OBJECTIVE: To explore the genetic variants and phenotypic characteristics of patients with Neurofibromatosis type I (NF1). METHODS: Twenty two NF1 patients who presented at Enze Medical (Center) Group in Taizhou between 2018 and 2024 were selected as the study subjects. Clinical phenotype and family history were collected for the patients. Whole exome sequencing (WES) was carried out for the 22 probands to screen the variants of NF1 gene. Candidate variants were verified by Sanger sequencing of their family members. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: K20230902). RESULTS: The 22 probands were diagnosed between the age of 5 months to 47 years old, and have all shown cafe au lait spots on their skin. Seventeen patients exhibited the phenotype at birth, and 11 had various degrees of neurofibromatosis. Among them, probands 1 and 13 underwent surgical resection of the tumor but had recurred, while proband 12 had amputation due to the huge size and serious impact of the neurofibroma and had no recurrence. Five patients had various degrees of scoliosis. In total 22 germline mutations and one somatic mutation were identified among the 22 families, with 5 variants unreported previously, including 1 nonsense mutation c.1603C>T (Q535*), 3 frameshift mutations [c.7268_7269delCA (Thr2423fs), c.2293del (Arg765Alafs*26), and c.5433_5438delinsGC (Phe1812ArgfsTer50)], and 1 deletion involving exons 41-44 of the NF1 gene and adjacent introns. Proband 13 was found to harbor germline mutation c.6796C>T (Gln2266Ter) and somatic mutation c.1019_1020del (Ser340Cysfs Ter12) in the peripheral blood and tumor tissue, respectively. Among the 22 NF1 probands, 6 had received treatment due to severe illness. Proband 1 had tumor resection in the right upper limb, but was found to have malignant lung tumor and died during follow-up. Proband 12 had multiple recurrence of neurofibroma in the left ring finger. Proband 4 underwent spinal correction surgery due to severe scoliosis. Proband 11 had died due to a central nervous system disease. Among the 22 germline mutations, 6 had led to the occurrence of truncated proteins, which may have a more severe impact on the phenotype. CONCLUSION This study investigated the genetic variants and clinical phenotypes of 22 NF1 families and identified 5 novel variants of the NF1 gene, which has expanded the genotypic and phenotypic spectra of the NF1. Preliminary studies have identified an association between truncated mutations, young age, and severe phenotypes, which may provide important clues for prognosis evaluation. For the clinical diagnosis and treatment of NF1, it is necessary to consider the phenotypic characteristics and genetic testing in combination with genetic counseling and long-term follow-up.
Humans ; Neurofibromatosis 1/pathology* ; Male ; Female ; Pedigree ; Adult ; Child ; Child, Preschool ; Middle Aged ; Adolescent ; Infant ; Young Adult ; Neurofibromin 1/genetics* ; Phenotype ; Asian People/genetics* ; Mutation ; Exome Sequencing ; East Asian People

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with Hereditary spastic paraplegia type 3A (SPG3A) and the genotype-phenotype correlation. METHODS: A three-generation pedigree presented at Huantai Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Whole-exome sequencing (WES) and pedigree analysis was carried out. Candidate variant was validated by Sanger sequencing of the members from the pedigree. Haplotype analysis was used to trace the origin of the variant, and pathogenicity was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-12). RESULTS: A c.1024C>T (p.Pro342Ser) variant of the ATL1 was identified in the four affected members, including the proband, but none of the three unaffected relatives. Haplotype analysis suggested that the variant was derived from the proband's mother and has co-segregated with the disease phenotype. Based on the guidelines of the ACMG, it was classified as likely pathogenic. CONCLUSION The ATL1 c.1024C>T (p.Pro342Ser) variant probably underlay the pathogenesis in this pedigree. Above finding has enriched the mutational spectrum of ATL1 and phenotypic spectrum of SPG3A in the Chinese population, and enabled genetic counseling for this pedigree.
Humans ; Pedigree ; Spastic Paraplegia, Hereditary/genetics* ; Male ; Female ; Asian People/genetics* ; Adult ; Haplotypes ; Membrane Proteins/genetics* ; Exome Sequencing ; GTP-Binding Proteins/genetics* ; Mutation ; Middle Aged ; China ; Genetic Association Studies ; East Asian People

