Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population.

BACKGROUND: Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs. METHODS: We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines. RESULTS: Sixty-six patients with pre-biopsy MDC scores of 3-8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC. CONCLUSIONS: We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

Correlation of urodynamic studies and somatosensory evoked potential and their prognostic value in children with closed spinal dysraphism.

INTRODUCTION: Somatosensory evoked potential (SSEP) and urodynamic studies (UD) are valuable tools for assessing patients with closed spinal dysraphism (CSD) before neurosurgical intervention. No studies have correlated their findings in this cohort and our aim is to study their correlation and prognostic value in pediatric patients with closed spinal dysraphism. METHODS: Retrospective review of all patients referred to a multidisciplinary clinic in a tertiary pediatric surgical center over a 17 years period between April 2004 to September 2021 was performed. Inclusion criteria were <18 years old, diagnosed with CSD, with SSEP and UD done within 1 year of each other. Demographics data collected include age at presentation/at referral/at neurosurgical operation, gender, symptoms at presentation and intra-operative diagnoses. Pre-operative SSEP and UD findings were documented. Primary outcome was UD results in the group with normal and abnormal SSEP. Secondary outcome was urological and bowel function outcome in 4 groups of patients (Group A-both normal SSEP and UD, Group B- abnormal SSEP only, Group C - abnormal UD only and Group D-both abnormal SSEP and UD). RESULTS: A total of 45 patients were included for analysis. Mean follow up time was 118.9 months (24-216 months, SD 55.8 months). SSEP was normal in 20 patients and abnormal in 25 patients. Baseline demographics, preoperative symptoms and imaging were similar between 2 groups. Primary outcome Patients with abnormal SSEP were more likely to have abnormal UD results with a statistically significant difference (84% vs 40%, p < 0.05). They have a significantly higher end-fill detrusor pressure (12% vs 0%, p < 0.05), abnormal bladder compliance (20% vs 0%, p < 0.05), abnormal cystometric capacity (48% vs 10%, p < 0.05), poor emptying efficiency (24% vs 5%, p < 0.05) and sphincter incompetence (8% vs 0%, p < 0.05). Secondary outcome When compared to Groups A to C, patients in group D were more likely to be on anti-cholinergic (33.3% vs 4.3%, p < 0.05), required clean intermittent catheterization (42.9% vs 4.3%, p < 0.05) and had intravesical botulinum injection (19% vs 0%, p < 0.05). All the patients who had augmentation cystoplasty were in this group as well. Bowel function in terms of regular enema use was also statistically significantly higher in this group (33.4% p < 0.05). CONCLUSION: Pre-operative SSEP and UD results correlate well in patients with closed spinal dysraphism. Patients with abnormal SSEP and UD preoperatively have higher risk of urological deterioration over time. Close monitoring in this group is warranted.

Guillain-Barré syndrome in children - High occurrence of Miller Fisher syndrome in East Asian region.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare acquired immune-mediated polyneuropathy. Updated population-based data concerning paediatric GBS is needed. METHODS: Paediatric patients aged below 18 years diagnosed with GBS between 2009 and 2018 in all 11 paediatric departments in Hong Kong were identified from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. The collected data from medical health records were reviewed by paediatric neurologist from each department. Estimated incidence of paediatric GBS was calculated. We also compared our findings with other paediatric GBS studies in Asia. RESULTS: 63 subjects of paediatric GBS were identified, giving an estimated annual incidence of 0.62 per 100,000 population. Half of the subjects had acute inflammatory demyelinating polyneuropathy (AIDP) (n = 31; 49.2%), one quarter had Miller Fisher Syndrome (MFS) (n = 16; 25.4%), one-fifth had axonal types of GBS (n = 12; 19.0%), and four were unclassified. Paediatric subjects with axonal subtypes of GBS compared to the other 2 subtypes, had significantly higher intensive care unit (ICU) admission rates (p = 0.001) and longest length of stay (p = 0.009). With immunomodulating therapy, complete recovery was highest in those with MFS (100%), followed by AIDP (87.1%) and axonal GBS (75%). Our study also confirms a higher MFS rate for paediatric GBS in East Asia region and our study has the highest MFS rate (25.4%). CONCLUSION: Our population-based 10-year paediatric GBS study provides updated evidence on estimated incidence, healthcare burden and motor outcome of each subtype of paediatric GBS and confirmed a higher occurrence of paediatric MFS in East Asia.

Spinal Muscular Atrophy With Respiratory Distress Type 1-A Child With Atypical Presentation.

The authors report a child with spinal muscular atrophy with respiratory distress type 1 (SMARD1). She presented atypically with hypothyroidism and heart failure due to septal defects that required early heart surgery and microcephaly in association with cerebral atrophy and thin corpus collosum. The subsequent asymmetrical onset of diaphragmatic paralysis, persistent hypotonia, and generalized muscle weakness led to the suspicion of spinal muscular atrophy with respiratory distress type 1. Sanger sequencing confirmed a compound heterozygous mutation in the Immunoglobulin Mu Binding Protein 2 (IGHMBP2) gene, with a known mutation c.2362C > T (p.Arg788*) and a novel frameshift mutation c.2048delG (p.Gly683A1afs*50). Serial nerve conduction study and electromyography confirmed progressive sensorimotor polyneuropathy and neuronopathy. In summary, this case report describes a child with spinal muscular atrophy with respiratory distress type 1 also with congenital cardiac disease and endocrine dysfunction, expanding the phenotypic spectrum of this condition. A high index of suspicion is needed in diagnosing this rare condition to guide the management and genetic counseling.

Galactorrhea-a strong clinical clue towards the diagnosis of neurotransmitter disease.

Two siblings from a Hong Kong Chinese family are diagnosed to have heterozygous mutation in tyrosine hydroxylase gene-a novel mutation R169X and the common Dutch mutation R233H. Presented with developmental delay and dystonia before 6 months of age, both had hyperprolactinemia with persistent galactorrhea present in the elder brother since birth. Serum prolactin level is a good screening test for those suspected of underlying neurotransmitter diseases. To our knowledge, this is the first Chinese family diagnosed with such condition. Clinicians must be aware of this rare disease especially in those unexplained 'cerebral palsy' like children.

Prevalence and Characteristics of Chinese Patients With Duchenne and Becker Muscular Dystrophy: A Territory Wide Collaborative Study in Hong Kong.

The aim of this collaborative study on Duchenne muscular dystrophy and Becker muscular dystrophy is to determine the prevalence and to develop data on such patients as a prelude to the development of registry in Hong Kong. Information on clinical and molecular findings, and patient care, was systematically collected in 2011 and 2012 from all Pediatric Neurology Units in Hong Kong. Ninety patients with dystrophinopathy were identified, and 83% has Duchenne muscular dystrophy. The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per 10 000 males aged 0 to 24 years. Among the Duchenne group, we observed a higher percentage (40.6%) of point mutations with a lower percentage (45.3%) of exon deletions in our patients when compared with overseas studies. Although we observed similar percentage of Duchenne group received scoliosis surgery, ventilation support, and cardiac treatment when compared with other countries, the percentage (25%) of steroid use is lower.