Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Improving Consistency and Accuracy of Neonatal Amplitude-Integrated Electroencephalography.

OBJECTIVE: This study aimed to improve the utilization of amplitude-integrated electroencephalography (aEEG) in a neonatal unit by improving aEEG documentation, aEEG knowledge, and pattern recognition ability of neonatal staff. METHODS: A quality improvement (QI) program comprising the two Plan-Do-Study-Act (PDSA) cycles was conducted in a level-3 neonatal intensive care unit. The first cycle was focused on improving aEEG documentation with the primary outcome indicator being compliance with aEEG documentation. The second cycle was focused on aEEG interpretation in a health care professional education program with the outcome indicators being accuracy of seizure identification on aEEG and change in conventional EEGs (cEEG) performed. Other outcome indicators included accuracy in identification of background pattern, sleep-wake cycles and artifacts. Process indicators included improvement in aEEG-related knowledge. RESULTS: First PDSA cycle includes lectures on aEEG interpretation, a bedside key, and documentation form. Second PDSA cycle includes online aEEG education pack and detailed aEEG guideline. There was a significant improvement in aEEG documentation after the implementation of both PDSA cycles. Seven of the 46 patients (15.2%) had isolated electrographic seizures which would not have been identified in the pre-aEEG monitoring era. There was an increase in the number of patients with cEEGs done but a steady decrease in number of cEEGs per patient. CONCLUSION: With the successful application of standardized QI methods, improvements in outcome indicators, such as correct aEEG pattern recognition and improved coverage of at risk infants with cEEGs, were observed. Our QI measures were associated with improvement in aEEG pattern recognition. KEY POINTS: · Consistent and accurate use of aEEG is challenging.. · Standardized forms and guidelines improve aEEG interpretation consistency and documentation.. · Interactive self-paced online education packs can improve aEEG knowledge and pattern recognition..

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.

OBJECTIVE: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants. METHODS: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed. RESULTS: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified. CONCLUSIONS: This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

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.

Early consideration of anti-NMDAR encephalitis in unexplained encephalopathy.

With the identification of anti-NMDAR (N-methyl-D-aspartate receptor) antibody, the spectrum of anti-NMDAR encephalitis has been expanding. The condition is also increasingly recognised in children, though younger patients are less likely to have tumours, while behavioural and speech problems, seizures, and abnormal movements are common early presenting features. Here we present yet another case with subtle, non-specific clinical symptoms that responded promptly to intravenous immunoglobulin. We believe this illustrates the importance of considering this uncommon differential diagnosis in the management of unexplained neurological conditions.

Carnitine level in Chinese epileptic patients taking sodium valproate.

Previous studies have demonstrated that carnitine levels were lower in patients taking valproate, especially in those who are younger than 24 months of age, those with concomitant neurologic or metabolic disorders, and those on multiple antiepileptic drugs. We performed a cross-sectional surveillance study on pediatric patients taking valproate to evaluate the relationship between carnitine levels and demographic data including age, daily dosage of valproate, number of antiepileptic drugs, body mass index, and feeding problems. Among the 43 patients studied, only two patients were found to have carnitine levels below the normal limit. There were no statistically significant associations between carnitine levels and age, body mass index, additional antiepileptic drugs used, presence of mental retardation, cerebral palsy, or feeding problems, nonambulatory status, or dosage of valproate. We conclude that routine carnitine level checking is not justified in pediatric patients taking valproate.