Novel mutation of COG5 in a Taiwanese girl with congenital disorders of glycosylation manifesting as developmental delay.

We are documenting the case of An 11-year-old girl who has been followed up at our out-patient clinic since birth with clinical presentations including intrauterine growth restriction, recurrent periodic fever in infancy, hypotonia, global developmental delay, liver function impairment with cirrhotic changes, and clinodactyly. Congenital abnormalities were suspected but a series of examinations including brain MRI, liver biopsy and muscle biopsy yielded insignificant findings. Whole genome sequencing (WGS) was conducted and revealed three novel mutations (c2T > G, c1826T > C, c.556-560delAGTAAinsCT) of the COG5 gene. A diagnosis of COG5-congenital disorders of glycosylation (COG5-CDG, or CDG IIi), with neurologic presentation was established. Sanger sequencing in the patient and her parents confirmed the compound heterozygous mutation. Upon literature review, we identified the patient as the first case of COG5-CDG in Taiwan. Our study enhances the clarity of the correlation between the mutative genes and the presentation of COG5-CDG.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

Long-term outcomes of very early treated infantile-onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme.

BACKGROUND: Starting enzyme replacement therapy (ERT) before severe irreversible muscular damage occurs is important in infantile-onset Pompe disease (IOPD). This long-term follow-up study demonstrates our diagnostic and treatment strategies for IOPD and compares our clinical outcomes with those of other medical centres. METHODS: In this long-term follow-up study, we analysed the outcomes of very early ERT with premedication hydrocortisone in patients with IOPD. Out of 1 228 539 infants screened between 1 January 2010 and 28 February 2021, 33 newborns had confirmed IOPD in Taipei Veterans General Hospital. Twenty-six were regularly treated and monitored at Taipei Veterans General Hospital. Echocardiographic parameters, biomarkers, IgG antibodies against alglucosidase alpha, pulmonary function variables and developmental status were all assessed regularly over an average follow-up duration of 6.18±3.14 years. We compared the long-term treatment outcomes of our patients with those of other research groups. RESULTS: The average age at ERT initiation was 9.75±3.17 days for patients with classic IOPD. The average of the latest antialglucosidase alpha IgG titre was 669.23±1159.23. All enrolled patients had normal heart sizes, motor milestones, cognitive function and pulmonary function that were near-normal to normal. Compared with patients in other studies, our patients had better outcomes in all aspects. CONCLUSION: Very early ERT using our rapid diagnostic and treatment strategy enabled our patients with IOPD to have better outcomes than patients in other medical centres.

Novel mutation of IFT140 in an infant with Mainzer-Saldino syndrome presenting with retinal dystrophy.

A seven-month-old girl presented with bilateral roving nystagmus, hyperopia, and retinal dystrophy, and was brought to our ophthalmology clinic. Visual-evoked potentials (VEPs) were non-recordable in both the eyes. No other systemic symptoms or abnormalities were observed. Whole exome sequencing (WES) identified a compound heterozygous mutation in the IFT140 gene: c.1990G > A (p. Glu664Lys) and c.2214_2217del (p.Asp738GlufsTer47). The genetic results support a diagnosis of Mainzer-Saldino syndrome (MSS). Importantly, c.2214_2217del is a novel mutation in the IFT140 gene. Although the patient presents with isolated retinal dystrophy, it is crucial to monitor renal function overtime. Taken together, our results reinforce the role of IFT140 in syndromic ciliopathies. This report also highlights the role of combined WES approaches in identifying underlying mutations in infants presenting with isolated retinal dystrophy, considering MSS may present differently over time.

Flexible Endoscopy With Non-invasive Ventilation Enables Clinicians to Assess and Manage Infants With Severe Bronchopulmonary Dysplasia.

