Publications by authors named "Chitra Prasad"

88 Publications

The conundrum of molar distalization or mandibular relocation in Class II malocclusions.

Am J Orthod Dentofacial Orthop 2021 02;159(2):e89

Secunderabad, Telangana, India.

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http://dx.doi.org/10.1016/j.ajodo.2020.09.016DOI Listing
February 2021

Bolton's analysis using a photogrammetric method on occlusal photographs.

Eur Oral Res 2020 May;54(2):55-61

Orthodontics, Army College of Dental Sciences, Secunderabad, Telangana,India.

Purpose: The aim of the study is to present a photogrammetric technique using standardized occlusal photographs to perform Bolton's analysis and assess reliability of this new method with plaster study casts.

Materials And Methods: The study was conducted on 16 subjects (8 males, 8 females), aged 18-25 years. Standardized occlusal photographs and plaster study casts were obtained. The occlusal photographs were calibrated in Nemoceph® software. Mesio-distal dimensions of all teeth up to first molars were calculated and Bolton's analysis was performed. Similarly, a digital calliper with 0.1 mm sensitivity was used to measure mesio-distal dimensions of all teeth on plaster study casts to perform Bolton's analysis. 28 parameters were measured on study models and corresponding occlusal photographs. Paired t test and intraclass correlation tests were carried out to test validity and reliability of the photogrammetric method. An intraclass correlation test was calculated for 4 derived parameters to test reliability of Bolton's analysis measurements obtained from occlusal photographs as compared to study models.

Results: All 28 parameters showed a statistically significant and excellent correlation (r>.80) in the Intra Class Correlation test. 4 variables used to calculate Bolton's analysis showed statistically significant correlation (r>.96) in the intraclass correlation test.

Conclusion: Photogrammetry is a reliable tool to measure mesio-distal tooth size. Bolton's analysis from standardized occlusal photographs using the described photogrammetric technique can be used as an effective clinical tool.
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http://dx.doi.org/10.26650/eor.20200005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787516PMC
May 2020

Two cases of carbonic anhydrase VA deficiency-An ultrarare metabolic decompensation syndrome presenting with hyperammonemia, lactic acidosis, ketonuria, and good clinical outcome.

JIMD Rep 2021 Jan 1;57(1):9-14. Epub 2020 Oct 1.

Clinical and Metabolic Genetics The Hospital for Sick Children Toronto Ontario Canada.

The combination of neonatal hyperammonemia, lactic acidosis, ketonuria, and hypoglycemia is pathognomonic for carbonic anhydrase VA (CA-VA) deficiency. We present two cases of this rare inborn error of metabolism. Both newborns with South Asian ancestry presented with a metabolic decompensation characterized by hyperammonemia, lactic acidosis and ketonuria; one also had hypoglycemia. Standard metabolic investigations (plasma amino acids, acylcarnitine profile, and urine organic acids) were not indicative of a specific organic aciduria or fatty acid oxidation defect but had some overlapping features with a urea cycle disorder (elevated glutamine, orotic acid, and low arginine). Hyperammonemia was treated initially with nitrogen scavenger therapy and carglumic acid. One patient required hemodialysis. Both have had a favorable long-term prognosis after their initial metabolic decompensation. Genetic testing confirmed the diagnosis of carbonic anhydrase VA (CA-VA) deficiency due to biallelic pathogenic variants in . These cases are in line with 15 cases previously described in the literature, making the phenotypic presentation pathognomonic for this ultrarare (potentially underdiagnosed) inborn error of metabolism with a good prognosis.
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http://dx.doi.org/10.1002/jmd2.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802620PMC
January 2021

Bulging anterior fontanelle and dense bones in an infant.

Paediatr Child Health 2020 Mar 20;25(2):69-71. Epub 2019 Mar 20.

Department of Genetics, Metabolism and Department of Paediatrics, London Health Sciences Centre, Schulich School of Medicine and Dentistry, Western University, London, Ontario.

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http://dx.doi.org/10.1093/pch/pxz004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757777PMC
March 2020

Stress distribution patterns in mini-implant and bone in the infra-zygomatic crest region at different angulations: A finite element study.

J World Fed Orthod 2020 Dec 22. Epub 2020 Dec 22.

Professor and Head, Department of Orthodontics and Dentofacial Orthopaedics, Army College of Dental Sciences, Secunderabad, India. Electronic address:

Purpose: To evaluate, using the finite element method (FEM), von Mises stress patterns produced both in a mini-implant (MI) and the infra-zygomatic crest region (IZC) at different placement angles and force magnitudes.