BACKGROUND

Spinocerebellar Ataxia (SCA) represents a rare and heterogeneous group of neurodegenerative disorders, typically characterized by the progressive loss of coordination of movement, resulting primarily from cerebellar dysfunction. This case report discusses the history, clinical presentation, and diagnostic findings of a patient who exhibited symptoms suggestive of SCA. Given the notable familial pattern, further evaluation was undertaken using genetic testing. The objective of this paper is to present the clinical, genetic findings, and inheritance pattern of a patient and her family with SCA.

CASE PRESENTATION

Our case is a 36-year-old Filipino female with progressive cerebellar dysfunction for over a decade. Cranial Magnetic Resonance Imaging (MRI) revealed bilateral cerebellar atrophy. Genetic testing identified a Variant of Uncertain Significance (VUS) in the inositol 1,4,5- triphosphate receptor type 1 (ITPR1) gene, a finding consistent with Spinocerebellar Ataxia type 15 (SCA 15). This represents the first reported case of SCA 15 in the Philippines and in Asia.

A detailed pedigree assessment revealed that 18 immediate and extended family members had similar symptoms suggestive of hereditary ataxia. Ten relatives had already passed away, and four could not be contacted for further evaluation. Three available family members were examined and likewise demonstrated comparable cerebellar findings, supporting a familial pattern of the disease.

CONCLUSION

The findings from this case series suggest that SCA 15 may be present in Filipino families, with an autosomal dominant (AD) inheritance pattern. While no data on the prevalence or incidence of SCA15 in the Philippines currently exists, this report calls attention to the need for further research and genetic studies within the Filipino population.

Human ; Female ; Adult: 25-44 Yrs Old ; Spinocerebellar Ataxias ; Ataxia ; Mutation ; Genes ; Asia

OBJECTIVE

To present a long-term follow-up report of a 10-year-old male with optic nerve glioma who underwent surgical removal and postoperative chemotherapy.

METHODS

Case report.

RESULTS

A 10-year-old Filipino boy was referred to a tertiary institution for a five-year history of progressive right eye proptosis with vision loss. Pertinent findings included right eye proptosis, lagophthalmos, and limited elevation and adduction. He also had several hyperpigmented lesions on the abdomen and upper torso. Vision on the right was no light perception, with a relative afferent pupillary defect, exposure keratopathy, and optic nerve pallor. Vision on the left eye was 20/20 with a temporal visual field defect. Cranial and orbital computed tomography (CT) scan showed a circumscribed enhancing mass within the right intraconal space with widened right optic nerve canal. Additional magnetic resonance imaging (MRI) revealed a heterogeneously enhancing mass diffusely involving the intraorbital and intracanalicular segments of the right optic nerve suspicious for optic nerve glioma. He underwent excision of the orbital portion of the mass via lateral orbitotomy. Histopathology showed pilocytic astrocytoma. Eight cycles of chemotherapy with carboplatin and vincristine was completed. Significant improvement of globe position and resolution of ocular exposure was achieved postoperatively with residual right ptosis. These findings remained stable at six years after treatment.

CONCLUSION

Optic nerve gliomas with intracanalicular and chiasmal extension can be managed with surgical removal of the orbital component and postoperative chemotherapy. This can result in improvement of proptosis and long-term remission.

Human ; Male ; Child: 6-12 Yrs Old ; Optic Nerve Glioma ; Neurofibromatosis 1 ; Pilocytic Astrocytoma ; Astrocytoma ; Chemotherapy ; Drug Therapy

INTRODUCTION

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited condition seen in one of 4000 live births, predisposing to peripheral and central neurofibromas. Spinal tumors are seen in 40% of cases with NF1 and only 2% will develop symptoms, and among those who develop symptoms where 33% showed intradural extramedullary location. Thoracic spinal dumbbell neurofibroma is even rarer, and cases that extend to obliterate the posterior mediastinum even more so, with the case presented being the largest in size documented to date.

