Sunita Bijarnia-Mahay

Newborn Screening: Need of the Hour in India

After a review of the current health scene in India, the authors suggest that the Government of India should consider seriously, the introduction of new born screening. As a first step, a central advisory committee should be constituted to recommend what is required to be done to strengthen the infrastructure and the manpower to carry out new born screening, and the disorders to be screened. In the urban hospitals newborn screening (NBS) for three disorders can be easily introduced (congenital hypothyroidism, congenital adrenal hyperplasia and G-6-PD deficiency), while in the rural areas this should begin with congenital hypothyroidism, especially in the sub Himalayan areas. Concurrently, logistic issues regarding diets and special therapies for inborn errors of metabolism should be sorted out, laboratories to confirm the diagnosis should be set up, and a cadre of metabolic physicians should be build up to treat those identified to have inborn errors of metabolism. Once these are established on a firm footing, tandem mass spectrometry should be introduced as it allows the identification of a number of disorders in an affordable manner. The recent improvements and current trends in health care in India have created the necessary infrastructure for adopting NBS for the benefit of infants in India.

Novel and recurrent mutations in WISP3 and an atypical phenotype

Novel and Recurrent Mutations in WISP3 and an Atypical Phenotype Gandham SriLakshmi Bhavani, Hitesh Shah, Ashwin B. Dalal, Anju Shukla, Sumita Danda, Shagun Aggarwal, Shubha R. Phadke, Neerja Gupta, Madhulika Kabra, Kalpana Gowrishankar, Anju Gupta, Meenakshi Bhat, Ratna D. Puri, Sunita Bijarnia-Mahay, Sheela Nampoothiri, Kavitha M. Mohanasundaram, S. Rajeswari, Akhil M. Kulkarni, Muralidhar L. Kulkarni, Prajnya Ranganath, A. Radha Ramadevi, Sankar V. Hariharan, and Katta Mohan Girisha* Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India Department of Orthopedics, Pediatric Orthopedics Services, Kasturba Medical College, Manipal University, Manipal, India Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, India Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, India Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Department of Pediatrics, Division of Genetics, All India Institute of Medical Science, New Delhi, India Department of Medical Genetics, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India Centre for Human Genetics, Bangalore, India Centre of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Ponekkara, Cochin, Kerala, India Department of Rheumatology, Madras Medical College, Chennai, India Department of Radiodiagnosis, SS Institute of Medical Sciences and Research Centre, Davangere, India Department of Pediatrics, Jagadguru Jayadeva Murugarajendra Medical College, Davangere, India Department of Clinical Genetics, Genetics Unit, Rainbow Children Hospital, Hyderabad, India Department of Pediatrics, Sree Avittom Thirunal Hospital, Government Medical College, Trivandrum, India

Citrin deficiency: A treatable cause of acute psychosis in adults

Citrin deficiency is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. The disorder manifests either as neonatal intra-hepatic cholestasis or occurs in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances. It has a high prevalence in the East Asian population, but is actually pan-ethnic. We report the case of a 26-year-old male patient presenting with episodes of abnormal neuro-psychiatric behavior associated with hyperammonemia, who was diagnosed to be having citrin deficiency. Sequencing of the SLC25A13 gene revealed two novel mutations, a single base pair deletion, c. 650delT (p.Phe217SerfsFNx0133) in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr) in exon 9. Confirmation of the diagnosis allowed establishment of the appropriate management. The latter is an essential pre-requisite for obtaining a good prognosis as well as for family counseling.

Mitochondrial DNA depletion syndrome causing liver failure

BackgroundMitochondrial DNA depletion syndromes are disorders of Mitochondrial DNA maintenance causing varied manifestations, including fulminant liver failure.Case characteristicsTwo infants, presenting with severe fatal hepatopathy.ObservationRaised serum lactate, positive family history (in first case), and absence of other causes of acute liver failure.OutcomeCase 1 with homozygous mutation, c.3286C>T (p.Arg1096Cys) in POLG gene and case 2 with compound heterozygous mutations, novel c.408T>G (p.Tyr136X) and previously reported c.293C>T (p.Pro98Leu), in MPV17 gene.MessageMitochondrial DNA depletion syndrome is a rare cause of severe acute liver failure in children.

Inherited Metabolic Disorders: Efficacy of Enzyme Assays on Dried Blood Spots for the Diagnosis of Lysosomal Storage Disorders