Material And Methods: FEM modeling of an infra-zygomatic crest MI, of dimensions 2 mm × 12 mm, was designed and placed in the IZC bone. The MI was inserted at 50°, 60°, 70°, 80°, and 90° angulations to the IZC surface. Simulated orthodontic forces of magnitudes 8, 9, 10, 11, and 12 oz were applied to the MI head. Von Mises stress and magnitude both in the MI and surrounding bone were measured.

Results: Von Mises stress in the MI and bone was maximum at 90°. Least stresses were observed at 50° and 60° angulations. As force magnitude increased, von Mises stress increased linearly. Maximum stresses in the MI and bone were observed when loads were 12 oz and minimum stresses were observed at 8 oz.

Conclusion: To achieve optimum primary stability, angles of insertion between 50° and 60° are recommended in the IZC region. Highest von Mises stress values were detected in the MI, followed by cortical and cancellous bone. Also, loading force between 8 and 12 oz exerted stresses below the tolerable threshold of bone and MI. Hence, proper placement of MI in IZC using these findings might provide better biomechanical stability during retraction and may help in preserving the bone-implant interface.
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http://dx.doi.org/10.1016/j.ejwf.2020.11.004DOI Listing
December 2020

Isolated sulfite oxidase deficiency: a founder mutation.

Cold Spring Harb Mol Case Stud 2020 Dec 17;6(6). Epub 2020 Dec 17.

London Health Sciences Centre, Western University, London, Ontario N6A 5A5, Canada.

Isolated sulfite oxidase deficiency is a rare autosomal recessive inborn error of sulfur metabolism. Clinical features generally include devastating neurologic dysfunction, ectopia lentis, and increased urinary excretion of sulfite, thiosulfate, and -sulfocysteine. Missed diagnosis is not unusual because of variability in the sensitivity of the urinary sulfite and thiosulfate screening test. We present clinical, biochemical, and molecular data on two unrelated patients with isolated sulfite oxidase deficiency. The two patients belong to an Indigenous genetic isolate in Manitoba, Canada. Both patients (one male and one female, both now deceased) developed neonatal seizures and demonstrated progressive neurodevelopmental delay. Based on increased urinary excretion of sulfite, thiosulfate, and -sulfocysteine and normal serum uric acid levels, sulfite oxidase deficiency was suspected. Both patients have a homozygous 4-bp deletion, 1347-1350delTTGT in the sulfite oxidase gene (), predicting a premature termination of the sulfite oxidase protein leading to absence of the carboxy-terminal third portion of the protein. This domain contains most of the contact sites essential for enzyme dimerization. This deletion mutation resulted in sulfite oxidase deficiency with early-onset severe clinical phenotype.
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http://dx.doi.org/10.1101/mcs.a005900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784486PMC
December 2020

X-linked BCOR-related syndrome in two male siblings.

Clin Dysmorphol 2020 Nov 20. Epub 2020 Nov 20.

Department of Paediatrics, London Health Sciences Centre and Western University, London.

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http://dx.doi.org/10.1097/MCD.0000000000000359DOI Listing
November 2020

Performance comparison of vibration devices on orthodontic tooth movement - A systematic review and meta-analysis.

J Oral Biol Craniofac Res 2020 Oct-Dec;10(4):814-823. Epub 2020 Nov 5.

Department of Orthodontics, Army College of Dental Sciences, KNR University, Secunderabad, Telangana, India.

Background: To evaluate the efficiency of vibratory devices in altering rate of orthodontic tooth movement.

Methods: A literature search up to January 31, 2020 was conducted in three electronic databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Science Direct, to identify studies on vibratory devices reporting any alteration in tooth movement as a primary outcome. Only articles published in English language were included. A meta-analysis was done to compare the amount of tooth movement (in mm) in patients treated with vibratory devices compared to control groups, to quantify weighted treatment effects.

Results: A total of two split mouth studies, six parallel arm randomized control trials (RCT) one split mouth RCT, and three regular RCTs were assessed qualitatively. Quantitative assessment was done for 8 randomized trials using a forest plot (310 patients). Pooled data showed increase in the amount of tooth movement by 0.34 ​mm (95% CI:0.25,0.42). There was a statistically significant difference noted for this result at p ​< ​0.00001.

Conclusion: Current evidence suggests a moderate to high level of certainty in regard to included studies in this systematic review and meta-analysis. Vibratory devices when used in conjunction with fixed orthodontic appliances show significant increase in the rate of tooth movement. These devices can be used by clinicians to reduce treatment duration and patient discomfort.

