Review: Understanding Rare Genetic Diseases in Low Resource Regions Like Jammu and Kashmir - India.

Rare diseases (RDs) are the clinical conditions affecting a few percentage of individuals in a general population compared to other diseases. Limited clinical information and a lack of reliable epidemiological data make their timely diagnosis and therapeutic management difficult. Emerging Next-Generation DNA Sequencing technologies have enhanced our horizons on patho-physiological understanding of many of the RDs and ushered us into an era of diagnostic and therapeutic research related to this ignored health challenge. Unfortunately, relevant research is meager in developing countries which lack a reliable estimate of the exact burden of most of the RDs. India is to be considered as the "Pandora's Box of genetic disorders." Owing to its huge population heterogeneity and high inbreeding or endogamy rates, a higher burden of rare recessive genetic diseases is expected and supported by the literature findings that endogamy is highly detrimental to health as it enhances the degree of homozygosity of recessive alleles in the general population. The population of a low resource region Jammu and Kashmir (J&K) - India, is highly inbred. Some of its population groups variably practice consanguinity. In context with the region's typical geographical topography, highly inbred population structure and unique but heterogeneous gene pool, a huge burden of known and uncharacterized genetic disorders is expected. Unfortunately, many suspected cases of genetic disorders remain undiagnosed or misdiagnosed due to lack of appropriate clinical as well as diagnostic resources in the region, causing patients to face a huge psycho-socio-economic crisis and many a time suffer life-long with their ailment. In this review, the major challenges associated with RDs are highlighted in general and an account on the methods that can be adopted for conducting fruitful molecular genetic studies in genetically vulnerable and low resource regions is also provided, with an example of a region like J&K - India.

A case report on a novel MT-ATP6 gene variation in atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications.

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

LoCa LoPa myelopathy: is prevention better than cure?

Manifestations of primary hypoparathyroidism are produced by neuromuscular irritability or by extraosseous calcifications. We present a patient of primary hypoparathyroidism who had extensive calcification of brain parenchyma, and was suffering from chronic, generalised and progressive stiffness of body due to cervical compressive myelopathy, caused by calcification of posterior longitudinal ligament and ligamentum flavum. By presenting this case we wanted to emphasize the usefulness of meticulous clinical examination to differentiate the stiffness caused by myelopathy from that which is caused by possible coexisting extrapyramidal disorder. This case presentation also builds the hypothesis that early diagnosis and institution of early and appropriate treatment has potential to prevent the complications arising from extraosseous calcifications in patients with primary hypoparathyroidism.

Whole Exome Screening Identifies Novel and Recurrent WISP3 Mutations Causing Progressive Pseudorheumatoid Dysplasia in Jammu and Kashmir-India.

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP_003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.

"Peripheral neuropathy crippling bronchial asthma": two rare case reports of churg-strauss syndrome.

Churg-Strauss syndrome (CSS) is a rare cause of vasculitic neuropathy. Although rare and potentially fatal, Churg-Strauss syndrome (CSS) is easily diagnosable and treatable. The presence of bronchial asthma with peripheral neuropathy in a patient alerts a physician to this diagnosis. This is vividly illustrated by the presented two cases who had neuropathy associated with bronchial asthma, eosinophilia, sinusitis, and positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) test, which improved with administration of steroids.

"Excess gooD can be Dangerous". A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D.

Vitamin D is increasingly recognized to have several beneficial effects. Its toxicity, causing hypercalcemia, is considered as extremely rare. We report case series of 15 patients (most of them being elderly subjects) with iatrogenic symptomatic hypercalcemia in whom toxicity occurred due to empirical excessive administration of vitamin D by oral and parenteral route.

Double osteomalacia.

A 35-year old woman presented, with chronic vague ill health, subacute symptoms of decreased appetite, increased thirst, excessive urination, and rib pains, and acute quadriparesis. On evaluation, she was found to have type 1 Renal tubular acidosis, pseudofractures of ribs and Hypovitaminosis D. Administration of oral solution containing potassium citrate and citric acid along with pharmacological doses of Vitamin D and supportive treatment improved her condition remarkably. This case report highlights interesting coexistence of two disorders, one very common (Hypovitaminosis D) and one rare (Distal Renal Tubular Acidosis dRTA), in same patient, producing same pathology (osteomalacia).

"Toxic" beef bone soup.

Hypercalcaemia is most commonly caused by primary hyperparathyroidism or malignancy. Vitamin D intoxication, also a cause of hypercalcaemia, is mostly caused by excessive administration of vitamin D-containing medications and excessive intake of foods fortified with vitamin D. We present a young cricketer, with recurrent vomiting due to hypercalcaemia and hypervitaminosis D, who used to drink large volumes of soup prepared by boiling long beef bones, for many months. This case presentation highlights the importance of in-depth dietary history for arriving at proper diagnosis.

Incidence of dementia in a Kashmiri migrant population.

BACKGROUND: Mishriwala is one of five exclusive clusters of Kashmiri migrants established in 1990 to accommodate Kashmiri Pandit families who left Kashmir valley in the wake of militancy. Mishriwala migrant camp has seen minimal immigration and out-migration since its establishment. In an earlier study we reported on the prevalence of dementia amongst a Kashmiri migrant population. That study was conducted in the migrant camp at Mishriwala, 12 km west of Jammu city, the winter capital of Jammu and Kashmir State. We have developed standardized study methods and instruments for use in the Kashmiri-speaking population, which we used for screening for dementia during the prevalence study. We now report the results of a 1-year prospective study carried out to find out the incidence of dementia in the same population. AIM: To ascertain the incidence of dementiain the Kashmiri Pandit population aged 60 years and above. MATERIALS AND METHODS: A 1-year, prospective, epidemiological study of 186 subjects aged 60 years and above, using cognitive and functional ability screening and clinical evaluation. RESULTS: The incidence of dementia in this population was 5.34 cases per 1000 person-years.