Variable phenotypes and outcomes associated with the MMACHC c.609G>A homologous mutation: long term follow-up in a large cohort of cases.

BACKGROUND: Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention. METHODS: We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019. RESULTS: Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group. CONCLUSIONS: Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.

Hypothalamic Hamartoma, Gray Matter Heterotopia, and Polymicrogyria in a Boy: Case Report and Literature Review.

BACKGROUND: Hypothalamic hamartomas (HHs) are rare, and it is even rarer when combined with gray matter heterotopia (GMH) and polymicrogyria (PMG). CASE DESCRIPTION: A 5-year-old boy with HH, GMH, and PMG was retrospectively evaluated. The clinical data, including the symptoms, examinations, diagnosis, and treatment, were collected. The patient had a chief complaint of gelastic seizures and intellectual deficiency. Brain magnetic resonance imaging showed HH, paraventricular nodular heterotopia, and PMG. Video electroencephalographs were normal. The patient underwent resection of the HH via transcallosal transseptal interforniceal approach. Seizures disappeared immediately after complete resection of HH, and the intellectual development improved. CONCLUSIONS: In this extremely rare case, resection of the HH eliminated the symptoms. Nonetheless, we still need to be cautious about the possible epilepsy that may be caused by GMH and PMG.

Predictive Factors of Postoperative Seizure for Pediatric Patients with Unruptured Arteriovenous Malformations.

BACKGROUND: Seizure is the second-most common presentation in patients with arteriovenous malformations (AVMs) and superimposes a significant burden on pediatric patients. Postoperative seizure risk in unruptured AVMs is underreported in the pediatric AVM literature. We aimed to characterize and identify predictive factors for postoperative seizures in this study. METHODS: We performed a retrospective review of all surgically treated pediatric patients with unruptured AVM at our institution from 2001 to 2014. Patients younger than 18 years of age were included. Baseline variables was compared against our outcome of interest, which was defined as patients with or without follow-up seizures. Multivariable Cox regression was performed to identify potential predictive factors. RESULTS: The average age of all patients was 13.1 years, and 68.2% were male. Nine patients were asymptomatic (13.6%), and seizure presentation occurred in 57.6% (n = 38). During an average follow-up of 4.2 years, 12 (18.2%) patients experienced postoperative seizures, with 5 (17.9%) of 28 patients with seizures being de novo. In patients with seizure presentation, 81.6% were completely seizure-free throughout follow-up. In multivariable analysis, larger AVM size (hazard ratio [HR] 1.63, P = 0.023) and temporal location (HR 8.35, P = 0.007) were found to increase the risk of follow-up seizures. On the contrary, seizure presentation (HR 1.91, P = 0.369) and postoperative infection (HR 2.37, P = 0.265) were not associated. CONCLUSIONS: Surgery may eliminate most seizures with low risk of inducing de novo seizures in pediatric patients with unruptured AVM. Predictive factors for postoperative seizures included large AVM size and temporal location. For selected unruptured AVMs with small size and nontemporal location, consideration of surgery as primary treatment for persistent seizures is a reasonable option.

[Peri-operation treatment for patients with hemophilia A in children with intracranial malignant tumor: a report of 2 cases].

Hemophilia A is aninherited bleeding disorder, lack of coagulation factor VIII (FVIII), and if combined with intracranial malignant tumor, the operation risk is very high. Department of Pediatric Surgery in Peking University First Hospital used coagulation factor replacement therapy, succeeded in the operation of 2 cases of intracranial malignant tumor with hemophilia A in children, with no abnormal bleeding events. The establishment of the multi subject cooperation group before operation, good preoperative preparation, enough alternative factors, and close postoperative monitoring, are the key to the successful treatment.

Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer.

Secreted protein acidic and rich in cysteine (SPARC) gene has been shown to be epigenetically silenced in several cancers. We investigated the loss of expression and promoter methylation of this tumor suppressor gene in gastric cancers and correlated the data with clinicopathological features. We observed the loss of SPARC mRNA and SPARC protein expression in 7 of 10 (70%) gastric cancer cell lines. Upon treatment of expression-negative cell lines with a demethylating agent, expression of mRNA and protein was restored in all cells. Methylation rate of SPARC gene was 80% in ten gastric cancer cell lines and 74% (163 of 220) in primary tumors, while it was 5% in normal gastric mucosa (n = 40). In intestinal gastric cancer, SPARC methylation correlated with a negative prognosis (P < 0.001; relative risk 2.754, 95% confidence interval 1.780-4.261). Immunostaining revealed that SPARC protein was overexpressed in stromal fibroblasts adjacent to neoplastic epithelium but rarely expressed in the primary gastric cancer cells. These results implicate SPARC promoter methylation as an important factor in the tumorigenesis of gastric carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and the potential clinical importance in human gastric cancers.

[Children primary intestinal inflammatory myofibroblastic tumor: a case report].

Children intestinal inflammatory myofibroblastic tumor (IMT) is rare, and its clinical differential is very difficult to the malignant tumor. Its diagnosis depends on pathology, and operation is the most effective therapy method. We preset here a case of a 5-year-old girl who was admitted to the hospital for intestinal obstruction. A malignant tumor in the intestinal wall showed on the enhanced CT. Exploratory laparotory found the tumor and then it was resected. Postoperative pathology and immunohistochemistry proved that it was an intestinal IMT. Three months' follow-up found no tumor recurrence and metastasis.

[Cause and treatment of intracranial hypertension after sylvian cystoperitoneal shunting].

OBJECTIVE: To analyze the cause and treatment of intracranial hypertension after sylvian cystoperitoneal shunting. METHODS: Sixteen cases were retrospectively reviewed. There were 10 males and 6 females. The age range was 2-19 years old (mean: 9.94). All patients had a sylvian cystoperitoneal shunt via a common low-pressure tube. RESULTS: The onset time of intracranial hypertension after cystoperitoneal shunting was 3 months to 7 years (mean: 3.20 yr). Three cases underwent the operation of adjusting intracranial location of shunt tube. The original tube was removed in 12 cases. Among them, 10 cases were operated by lateral ventricle-peritoneal shunt. The other two and two cases with a remaining tube were treated successfully with dehydration drugs. CONCLUSION: The cause of intracranial hypertension is probably due to tube blockage or less draining after the shrinking or disappearance of arachnoid cyst. Adjusting the location of intracranial tube or performing a lateral ventricle-peritoneal shunt has an excellent efficacy if a dehydration therapy is unresponsive or auto-compensation fails.

[Complications after transcallosal transseptal interforniceal resection of hypothalamic hamartoma: analysis of 37 cases].

OBJECTIVE: To summarize the post-operative complications of resection of hypothalamic hamartoma (HH) through transcallosal transseptal interforniceal approach. METHODS: Thirty-seven HH patients, 26 males and 11 females, aged 8.7 underwent resection of the tumor via the transcallosal transseptal interforniceal approach. The symptoms and blood electrolytes were observed. RESULTS: After operation blood electrolyte test showed that 8 cases were normal, 19 cases showed hyponatremia as prime abnormality, and 10 cases had hypernatremia primarily. Among the 19 cases with hyponatremia transient apathy occurred in 2 cases, general epilepsy occurred in one patient, continuous minor epilepsy occurred in another one, 4 patients suffered minor epilepsy, 25 had fever the temperature of 3 of which were beyond 40 degrees C, and 2 had transient diabetes insipidus and 1 had diabetes. CONCLUSION: Resection of HH through the transcallosal transseptal interforniceal approach achieves significant improvement of gelastic seizures with fewer complications. The most common complication is disturbance of serum natrium, which, however, is mild and well managed.