Publications by authors named "Madhulika Kabra"

259 Publications

Late onset Pompe Disease in India - Beyond the Caucasian phenotype.

Neuromuscul Disord 2021 Feb 16. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

We evaluated the clinical histories, motor and pulmonary functions, cardiac phenotypes and GAA genotypes of an Indian cohort of twenty patients with late onset Pompe disease (LOPD) in this multi-centre study. A mean age at onset of symptoms and diagnosis of 9.9 ± 9.7 years and 15.8 ± 12.1 years respectively was identified. All patients had lower extremity limb-girdle muscle weakness. Seven required ventilatory support and seven used mobility assists. Of the four who used both assists, two received ventilatory support prior to wheelchair use. Cardiac involvement was seen in eight patients with various combinations of left ventricular hypertrophy, tricuspid regurgitation, cardiomyopathy, dilated ventricles with biventricular dysfunction and aortic regurgitation. Amongst 20 biochemically diagnosed patients (low residual GAA enzyme activity) GAA genotypes of 19 patients identified homozygous variants in eight and compound heterozygous in 11: 27 missense, 3 nonsense, 2 initiator codon, 3 splice site and one deletion. Nine variants in 7 patients were novel. The leaky Caucasian, splice site LOPD variant, c.-32-13T>G mutation was absent. This first study from India provides an insight into a more severe LOPD phenotype with earlier disease onset at 9.9 years compared to 33.3 years in Caucasian patients, and cardiac involvement more than previously reported. The need for improvement in awareness and diagnosis of LOPD in India is highlighted.
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http://dx.doi.org/10.1016/j.nmd.2021.02.013DOI Listing
February 2021

Spine radiograph in dysplasias: A pictorial essay.

Indian J Radiol Imaging 2020 Oct-Dec;30(4):436-447. Epub 2021 Jan 13.

Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

Spine radiograph is an essential component of a skeletal survey. It provides important diagnostic clues to various types of skeletal dysplasia. In some conditions, a spine radiograph alone may be diagnostic and characteristic; but mostly, it yields more value as a part of the complete skeletal survey. In this article we will discuss about a few common lethal and non-lethal skeletal dysplasias and their characteristic imaging findings; primarily focusing on the spine radiograph.
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http://dx.doi.org/10.4103/ijri.IJRI_395_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954163PMC
January 2021

Hydrops fetalis in PKD1L1-related heterotaxy: Report of two foetuses and expanding the phenotypic and molecular spectrum.

Ann Hum Genet 2021 Mar 2. Epub 2021 Mar 2.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Abnormalities in the normal left-right axis asymmetry range from situs inversus totalis to situs ambiguous or heterotaxy. More than 80 genes have been described to have a role in the establishment of the normal situs of the internal organs. Pathogenic variants in the PKD1L1 gene have recently been described in heterotaxy and congenital heart disease. Till date, 11 families have been described with PKD1L1-related heterotaxy. We describe the first Indian family with two affected foetuses with PKD1L1-related nonimmune hydrops, congenital heart disease, situs inversus, and heterotaxy, with biallelic variants in the compound heterozygous state.
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http://dx.doi.org/10.1111/ahg.12417DOI Listing
March 2021

A Novel Homozygous HAX1 Mutation in a Child With Cyclic Neutropenia: A Case Report and Review.

J Pediatr Hematol Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Pediatrics, Division of Pediatric Pulmonology Department of Pediatrics, Division of Pediatric Oncology Department of Pediatrics, Division of Genetics Laboratory Oncology Unit, Dr B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.

Background: Cyclic neutropenia is a rare genetic disorder causing the arrest of neutrophil function and is characterized by periodic neutropenia and recurrent infections. Patients with cyclic neutropenia with autosomal dominant, sporadic, and X-linked may have mutations in the ELANE gene, and autosomal recessive cases have homozygous/compound heterozygous variants in the HAX1 gene primarily.

Observation: The authors describe a novel variant in the HAX1 gene, which was detected by next-generation sequencing in an 8-year-old male child who presented with recurrent infections and neutropenia.

Conclusion: The patient extends the clinical variability associated with HAX1 variants and highlights the importance of genetic investigations in patients with suspected cyclic neutropenia.
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http://dx.doi.org/10.1097/MPH.0000000000002110DOI Listing
February 2021

A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians.

