Diagnosis and Management of Gaucher Disease in India – Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics

Justification: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinicalmanifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD haspaucity of information and optimal management guidelines for Indian patients.Process: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invitedexperts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed andthe draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016at the annual meeting of the Indian Academy of Medical Genetics.Objectives: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems foroptimal management of Gaucher disease in India and to define unique needs of this patient population.Recommendations: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequentlyexperience diagnostic delays during which severe irreversible complications occur. Leucocyte acid ?-glucosidase activity ismandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathicdisease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved byearly initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such asseizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein arefor diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrenceof the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encounteredin our population

Outcome of Gaucher Disease in India: Lessons from Prevalent Diagnostic and Therapeutic Practices.

Objectives: To study disease severity and response to enzyme replacement therapy in Gaucher disease. Methods: Updated data was captured from records of 37 patients (35 reported previously) with confirmed diagnosis of Gaucher disease from January 1995 through December 2011 (31, 83.8 %) and prospectively from January 2012 through June 2013 (6, 16.2 %). Severity of manifestations was determined by Gaucher disease Severity Score Index. Response to enzyme replacement therapy was assessed in terms of attainment of therapeutic goals. Results: Moderate to severe manifestations (domain score of > 2) were observed in treated patients at baseline (83%, 58%, 66% and 25% for anemia, thrombocytopenia, hepatomegaly and leucopenia, respectively and 100% for splenomegaly and elevated plasma chitotriosidase). None of the 11 patients treated with synthetic enzyme (average annual dose 23 to 53 units/kg) attained all therapeutic goals in the recommended time frame, particularly the visceral, skeletal and growth domains. Conclusions: Early onset of moderate to severe disease in Indian patients mandates early therapy with optimum doses to ensure attainment of all recommended therapeutic goals.

Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI.

Background & objectives: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. Methods: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. Results: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. Interpretation & conclusions: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI.

Extracardiac Birth Defects in Children with Congenital Heart Defects.

Objective: To assess the proportion and pattern of extracardiac birth defects in children with congenital heart defects referred to a tertiary care institute. Methods: Cross-sectional observational study from January 2010 to June 2011. Results: Out of 560 children with congenital heart defects, 98 (17.5%) had extracardiac birth defects. Fifty-six had multiple congenital defects; 36 were syndromic cases and 6 had laterality defects. A total of 386 extracardiac birth defects (103 major and 283 minor) were documented, with craniofacial and skeletal birth defects being the commonest. Conclusion: Extracardiac birth defects are common in children with congenital heart defects.

Novel Biochemical Abnormalities and Genotype in Farber Disease.

We present five cases of paediatric Scrub typhus from Community Health Centre, Namchi, South Sikkim emphasize timely diagnosis of scrub typhus for appropriate management. Response to doxycycline was good, with fever subsiding within 48-72 hrs of starting the treatment. Four out of five cases completely recovered once appropriate medication was given.

An Observational, Health Service Based Survey for Missed Opportunities for Immunization.

Studies cite missed opportunities for immunization (MOI) as a contributor to undervaccination. The present prospective survey aimed at determining the magnitude of MOI, its contribution to under-vaccination, and identifying risk factors for MOI. Mothers of 1384 indoor patients 6 years were interviewed. There were 266 (19.2%) children with MOI, accounting for 79.6% of under-vaccination and 93% of under-vaccination time. MOI occurred significantly more often with home delivery (P <0.001, Odds ratio 5.1), incomplete or incorrect maternal knowledge of immunization (P=0.001, Odds ratio 4.8) and, general practice and non-Pediatric/ non- Medical college based practice (P=0.001, Odds ratio 4.0). The impact of sociodemographic factors on likelihood of MOI was not significant.

Phenotypic Heterogeneity and Parental Origin of Extra Chromosome 21 in Down Syndrome.

We compared the frequency of phenotypic features of 40 children with Down syndrome between individuals with a maternally or paternally derived extra chromosome 21, using quantitative FISH for comparing heteromorphisms of the nucleolar organizing region. Parental origin was determined in 90% of families. Hypotonia and craniofacial abnormalities were present in 90% or more individuals, irrespective of parental origin of chromosome 21. Congenital heart defects were more frequent in cases with a maternally derived extra chromosome 21. Imprinted gene(s) may contribute to the development of congenital heart defects in Down syndrome.

Psychological consequences in pediatric intensive care unit survivors: the neglected outcome.

