Insights into clinical phenotypes and treatment responses in a Small cohort of Taiwanese patients with SCN1A variants: A Preliminary study.

BACKGROUND: SCN1A channelopathy is the most well-known cause for epileptic encephalopathies and contributes to a wide phenotypic spectrum. The variable expressivity is troublesome for the interpretation of clinical significance and prognoses. To investigate the clinical manifestations, medications and outcomes of patients with SCN1A channelopathies, we conducted this observation retrospective study in Taiwan. METHODS: A cohort consisting of 16 patients (5 males and 11 females) from multiple centers with identified SCN1A variants was investigated and phenotypically relevant factors were recorded. The variants were identified using NGS and confirmed by Sanger sequencing. A panel of 90 epileptic-related genes was used to identify SCN1A variants and to evaluate some of the potential SCN1A modifier genes. RESULTS: The mean age of seizure onset was 10.4 months. Twelve of the sixteen patients (75%) had different degrees of neurocognitive sequela and psychobehavioral comorbidity in our cohort. Cognitive impairment was noted in all ten patients with Dravet syndrome (DS) and in two of the patients with non-DS phenotypes. A lower response rate to medications was also noted in patients with DS. Notably, a medication-specific tendency towards valproic acid (VPA), clobazam (CLB), and levetiracetam (LEV) was observed, revealing the effective pharmacotherapies for SCN1A-related seizures. An asymptomatic carrier with a reported pathogenic SCN1A variant was reviewed along with her monozygotic twin sister with DS. Nine novel SCN1A mutations are herein reported, eight of which being classified as pathogenic. CONCLUSION: Our study revealed unfavorable outcomes for patients with SCN1A variants. Some patients with SCN1A channelopathy showed specific responsiveness to the pharmacotherapies previously either recommended or contraindicated for these patients. Our study also expands the genotype and provides valuable prognostic insights in patients with SCN1A channelopathy.

De Novo Mosaic 6p23-p25.3 Tetrasomy Caused by a Small Supernumerary Marker Chromosome Presenting Trisomy Distal 6p Phenotype: A Case Report and Literature Review.

Small supernumerary marker chromosomes (sSMCs) derived from the chromosome 6 short arm are rare and their clinical significance remains unknown. No case with sSMC(6) without centromeric DNA has been reported. Partial trisomy and tetrasomy of distal 6p is a rare but clinically distinct syndrome. We report on a de novo mosaic sSMC causing partial tetrasomy for 6p23-p25.3 in a male infant with symptoms of being small for gestational age, microcephaly, facial dysmorphism, congenital eye defects, and multi-system malformation. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+mar [25]/46,XY [22]. Array comparative genomic hybridization (aCGH) revealed mosaic tetrasomy of distal 6p. This is the first case of mosaic tetrasomy 6p23-p25.3 caused by an inverted duplicated neocentric sSMC with characteristic features of trisomy distal 6p. Comparison of phenotypes in cases with trisomy and tetrasomy of 6p23-p25.3 could facilitate a genotype-phenotype correlation and identification of candidate genes contributing to their presentation. The presentation of anterior segment dysgenesis and anomaly of the renal system suggest triplosensitivity of the FOXC1 gene. In patients with microcephaly growth retardation, and malformation of the cardiac and renal systems, presentation of anterior segment dysgenesis might be indicative of chromosome 6p duplication, and aCGH evaluation should be performed for associated syndromic disease.

Efficacy of Intravenous Elosulfase Alfa for Mucopolysaccharidosis Type IVA: A Systematic Review and Meta-Analysis.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were -0.260, -0.102, -0.182, -0.360, -0.408, -0.587, -0.293, -0.311, and -0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.