Hum Mutat 2021 Apr 1;42(4):e15-e61. Epub 2021 Mar 1.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Given the genomic uniqueness, a local data set is most desired for Indians, who are underrepresented in existing public databases. We hypothesize patients with rare monogenic disorders and their family members can provide a reliable source of common variants in the population. Exome sequencing (ES) data from families with rare Mendelian disorders was aggregated from five centers in India. The dataset was refined by excluding related individuals and removing the disease-causing variants (refined cohort). The efficiency of these data sets was assessed in a new set of 50 exomes against gnomAD and GenomeAsia. Our original cohort comprised 1455 individuals from 1203 families. The refined cohort had 836 unrelated individuals that retained 1,251,064 variants with 181,125 population-specific and 489,618 common variants. The allele frequencies from our cohort helped to define 97,609 rare variants in gnomAD and 44,520 rare variants in GenomeAsia as common variants in our population. Our variant dataset provided an additional 1.7% and 0.1% efficiency for prioritizing heterozygous and homozygous variants respectively for rare monogenic disorders. We observed additional 19 genes/human knockouts. We list carrier frequency for 142 recessive disorders. This is a large and useful resource of exonic variants for Indians. Despite limitations, datasets from patients are efficient tools for variant prioritization in a resource-limited setting.
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http://dx.doi.org/10.1002/humu.24172DOI Listing
April 2021

Weak Ligaments and Sloping Joints: A New Hypothesis for Development of Congenital Atlantoaxial Dislocation and Basilar Invagination.

Neurospine 2020 Dec 31;17(4):843-856. Epub 2020 Dec 31.

Genetics Center, All India Institute of Medical Sciences, New Delhi, India.

Objective: Developmental bony craniovertebral junction (CVJ) anomalies seem to have a genetic basis and also abnormal joint morphology causing atlantoaxial dislocation (AAD) and basilar invagination (BI).

Methods: DNA extracted polymerase chain reaction single-stranded conformation polymorphism (SSCP) performed for mutation screening of FBN1 gene (n = 50 cases+ 50 age/sex-matched normal; total: 100). Samples with a deviated pattern of bands in SSCP were sequenced to detect the type of variation. Computed tomography (CT) scans of 100 patients (15-45 years old) compared with an equal number of age/sex-matched controls (21.9 ± 8.2 years). Joint parameters studied: sagittal joint inclination (SI), craniocervical tilt (CCT), coronal joint inclination (CI).

Results: Thirty-nine samples (78%) showed sequence variants. Exon 25, 26, 27, and 28 showed variable patterns of DNA bands in SSCP, which on sequencing gives various types of DNA sequence variations in intronic region of the FBN1 gene in 14%, 14%, 6%, and 44% respectively. CT radiology:SI and CCT correlated with both BI and AAD (p < 0.01). The mean SI value in controls: 83.35° ± 8.65°, and in patients with BI and AAD:129° ± 24.05°. Mean CCT in controls: 60.2° ± 9.2°, and in patients with BI and AAD: 86.0° ± 18.1°. Mean CI in controls:110.3° ± 4.23°, and in cases: 125.15° ± 16.4°.

Conclusion: The study showed mutations in FBN1 gene (reported in Marfan syndrome). There is also an alteration of joint morphology, correlating with AAD and BI severity. Hence, we propose a double-hit hypothesis: the presence of weak ligaments (due to FB1 gene alterations) and abnormal joint morphology may contribute to AAD and BI.
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http://dx.doi.org/10.14245/ns.2040434.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788422PMC
December 2020

Association of Sleep Apnea With Development and Behavior in Down Syndrome: A Prospective Clinical and Polysomnographic Study.

Pediatr Neurol 2021 Mar 19;116:7-13. Epub 2020 Nov 19.

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Background: The prevalence of sleep-disordered breathing is high in children with Down syndrome. Although the association between sleep-disordered breathing and developmental delay and behavioral abnormalities are proven among typically developing children, there are few such studies of children with Down syndrome. This study assesses the relationship between the severity of sleep apnea and development and behavioral abnormalities in individuals with Down syndrome.

Methods: In a cross-sectional prospective study, 53 children with Down syndrome were assessed for sleep-disordered breathing by overnight polysomnography. Behavior was assessed using Child Behavior Checklist (CBCL) and developmental quotient (DQ) using Developmental Profile 3. The association between various domains of behavior and development with the Apnea-Hypopnea Index (AHI) was assessed using Spearman rank correlation. Multiple linear regression assessed the independent effects of various factors on development and behavior.

