exon sequencing, and mutation sites and types of PRRT2 gene were analyzed. SWISS-MODEL website was used to predict the changes in protein structure caused by PRRT2 gene mutation. The relations of gene mutation type and clinical phenotype with prognosis of these patients were analyzed. Results:(1) All 18 patients with PRRT2 gene mutation were heterozygous mutation, including 12 frameshift mutations, 5 missense mutations, and 1 integer mutation. The clinical phenotype included benign familial infantile epilepsy (BFIE) in 5 patients, epilepsy in 6 patients, exercise-induced paroxysmal kinesigenic dyskinesia (PKD) in 5 patients, and infantile convulsion and choreoathetosis (ICCA) in 2 patients. A total of 8 mutation sites were found in 18 patients with PRRT2 gene mutation, of which 3 mutation sites have been reported, and 5 mutation sites have not been reported, including c.647(exon2)C>A, c.647(exon2)C>G, c.170(exon2)delC, c.981(exon3)C>G, and lossl(EXON: 2)(all). (2) Eighteen patients mainly accepted oxcarbazepine, levetiracetam, and sodium valproate in combination or monotherapy. Among them, 5 BFIE patients, 2 ICCA patients and 3 epilepsy patients were seizure-free after treatment. PKD patients did not respond well to oxcarbazepine. (3) Three frameshift mutations (mutation sites: c.649 [exon2]_c.650 [exon2] insC, c.640 [exon2]_c.641 [exon2] insC, and c.170 [exon2] delC) led to premature termination of protein translation, resulting in significant changes in protein structure. Four missense mutations (mutation sites: c.640[exo2]G>C, c.647[exon2]C>A, c.647[exon2]C>G, and c.981[exon3]C>G) had little effect on protein structure changes. No relation was found between changes of protein structure caused by different mutation types and prognosis. Conclusion:PRRT2 gene mutation patients with clinical phenotypes of BFIE and ICCA have good prognosis, but the mutation type is not related with the prognosis of patients.

Objective:To report the clinical phenotype and mutation site of a patient with grey matter heterotopia caused by a de novo heterozygous missense mutation in the TUBB2B gene, and to expand the phenotypic and mutational spectrum of TUBB2B mutations. Methods:One patient with TUBB2B mutation who presented to the Department of Neurology, the First Affiliated Hospital of Air Force Medical University in July 2017 was collected and analyzed for clinical features and mutation site, and a review of previous studies was performed. Results:The male patient started at the age of 18 and presented mainly with seizures, poor left-handed fine motor skills and poor spatial imagination. Magnetic resonance imaging showed nodular grey matter heterotopia in the right cerebral hemisphere, right frontoparietal-temporal localized cerebral gyrus, and cerebral sulcus shallow flat.The whole exon gene test suggested a heterozygous missense mutation in the TUBB2B gene: c.776 C>T (p.Pro259Leu), which was wild-type in both of his parents. The mutation site was located between the tubulin and tubulin-c structural domains and did not affect the function of the essential structural domain. After treatment with magnesium valproate in combination with levetiracetam, the patient′s seizure symptoms were significantly controlled and he has been seizure-free for 3 years now. Conclusions:The TUBB2B gene c.776 C>T (p.Pro259Leu) heterozygous missense mutation is a novel missense mutation causing grey matter heterotopia. The patient had a good prognosis, and the combination of two antiepileptic drugs resulted in complete seizure control.