Objectives: The objectives of the study were to determine the efficacy of flexible endoscopy (FE) to assess the approachable aeroesophageal tract (AET) and subsequent changes in clinical management in infants with severe bronchopulmonary dysplasia (sBPD). Methods: This retrospective study investigated sBPD infants who received FE measurement from 2011 to 2020. FE was supported with non-invasive ventilation (FE-NIV) of pharyngeal oxygen with nose closure and abdominal compression without any mask or laryngeal mask airway. Data on AET lesions, changes in subsequent management, and FE therapeutic interventions were collected and analyzed. Results: Forty-two infants were enrolled in the study. Two thin scopes (1.8- and 2.6-mm outer diameter) were used. FE analysis revealed 129 AET lesions in 38 (90.5%) infants. Twenty-eight infants (66.7%) had more than one lesion. Thirty-five (83.3%) infants had 111 airway lesions where bronchial granulations (28, 25.2%), tracheomalacia (18, 16.2%), and bronchomalacia (15, 13.5%) were the main complications. Eighteen esophageal lesions were found in 15 (35.7%) infants. No significant FE-NIV complications were observed. The FE findings resulted in changes in management in all 38 infants. Thirty-six (85.7%) infants underwent altered respiratory care with pressure titrations (29, 45.3%), shortened suction depth (17, 26.6%), immediate extubation (8, 12.5%), changed insertion depth of endotracheal tube (7, 10.9%) and tracheostomy tube (3, 4.7%). Twenty-one (50%) infants had 50 pharmacotherapy changes, including added steroids, anti-reflux medicine, antibiotics, and stopped antibiotics. Eighteen (42.8%) infants received 37 therapeutic FE-NIV procedures, including 14 balloon dilatations, 13 laser-plasty, and 10 stent implantations. Seven (16.7%) infants underwent surgeries for four tracheostomies and three fundoplications. Conclusion: Flexible endoscopy with this non-invasive ventilation could be a safe and valuable technique for direct and dynamic visual measurement of AET, which is essential for subsequent medical decision making and management in infants with sBPD.

Early detection of laryngeal cleft in infants by novel technique of flexible endoscopy with sustained pharyngeal inflation.

OBJECTIVE: We report a novel technique of flexible endoscopy with noninvasive ventilation (NIV) and sustained pharyngeal inflation (FE-NIV-SPI) in assessing aeroesophageal tracts (AET) to facilitate early detection of laryngeal clefts in infants. METHODS: Medical charts and flexible endoscopy videos of the children who were diagnosed with laryngeal cleft in a tertiary care hospital between January 2000 and December 2020 were retrospectively reviewed and analyzed. The FE-NIV-SPI technique had been applied to all these children. RESULTS: Totally, 12 infants with laryngeal cleft were identified. This equates to a prevalence of 0.28% in all the children who underwent flexible endoscopy at our institution. Their mean age was 5.0 ± 4.9 months and mean body weight was 4.7 ± 2.3 kg. Nine (75%) infants were referred in without laryngeal cleft diagnosis, which was missed by 11 prior bronchoscopy and 5 computer tomography examinations. With the FE-NIV-SPI technique, the pharyngolaryngeal space could be pneumatically dilated permitting a detailed assessment. All laryngeal cleft types and coexisting AET lesions were visualized at the first FE-NIV-SPI examination with a mean time of 4.2 ± 0.9 min; they were eight Type I, two Type II, and one Type III. Ten (83.3%) infants had coexisting airway malacia. CONCLUSION: Routine use of FE-NIV-SPI technique can help in early detection of laryngeal clefts and other associated AET lesions. Further multicenter collaborative investigations are essential to verify the early detection of this rare and occult lesion of the laryngeal cleft with this technique.

Prevalence of lower urinary tract symptoms in children with early-treated infantile-onset Pompe disease: A single-centre cross-sectional study.

AIM: To evaluate lower urinary tract symptoms (LUTS) in children with infantile-onset Pompe disease (IOPD) who received early treatment. METHODS: Pompe disease (PD), or glycogen storage disease II is a rare autosomal recessive lysosomal storage disease that affects multiple organ systems. To our knowledge, only one study has focused on the relationship between LUTS and incontinence in children with PD. This cross-sectional study was conducted from August 2019 through March 2021 and children with IOPD, who had received early and regular enzyme replacement therapy, were enrolled. Participants or their parents completed the Dysfunctional Voiding Scoring System (DVSS) questionnaire. All children underwent uroflowmetry and postvoid residual urine measurements. Fourteen children (age, 4-9 years) with IOPD were enrolled. RESULTS: Ten patients (71.4%) had abnormal uroflow curves. In addition, results of the DVSS revealed that approximately half (42.9%) of our IOPD patients had voiding dysfunction, with urinary incontinence as the most common symptom (64.3%, 9/14). No significant correlations were found between LUTS and uroflow curves in children with IOPD. CONCLUSIONS: The frequency of LUTS and lower urinary tract dysfunction noted on uroflowmetry should encourage pediatricians to actively identify IOPD patients with LUTS, regardless of the timing and frequency of their treatments, and refer them to a urologist for further evaluation and appropriate treatment.

Safety and long-term outcomes of early liver transplantation for pediatric methylmalonic acidemia patients.