Results: Of 53 subjects (three to 11.8 years), 51 (96%) were found to have obstructive sleep apnea (OSA). In both three to five year and six to 12 year age groups, there was a statistically significant positive correlation between the CBCL scores and the AHI (rho = 0.77 and 0.83, respectively). There was a statistically significant negative correlation between the DQ and the AHI (rho = -0.62). In multiple linear regression, AHI was the only independent variable that was associated with CBCL and DQ.

Conclusions: This study provides robust evidence that OSA can negatively influence the development and behavior in children with Down syndrome as in typically developing children. Moreover, with increasing severity of OSA, children with Down syndrome have more behavioral abnormalities, especially attention deficit and hyperactivity, and also have poorer development scores.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.10.007DOI Listing
March 2021

Fabry disease in India: A multicenter study of the clinical and mutation spectrum in 54 patients.

JIMD Rep 2020 Nov 15;56(1):82-94. Epub 2020 Aug 15.

Lysosomal Disorders Unit, Institute of Immunity and Transplantation Royal Free London NHS Foundation Trust London UK.

Fabry disease (FD) is a treatable X linked lysosomal storage disorder with a wide phenotypic spectrum. There is a scarcity of published data on the burden of FD in India. This study evaluates the clinical and molecular spectrum of Indian patients with FD. In this multicentric study involving 10 tertiary referral centers in India, we analyzed the clinical course and genotype of 54 patients from 37 families. Family screening identified 19 new patients (35%) from 12 index cases. Then, 33 gene variants were identified in 49/54 (90.7%) which included 11 novel and 22 known pathogenic variants. Of the 54 patients in our cohort, 40 patients had "classical" and 10 patients had a "nonclassical" presentation. The symptoms and signs included kidney dysfunction in 38/54 (70.3%), neuropathic pain in 34/54 (62.9%), left ventricular hypertrophy in 22/49 (44.8%) and stroke in 5/54 (9.2%). Female heterozygotes were 10/54 (18.5%) of whom 2 were index cases. There was a significant delay in reaching the diagnosis of 11.7 years. Enzyme replacement therapy was initiated in 28/54 (51.8%) patients with significant improvement of neuropathic pain and gastrointestinal symptoms. This study highlights the clinical presentation and mutational spectrum of FD in India and suggests that family screening and screening of high-risk groups (hypertrophic cardiomyopathy, idiopathic chronic renal failure and cryptogenic stroke) could be the most cost-effective strategies for early identification of FD.
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http://dx.doi.org/10.1002/jmd2.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653245PMC
November 2020

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective.

Mol Genet Metab 2020 11 25;131(3):285-288. Epub 2020 Sep 25.

Translational Metabolic laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.
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http://dx.doi.org/10.1016/j.ymgme.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518833PMC
November 2020

Stippled keratoderma and nail dystrophy associated with hyperkeratotic pustular lesions in a 2-year-old boy.

Pediatr Dermatol 2020 Sep;37(5):e64-e66

Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.1111/pde.14313DOI Listing
September 2020

Report of an Indian Family with Sengers Syndrome.

Indian J Pediatr 2021 Jan 27;88(1):92. Epub 2020 Aug 27.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

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http://dx.doi.org/10.1007/s12098-020-03471-0DOI Listing
January 2021

Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome.

J Pediatr Endocrinol Metab 2020 Sep;33(9):1155-1163

Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.

Objectives To evaluate if the parental origin of X-chromosome has an impact on the phenotype and biochemical profile in Turner syndrome (TS). Result of the previous studies have been equivocal and could be attributable to the multicentric study design with different experts examining heterogeneous TS population of various ethnic background. Methods A cross-sectional single center study from Northern India. Fifty nine diagnosed subjects of TS and their parents participated in the study. Parental origin of intact X-chromosome was determined using 12 highly polymorphic short tandem repeats (STR) on X-chromosome. For the evaluation of parent-of-origin effects, typical phenotypic traits including congenital malformations, anthropometry, body composition by dual energy X-ray absorptiometry (DXA) and biochemical profile were compared. Clinical stigmata of TS in all subjects were examined by a single expert. Results The intact X-chromosome was of maternal origin (Xm) in 49.1% subjects while 50.9% had paternal origin (Xp). Skeletal anomalies were more common in Xm group, out of which prevalence of short neck and short fourth metatarsal reached statistical significance (p=0.04 and 0.01 respectively). A strong correlation was observed between subject's baseline height standard deviation score (Ht SDS) and paternal height (r=0.593, p<0.001), maternal height (r=0.564, p<0.001) and mid-parental height (MPH) (r=0.372, p=0.047) in Xp group. This effect was not seen in Xm subjects whose baseline Ht SDS showed no significant correlation with maternal height, paternal height or MPH. No differences were detected between the groups with regard to biochemical profile or body composition. Conclusions We speculate that the differences in skeletal anomalies and height correlations between Xm and Xp groups could be due to the modifying effect of epigenetic signature on short stature homeobox (SHOX) gene of Xm. SHOX gene is not modified on Xp thereby explaining the paucity of skeletal changes and height correlations in Xp subjects.
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http://dx.doi.org/10.1515/jpem-2020-0104DOI Listing
September 2020

Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III.

J Hum Genet 2020 Nov 10;65(11):971-984. Epub 2020 Jul 10.

Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

Mucolipidosis (ML) (OMIM 607840 & 607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)- N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.
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http://dx.doi.org/10.1038/s10038-020-0797-8DOI Listing
November 2020

Cystic Fibrosis Presenting as Pseudo-Bartter Syndrome: An Important Diagnosis that is Missed!

Indian J Pediatr 2020 09 5;87(9):726-732. Epub 2020 Jun 5.

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Cystic fibrosis (CF), an autosomal recessive disorder, occurs due to mutations in CFTR gene resulting in impaired cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function in various epithelia. In addition to the well-known pulmonary and pancreatic morbidities, CF is characterized by electrolyte and acid-base abnormalities- hypochloremia, hyponatremia, hypokalemia and metabolic alkalosis. These are collectively known as Pseudo-Bartter syndrome, as similar abnormalities are seen in Bartter syndrome- an inherited tubulopathy affecting thick ascending limb of loop of Henle. There may be a significant clinical overlap between the Classic Bartter syndrome, Gitelman syndrome and CF presenting as Pseudo-Bartter syndrome, especially in early childhood. This review focuses on Pseudo-Bartter syndrome in CF, its pathogenesis and differentiation from Bartter/Gitelman syndrome. Other causes of metabolic abnormalities resembling Bartter syndrome are also highlighted.
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http://dx.doi.org/10.1007/s12098-020-03342-8DOI Listing
September 2020

Methylene Tetrahydrofolate Reductase Deficiency.

Indian J Pediatr 2020 Nov 26;87(11):951-953. Epub 2020 May 26.

Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi, 110029, India.

5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a rare, autosomal recessive, metabolic disorder of folate metabolism, which affects homocysteine remethylation. Elevated homocysteine with normal or low methionine level is the key to diagnosis. Early recognition and treatment with betaine, has been shown to improve the survival and neurological outcomes. The authors report five Indian patients from three unrelated families, with MTHFR deficiency to emphasize the importance of early recognition and initiation of specific treatment.
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http://dx.doi.org/10.1007/s12098-020-03290-3DOI Listing
November 2020

Bi-allelic loss-of-function novel variants in LTBP3-related skeletal dysplasia: Report of first patient from India.

Am J Med Genet A 2020 08 20;182(8):1944-1946. Epub 2020 May 20.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Dental anomalies and short stature (DASS) has been recently identified as a distinct entity, associated with bi-allelic hypomorphic variants in LTBP3 gene. Only 20 individuals from nine families have been previously reported, with a consistent phenotype of short stature, brachyolmia, and amelogenesis imperfecta. We report the first case from India, with novel radiographic and molecular findings in LTBP3 gene, thereby expanding the phenotypic spectrum of DASS.
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http://dx.doi.org/10.1002/ajmg.a.61629DOI Listing
August 2020

Duchenne Muscular Dystrophy- Where Genetic Testing is Inevitable and Vital!

Indian J Pediatr 2020 07 16;87(7):487-488. Epub 2020 May 16.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

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http://dx.doi.org/10.1007/s12098-020-03324-wDOI Listing
July 2020

Identification of a Novel 19-bp Deletion Mutation in Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C.

J Pediatr Genet 2020 Jun 22;9(2):125-131. Epub 2019 Oct 22.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, India.

