Neerja Gupta

Vitamin D status in primary hyperparathyroidism in India

OBJECTIVES Primary hyperparathyroidism is a syndrome with variable clinical expression, presenting as asymptomatic hypercalcaemia in Western countries and with predominant bone disease in developing countries. Vitamin D deficiency has been implicated as the cause of bone disease. There is a paucity of information on the vitamin D (25‐OHD3) status of patients with primary hyperparathyroidism presenting with bone disease. The present study aims to evaluate the vitamin D status in patients with primary hyperparathyroidism and to correlate it with the bone disease.

Secular Trends in Prevalence of Overweight and Obesity from 2006 to 2009 in Urban Asian Indian Adolescents Aged 14-17 Years

The present study examines the secular trends in prevalence of overweight and obesity among urban Asian Indian adolescents in New Delhi (North India). The data were derived from cross-sectional sampling of children, 3493 in year 2006 and 4908 in year 2009, aged 14–17 years studying in privately-funded and government-funded schools. Age, gender and Asian Indian-specific cut offs of body mass index (BMI) were used to define overweight and obesity. The prevalence of obesity increased significantly from 9.8% in 2006 to 11.7% in 2009 (p<0.01), whereas underweight decreased from 11.3% to 3.9% (p<0.001). There was a significantly higher risk of being overweight (OR 1.28; 95% CI, 1.15–1.42) and obese (OR 1.44; 95% CI, 1.24–1.66) in year 2009 than 2006, after adjusting for age, gender and type of school. Males and privately-funded school children had significantly higher increase in prevalence and risk of being overweight and obese over the three years. In conclusion, this study showed an increasing trend in prevalence of overweight and obesity in urban Asian Indian adolescents. More specifically, the study showed the association of this increasing trend of overweight and obesity prevalence with male gender and high socio-economic status, calling for an urgent need for immediate and targeted preventive measures.

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9‐month, global, randomized, double‐blind, non‐inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment‐naïve patients aged 3–73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent‐to‐treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per‐protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent‐to‐treat and per‐protocol populations, respectively. The lower bound of the 97.5% one‐sided confidence interval in both populations lay within the pre‐defined non‐inferiority margin of −1.0 g/dL, confirming that velaglucerase alfa is non‐inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross‐reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am. J. Hematol. 88:179–184, 2013.

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48–60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.

Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa

Autosomal recessive cutis laxa type 2B (ARCL2B; OMIM # 612940) is a segmental progeroid disorder caused by mutations in PYCR1 encoding pyrroline-5-carboxylate reductase 1, which is part of the conserved proline de novo synthesis pathway. Here we describe 33 patients with PYCR1-related ARCL from 27 families with initial diagnoses varying between wrinkly skin syndrome, gerodermia osteodysplastica, De Barsy syndrome or more severe progeria syndromes. Given the difficult differential diagnosis of ARCL syndromes we performed a systematic comparison of clinical features of PYCR1-related ARCL. Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects. Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value. In our cohort we identified 20 different PYCR1 mutations of which seven were novel. Most of the mutations accumulated in exons 4 to 6. Missense alterations of highly conserved residues were most frequent followed by splice site changes and a single nonsense mutation. Analysis of genotype-phenotype correlation revealed that patients with mutations in the first two exons had lower average clinical scores and absent or only mild intellectual disability. Structural analyses predicted interference with PYCR1 multimerization for a subset of missense mutations. These findings have implications for the clinics as well as the pathomechanism of PYCR1-related ARCL.

Mosaic 22q11.2 microdeletion syndrome: diagnosis and clinical manifestations of two cases

Chromosome 22q11.2 microdeletion syndrome is due to microdeletion of 22q11.2 region of chromosome 22. It is a common microdeletion syndrome however mosaic cases are very rare and reported only few previous occasions. In this report we describe two unrelated male children with clinical features consistent with 22q11.2 microdeletion syndrome characterized by cardiac defect, facial dysmorphism and developmental deficiency. One of the cases also had trigonocephaly. Interphase & metaphase FISH with 22q11.2 probe demonstrated mosaicism for hemizygous deletion of 22q11.2 region. Mosaicism is also observed in buccal cells as well as urine cells. Parents were without any deletion. These two cases represent rare cases of mosaic 22q11.2 microdeletion syndrome.