Prospero Registration: CRD42020169675.
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http://dx.doi.org/10.1016/j.jobcr.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666347PMC
November 2020

Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario.

J Hum Genet 2020 Oct 23. Epub 2020 Oct 23.

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.

The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease. Our analysis showed that despite a higher average read depth in panels (3058 vs. 855), MedExome yielded full coverage of the enriched regions (>20X) and 99% variant concordance rate with panels. The discordance rate was associated with low-complexity regions, high-GC content, and low allele fractions, observed in both platforms. MedExome yielded full sensitivity in detecting clinically actionable variants, and the assessment of 138 patients with suspected genetic conditions resulted in 76 clinical reports (31 full [22.1%], 3 partial, and 42 uncertain/possible molecular diagnoses). MedExome sequencing has comparable performance in variant detection to gene panels. Added diagnostic yield justifies expanded implementation of broad genomic approaches in unresolved patients; however, cost-benefit and health systems impact warrants assessment.
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http://dx.doi.org/10.1038/s10038-020-00860-3DOI Listing
October 2020

Parental psychosocial aspects and stressors involved in the management of inborn errors of metabolism.

Mol Genet Metab Rep 2020 Dec 5;25:100654. Epub 2020 Oct 5.

Department of Medical Genetics, London Health Sciences Centre, London, ON, Canada.

Parents of children with inborn errors of metabolism (IEM) face numerous psychosocial challenges. An increased understanding and awareness of these stressors can ensure better overall outcomes for the entire family. We conducted semi-structured, in-person interviews with ten parents to identify psychosocial stressors, strategies, and supports they utilized to overcome their challenges. Our interview guide was designed to elicit familial experiences during the pre- and post-diagnosis periods. The themes and sub-themes were identified through qualitative descriptive textual analysis of audio-recorded transcripts. Major themes identified include ambiguity of illness, changing family and spousal dynamics, and navigating the healthcare system. Sub-themes revolved around disease effects, psychological stressors, health systems, support, and facing the disease. Healthcare professionals have an opportunity to minimize the impact of negative emotional outcomes by assisting families as they navigate the experience of having a child with an IEM. Our findings can be used to develop and continue a more well-rounded, family-oriented framework for IEM management.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536737PMC
December 2020

Effect of fluoride agents on surface characteristics of NiTi wires. An ex vivo investigation.

J Oral Biol Craniofac Res 2020 Oct-Dec;10(4):435-440. Epub 2020 Aug 5.

Department of Mechanical Engineering, M.S.Ramaiah University of Applied Sciences, Bengaluru, Karnataka, 560054, India.

Aim: To analyze the degree of corrosion of nickel titanium arch wires in patients with and without exposure to fluorides.

Material And Methods: This was an ex vivo study comprising of 60 subjects undergoing fixed orthodontic treatment. Group 1(controls) comprised of 30 sets of new unused NiTi wires and unused 11, 15 brackets, Group 2(patients) comprised of 30 sets of non fluoridated NiTi wires and 11, 15 brackets and Group 3(patients) had 30 sets of fluoridated NiTi wires and 11, 15 brackets. NiTi wires were used over 6 months of treatment(0.014″,0.016″, 16 × 22", each wire was used for 2 months and replaced with the next size). All wires were retrieved, stored and analyzed. At 6 months, brackets from 11 to 15 were debonded in both treatment groups. Archwires and brackets in 3 groups were subjected to SEM analysis at 500 and 1000 to observe differences. Additionally, EDX Spectroscopy was undertaken to evaluate surface elemental compositional differences in groups.

Results: Significant differences among groups were evident in brackets and archwires tested. Maximum degradation, cracks and dark spots were seen in wires and brackets exposed to fluoride agents. EDX spectroscopy revealed least Ni% in fluoridated wires and brackets.

Conclusions: Increased leaching of metal ions was evident when wires and brackets are exposed to fluoride agents during treatment. Use of non fluoridated mouthwash and toothpastes may be considered in orthodontic patients without risk of caries to mitigate such effects.
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http://dx.doi.org/10.1016/j.jobcr.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426570PMC
August 2020

The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome.

Hum Mutat 2020 Jul 9. Epub 2020 Jul 9.

Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.