Autosomal recessive type I cutis laxa is genetically heterogeneous. Biallelic mutations in latent transforming growth factor β-binding protein 4 (LTBP4; MIM*604710) lead to type 1C cutis laxa due to nonsense, frameshift, single base pair indels, or duplication mutations. In this report, we describe the first Indian family with cutis laxa as a result of a novel 19 base pair homozygous deletion leading to premature termination of short isoform LTBP-4S.
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http://dx.doi.org/10.1055/s-0039-1698806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183407PMC
June 2020

Natural history of non-lethal Raine syndrome during childhood.

Orphanet J Rare Dis 2020 04 16;15(1):93. Epub 2020 Apr 16.

Department of Pediatrics, Vittore Buzzi Children's Hospital, Department of Biomedical and Clinical Science L. Sacco, Università degli Studi di Milano, Milan, Italy.

Background: Raine syndrome (RS) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations of FAM20C. The most common clinical features are microcephaly, exophthalmos, hypoplastic nose and severe midface hypoplasia, leading to choanal atresia. The radiological findings include generalized osteosclerosis and brain calcifications. RS is usually lethal during the neonatal period due to severe respiratory distress. However, there exists a non-lethal RS form, the phenotype of which is extremely heterogeneous. There is paucity of data about clinical course and life expectancy of these patients.

Results: This is the first description of follow-up features of non-lethal RS patients. Moreover, we present three unpublished cases. There are five Asian and two Arab patients. All were born to consanguineous parents. The most common neonatal comorbidity was respiratory distress secondary to choanal atresia. A variable degree of neurodevelopmental delay was seen in the majority of our cases and seizures and hearing or vision involvement were also frequent. Neurological and orthopedic issues were the most frequent complications seen at follow-up in our group. Persistent hypophosphatemic rickets was the most striking endocrinological manifestation, which was scarcely responsive to therapy with phosphate salts and alfacalcidol. Life expectancy of our patients goes beyond childhood, with the oldest of those described being 18 years old at present.

Conclusions: Manifestations of RS in those surviving the neonatal period are being increasingly recognized. Our study supports previous findings and provides clinical and biochemical observations and data from longer follow up. Finally, we propose multidisciplinary follow up for patients with non-lethal RS.
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http://dx.doi.org/10.1186/s13023-020-01373-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164176PMC
April 2020

Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III.

Am J Med Genet A 2020 05 28;182(5):1190-1200. Epub 2020 Mar 28.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Glycogen storage disease type III (GSD III) is a rare autosomal recessive inborn error of glycogen degradation pathway due to deficiency or reduced activity of glycogen debranching enzyme (GDE) that results in accumulation of abnormal glycogen in the liver, muscle, and heart. The cardinal hallmarks are hepatomegaly, fasting hypoglycemia, seizures, growth retardation, progressive skeletal myopathy, and cardiomyopathy in few. To date, 258 mutations in amyloglucosidase (AGL) gene have been identified worldwide. However, the mutation spectrum in the Asian Indian region is yet to be well characterized. We investigated 24 patients of Asian origin from 21 unrelated families with a provisional diagnosis of GSD III based on clinical and biochemical criteria. Molecular diagnosis was assessed by bidirectional sequencing and the impact of novel missense variants on the tertiary (three-dimensional) structure of GDE was evaluated by molecular modeling approach. Eighteen different pathogenic variants were identified, out of which 78% were novel. Novel variants included five nonsense, three small duplications and two small deletions, a splice site variant, and three missense variants. Variations in Exons 4, 14, 19, 24, 27, and 33 accounted for 61% of the total pathogenic variants identified and Allele p.Gly798Alafs*3 showed a high allele frequency of 11%. Molecular modeling study of novel pathogenic missense variants indicated the probable underlying molecular mechanism of adverse impact of variations on the structure and catalytic function of human GDE. Our study is the first large study on GSD III from the Asian subcontinent, which further expands the mutation spectrum of AGL.
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http://dx.doi.org/10.1002/ajmg.a.61547DOI Listing
May 2020

'Go for it, dream big, work hard and persist': A message to the next generation of CF leaders in recognition of International Women's Day 2020.

J Cyst Fibros 2020 03 7;19(2):184-193. Epub 2020 Mar 7.

Respiratory and Sleep Medicine, Queensland Children's Hospital and Faculty of Medicine, University of Queensland, Brisbane, Australia.