Objective:To compare the maternal and fetal outcomes of women with cervical insufficiency (CI) undergoing McDonald cerclage (MC) and laparoscopic cervicoisthmic cerclage (LCC), so as to provide evidence for the selection of cerclage methods.Methods:A retrospective trial was carried out in the First Affiliated Hospital of Sun Yat-sen University from January 2010 to December 2020. A total of 221 women who underwent the prophylactic cerclage were divided into MC group ( n=54), LCC with MC history group ( n=28) and LCC without MC history group ( n=129) by the mode of operation and whether the pregnant women who underwent LCC had MC history. General clinical data, pregnancy complications and pregnancy outcomes were compared between the three groups. Results:(1) General clinical data: the proportion of women accepted cervical cerclage during pregnancy in MC group, LCC with MC history group and LCC without MC history group were 100.0% (54/54), 7.1% (2/28) and 27.1% (35/129), respectively ( P<0.001). The indications of the three groups showed statistical significance ( P=0.003), and the main indication was the history of abortion in the second and third trimester [75.9% (41/54) vs 89.3% (25/28) vs 84.5% (109/129)]. (2) Pregnancy complications: the incidence of abnormal fetal position [7.8% (4/51) vs 17.4% (4/23) vs 19.8% (24/121)], placenta accrete [5.9% (3/51) vs 13.0% (3/23) vs 11.6% (14/121)], uterine rupture [0 vs 4.3% (1/23) vs 5.8% (7/121)] in the MC group were all lower than those in LCC with MC history and LCC without MC history groups. However, there were no statistical significances (all P>0.05). Intrauterine inflammation or chorioamnionitis [15.7% (8/51) vs 0 vs 0.8% (1/121)] and premature rupture of membrane [23.5% (12/51) vs 4.3% (1/23) vs 0] were both significantly higher in MC group than those in LCC with MC history and LCC without MC history groups (all P<0.001). (3) Pregnancy outcomes: the cesarean section rate was significantly lower in MC group (41.2%, 21/51) than that in LCC with MC history group (100.0%, 23/23) and LCC without MC history group (100.0%, 121/121; P<0.001). MC group was associated with lower expenditure than LCC with MC history and LCC without MC history groups (12 169 vs 26 438 vs 27 783 yuan, P<0.001). The success rates of live birth cerclage did not differ significantly in MC (94.4%, 51/54), LCC with MC history (82.1%, 23/28) and LCC without MC history (93.8%, 121/129) groups ( χ2=5.649, P=0.059). There was no significant difference in neonatal intensive care unit occupancy, neonatal birth weight and neonatal asphyxia between the three groups (all P>0.05). Conclusions:Both LCC and MC are the treatment choice for women with CI, which may get similar liver birth. However, MC has the advantages of low cesarean section rate, economical and easy operation. Therefore, MC is recommended as the first choice for CI patients, and LCC is for women with failed MC.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare genetic diseases of nervous system. NBIA is characterized by varying degrees of abnormal iron metabolism and excessive iron deposition in brain tissue. The most common symptoms of NBIA are extrapyramidal symptoms. NBIA can also be associated with varying degrees of dysfunction of the pyramidal tract, cerebellum, peripheral nervous system, autonomic nervous system, mental cognition and vision functions. A patient with NBIA admitted to the Department of Neurology of Xijing Hospital in December 2020 was collected and analyzed for clinical features. Whole exome sequencing (WES) was employed to gene mutation screening, and pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics (ACMG) guideline. The patient was a 13-year-old male with a chronic course of disease that began at the age of 4. The first symptom was spastic gait. With the progress of the disease, the patient developed mental retardation, arrhythmia, coughing from drinking water and loss of vision. Magnetic resonance imaging of the head showed atrophy of the optic nerve and hypointensity signal in bilateral substantia nigra and globus pallidus on T 2WI, fluid attenuated inversion recovery sequency, diffusion weighted imaging and susceptibility weighted imaging without "tiger eye sign" which was commonly found in pantothenate kinase associated neurodegeneration. The homozygous mutation c.172G>A (p.Gly58Ser) was found through WES. The proband′s father and mother are cousins (inbreeding), carried heterozygous variation of this locus. This novel mutation was not reported in mutation database. According to ACMG guideline, C19orf12 gene c.172G>A (p.Gly58Ser) was identified for possible pathogenic mutations. The conservative prediction of this locus suggests high conservatism. The final diagnosis of the patient was mitochondrial membrane protein-associated neurodegeneration (MPAN,NBIA type 4). This finding enriched the known mutation database of MPAN and provided a basis for further study of the disease.

Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited childhood white-matter disorders, and the pathogenic gene has been confirmed as EIF2B gene. VWM is characterized by chronic progressive neurological deterioration with cerebellar ataxia, usually less prominent spasticity and relatively mild mental decline. There are episodes of rapid and major neurological deterioration provoked by stresses, such as fever, minor physical trauma and acute fright, which is a characteristic clinical feature of VWM. Brain magnetic resonance imaging findings are diagnostic in almost all patients,and the disappearance of the cerebral white matter occurs in a diffuse "melting away" pattern. The onset of VWM can be at any age from fetal stage to adult stage, and the clinical phenotypes vary immensely. Gene diagnosis is the golden standard for VWM. This article reported a patient with a course of 17 years, who was misdiagnosed as Wilson′s disease because of low serum ceruloplasmin, and was finally diagnosed as VWM by reinterpretation of whole exome sequencing, which is worthy of clinicians′ vigilance and consideration.