Congenital heart defects and skeletal malformations syndrome (CHDSKM) is a rare autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. CHDSKM is caused by germline mutations in ABL1. To date, three variants have been in association with CHDSKM. In this study, we describe three de novo missense variants, c.407C>T (p.Thr136Met), c.746C>T (p.Pro249Leu), and c.1573G>A (p.Val525Met), and one recurrent variant, c.1066G>A (p.Ala356Thr), in six patients, thereby expanding the phenotypic spectrum of CHDSKM to include hearing impairment, lipodystrophy-like features, renal hypoplasia, and distinct ocular abnormalities. Functional investigation of the three novel variants showed an increased ABL1 kinase activity. The cardiac findings in additional patients with p.Ala356Thr contribute to the accumulating evidence that patients carrying either one of the recurrent variants, p.Tyr245Cys and p.Ala356Thr, have a high incidence of cardiac abnormalities. The phenotypic expansion has implications for the clinical diagnosis of CHDSKM in patients with germline ABL1 variants.
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http://dx.doi.org/10.1002/humu.24075DOI Listing
July 2020

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.

Am J Med Genet A 2020 07 23;182(7):1785-1790. Epub 2020 Apr 23.

Division of Genetics, Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, Louisiana, USA.

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient's phenotype was complicated by a dual diagnosis. More recently, an article describing a set of affected siblings was published. We describe three, previously unreported, patients showing clinical variability for this newly defined syndrome. The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features. The authors suggest the delineation of an acronym using the gene name and common features seen across the majority of patients reported so far. This new nomination, MED-DOCS, may help clinicians to recognize, suspect, and remember this novel syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61603DOI Listing
July 2020

Evaluation of the quality of clinical data collection for a pan-Canadian cohort of children affected by inherited metabolic diseases: lessons learned from the Canadian Inherited Metabolic Diseases Research Network.

Orphanet J Rare Dis 2020 04 10;15(1):89. Epub 2020 Apr 10.

University of Ottawa, Ottawa, Ontario, Canada.

Background: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases.

Methods: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data.

Results: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing).

Discussion: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.
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http://dx.doi.org/10.1186/s13023-020-01358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149838PMC
April 2020

Comparison of pain levels in patients treated with 3 different orthodontic appliances - a randomized trial.

Med Pharm Rep 2020 Jan 31;93(1):81-88. Epub 2020 Jan 31.

Department of Orthodontics and Dentofacial Orthopedics, Army College of Dental Sciences, Secunderabad, Telangana, India.

Background And Aims: To compare pain levels experienced during initial alignment with three different orthodontic appliance types and to correlate pain with male and female differences, if any.

Methods: A prospective, randomized 3-arm parallel trial allocated 36 adult orthodontic patients into three appliance groups: MBT 0.022" slot (Mini Twin, Ormco, Glendora, USA), self ligating 0.022" slot Damon 3MX (Ormco, Glendora, USA) and clear aligners (Smile align, Mumbai, India). The level of discomfort was assessed through a questionnaire based on the visual analogue scale at four hours, twenty four hours, third and seventh day after appliance placement.

Results: Patients treated with clear aligners reported less pain than patients treated with conventional and self ligating fixed appliances. Patients treated with MBT conventional appliances showed greater pain levels than Damon appliances. A significantly higher visual analogue scale score was observed at 24 hours and the least visual analogue scale scores on the seventh day post appliance placement.

Conclusion: During the first week of orthodontic treatment, patients treated with clear aligners reported lower pain than those treated with conventional and self-ligating appliances.
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http://dx.doi.org/10.15386/mpr-1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051823PMC
January 2020

Use of complementary and alternative medicine in patients with inborn errors of metabolism: A single-center study.

JIMD Rep 2020 Jan 18;51(1):105-112. Epub 2019 Dec 18.

Department of Paediatrics Western University London Ontario Canada.

Background And Objectives: There is a paucity of information on the use of complementary and alternative medicine (CAM) in patients with inborn errors of metabolism (IEM). This study's objective was to evaluate the self-reported use and perceived effectiveness of CAM in adults and children with IEM.

Methods: Patients aged 0-70 years and caregivers seen at the London Health Sciences Centre Metabolic Clinic (London, Ontario, Canada) between July 2017 and August 2017 were recruited to complete a questionnaire regarding CAM use to help their IEM diagnosis and perceived effectiveness of these therapies. Survey responses were analyzed using descriptive statistics; age, sex, and education level associations among CAM users were tested using the Pearson test.