The focus for International Women's Day 2020 is gender equity:'We can actively choose to challenge stereotypes, fight bias, broaden perceptions, improve situations and celebrate women's achievements. Collectively, each one of us can help create a gender equal world.' We have come together as an international group of women holding senior positions within CF to raise awareness. There is growing recognition of gender imbalance within our sector in senior leadership, grant and publication success. Several institutions, such as National Institutes of Health, have missions to tackle this. The issues raised by our panellists were wide-ranging: decisions around starting a family, impact on career progression; experiences of bias in appointments or promotions; selfbelief. We hope that raising these issues will encourage future leaders in CF to step up, to build teams based on fairness, equity and diversity, and to catalyse steps towards this goal in their institutions and society more widely.
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http://dx.doi.org/10.1016/j.jcf.2020.02.021DOI Listing
March 2020

Management of Infants with Congenital Adrenal Hyperplasia.

Indian Pediatr 2020 02;57(2):159-164

Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India. Correspondence to: Prof Sangeeta Yadav, Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital. New Delhi 110 002, India.

Treatment of congenital adrenal hyperplasia (CAH) requires lifelong replacement of glucocorticoids with regular follow up to manage associated morbidities. The current review focuses on follow-up and management of infants diagnosed with classical CAH pertinent to Indian context. Early initiation of oral hydrocortisone in divided doses is recommended after diagnosis in newborn period, infancy and childhood. Fludrocortisone is recommended for all infants with classical CAH. All infants should be monitored as per protocol for disease and treatment related complications. The role of prenatal steroids to pregnant women with previous history of CAH affected infant for prevention of virilization of female fetus is controversial.
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February 2020

Epigenetic Abnormalities of 11p15.5 Region in Beckwith-Wiedemann Syndrome - A Report of Eight Indian Cases.

Indian J Pediatr 2020 03 29;87(3):175-178. Epub 2020 Jan 29.

Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi, India.

Objectives: To report a phenotypic series of eight patients of Beckwith-Wiedemann Syndrome (BWS) with abnormalities of 11p15.5 region to highlight the spectrum of phenotypic manifestations.

Methods: All the cases were evaluated using Methylation Specific Multiplex Ligation Dependent Probe Amplification (MS-MLPA) of 11p15.5 region to detect the abnormal methylation status of ICR1 (H19DR) and ICR2 (KvDMR) regions.

Results: The median age at diagnosis was 5.7 mo (range 1.5-13 mo) with female preponderance. Macroglossia, ear creases and abdominal wall defects were the major features. Hypomethylation at ICR2 and hypermethylation at ICR1 was observed in 6/8 and 2/8 patients respectively. No specific genotype and phenotype correlation was observed.

Conclusions: This report highlights the major clinical features of BWS that should prompt pediatricians to offer genetic testing to evaluate the epigenetic abnormalities using MS-MLPA, as it not only helps in appropriate counseling but also provides further guidance about the tumor risk surveillance.
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http://dx.doi.org/10.1007/s12098-019-03148-3DOI Listing
March 2020

Newborn Screening and Diagnosis of Infants with Congenital Adrenal Hyperplasia.

Indian Pediatr 2020 01;57(1):49-55

Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India. Correspondence to: Dr Seema Kapoor, Director Professor, Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive endocrine disorder which can manifest after birth with ambiguous genitalia and salt-wasting crisis. However, genital ambiguity is not seen in male babies and may be mild in female babies, leading to a missed diagnosis of classical CAH at birth. In this review, we provide a standard operating protocol for routine newborn screening for CAH in Indian settings. A standardization of first tier screening tests with a single consistent set of cut-off values stratified by gestational age is also suggested. The protocol also recommends a two-tier protocol of initial immunoassay/time resolved fluoroimmunoassay followed by liquid chromatography tandem mass spectrometry for confirmation of screen positive babies, wherever feasible. Routine molecular and genetic testing is not essential for establishing the diagnosis in all screen positive babies, but has significant utility in prenatal diagnosis and genetic counseling for future pregnancy.
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January 2020

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature.

J Pediatr Endocrinol Metab 2020 Jan;33(1):79-88

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Background Our objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation. Methods We recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <-1 standard deviation. The genotype-phenotype correlation was studied. Results Four children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as 'disease causing', and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop. Conclusions Pathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.
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http://dx.doi.org/10.1515/jpem-2019-0234DOI Listing
January 2020

Decoding of novel missense TSC2 gene variants using in-silico methods.

BMC Med Genet 2019 10 26;20(1):164. Epub 2019 Oct 26.

Division of Genetics, Department of Pediatrics, AIIMS, New Delhi, India.