OBJECTIVE: To summarize the clinical phenotype and genotypic characteristics of 3 patients with KBG syndrome and epileptic seizure. METHODS: Clinical data of the patients were collected. Family-trio whole exon sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: Patients 1 and 2 were boys, and patient 3 was an adult woman. All patients had epileptic seizures and mental deficiency. Their facial features included triangular face, low hair line, hypertelorism, large forward leaning auricles, broad nasal bridge, upturned nostrils, long philtrum, arched upper lip, and macrodontia. The two boys also had bilateral Simian creases. WES revealed that the three patients all harbored heterozygous de novo frameshift variants in exon 9 of the ANKRD11 gene including c.2948delG (p.Ser983Metfs*335), c.5397_c.5398insC (p.Glu1800Argfs*150) and c.1180_c.1184delAATAA (p.Asn394Hisfs*42). So far 291 patients with ANKRD11 gene variants or 16q24.3 microdeletions were reported, with over 75% being de novo mutations. CONCLUSION Above findings have enriched the spectrum of ANKRD11 gene mutations underlying KBG syndrome. WES is helpful for the early diagnosis of KBG, and provided reference for genetic counseling of this disease.
Abnormalities, Multiple/genetics* ; Bone Diseases, Developmental/genetics* ; Epilepsy/genetics* ; Facies ; Humans ; Intellectual Disability/genetics* ; Phenotype ; Repressor Proteins/genetics* ; Seizures/genetics* ; Tooth Abnormalities/genetics*

OBJECTIVE: To explore the genetic bases of 3 patients with periventricular nodular heterotopia and epileptic seizure. METHODS: The clinical data of three patients presenting with periventricular nodular ectopic with epileptic seizure were analyzed. Whole exome sequencing (WES) was performed on the patients, and Sanger sequencing was used to validate the suspected variants. RESULTS: In three female patients, head MRI showed nodular gray matter ectopic in the bilateral ventricle. WES identified the heterozygous c.2720del T(p.Leu907Argfs*39) variant of FLNA gene in case 1 and her mother (case 2), and heterozygous c.1387_1390del GTGC(p.Val463Profs*34) of FLNA gene in case 3. According to the American College of Medical Genetics and Genomics standards and guidelines, the c.2720delT(p.Leu907Argfs*39) and c.1387_1390del GTGC (p.Val463Profs*34) variants of FLNA gene were predicted to be pathogenic (PVS1+PM2+PP1) and likely pathogenic(PVS1+PM2), respectively. CONCLUSION The c.2720delT(p.Leu907Argfs*39) and c.1387_1390del GTGC(p.Val463Profs*34) variants of FLNA gene may be the genetic cause of the three patients.
Epilepsy/genetics* ; Female ; Filamins/genetics* ; Heterozygote ; Humans ; Magnetic Resonance Imaging ; Mutation ; Periventricular Nodular Heterotopia/genetics* ; Seizures

Objective:To explore the clinical manifestations of 4 pedigrees with transthyretin related familial amyloid polyneuropathy (TTR-FAP).Methods:The clinical data were collected and analyzed from 4 pedigrees with TTR-AFP, admitted to our hospital from July 2017 to May 2019; 20 patients and 2 asymptomatic carriers of the TTR mutation gene were included. In particular, the detailed data of the 4 probands affected with TTR-FAP came from the 4 different pedigrees were collected. Results:In these 20 patients, the age of onset ranged from 30 to 65; the first symptoms of diarrhea, constipation, alternating episodes of constipation and diarrhea were found; there were damaged peripheral nerve and inexplicable weight loss; cardiomyopathy was noted in 9 patients; orthostatic hypotension was noted in 9 patients, sexual dysfunction in 5, abnormal urination in 6, and blurred vision or corestenoma in 3. TTR mutation gene was confirmed in 7 patients and pathological diagnosis was found in 3 patients. Diflunisal was used in one patient and tafamidis was used 2 patients. Twelve died and 8 patients survived among 20 patients with disease progression. All the 4 probands were male, with an average age of 49.3 years; all patients had different degrees of sensorimotor peripheral neuropathy, autonomic neuropathy and cardiomyopathy; electrophysiological examination suggested length dependent sensory motor peripheral neuropathy of the extremities, with axonal damage as the evidence; and cardiac hypertrophy was noted in echocardiography. The sural nerve biopsy of the 3 probands showed positive Congo red staining. Medical whole exon sequencing indicated that 2 probands had pathogenic mutations (TTR-E74K and TTR-A140S), and 1 proband had likely pathogenic mutation (TTR-S70R). Two asymptomatic carriers of the TTR gene mutation remained normal condition. Conclusion:The clinical manifestations of TTR-FAP include progressive sensorimotor and autonomic neuropathy, and multi-system disorders, such as combining with gastrointestinal problems, hypertrophic myocardium, inexplicable weight loss and blurred vision or corestenoma, which might be important reminders for diagnosis of TTR-FAP.