CASE

A 34-year-old female presented since childhood clinical findings consistent with Neurofibromatosis Type I: generalized cafe-au-lait macules, axillary freckling, cutaneous neurofibromas, two iris Lisch nodules identified via slit lamp examination, and anterolateral bowing of the right tibia, and no known parental history of Neurofibromatosis Type I. Prior to admission, the patient presented with progressive loss of motor strength of the lower extremities, and progressive dyspnea. Work-up revealed a Thoracic Intradural Extramedullary Neurofibroma extending to the Right Posterior Mediastinum measuring 15.3 cm x 12.9 cm x 9.7 cm in the thoracic cavity compressing the right lung and bronchus. An extensive two stage surgery was contemplated involving an initial resection of the Intradural mass, with spine instrumentation for support, and subsequent resection of the mediastinal extension. However, complications from the compressing tumor: complete cord transection syndrome causing spinal autonomic dysfunction, lung and airway compromise causing prolonged intubation and difficulty in weaning from mechanical ventilatory support, extensive thrombus formation in the right jugular vein, and nosocomial infections all created compounding difficulties for the surgical technique and anesthetic plan.

Cornerstone management for dumbbell spinal neurofibromas involves their total removal. The best results are obtained in patients showing minimal neurological deficits during the preoperative period. However, little improvement may be expected from patients who develop complete transection syndrome during the postoperative period. Concurrent medical management to prepare the patients are equally important. The multi-subspecialty approach required in managing these cases entails a good balance between the disability before the surgery, anticipated outcomes, and quality of life of the patients.

Human ; Female ; Adult: 25-44 Yrs Old ; Neurofibromatosis 1

Wunderlich Syndrome is a rare potentially life-threatening phenomenon that involves spontaneous non-traumatic retroperitoneal hemorrhage. At present, identifying the course of conservative management in these patients, especially in pregnancy, has not been clinically established. Presented here is a known case of Tuberous Sclerosis Complex with a Bilateral, 10cm Angiomyolipoma in a 31-year-old female, initially managed with active surveillance. At 27 weeks of pregnancy, she presented with a sudden onset of left flank pain with a hematocrit of 22%. Anemia was corrected with blood transfusions. A contrast-enhanced MRI of the abdomen showed a large subcapsular perirenal hematoma of the left kidney. Renal angioembolization of the bleeding segmental renal artery was done. The patient was conservatized until 37 weeks of pregnancy and underwent cesarean section delivery.

Four months after angioembolization, she had a recurrence of the left flank pain associated with gross hematuria and hypovolemic shock. The patient underwent emergency renal exploration of the left kidney via a transabdominal approach. Three liters of hemoperitoneum and a large expanding left retroperitoneal hematoma were noted intraoperatively. Early vascular control before nephrectomy of the left kidney was done. The postoperative course was unremarkable and the patient was discharged with improved condition.

This case displays a unique course in the management of a bleeding angiomyolipoma especially during pregnancy. Renal angioembolization can aid in achieving the age of viability in pregnancy. However, close monitoring for rebleeding should be kept in mind. A lower threshold for conservative management should be utilized when patients have a previous history of bleeding.