Functional Independence of Taiwanese Children with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a group of rare genetic disorders that affect bone formation. Patients with OI present mainly with increased bone fragility and bone deformities. Twenty-seven Taiwanese children between 2 and 21 years of age with OI and their parents were recruited at MacKay Memorial Hospital from January 2013 to December 2019. We used the Functional Independence Measure for Children (WeeFIM) questionnaire to assess the functional independence of the children and describe any functional limitations or additional burden of daily care. Out of a potential score of 126, the mean total WeeFIM score was 113.7. There was a statistically significant difference between the scores of type I, type III and type IV OI (121.88 [SD 7.01] vs. 80.8 [SD 26.25] vs. 119.17 [SD 10.89]; p < 0.001). There were no statistically significant differences between the scores in different age groups, the male and female participants, and patients with pathogenic variants in COL1A1 and COL1A2. The mean scores for the self-care, mobility, and cognition domains were 48.78 (maximum 56, mean quotient 91.14%), 30.44 (maximum 35, mean quotient 87.12%), and 34.44 (maximum 35, mean quotient 99.05%), respectively. The best performance was in the cognition domain (mean quotient 99.05%), and the worst was in the mobility domain (mean quotient 87.12%). There were no statistically significant correlations between WeeFIM scores and age, or age when symptoms began. The total WeeFIM score and 13 subscores for the self-care and mobility domains were all positively correlated with body height (p < 0.01). The correlation was lowest for bowel and walking/wheelchair tasks, and the highest for bathing and dressing-upper tasks. For tasks in bathing, over 40% of the patients needed help. For tasks in the cognition domain, most patients required no help. For the Taiwanese children with OI, some support and supervision were required for self-care and mobility tasks, and the functional independence in these two domains was correlated with body height and disease types. The WeeFIM questionnaire may be a useful tool to assess the functional strengths and weaknesses of children with OI.

Rapid Weight Loss and Severe Failure to Thrive Mimicking Lipodystrophy Syndrome in a 1-Year-Old Taiwanese Girl with Costello Syndrome.

Costello syndrome (CS) is a type of RASopathy caused mainly by de-novo heterozygous pathogenic variants in the HRAS gene located on chromosome 11p15.5. The phenotype of CS is characterized by prenatal overgrowth, postnatal failure to thrive, curly or sparse fine hair, coarse facial features, and multisystem involvement, including cardiovascular, endocrine, and gastroenterological disorders. We present a one-year-old girl with rapid weight loss and severe failure to thrive. She had gastroesophageal reflux at the age of four months with subsequent rapid weight loss. The loss of fat tissue over the whole body, refractory to a hypercaloric diet, mimicked the presentation of progressive lipodystrophy and masked the dysmorphic features of CS. The final diagnosis of CS was made by whole exome sequencing, which demonstrated a hot-spot, heterozygouspathogenic variant in the HRAS gene (c.34G > A, rs104894229). Our patient illustrates that the excessive energy needs in CS patients may lead to severe failure to thrive and cause challenges in diagnosing CS. This case also highlights the importance of recognizing CS in patients with a history of prenatal overgrowth, polyhydramnios presenting with severe failure to thrive refractory to pharmacotherapy and tube feeding.

Long-Term Cardiovascular Findings in Williams Syndrome: A Single Medical Center Experience in Taiwan.

Williams syndrome (WS) is a rare genetic disorder caused by the microdeletion of chromosome 7q11.23. Cardiovascular defects (CVDs) are the leading causes of morbidity and mortality in patients with WS. The most common CVD in patients with WS is supravalvular aortic stenosis (SVAS), which recovers spontaneously similar to branch pulmonary stenosis (PS). Recently, conventional beliefs, such as SVAS improving rather than worsening in WS, have been challenged. This study thoroughly reviews the medical records of 30 patients with a molecular diagnosis of WS. We followed up these patients at Taipei MacKay Memorial Hospital from January 1999 to December 2021. The long-term outcomes of cardiovascular lesions as well as the change in peak pressure gradient in obstructive cardiovascular lesions over time were studied. Among these 30 patients, the most common cardiovascular lesion was SVAS (50.0%), followed by branch PS (36.7%). During the follow-up period, severe SVAS was aggravated (p = 0.021). The peak pressure gradient decreased from 38.4 to 25.3 mmHg (p = 0.001) in patients with branch PS. Among patients with WS, those with severe SVAS deteriorated over time, whereas those with branch PS improved on their own. In patients with WS who presented with branch PS, no disease-specific intervention was needed.