Intravenous pamidronate therapy in osteogenesis imperfecta: response to treatment and factors influencing outcome.

Pamidronate treatment has been shown to improve outcome in osteogenesis imperfecta (OI); however, factors influencing outcome are unclear. The present study was conducted to evaluate the response to pamidronate therapy with special emphasis on factors influencing outcome. Twenty children with OI treated with pamidronate were evaluated in a prospective, open clinical trial. Pamidronate (9 mg · kg−1 · yr−1) was administered intravenously at the age of 4.5 ± 4.2 years for 2.9 ± 0.7 years (range, 2-3.8 years). Treatment led to increase in bone mineral density (BMD) Z score by 0.7 ± 0.3 every year resulting in significant improvement in BMD Z score (from −4.6 ± 1.1 to −2.5 ± 1.1, P < 0.001). BMD Z score was within the reference range (>−2) in 9 subjects (45%) at the last follow-up as against none at initiation of treatment (P < 0.001). Fracture rate decreased significantly during treatment (3.3 ± 1.4 to 0.8 ± 0.9, P < 0.001) with 8 subjects (40%) having no fracture during the treatment period. Significantly greater proportion (88.2%) of children were able to walk at last follow-up compared with those at initiation of treatment (45.4%). Increase in BMD Z score and final BMD Z score was not influenced by age at initiation of treatment, duration of treatment, or initial BMD Z score. Treatment before infancy (n = 7) was associated with higher final subjective score (6.3 ± 0.5 vs 4.9 ± 1.5, P = 0.03). Our study reiterates the efficacy of pamidronate in OI. The poorer response of our subjects may be related to compromised calcium and vitamin D status.

Cutis Laxa Type II and Wrinkly Skin Syndrome: Distinct Phenotypes

Abstract:  Cutis laxa is a heterogeneous group of disorders with variable phenotypes and inheritance patterns. Type II cutis laxa has features overlapping with wrinkly skin syndrome, as a result of which they are regarded as one disorder with a variable spectrum of severity by some authors. To overcome this existing confusion, we present three patients with cutis laxa type II and review the literature to highlight the important differentiating features between cutis laxa type II and wrinkly skin syndrome.

Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations in arylsulfatase A (ARSA) gene. No work on molecular genetics of MLD has been reported from India and the mutational spectrum in Indian patients is not known. The present study was undertaken to identify mutations in arylsulfatase A gene in Indian MLD patients, to evaluate genotype-phenotype correlation, and to see the effect of the novel mutants on the protein. Twenty MLD patients (16 families) were screened by ARMS PCR for the most common mutation (c.459+1G>A). Pseudodeficiency alleles were tested by RFLP method whereas rare and novel mutations were scanned by Conformation Sensitive Gel Electrophoresis (CSGE), followed by sequencing. The genotype-phenotype correlation was also attempted. Protein homology modeling analysis was carried out for two novel missense mutations identified, to assess the effect of these mutations on the protein conformation. Nine pathogenic alleles were found in 13 patients (65%). Four previously reported mutations and five novel variants were identified. Five patients (35%) were found to have pseudodeficiency alleles, c.1049A>G (p.Asn350Ser) and c.1524+95A>G. Genotype-phenotype correlation was found to be difficult to establish. Protein modeling studies showed that the mutations cause loss of interactions leading to conformational change in ASA protein. The study identified the mutational spectrum of Indian MLD patients, which will be helpful in genetic counseling, carrier detection and establishing prenatal diagnosis. Homology modeling helped to study conformational change in protein and has implications in generating novel therapeutic molecules.

Unbalanced X; Autosome Translocation

Unbalanced X; autosome translocation can result in multiple congenital abnormalities/mental retardation syndrome due to chromosomal imbalance. Here is described a patient with developmental delay, microcephaly, agenesis of corpus callosum spasticity, seizures and dysmorphism as a result of meiotic malsegregation of balanced X; autosome translocation in mother. Present case signifies the importance of chromosomal analysis in a patient with developmental delay/ mental retardation and discuss lyonization in cases with X; autosome translocation.