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.

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.

OBJECTIVE: To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. METHODS: The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. RESULTS: NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. CONCLUSION Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.
Humans ; Neurofibromatosis 1/pathology* ; Neurofibromin 1/metabolism* ; GTPase-Activating Proteins ; Mutation ; Genetic Predisposition to Disease ; Genetic Therapy

OBJECTIVE

Our study aimed to determine the clinical profile and pulmonary function of pediatric patients with Duchenne Muscular Dystrophy (DMD). We also characterized the stages of progression of the disease and determined their potential association with spirometry variables.

In this cross-sectional study, we used data obtained from a review of medical records of all pediatric patients (0-18 years old) with DMD seen in a multidisciplinary neuromuscular clinic of a tertiary government hospital from August 2018 until March 2020.

Included were 30 patients subdivided into groups according to the stage of disease progression. Overweight (26.7%), obesity (20%), and scoliosis (26.7%) were common among non-ambulatory patients. Only one late ambulatory patient had evidence of ineffective airway clearance. Symptoms of sleep-disordered breathing, particularly snoring (66.7%) and apnea (6.7%), were common across all disease stages. All patients had normal peripheral oxygen saturation on room air. The mean peak expiratory flow rate was 215.6 (±84) L/min. The mean Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), and FEV1/FVC were 66.2% (±23.7), 67.7% (±23.8), and 97.5 (±3.2), respectively. Among patients with polysomnography results, the average apnea-hypopnea index (AHI) per hour was 3 (±1.6). When patients were compared according to their stage disease progression, however, no significant differences exist.

This is the first study on the pulmonary function of Filipino pediatric patients with DMD. Spirometry patterns characteristic of restrictive lung disease were observed. Prospective studies may help identify respiratory variables that significantly correlate with pulmonary function.

Humans ; Muscular Dystrophy, Duchenne/epidemiology* ; Prevalence ; Myocardium

Humans ; Herpesvirus 3, Human ; Myelitis, Transverse/complications* ; Guillain-Barre Syndrome/complications* ; Herpes Zoster/complications* ; Varicella Zoster Virus Infection/complications*

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with hereditary spastic paraplegia type 30 (HSP30). METHODS: A proband presented at the Second Hospital of Shanxi Medical University in August 2021 was selected as the study subject. The proband was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The proband was found to have harbored a heterozygous c.110T>C variant in exon 3 of the KIF1A gene, which can cause substitution of isoleucine by threonine at position 37 (p.I37T) and alter the function of its protein product. The same variant was not found in his parents, elder brother and elder sister, suggesting that it has a de novo origin. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PM2_Supporting+PP3+PS2). CONCLUSION The c.110T>C variant of the KIF1A gene probably underlay the HSP30 in the proband. Above finding has enable genetic counseling for this family.
Humans ; Male ; East Asian People ; Kinesins/genetics* ; Mutation ; Pedigree ; Spastic Paraplegia, Hereditary/genetics* ; Female

OBJECTIVE: To explore the genetic basis for 7 families with gonadal mosaicism for Duchenne muscular dystrophy (DMD). METHODS: For the 7 families presented at the CITIC Xiangya Reproductive and Genetic Hospital from September 2014 to March 2022, clinical data were collected. Preimplantation genetic testing for monogenic disorders (PGT-M) was carried out for the mother of the proband from family 6. Peripheral venous blood samples of the probands, their mothers and other patients from the families, amniotic fluid samples from families 1 ~ 4 and biopsied cells of embryos cultured in vitro from family 6 were collected for the extraction of genomic DNA. Multiplex ligation-dependent probe amplification (MLPA) was carried out for the DMD gene, and short tandem repeat (STR)/single nucleotide polymorphism (SNP)-based haplotypes were constructed for the probands, other patients, fetuses and embryos. RESULTS: The results of MLPA showed that the probands and the fetuses/probands' brothers in families 1 ~ 4, 5, 7 had carried the same DMD gene variants, whilst the probands' mothers were all normal. The proband in family 6 carried the same DMD gene variant with only 1 embryo (9 in total) cultured in vitro, and the DMD gene of the proband's mother and the fetus obtained through the PGT-M were normal. STR-based haplotype analysis showed that the probands and the fetuses/probands' brothers in families 1 ~ 3 and 5 have inherited the same maternal X chromosome. SNP-based haplotype analysis showed that the proband from family 6 has inherited the same maternal X chromosome with only 1 embryo (9 in total) cultured in vitro. The fetuses in families 1 and 6 (via PGT-M) were both confirmed to be healthy by follow up, whilst the mothers from families 2 and 3 had chosen induced labor. CONCLUSION Haplotype analysis based on STR/SNP is an effective method for judging gonad mosaicism. Gonad mosaicisms should be suspected for women who have given births to children with DMD gene variants but with a normal peripheral blood genotype. Prenatal diagnosis and reproductive intervention may be adapted to reduce the births of further affected children in such families.
Male ; Pregnancy ; Child ; Humans ; Female ; Muscular Dystrophy, Duchenne/diagnosis* ; Dystrophin/genetics* ; Mosaicism ; Exons ; Prenatal Diagnosis/methods* ; Nucleotides

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a child with Hereditary spastic paraplegia (HSP). METHODS: A child with HSP who was admitted to the Third Affiliated Hospital of Zhengzhou University on August 10, 2020 due to discovery of tiptoeing for 2 years was selected as the study subject, and relevant clinical data was collected. Peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. And trio-whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. Bioinformatic software was used to analyze the conservation of variant sites. RESULTS: The child was a 2-year-and-10-month-old female with clinical manifestations including increased muscle tone of lower limbs, pointed feet, and cognitive language delay. Trio-WES results showed that she had harbored compound heterozygous variants of c.865C>T (p.Gln289*) and c.1126G>A (p.Glu376Lys) of the CYP2U1 gene. And the corresponding amino acid for c.1126G>A (p.Glu376Lys) is highly conserved among various species. Based on guidelines from the American College of Medical Genetics and Genomics, the c.865C>T was predicted as a pathogenic variant (PVS1+PM2_Supporting), and c.1126G>A was rated as a variant of uncertain significance (PM2_Supporting+PM3+PP3). CONCLUSION The child was diagnosed with HSP type 56 due to compound variants of the CYP2U1 gene. Above findings have enriched the mutation spectrum of the CYP2U1 gene.
Female ; Humans ; Cytochrome P450 Family 2/genetics* ; Mutation ; Pedigree ; Phenotype ; Spastic Paraplegia, Hereditary/genetics* ; Infant

OBJECTIVE: To carry out carrier screening for Spinal muscular atrophy (SMA) in reproductive-aged individuals from Dongguan region and determine the carrier frequency of SMN1 gene mutations. METHODS: Reproductive-aged individuals who underwent SMN1 genetic screening at the Dongguan Maternal and Child Health Care Hospital from March 2020 to August 2022 were selected as the study subjects. Deletions of exon 7 and 8 (E7/E8) of the SMN1 gene were detected by real-time fluorescence quantitative PCR (qPCR), and prenatal diagnosis was provided for carrier couples by multiple ligation-dependent probe amplification (MLPA). RESULTS: Among the 35 145 subjects, 635 were found to be carriers of SMN1 E7 deletion (586 with heterozygous E7/E8 deletion, 2 with heterozygous E7 deletion and homozygous E8 deletion, and 47 with sole heterozygous E7 deletion). The carrier frequency was 1.81% (635/35 145), with 1.59% (29/1 821) in males and 1.82% (606/33 324) in females. There was no significant difference between the two genders (χ² = 0.497, P = 0.481). A 29-year-old woman was found to harbor homozygous deletion of SMN1 E7/E8, and was verified to have a SMN1∶SMN2 ratio of [0∶4], none of her three family members with a [0∶4] genotype had clinical symptoms. Eleven carrier couples had accepted prenatal diagnosis, and one fetus was found to have a [0∶4] genotype, and the pregnancy was terminated. CONCLUSION This study has determined the SMA carrier frequency in Dongguan region for the first time and provided prenatal diagnosis for carrier couples. The data can provide a reference for genetic counseling and prenatal diagnosis, which has important clinical implications for the prevention and control of birth defects associated with SMA.
Humans ; Child ; Pregnancy ; Male ; Female ; Adult ; Homozygote ; Sequence Deletion ; Prenatal Diagnosis ; Genetic Testing ; Muscular Atrophy, Spinal/genetics* ; Survival of Motor Neuron 1 Protein/genetics* ; Genetic Carrier Screening

Humans ; Muscular Dystrophy, Duchenne/diagnosis* ; Cardiomyopathy, Dilated/diagnosis* ; Echocardiography ; Patients