BACKGROUND: LT is a treatment option for MMA patients, but renal function impairment is one of the long-term concerns. The aim of this study was to evaluate the outcomes of early LT in these patients. METHODS: A total of 11 MMA mut-type patients (including 10 mut0 cases and 1 mut-case) who received LT in our institute were reviewed. Their metabolic profiles were compared between the pre/post-transplant periods. Their immunosuppressant and renal function changes after transplantation were assessed. RESULTS: After a mean follow-up of 97.5 ± 38.4 months, there were two deaths, and the actual survival rate was 81.8%. Their metabolic profiles had improved (mean blood ammonia level 366.8 ± 105.5 vs. 53.1 ± 17.4 µg/dl, p < .001; C3/C2 ratio 2.68 ± 0.87 vs. 0.73 ± 0.22, p = .003; mean urine MMA level 920.5 ± 376.6 vs. 196.2 ± 85.4, p = .067), and hospital stays were decreased (78.8 ± 74.5 vs. 7.4 ± 7.0 days/year, p = .009) after transplantation. The mean age at transplant was 1.81 ± 2.02 years old, and nine of these patients received LT before the age of 1.5 years old (early LT). Under prospective immunosuppressant dose reduction, three of these early LT patients discontinued the drug and were sustained for more than 5 years. Most of the patients had a preserved renal function, and no patient is currently on dialysis. CONCLUSIONS: In addition to the improvement in the metabolic parameters, early LT in MMA patients may allow for a dose reduction of the immunosuppressant, and the patient's renal function could be preserved in the long term.

Airway abnormalities and pulmonary complications in long-term treated late-onset Pompe disease: Diagnostic and interventional by flexible bronchoscopy.

This study evaluates the whole airway abnormalities of long-term treated late-onset Pompe disease (LOPD) patients, with interventions using the flexible bronchoscope (FB). As a retrospective study, we follow up with our five LOPD patients treated with Myozyme from 2012 to 2021 regularly, but with a focus on the whole airway abnormalities of these patients visualized through FB. The long-term clinical outcomes and relevant airway symptoms were assessed. Pulmonary function test and polysomnography were performed to evaluate the degree of respiratory compromise. All patients in the study had varying degrees of airway collapsibility, pulmonary complications, sleep apnea syndrome, and facial anomalies. Pulmonary function could preserve after Myozyme treatment, but potential deterioration thereafter. This is the first study that focuses on airway abnormalities and pulmonary complications in long-term treated LOPD patients using FB. Despite years of Myozyme treatment, we still observed airway abnormalities in these patients. In our series, the pulmonary complications seem more obvious than those observed in patients with infantile-onset Pompe disease, which might be related to the late diagnosis and treatment. We might recommend that FB could provide dynamic evaluation and interventions of airway abnormalities simultaneously. Early diagnosis of respiratory dysfunction is a critical prognostic factor of the long-term outcome of treated LOPD patients.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Beckwith-Wiedemann Syndrome.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. The aim of this study was to identify the epigenotype-phenotype correlations of these patients using quantitative DNA methylation analysis. METHODS: One hundred and four subjects with clinically suspected BWS were enrolled in this study. All of the subjects had been referred for diagnostic testing which was conducted using methylation profiling of H19-associated imprinting center (IC) 1 and KCNQ1OT1-associated IC2 in high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between the quantitative DNA methylation status and clinical manifestations of the enrolled subjects were analyzed. RESULTS: Among the 104 subjects, 19 had IC2 hypomethylation, 2 had IC1 hypermethylation, and 10 had paternal uniparental disomy (pUPD). The subjects with IC2 hypomethylation were characterized by significantly more macroglossia but less hemihypertrophy compared to the subjects with pUPD (p < 0.05). For 19 subjects with IC2 hypomethylation, the IC2 methylation level was significantly different (p < 0.05) between the subjects with and without features including macroglossia (IC2 methylation level: 11.1% vs. 30.0%) and prenatal or postnatal overgrowth (8.5% vs. 16.9%). The IC2 methylation level was negatively correlated with birth weight z score (p < 0.01, n = 19) and birth height z score (p < 0.05, n = 13). For 36 subjects with clinically diagnosed BWS, the IC2 methylation level was negatively correlated with the BWS score (r = -0.592, p < 0.01). The IC1 methylation level showed the tendency of positive correlation with the BWS score without statistical significance (r = 0.137, p > 0.05). CONCLUSIONS: Lower IC2 methylation and higher IC1 methylation levels were associated with greater disease severity in the subjects with clinically diagnosed BWS. Quantitative DNA methylation analysis using the MassARRAY assay could improve the detection of epigenotype-phenotype correlations, which could further promote better genetic counseling and medical care for these patients.

Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver-Russell Syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. METHODS: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the "IC1 hypomethylation" and "mUPD7" groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). CONCLUSIONS: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

Congenital hypopituitarism due to novel compound heterozygous POU1F1 gene mutation: A case report and review of the literature.

Failure to thrive is one of the most common complaints in the endocrinology and genetics clinic. An 8-month-old girl with presentation of motor developmental delay, failure to thrive, and midline facial defects, with history of hypoglycemia at birth and central congenital hypothyroidism (CCH), was brought to our genetic clinic. Hormone test demonstrated combined pituitary hormone deficiency with growth hormone deficiency (GHD), central hypothyroidism, and hypoprolactinemia. Brain magnetic resonance imaging (MRI) showed anterior pituitary hypoplasia (APH), abnormal pituitary stalk, and preserved posterior pituitary lobe. Whole exome sequence (WES) identified a compound heterozygous mutation of the POU1F1 gene: c.649C>T (p.Arg217Ter) and c.662T>C (p.Ile221Thr), which are de novo mutation and inherited from mother, respectively. The patient's phenotype was consistent clinically with congenital hypopituitarism due to the POU1F1 gene mutation. Based on our literature review, this is the first report of the c.662T>C mutation, to the best of our knowledge. Our study demonstrates the power of WES for early diagnosis of congenital hypopituitarism with its relative phenotype for improving prognosis and preventing irreversible deficit.

Hearing characteristics of infantile-onset Pompe disease after early enzyme-replacement therapy.

BACKGROUND: Studies suggest that enzyme-replacement therapy (ERT) is crucial to the survival of patients with infantile-onset Pompe disease (IOPD). Hearing impairment (HI) is one of the clinical sequelae observed in long-term survivors. However, the benefits of early ERT for hearing outcomes have not yet been reported. This study aimed to investigate the impact of early ERT on IOPD patients. METHODS: This retrospective longitudinal study recruited IOPD patients who were referred by newborn screening for confirmatory diagnosis based on our rapid diagnostic criteria and received early ERT treatment between January 1, 2010, and January 31, 2018. The hearing test battery included a tympanogram, otoacoustic emission, auditory brainstem evoked response (ABR), pure-tone audiometry or conditioned play audiometry. RESULTS: Nineteen patients with IOPD were identified, 6 of whom had hearing impairment (HI); 1 had conductive HI, 2 had sensorineural HI (one had bilateral mild HI and one had mild HI in a single ear) and 1 had moderate mixed-type HI. Two patients failed the newborn screening test and had mild HI in the ABR. The mean age of the initial time to ERT was 11.05 ± 4.31 days, and the HI rate was 31.6% (6/19). CONCLUSION: Our study is the largest cohort to show the characteristic hearing outcomes of IOPD patients after ERT. Early ERT within 2 weeks after birth may contribute to better hearing outcomes. Clinicians should be vigilant in testing for the hearing issues associated with IOPD and should intervene early if any HI is detected.

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Diagnosis of Arboleda-Tham syndrome by whole genome sequencing in an Asian boy with severe developmental delay.

Diagnosis of a 9-month-old boy brought to our genetics clinic with chief complaints of developmental delay (DD), failure to thrive, microcephaly, trunk hypotonia and hypertonia of the extremities. Multiple congenital defects but no significant syndromes or diseases were impressed. The chromosomal analysis and array comparative genomic hybridization (aCGH) revealed no significant pathogenic changes. Whole Genome Sequencing (WGS) identified a p.Glu1139fs de novo mutation of the KAT6A gene. The patient's phenotype was consistent clinically with Arboleda-Tham syndrome (ARTHS). Reviewing the literature showed that this is the first patient in Taiwan detected by WGS and that it involves a novel mutation. Comparing the highly variable clinical presentations of this syndrome with our patient, this boy's features and severe developmental defects seem to be due to a late-truncating mutation at the carboxyl end of the KAT6A protein. Our study demonstrates the power of WGS to confirm a diagnosis within 4 weeks for this rare condition.

Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease.

OBJECTIVE: To provide strategies for monitoring and treating severe lung involvement in Gaucher disease. STUDY DESIGN: We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. RESULTS: His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of ß-glucocerebrosidase were reported in three months. CONCLUSION: This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

Language, speech, and oromotor function in children with Pompe disease.