Human ; Female ; Adult: 25-44 Yrs Old ; Abdomen ; Anemia ; Angiomyolipoma ; Arteries ; Blood ; Blood Transfusion ; Cesarean Section ; Conservative Treatment ; Emergencies ; Female ; Flank Pain ; Hematocrit ; Hematoma ; Hematuria ; Hemoperitoneum ; Hemorrhage ; History ; Hypovolemia ; Insemination, Artificial, Heterologous ; Kidney ; Life ; Nephrectomy ; Pain ; Patients ; Pregnancy ; Recurrence ; Renal Artery ; Research Report ; Sclerosis ; Shock ; Syndrome ; Tuberous Sclerosis ; Watchful Waiting

OBJECTIVE: To investigate the effects of acupuncture on the neurotransmitter levels and gut microbiota in a mouse model of Tourette syndrome (TS). METHODS: Thirty-six male C57/BL6 mice were randomly divided into 4 groups using a random number table method: 3,3'-iminodipropionitrile (IDPN) group, control group, acupuncture group, and tiapride group, with 9 mice in each group. In the IDPN group, acupuncture group, and tiapride group, mice received daily intraperitoneal injections of IDPN (300 mg/kg body weight) for 7 consecutive days to induce stereotyped behaviors. Subsequently, in the acupuncture intervention group, standardized acupuncture treatment was administered for 14 consecutive days to IDPN-induced TS model mice. The selected acupoints included Baihui (DU 20), Yintang (DU 29), Waiguan (SJ 5), and Zulinqi (GB 41). In the tiapride group, mice were administered tiapride (50 mg/kg body weight) via oral gavage daily for 14 consecutive days. The control group, IDPN group, and acupuncture group received the same volume of saline orally for 14 consecutive days. Stereotypic behaviors were quantified through behavioral assessments. Neurotransmitter levels, including dopamine (DA), glutamate (Glu), and aspartate (ASP) in striatal tissue were measured using enzyme-linked immunosorbent assay. Dopamine transporter (DAT) expression levels were additionally quantified through quantitative polymerase chain reaction (qPCR). Gut microbial composition was analyzed through 16S ribosomal RNA gene sequencing, while metabolic profiling was conducted using liquid chromatography-mass spectrometry (LC-MS). RESULTS: Acupuncture administration significantly attenuated stereotypic behaviors, concurrently reducing striatal levels of DA, Glu and ASP concentrations while upregulating DAT expression compared with untreated TS controls (P<0.05 or P<0.01). Comparative analysis identified significant differences in Muribaculaceae (P=0.001), Oscillospiraceae (P=0.049), Desulfovibrionaceae (P=0.001), and Marinifilaceae (P=0.014) following acupuncture intervention. Metabolomic profiling revealed alterations in 7 metabolites and 18 metabolic pathways when compared to the TS mice, which involved various amino acid metabolisms associated with DA, Glu, and ASP. CONCLUSIONS Acupuncture demonstrates significant modulatory effects on both central neurotransmitter systems and gut microbial ecology, thereby highlighting its dual therapeutic potential for TS management through gut-brain axis regulation.
Animals ; Tourette Syndrome/metabolism* ; Gastrointestinal Microbiome ; Neurotransmitter Agents/metabolism* ; Acupuncture Therapy ; Male ; Mice, Inbred C57BL ; Mice

Neurofibromatosis Type 1 （NF1） is an autosomal dominant hereditary neurological disorder. One of the typical manifestations of NF1 is neurofibroma, which can develop gradually over time. When the volume exceeds 100 cm², it is referred to as giant neurofibroma, representing a tumor-like proliferation of Schwann cells within the nerve fiber sheath. The Department of Otolaryngology at the Affiliated Hospital of Guangdong Medical University received a rare case involving a patient with giant neurofibromatosis affecting the maxillofacial region, neck, and chest. The patient underwent successful surgical treatment with the collaboration of various medical disciplines.
Humans ; Head and Neck Neoplasms/surgery* ; Neck ; Neurofibromatoses ; Neurofibromatosis 1/surgery* ; Thoracic Neoplasms/surgery*