OBJECTIVES: To determine whether Pediatric Intensive Care Unit (PICU) hospitalization results in adverse psychological effects and to identify the contributory factors. SETTING: Level III PICU of a tertiary center. DESIGN: Prospective cohort study. METHODS: Consecutive patients 5 years or older admitted to PICU for at least 48 hours constituted the study population. Controls were age and sex matched children hospitalized in the pediatric wards for at least 48 hours. Severity of illness was assessed by the Pediatric Risk of Mortality (PRISM) score. Level of therapeutic intervention was determined by the Therapeutic Interventions Scoring System (TISS--76 score). Temperament Measurement Schedule was used to assess the premorbid temperament. Psychological assessment was performed using Impact of Event Scale (IES), Birleson Depression Scale and the Self-Esteem Scale. Follow-up evaluation was done one month after discharge. RESULTS: There were 30 children each in the study and control groups. They had comparable pre-morbid temperament as well as scores on the self-esteem and depression scales. Significantly higher proportion of patients in PICU had intrusive thoughts (43%) as compared to controls (6.7%). Development of intrusive thoughts correlated significantly with the degree of intervention. Demographic parameters, nature of the disease, duration of hospitalization and severity of illness did not correlate with the psychological outcome. One month after discharge, scores in both groups were comparable. CONCLUSIONS: Children subjected to therapeutic interventions in the PICU develop transient psychological impairment manifested by experiencing intrusive thoughts that resolve within a month.

Wolman disease: diagnosis by leucocyte acid lipase estimation.

Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester. Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms. Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of Wolman disease. For the first time in Indian literature, the authors report a case of Wolman disease that was confirmed by acid lipase enzyme estimation.

Effect of deferiprone on urinary zinc excretion in multiply transfused children with thalassemia major.

A prospective multi-centric study was conducted to determine if iron-chelating agent deferiprone also chelates zinc. Twenty four-hour urinary zinc levels were compared in multiply transfused children with thalassemia major not receiving any chelation therapy (Group A, n = 28), those receiving deferiprone (Group B, n = 30) and age and sex-matched controls of subjects in Group B (Group C, n = 29) by a colorimetric method. The 24-hour mean urinary excretion of zinc was significantly higher in Group B than in the other two groups indicating that deferiprone chelates zinc.

Rabson-Mendenhall syndrome.

Rabson-Mendenhall syndrome is characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, premature and dysplastic dentition, coarse facial features, paradoxical fasting hypoglycemia and post-prandial hyperglycemia, extreme hyperinsulinemia and pineal hyperplasia. We describe a six-month-old female child with physical features suggestive of the Rabson-Mendenhall syndrome. The child also had medullary nephrocalcinosis.

Incomplete monosymptomatic leptomeningeal angiomatosis.

Phakomatoses or neurocutaneous syndromes are an important cause of seizures in the pediatric age group. The Sturge-Weber syndrome may affect the eye, skin and brain at different times. The skin lesions need not always manifest. We report a case of isolated affection of the central nervous system in a case of Sturge-Weber syndrome in the absence of ocular or cutaneous manifestations. Our case qualifies to be called incomplete monosymptomatic leptomeningeal angiomatosis.

Recurrent acute transverse myelopathy: association with antiphospholipid antibody syndrome.

A seven-year-old boy presented with a second episode of acute transverse myelopathy. The first episode had responded dramatically to methylprednisolone. The manifestations of the second episode did not respond to methylprednisolone or IVIG. He showed persistently raised levels of antiphospholipid antibodies in the serum. Primary conditions like collagen vascular diseases, malignancy, exposure to drugs and HIV infection, which are known to be associated with the raised titers of these antibodies were ruled out clinically and by investigations. Recurrent transverse myelopathy is a rare event in childhood and reports of its association with Antiphospholipid Antibody Syndrome (APLAS) are scanty. The etiological role for these antibodies remains to be established. However, once the diagnosis is established, it may be prudent to treat the condition with agents and procedures to bring about a decrease in their titers. Long-term therapy to prevent thromboembolic complications of APLAS may also be instituted.

Congenital factor VII deficiency.

A 1(1/2)-month-old baby with seizures, lethargy and refusal of feeds was diagnosed to have intracranial hemorrhage due to factor VII deficiency. MRI also demonstrated the unusual presence of a hemorrhagic infarct. The case underscores the importance of carrying out neuroimaging and appropriate hematological studies even in the absence of obvious external bleeding. Hypothesis for increased propensity for intra-cranial hemorrhage is discussed.