Results: Of 50 potential participants, 44 (88%) completed the questionnaire, including 21 adults (6 by caregivers) and 23 children (22 by caregivers). The most common IEM category was Aminoacidopathies and Small Molecule Disorders (50%). Twenty-seven (61%) participants reported CAM use to help their IEM diagnosis. The most common CAM therapies used were chiropractic manipulation, omega-3 fatty acids, probiotics, and aromatherapy/essential oils. Most CAM users and caregivers (74%) perceived their CAM therapies as effective overall. Among CAM users, 40% had not discussed CAM use with a health care professional (HCP). CAM use was similar when comparing age, sex and education level.

Conclusions: CAM is commonly used among patients with IEM. The safety and efficacy of CAM therapies for IEM should be further investigated. HCPs and patients should openly discuss CAM use in order to evaluate safety.
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http://dx.doi.org/10.1002/jmd2.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012736PMC
January 2020

Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review.

Orphanet J Rare Dis 2020 01 14;15(1):12. Epub 2020 Jan 14.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Background: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes.

Methods: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death.

Results: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles.

Conclusions: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.
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http://dx.doi.org/10.1186/s13023-019-1276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961328PMC
January 2020

High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses.

JIMD Rep 2019 Nov 3;50(1):20-30. Epub 2019 Sep 3.

Division of Clinical and Metabolic Genetics, Department of Paediatrics University of Toronto, The Hospital for Sick Children Toronto Ontario Canada.

Background: Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the genes from a single clinical molecular diagnostic laboratory.

Methods: We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the genes.

Results: Six hundred and ninety three individuals underwent the direct Sanger sequencing of the genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety-one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including (n = 10), () (n = 33), (n = 17), (n = 7), (n = 10), () (n = 10), and (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset () and adult onset diseases were nonclassical phenotypes.

Conclusion: In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
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http://dx.doi.org/10.1002/jmd2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850977PMC
November 2019

Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA.

Am J Med Genet A 2020 01 15;182(1):162-168. Epub 2019 Nov 15.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies.
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http://dx.doi.org/10.1002/ajmg.a.61403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262792PMC
January 2020

Cohesin complex-associated holoprosencephaly.

Brain 2019 09;142(9):2631-2643

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
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http://dx.doi.org/10.1093/brain/awz210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245359PMC
September 2019

Photogrammetric reliability of frontal facial photographs with radiographs and anthropometric measurements.

J Oral Biol Craniofac Res 2019 Jul-Sep;9(3):280-285. Epub 2019 Jun 19.

Department of Orthodontics and Dentofacial Orthopedics, Army College of Dental Sciences, Secunderabad, Telangana, India.

Aim: To evaluate relationships between frontal cephalograms and photographic measurements of Indian population with anthropometric measurements and if frontal photographic analysis could be utilized with precision for orthodontic diagnosis.

Material And Methods: A cross-sectional ex vivo study was conducted on 300 subjects with age range of 18-25yrs. Standardized frontal cephalograms and photographs were obtained for all subjects and were analysed with Nemoceph 10.4.2 (Nemotec Dental Systems, Madrid, Spain) software program. Linear anthropometric measurements were recorded with the help of a digital Vernier caliper. 21 linear measurements were made, of which 10 were horizontal and 11 were vertical. Repeated measures of ANOVA followed by Bonferroni's Post hoc Analysis was used to compare mean values of horizontal and vertical parameters between 3 different methods. The level of significance was set at  < 0.05.

Results: Statistically significant differences were found with most parameters. Between the analogous photographic, cephalometric and anthropometric measurements, only N'-Me' showed reliability with all three methods (0.53,0.53,0.53).

Conclusion: The photographic method has proven to be a repeatable and reproducible tool for only few parameters. Therefore, it cannot be considered a reliable diagnostic tool.
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http://dx.doi.org/10.1016/j.jobcr.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593212PMC
June 2019

Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review.

Can J Neurol Sci 2019 07 6;46(4):459-463. Epub 2019 May 6.

Department of Pediatrics, London, Ontario,Canada.

We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss. Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy. Clinical phenotyping enabled a targeted approach to the investigation and identification of a novel homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). We compare our patients with those recently described and review the current literature for IMNEPD.
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http://dx.doi.org/10.1017/cjn.2019.35DOI Listing
July 2019

Kidney disease and organ transplantation in methylmalonic acidaemia.

Pediatr Transplant 2019 06 11;23(4):e13407. Epub 2019 Apr 11.

Department of Paediatrics, Western University, London, Ontario, Canada.

Objectives: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers.

Design And Methods: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years.

Results: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 μmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant.

Conclusions: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear.
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http://dx.doi.org/10.1111/petr.13407DOI Listing
June 2019

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Am J Hum Genet 2019 04 28;104(4):685-700. Epub 2019 Mar 28.

Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada. Electronic address:

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451739PMC
April 2019

Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: a cohort study in Ontario, Canada.

Orphanet J Rare Dis 2019 03 22;14(1):70. Epub 2019 Mar 22.

School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, 600 Peter Morand Cr, Ottawa, ON, K1G 5Z3, Canada.

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort.

Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence.

Results: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined.

Conclusions: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.
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http://dx.doi.org/10.1186/s13023-019-1001-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431026PMC
March 2019

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Nat Commun 2018 11 20;9(1):4885. Epub 2018 Nov 20.

Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.
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http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018

Twinkle-Associated Mitochondrial DNA Depletion.

Pediatr Neurol 2019 01 9;90:61-65. Epub 2018 Aug 9.

Department of Paediatrics, Children's Health Research Institute, Western University, London, Ontario, Canada. Electronic address:

Background: Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy.

Methods: We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed.

Results: Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years.

Conclusions: In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered.
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http://dx.doi.org/10.1016/j.pediatrneurol.2018.08.007DOI Listing
January 2019

Nephrological and urological complications of homozygous c.974G>A (p.Arg325Gln) OSGEP mutations.

Pediatr Nephrol 2018 11 23;33(11):2201-2204. Epub 2018 Aug 23.

Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, Children's Hospital, London Health Science Centre, 800 Commissioners Road East, London, ON, N6A 5W9, Canada.

Background: Galloway-Mowat syndrome (GAMOS) (OMIM #251300) is a severe autosomal recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies caused by WDR73 as well as OSGEP, TP53RK, TPRKB, or LAGE3 mutations.

Objective: We report on the hitherto undescribed urological and nephrological complications of the homozygous c.974G>A (p.Arg325Gln) OSGEP mutations in a 7-year-old Caucasian girl.

Case Diagnosis: The patient came to the attention of pediatric nephrology at the age of 3 years and 11 months, when she presented with status epilepticus due to profound hypomagnesemia (0.31 mmol/L, normal 0.65-1.05). A 24-h urine demonstrated a magnesium loss of 0.6 mmol/kg/day with associated proteinuria suggesting renal tubulopathy. Subsequently, she developed recurrent urinary tract infections (UTIs) and was diagnosed with neurogenic bladder dysfunction. The patient continued to have UTIs associated with seizures and sequential cultures growing multi-drug-resistant organisms despite of antibiotic prophylaxis. In addition, the proteinuria (median microalbumin/creatinine ratio 647 mg/mmol) increased, and she developed partial Fanconi syndrome. At age 7, she developed a large bladder calculus (3.3 × 3.2 cm) and three left non-obstructing renal calculi associated with elevated urinary cystine, hypercalciuria, and ongoing hypomagnesemia and required surgical intervention. Glomerular filtration rate (GFR) remained normal and she never developed frank nephrotic syndrome (average albumin 31 g/L).

Conclusions: It is unclear if patients with OSGEP mutations with tubular symptoms rather than nephrotic syndrome should be considered a different entity. Nephrological and urological complications of OSGEP mutations can be challenging and require a multidisciplinary approach.
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http://dx.doi.org/10.1007/s00467-018-4060-xDOI Listing
November 2018

Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3.

Eur J Med Genet 2019 Apr 11;62(4):273-277. Epub 2018 Aug 11.

Department of Paediatric Neurology, Children's Hospital London Health Science Centre, London, ON, Canada; Epidemiology and Statistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada. Electronic address:

Deleterious homozygous or compound heterozygous mutations in the TBCK (TBC1-domain-containing kinase) gene (implicated in the MTOR pathway) produce profound hypotonia, global developmental delay, facial dysmorphic features, and brain abnormalities. The disorder has been named "infantile hypotonia with psychomotor retardation and characteristic facies-3" (IHPRF3). Here we present two sisters with a novel mutation in TBCK (NM_001163435.2: c.753dup; p.(Lys252*)) who have this ultrarare disorder. We have reviewed the literature on the 33 previously reported cases to provide a characterization of this emerging phenotype. Pathogenic mutations in TBCK have a predominant involvement of the Central Nervous System with a progressive pattern, leading to the conclusion where pathogenic mutations of the said gene lead to a progressive neurodegenerative disease. This report adds novel mutation and features to this complex phenotype. Further investigation is required to understand the pathogenesis of TBCK.
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http://dx.doi.org/10.1016/j.ejmg.2018.08.004DOI Listing
April 2019