High consanguinity rates, poor access to accurate diagnostic tests, and costly therapies are the main causes of increased burden of lysosomal storage disorders (LSDs) in developing countries. Therefore, there is a major unmet need for accurate and economical diagnostic tests to facilitate diagnosis and consideration of therapies before irreversible complications occur. In cross-country study, we utilized dried blood spots (DBS) of 1,033 patients clinically suspected to harbor LSDs for enzymatic diagnosis using modified fluorometric assays from March 2013 through May 2015. Results were validated by demonstrating reproducibility, testing in different sample types (leukocytes/plasma/skin fibroblast), mutation study, or measuring specific biomarkers. Thirty percent (307/1,033) were confirmed to have one of the LSDs tested. Reference intervals established unambiguously identified affected patients. Correlation of DBS results with other biological samples (n = 172) and mutation studies (n = 74) demonstrated 100% concordance in Gaucher, Fabry, Tay Sachs, Sandhoff, Niemann-Pick, GM1, Neuronal ceroid lipofuscinosis (NCL), Fucosidosis, Mannosidosis, Mucopolysaccharidosis (MPS) II, IIIb, IVa, VI, VII, and I-Cell diseases, and 91.4% and 88% concordance in Pompe and MPS-I, respectively. Gaucher and Pompe are the most common LSDs in India and Pakistan, followed by MPS-I in both India and Sri Lanka. Study demonstrates utility of DBS for reliable diagnosis of LSDs. Diagnostic accuracy (97.6%) confirms veracity of enzyme assays. Adoption of DBS will overcome significant hurdles in blood sample transportation from remote regions. DBS enzymatic and molecular diagnosis should become the standard of care for LSDs to make timely diagnosis, develop personalized treatment/monitoring plan, and facilitate genetic counseling.

Sengers syndrome in Asian Indians – two novel mutations and variant phenotype-genotype correlation

Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the AGK gene cause Senger syndrome. We describe two unrelated Asian Indian families with two novel mutations, c.909 G>A (p.Trp303Ter) and c.982G>T (p.E328Ter), in the AGK gene. Similar nonsense mutations have previously been reported with a severe phenotype and early infantile death, while this patient is doing well at 3 years, suggesting a mild phenotype. The second child tested positive for two previously reported mutations, c.841C>T (p.Arg281Ter) and c.424-3C>G. The presence of a splice site mutation typically predicts a milder phenotype with one exception reported to date. The second patient we report died at 9 months of age adding to the one previously reported exception. Both these cases add onto the scant literature of genotype phenotype correlation in Sengers syndrome. We emphasize the importance of diagnosis of this clinically recognizable syndrome to counsel families of recurrence risks and option of prenatal diagnosis.

Lysinuric protein intolerance presenting with recurrent hyperammonemic encephalopathy

BackgroundLysinuric protein intolerance is an inherited disorder of transport of cationic amino acids, causing amino aciduria.Case characteristicsA 3-year-old boy with 12 month history of episodic change in behavior (decreased sleep, poor interaction), stunted growth and hyperammonemia.OutcomeGenetic analysis revealed a homozygous mutation, c.158C>T (p.Ser53Leu) in exon 1 of SLC7A7 gene. With appropriate management of hyperammonemia episodes, his neurodevelopmental outcome is normal.MessageLysinusic protein intolerance is a potentially treatable disorder and should not to be missed.

Ethylmalonic encephalopathy in an Indian boy

BackgroundEthylmalonic encephalopathy is a rare inborn error of metabolism characterized by neurodevelopmental delay / regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea.Case Characteristics4-year-old boy with developmental regression, chronic diarrhea, petechial spots and acrocyanosis. MRI brain showed T2W/FLAIR hyperintensities in bilateral caudate and putamen. Abnormal acyl-carnitine profile and metabolites on urinary GC-MS analysis suggested the diagnosis.InterventionSequencing of ETHE1 gene revealed mutations: c.488G>A and c.375+5G>T (novel).MessageEE is clinically-recognizable disorder with typical clinical features.

Is the diagnostic yield influenced by the indication for fetal autopsy

The utility of fetal autopsy to corroborate antenatal ultrasound findings and to aid genetic counseling is well known. However, the ability to identify an underlying cause for the common indications for which it is performed is not well studied. This study aimed to determine if the diagnostic yield of fetal autopsy in identifying the underlying cause is determined by the indication of the autopsy. Five groups of fetuses were defined based on the indication for the autopsy performed in 903 cases: (i) malformations, (ii) intrauterine death (IUD), (iii) cystic hygroma and hydrops fetalis, (iv) isolated abnormalities of amniotic fluid, and (v) intrauterine growth restriction (IUGR). The highest diagnostic yield was in fetuses with isolated abnormalities of amniotic fluid (77%), followed by those with IUGR (75%), with IUD (69.6%), those in group five (55.2%) and lowest (45%) in fetuses with malformations (P < 0.001). A cause was identified in 77.8% fetuses with multiple malformations compared to 37.5% with isolated malformations (P < 0.001), with chromosomal abnormalities in 31.8% versus 9.9% respectively (P < 0.001) and malformation syndromes in 42.5% versus 26.3% (P < 0.001). Placental examination provided the highest yield in IUD, IUGR, and oligohydramnios (43.1%; P < 0.003) whereas chromosomal analysis was most useful in cystic hygroma/NIHF (28.9%; P < 0.001). This information on the diagnostic yield in fetal autopsy related its common indications, can be utilized to counsel families of the utility of autopsy to establish cause and recurrence risks and thereby assist then to make an informed decision to consent for the procedure.

Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening

Background Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records. Materials and methods Selective screening for IMDs using gas chromatography–mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared. Results Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias. Conclusion The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.