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the abnormal expansion of CAG trinucleotide repeats in the Huntingtin gene (HTT) located on chromosome 4. It is transmitted in an autosomal dominant manner and is characterized by motor dysfunction, cognitive decline, and emotional disturbances. To date, there are no curative treatments for HD have been developed; current therapeutic approaches focus on symptom relief and comprehensive care through coordinated pharmacological and nonpharmacological methods to manage the diverse phenotypes of the disease. International clinical guidelines for the treatment of HD are continually being revised in an effort to enhance care within a multidisciplinary framework. Additionally, innovative gene and cell therapy strategies are being actively researched and developed to address the complexities of the disorder and improve treatment outcomes. This review endeavours to elucidate the current and emerging gene and cell therapy strategies for HD, offering a detailed insight into the complexities of the disorder and looking forward to future treatment paradigms. Considering the complexity of the underlying mechanisms driving HD, a synergistic treatment strategy that integrates various factors-such as distinct cell types, epigenetic patterns, genetic components, and methods to improve the cerebral microenvironment-may significantly enhance therapeutic outcomes. In the future, we eagerly anticipate ongoing innovations in interdisciplinary research that will bring profound advancements and refinements in the treatment of HD.
Huntington Disease/pathology* ; Humans ; Genetic Therapy/methods* ; Animals ; Huntingtin Protein/genetics* ; Cell- and Tissue-Based Therapy/methods*

OBJECTIVE: To explore the genetic testing outcomes of a fetal family with Thyroid dyshormonogenesis type 5 (TDH5) and familial Neurofibromatosis type 1 (NF1), and to clarify the association between clinical manifestations and genetic variations. METHODS: One case of a TDH5 combined with familiar NF1 fetus treated at Gansu Maternal and Child Health Hospital in January 2024 was selected as the research subject. The clinical and family history data of the fetus were collected by retrospective research method. 10-15 mL of fetal amniotic fluid, and 2-3 mL of peripheral blood from the parents, sister, and grandfather of the fetus were collected, and genomic DNA was extracted for trio whole-exome sequencing (trio-WES). The Sanger sequencing was utilized to validate candidate variants for family verification. According to the Standards and Guidelines for the Interpretation and Reporting of Sequence Variants of the American Society of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG guidelines), the pathogenicity of the detected variants was classified. This study has been approved by the Medical Ethics Committee of Gansu Maternal and Child Health Hospital [Ethics No.（2021）GSFY（65）]. RESULTS: The fetal ultrasound indicated the nuchal translucency (NT) thickening, and the thyroid function test results of the sister showed an increase in thyroid stimulating hormone and a decrease in free thyroid hormone. Simultaneously, there were cafe-au-lait macules of various sizes in multiple parts of the body of the sister, and the mother had a similar cafe-au-lait macules phenotype. The trio-WES results revealed that there was a c.413dupA (p.Tyr138*) frameshift mutation in exon4 and c.573G>A (p.Trp191*) nonsense mutation in exon5 of the fetal DUOXA2, which were inherited from the mother and father, respectively. In accordance with the ACMG guidelines, they were classified as pathogenic variant (PVS1+PM2_Supporting+PM3) and likely pathogenic variant (PVS1+PM2_Supporting), respectively. And the nonsense mutation c.6972C>A (p.Tyr2264*) was detected in exon46 of the NF1 in the fetus, inherited from the mother maternal grandfather. The genetic testing results of the first sister and proband in this case were consistent, and the DUOXA2 and NF1 of the second sister were both wild-type. According to the ACMG guidelines, c.6972C>A (p.Tyr2264 *) was classified as pathogenic variant (PVS1+PS4_Supporting+PP4+PM2_Supporting). CONCLUSION The mutations in the DUOXA2 gene c.413dupA (p.Tyr138*) and c.573G>A (p.Trp191*), and the NF1 gene c.6972C>A (p.Tyr2264*) might be the genetic causes of TDH5 combined with familiar NF1 in proband. The discovery of the DUOXA2 gene c.573G>A (p.Trp191*) enriches the spectrum of pathogenic gene variations.
Humans ; Female ; Pedigree ; Pregnancy ; Neurofibromatosis 1/complications* ; Male ; Genetic Testing ; Adult ; Thyroid Dysgenesis/genetics* ; Fetus ; Exome Sequencing ; Mutation