Background: Mutations in TSC1 or TSC2 gene cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the formation of non-malignant hamartomas in multiple vital organs. TSC1 and TSC2 gene products form TSC heterodimer that senses specific cell growth conditions to control mTORC1 signalling.

Methods: In the present study 98 TSC patients were tested for variants in TSC1 and TSC2 genes and 14 novel missense variations were identified. The pathogenecity of these novel variations was determined by applying different bioinformatics tools involving computer aided protein modeling.

Results: Protein modelling could be done only for ten variants which were within the functional part of the protein. Homology modeling is the most reliable method for structure prediction of a protein. Since no sequence homology structure was available for the tuberin protein, three dimensional structure was modeled by a combination of homology modeling and the predictive fold recognition and threading method using Phyre2 threading server. The best template structures for model building of the TSC1 interacting domain, tuberin domain and GAP domain are the crystal structures of clathrin adaptor core protein, Rap1GAP catalytic domain and Ser/Thr kinase Tor protein respectively.

Conclusions: In this study, an attempt has been made to assess the impact of each novel missense variant based on their TSC1-TSC2 hydrophobic interactions and its effect on protein function.
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http://dx.doi.org/10.1186/s12881-019-0891-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815426PMC
October 2019

Clinical and Molecular Disease Spectrum and Outcomes in Patients with Infantile-Onset Pompe Disease.

J Pediatr 2020 01 9;216:44-50.e5. Epub 2019 Oct 9.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC.

Objectives: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD).

Study Design: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes.

Results: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD.

Conclusions: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.058DOI Listing
January 2020

Rapid Eye Movement (REM) Sleep Behavior Disorder and REM Sleep without Atonia in the Young.

Can J Neurol Sci 2019 Sep 24:1-9. Epub 2019 Sep 24.

Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RWA) have assumed much clinical importance with long-term data showing progression into neurodegenerative conditions among older adults. However, much less is known about RBD and RWA in younger populations. This study aims at comparing clinical and polysomnographic (PSG) characteristics of young patients presenting with RBD, young patients with other neurological conditions, and normal age-matched subjects.

Methods: A retrospective chart review was carried out for consecutive young patients (<25 years) presenting with clinical features of RBD; and data were compared to data from patients with epilepsy, attention deficit hyperactivity disorder (ADHD), and autism, as well as normal subjects who underwent PSG during a 2-year-period.

Results: Twelve patients fulfilling RBD diagnostic criteria, 22 autism patients, 10 with ADHD, 30 with epilepsy, and 14 normal subjects were included. Eight patients with autism (30%), three with ADHD (30%), one with epilepsy (3.3%), and six patients who had presented with RBD like symptoms (50%) had abnormal movements and behaviors during REM sleep. Excessive transient muscle activity and/or sustained muscle activity during REM epochs was found in all patients who had presented with RBD, in 16/22 (72%) autistic patients, 6/10 (60%) ADHD patients compared to only 6/30 (20%) patients with epilepsy and in none of the normal subjects.

Conclusion: We observed that a large percentage of young patients with autism and ADHD and some with epilepsy demonstrate loss of REM-associated atonia and some RBD-like behaviors on polysomnography similar to young patients presenting with RBD.
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http://dx.doi.org/10.1017/cjn.2019.302DOI Listing
September 2019

First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.

Eur J Med Genet 2020 Mar 14;63(3):103742. Epub 2019 Aug 14.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Genetics, New Delhi, India.

THOC6 is a newly described causal gene for an autosomal recessive intellectual disability (ID) - Beaulieu Boycott Innes syndrome (BBIS) (OMIM # 613680). It is characterized by ID with dysmorphic facies, genitourinary, cardiac anomalies, and dentition problems. Here, we report the first two siblings of BBIS from the Indian subcontinent with previously unreported skeletal anomalies such as Sprengel shoulder, calcaneo valgus deformity, radioulnar dysostosis, and overlapping toes. Whole exome sequencing (WES) identified previously reported three missense variants (p.Trp100Arg, p.Val234Leu, p.Gly275Asp) in THOC6. THOC6 is a subunit of TRanscription and EXport (TREX) complex involved in mRNA transcription, processing, and nuclear export of spliced mRNAs and has a potential role in neurodevelopment. Till date, only 12 patients with BBIS have been reported. This report reviews the phenotypic and genetic data of known BBIS cases in addition to the new phenotypic features, thereby expanding the phenotype of this rare syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2019.103742DOI Listing
March 2020