Objective:The research was aimed to investigate the association between serum total homocysteine (tHcy) and subacute combined degeneration of the spinal cord (SCD).Methods:A retrospective survey of 106 newly diagnosed patients with SCD were enrolled in this research who were treated in the department of neurology of Xijing Hospital from January 2008 to February 2019, meanwhile, 121 patients with spinal cord lesion (not SCD) and 104 neurology mild outpatients were selected as controls. Serum tHcy level was determined by using the chemiluminescent immunoassay assay. A multivariate logistic regression model was used to analyze the risk factors for SCD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and Youden index were used to evaluate the diagnostic efficacy of tHcy. Spearman correlation analysis was used to observe the correlation between tHcy and SCD severity. The SCD patients were categorized into normal or mild tHcy group, moderate tHcy group, and severe tHcy group based on tHcy levels. Clinical symptoms, nerve conduction velocity, magnetic resonance imaging (MRI) findings from the patients were studied.Results:The serum tHcy levels in SCD patients were 64.3(26.5, 98.8) μmol/L, while in patients with spinal cord lesion (not SCD) group were 13.7(10.8, 19.2) μmol/L, neurology mild outpatients were 10.6(8.2, 13.0) μmol/L, which was higher in SCD group ( H=112.020, P<0.001), ( H=165.525, P<0.001).The multivariate logistic regression model showed tHcy is the impact factor of SCD ( OR=1.107, 95% CI:1.077-1.139, P<0.001). At ROC analysis, tHcy showed diagnostic value with an optimal cut-off value of 24.9 μmol/L (AUC 0.913, 95% CI: 0.875-0.951, sensitivity 79.2%, specificity 91.6%). Spearman correlation analysis showed that tHcy was positively correlated with functional disability rating scale ( r=0.254, P=0.009). Conclusions:Serum tHcy is the risk factor for SCD and related to its disability. Focus on the increased level of tHcy plays a positive role in the diagnosis of SCD.

Objective:The research was aimed to investigate the association between serum total homocysteine (tHcy) and subacute combined degeneration of the spinal cord (SCD).Methods:A retrospective survey of 106 newly diagnosed patients with SCD were enrolled in this research who were treated in the department of neurology of Xijing Hospital from January 2008 to February 2019, meanwhile, 121 patients with spinal cord lesion (not SCD) and 104 neurology mild outpatients were selected as controls. Serum tHcy level was determined by using the chemiluminescent immunoassay assay. A multivariate logistic regression model was used to analyze the risk factors for SCD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and Youden index were used to evaluate the diagnostic efficacy of tHcy. Spearman correlation analysis was used to observe the correlation between tHcy and SCD severity. The SCD patients were categorized into normal or mild tHcy group, moderate tHcy group, and severe tHcy group based on tHcy levels. Clinical symptoms, nerve conduction velocity, magnetic resonance imaging (MRI) findings from the patients were studied.Results:The serum tHcy levels in SCD patients were 64.3(26.5, 98.8) μmol/L, while in patients with spinal cord lesion (not SCD) group were 13.7(10.8, 19.2) μmol/L, neurology mild outpatients were 10.6(8.2, 13.0) μmol/L, which was higher in SCD group ( H=112.020, P<0.001), ( H=165.525, P<0.001).The multivariate logistic regression model showed tHcy is the impact factor of SCD ( OR=1.107, 95% CI:1.077-1.139, P<0.001). At ROC analysis, tHcy showed diagnostic value with an optimal cut-off value of 24.9 μmol/L (AUC 0.913, 95% CI: 0.875-0.951, sensitivity 79.2%, specificity 91.6%). Spearman correlation analysis showed that tHcy was positively correlated with functional disability rating scale ( r=0.254, P=0.009). Conclusions:Serum tHcy is the risk factor for SCD and related to its disability. Focus on the increased level of tHcy plays a positive role in the diagnosis of SCD.