Advances in the treatment of Pompe disease have improved life expectancy and quality of life, but speech and oromotor function remain significantly affected. The purpose of this study was to expand on existing data and present new findings of speech acoustic and physiologic outcomes in Pompe disease. A retrospective analysis was carried out on results of speech, language and oromotor tests carried out in 14 children diagnosed with Pompe disease. The assessment battery included standardized tests of language, picture naming, maximum performance tests, and oromotor resistance tasks. Speech production was scored with respect to intelligibility, hypernasality, and articulatory accuracy. Language delays ranged from mild to severe in 1/3 of the children. Reduced speech intelligibility, disordered articulation, and hypernasality were present in at least 2/3 of the children. Maximum performance tests all fell at least 1 SD below normative means. Significant correlations were identified between maximum phonation time and articulation and between the S/Z ratio and intelligibility. Positive correlations were also found between tongue strength and articulation. Results confirm previous reports of speech and language function in Pompe disease. Clinical acoustic measures provide important insights into the speech deficits in this group of children and suggest possible treatment strategies.

Vallecular cyst with coexisting laryngomalacia: Successful diagnosis and laser therapy by flexible endoscopy with a novel noninvasive ventilation support in infants.

OBJECTIVE: Vallecular cyst coexisting with laryngomalacia (VC-LM) can cause significant pharyngolaryngeal obstruction. Traditionally, it is diagnosed with flexible endoscopy (FE) and treated by rigid endoscopy. This study evaluates the effectiveness of solely using FE with novel noninvasive ventilation (NIV) of sustained pharyngeal inflation (SPI) support for both diagnosis and treatment in such infants. METHODS: A retrospective review of consecutive infants who were diagnosed and treated for VC-LM in the 12-year period, 2007 to 2018, was conducted. Clinical variables, techniques, and outcomes were analyzed and reported. RESULTS: Eighteen infants (10 males) were included. The mean age was 3.0 ± 0.6 months and the mean body weight was 4.6 ± 1.3 kg. Before FE, 14 infants were supported with bi-nasal prongs NIV (BN-NIV) and four infants with tracheal intubation. During diagnostic and therapeutic FE, all infants supported with a nasopharyngeal NIV (NP-NIV) only. All diagnoses were made in the first FE inspection of 3.5 ± 1.2 minutes. Thirteen lesions were immediately treated with FE laser therapy in 18.1 ± 1.7 minutes in the same FE course. Total FE time was 24.6 ± 2.8 minutes. Three infants needed revision laser therapy 4 days later. There was no desaturation (<90%), bradycardia (<100/min), or pneumothorax. After FE therapy, all infants were supported with BN-NIV only with significantly (<0.01) lower pressure and completely weaned off before being discharged 8.4 ± 1.5 days later. All infants, followed up for a 6-month period, showed many clinical improvements. CONCLUSIONS: FE, with this NP-NIV and SPI supports, could offer accurate diagnosis and successful laser therapy of the VC-LM with procedural sedation in the same session in infants.

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

Bisphenol a Exposure, DNA Methylation, and Asthma in Children.

Epidemiological studies have reported the relationship between bisphenol A (BPA) exposure and increased prevalence of asthma, but the mechanisms remain unclear. Here, we investigated whether BPA exposure and DNA methylation related to asthma in children. We collected urinary and blood samples from 228 children (Childhood Environment and Allergic Diseases Study cohort) aged 3 years. Thirty-three candidate genes potentially interacting with BPA exposure were selected from a toxicogenomics database. DNA methylation was measured in 22 blood samples with top-high and bottom-low exposures of BPA. Candidate genes with differential methylation levels were validated by qPCR and promoter associated CpG islands have been investigated. Correlations between the methylation percentage and BPA exposure and asthma were analyzed. According to our findings, MAPK1 showed differential methylation and was further investigated in 228 children. Adjusting for confounders, urinary BPA glucuronide (BPAG) level inversely correlated with MAPK1 promoter methylation (ß = -0.539, p = 0.010). For the logistic regression analysis, MAPK1 methylation status was dichotomized into higher methylated and lower methylated groups with cut off continuous variable of median of promoter methylation percentage (50%) while performing the analysis. MAPK1 methylation was lower in children with asthma than in children without asthma (mean ± SD; 69.82 ± 5.88% vs. 79.82 ± 5.56%) (p = 0.001). Mediation analysis suggested that MAPK1 methylation acts as a mediation variable between BPA exposure and asthma. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation.