Novel CAD gene mutations in a boy with developmental and epileptic encephalopathy 50 with dramatic response to uridine therapy: a case report and a review of the literature.

BACKGROUND: Developmental and epileptic encephalopathy-50 (DEE-50) is a rare clinical condition believed to be caused by a mutation in the CAD gene and is associated with a bleak prognosis. CAD-related diseases have a wide range of clinical manifestations and other symptoms that may be easily overlooked. Like other rare diseases, the clinical manifestations and the treatment of DEE-50 necessitate further investigation. CASE PRESENTATION: A 1-year-old male patient presented with developmental delay, seizures, and anaemia at 3 months of age. He further developed refractory status epilepticus (SE), rapid deterioration of cognitive and motor function, and even became comatose at 5 months of age. Whole-exome sequencing of trios (WES-trios) revealed a compound heterozygous variant in the CAD gene, with one locus inherited from his father (c.1252C>T: p.Q418* nonsense mutation) and one from his mother (c.6628G>A: p.G2210S, missense mutation). This compound heterozygous CAD variant was unreported in the Human Gene Mutation Database. After uridine treatment, his cognitive faculties dramatically improved and he remained seizure-free. Forty two cases with CAD gene mutation reported in the literatures were reviewed. Among them, 90% had onset before 3 years of age, with average of 1.6±1.8 years old. The average age of diagnosis was 7.7 ± 10 years. The mortality rate was approximately 9.5%, with all reported deaths occurring in patients without uridine treatment. The clinical entity could be improved dramatically when the patient treated with uridine. CONCLUSIONS: We present a boy with DEE 50 caused by novel CAD gene mutations and reviewed the clinical features of 42 patients reported previously. DEE 50 has early onset, refractory seizures, even status epilepticus leading to death, with favorable response to treatment with oral uridine. Early uridine treatment is recommended if CAD defect is suspected or genetically diagnosed. This study enhances the knowledge of DEE 50 and expands the spectrum of CAD gene mutations.

Whole-exome sequencing analysis identifies novel variants associated with Kawasaki disease susceptibility.

BACKGROUND: Kawasaki disease (KD) is an acute pediatric vasculitis affecting genetically susceptible infants and children. Although the pathogenesis of KD remains unclear, growing evidence links genetic susceptibility to the disease. METHODS: To explore the genes associated with susceptibility in KD, we applied whole-exome sequencing to KD and control subjects from Yunnan province, China. We conducted association study analysis on the two groups. RESULTS: In this study, we successfully identified 11 significant rare variants in two genes (MYH14 and RBP3) through the genotype/allele frequency analysis. A heterozygous variant (c.2650G > A, p.V884M) of the RBP3 gene was identified in 12 KD cases, while eight heterozygous variants (c.566G > A, p.R189H; c.1109 C > T, p.S370L; c.3917T > G, p.L1306R; c.4301G > A, p.R1434Q; c.5026 C > T, p.R1676W; c.5329 C > T, p.R1777C; c.5393 C > A, p.A1798D and c.5476 C > T, p.R1826C) of the MYH14 gene were identified in 8 KD cases respectively. CONCLUSION: This study suggested that nine variants in MYH14 and RBP3 gene may be associated with KD susceptibility in the population from Yunnan province.

Novel compound heterozygous mutations in the AFG3L2 gene in a Chinese child with microcephaly, early-onset seizures, and cerebral atrophy.

Background: The most common disease caused by biallelic AFG3L2 mutations is spastic ataxia type 5 (SPAX5). Identification of complex phenotypes resulting from biallelic AFG3L2 mutations has been increasing in recent years. Methods: A retrospective analysis was performed on a child with microcephaly and recurrent seizures. The child underwent physical and neurological examinations, laboratory tests, electroencephalography (EEG), and brain magnetic resonance imaging (MRI). Trio-whole-exome sequencing (trio-WES) was performed to identify possible causative mutations. Results: We described a child who exhibited early-onset and intractable epilepsy, developmental regression, microcephaly, and premature death. Neuroimaging revealed global cerebral atrophy (GCA) involving the cerebrum, cerebellum, corpus callosum, brainstem, cerebellar vermis, and basal ganglia. On trio-WES, two novel compound heterozygous mutations, c.1834G > T (p.E612*) and c.2176-6T > A in the AFG3L2 gene, were identified in this patient. Conclusions: Our findings have expanded the mutation spectrum of the AFG3L2 gene and identified a severe neurodegenerative phenotype of global cerebral atrophy caused by biallelic AFG3L2 mutations.

Spinal canal decompression for hypertrophic neuropathy of the cauda equina with chronic inflammatory demyelinating polyradiculoneuropathy: A case report.

BACKGROUND: Hypertrophic neuropathy of the cauda equina (HNCE) is a rare disease, especially in children. It can be caused by different etiological agents such as inflammation, tumor or hereditary factors. Currently, there is no uniform standard for clinical treatment of HNCE. Furthermore, it is unclear whether spinal canal decompression is beneficial for patients with HNCE. CASE SUMMARY: We report the case of a 13-year-old boy with enlargement of the cauda equina. The onset of the disease began at the age of 6 years and was initially marked by radiating pain in the buttocks and thighs after leaning over and weakness in the lower limbs when climbing a ladder. The child did not receive any medical treatment. As the disease slowly progressed, the child needed the help of others to walk, and he had a trendelenburg gait. He underwent spinal canal decompression and a nerve biopsy during his hospital stay. A diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was made based on electrophysiological findings and pathological examination results. Immunoglobulin or hormone therapy was recommended during hospitalization, but his mother refused. After discharge, the boy's mother helped him carry out postoperative rehabilitation training at home. His lower-limb muscle strength gradually increased, and he could stand upright and take steps. Six mo after surgery, the child was readmitted and began immunoglobulin therapy. Long-term oral steroid treatment was initiated after discharge. The movement and sensation of the lower limbs were further improved, and the boy could walk normally 1 year after surgery. CONCLUSION: Spinal canal decompression can improve the clinical symptoms of HNCE caused by inflammation, even in children. When combined with specific etiological interventions, spinal cord decompression can lead to optimal outcomes.

A novel TUBG1 mutation with neurodevelopmental disorder caused by malformations of cortical development.

Neurodevelopmental disorder caused by malformations of cortical development is a rare neurological disease. Heterozygous missense variants in the TUBG1 gene lead to malformations of human cortical development, which further result in intellectual disability, developmental retardation, and epilepsy. To the best of our knowledge, only thirteen patients and a total of nine pathogenic TUBG1 variants have been described in the published literature. This study reports the case details and genetic data analysis of a girl (aged 8 years, 9 months) with developmental delay, psychomotor regression, epilepsy, and left external ear deformity. A novel TUBG1 mutation was identified by whole-exome sequencing and Sanger sequencing, confirming that this mutation may be the cause of the neurodevelopmental disorders. This case report characterizes the phenotypic spectrum, molecular genetic findings, and functional consequences of novel pathogenic TUBG1 variants in neurodevelopmental disorders caused by cortical development malformations.