Kocher-Debre-Semelaigne syndrome: hypothyroidism with muscle pseudohypertrophy.

Kocher-Debre-Semelaigne syndrome is a rare association of muscular pseudohypertrophy and hypothyroidism in children. We report two cases of this syndrome in this communication. The first case was a seven-years-old female who presented with features of hypothyroidism and muscle pseudohypertrophy. The second child had similar manifestations but was only fifteen months of age at diagnosis. This is one of the youngest patients reported to have the Kocher-Debre-Semelaigne syndrome. A short review of the literature is also presented.

Congenital and inherited ophthalmologic abnormalities.

OBJECTIVE: To identify genetic disorders associated with ophthalmologic abnormalities; type and frequency of various ophthalmologic abnormalities associated with selected genetic and inherited disorders; and devise a suitable classification for ophthalmologic abnormalities. METHODS: Pediatric cases referred with mental retardation, congenital malformations and suspected genetic and metabolic disorders were enrolled prospectively. Relevant clinical details (including an ophthalmologic examination) and investigations were recorded. RESULT: Of the 1308 patients enrolled, 679 (51.9%) had ophthalmologic abnormalities. 458 cases (67.45%) out of these 679 had mental retardation and 20 (2.94%) had neuroregression. Environmental (12.22%) and chromosomal anomalies (10.9%) were the largest etiological groups. Down syndrome was the commonest of the chromosomal anomalies and mongoloid slant and epicanthic folds were its commonest ophthalmologic features. Mucopolysaccharidoses (21.4%), Wilson disease (19.64%), oculocutaneous albinism (16.07%) and lipid storage disorders (14.29%) were the most common inborn errors of metabolism associated with ophthalmologic abnormalities. Of the 39 cases with Mendelian inheritance of disorders, autosomal dominant disorders (56.41%) were the commonest associated with ocular abnormalities. A simple anatomical classification has been devised for various ophthalmologic abnormalities encountered (wherein, positional and adnexal abnormalities were the commonest). CONCLUSION: Up to 50% of cases referred to the genetic services have ophthalmologic abnormalities. Conditions including chromosomal abnormalities, metabolic disorders, Mendelian syndromes and environmental factors are associated with ocular abnormalities. Anatomically, positional and adnexal abnormalities are the commonest.

Neurological complications of rabies vaccines.

The rabies vaccines containing neural elements are used in some countries including India. We report three cases that presented with various neurological complications following the use of these vaccines. The presenting manifestations included those of encephalitis, radiculitis and acute inflammatory demyelinating polyradiculoneuropathy. These neurological complications are highlighted so that scientific evidence compels the community to discontinue the use of the neural tissue rabies vaccines. Newer generation cell culture rabies vaccines should be preferred over the neural tissue rabies vaccines for post-exposure prophylaxis.

Trisomy 21 with XYY.

A case of double aneuploidy involving chromosome 21 and Y is reported in an eight-month-old infant with developmental delay and failure to thrive. Patient had all classical phenotypical features of trisomy 21 except, absence of epicanthal folds. The diagnosis was confirmed by cytogenetic study performed on peripheral blood leucocyte culture using G-banding. Literature review revealed only 17 cases of XYY and trisomy 21 reported so far. No such case is reported in Indian literature. Relevant literature is reviewed and possible effects of trisomy 21 on XYY and that of XYY on trisomy 21 has been discussed. A routine chromosomal study even in patient with classical features of Down syndrome has been advocated. Interestingly, our patient also had left to right shunts at atrial and ductal level and tricuspid regurgitation. Given the rarity of the disorder and scanty published data the incidence, phenotype and recurrence risk are difficult to establish.

Mycotic aneurysm: an uncommon cause for intra-cranial hemorrhage.

Intra-cranial mycotic aneurysms due to an infective process elsewhere in the body constitute an uncommon cause of intra-cranial hemorrhage. The condition carries a grave prognosis. Mycotic aneurysms secondary to infective endocarditis (IE) rarely occur in children. This communication describes a seven-year-old girl who presented with fever and neurological abnormalities. She was diagnosed to have a mycotic aneurysm secondary to IE. Digital subtraction angiography (DSA) confirmed the diagnosis, delineated anatomical details and later detected the complete resolution of the aneurysm following conservative management with intravenous antimicrobial agents.