Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature.

Lysosomal storage disorders (LSDs) in adults have milder phenotype and variable age at presentation. Several studies have described the phenotype, genotype and treatment outcomes for adult-onset LSDs like Gaucher, Fabry, Pompe disease and others. We describe the first systematic study on the occurrence of LSDs in an adult population from India. It describes, the key clinical signs seen in these patients and those from literature review that can aid in early detection. Of 2102 biochemically diagnosed LSDs cases, 32 adult patients were identified with LSDs. Based on the clinical suspicion, screening test and enzyme study was carried out. Twenty-two patients were subjected to a genetic study to identify the causative variant in a respective gene. Of the 32 adult patients, we observed a maximum percentage of 37.5% (n = 12) cases with Gaucher disease, followed by 13% (n = 4) with Fabry disease. We found 10% of cases with MPS IVA and MPS I, and 9% cases with Pompe. Single case of adult mucolipidosis III and two cases each of Type 1 Sialidosis, Niemann-Pick disease B and metachromatic leukodystrophy were identified. We observed two common variants p.Leu483Pro and p.Ala487Thr in the GBA1 gene in 23% of Indian patients with adult Gaucher disease. No common variants were observed in other aforementioned LSDs. Study identified 50% of Fabry patients and 4% of Gaucher patients diagnosed at our centre to be adults. The prevalence of adult Pompe patients was low (3.4%) as compared to 80% reported in the Caucasian population. Adult LSDs such as, MPS III, GM1/GM2 gangliosidosis and Krabbe disease were not identified in our cohort.

Late infantile and adult-onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India.

Metachromatic leukodystrophy (MLD) due to Sap-B deficiency is a rare autosomal recessive disorder caused due to biallelic variants in the PSAP gene. The PSAP gene encodes a precursor protein prosaposin, which is subsequently cleaved to form four active glycoproteins: Sap-A, Sap-B, Sap-C, and Sap-D. In case of deficiency of the sphingolipid activator protein Sap-B, there is a gradual accumulation of cerebroside-3-sulfate in the myelin of the nervous system resulting in progressive demyelination. Only 12 variants have been reported in the PSAP gene causing Sap-B deficiency to date. Here, we report two cases of MLD due to Sap-B deficiency (late-infantile and adult-onset form) harboring two novel missense variants c.688T > G and c.593G > A in the PSAP gene respectively. This study reports the third case of adult-onset MLD due to Sap-B deficiency in the world. The proband, a 3-year-old male child presented with complaints of hypotonia, lower limb tremors and global developmental delay. His MRI showed hyperintense signals in the bilateral cerebellar white matter. Overall, the findings were suggestive of metachromatic leukodystrophy. The second case was a 19-year-old male child with clinical features of regression of speech, gait ataxia and bilateral tremors referred to our clinic. MRI data suggested metachromatic leukodystrophy. Normal enzyme activity of arylsulfatase-A led to a suspicion of saposin B deficiency. For both cases, targeted sequencing was performed. This identified homozygous variant c.688T > G (p.Cys230Gly) and c.593G > A (p.Cys198Tyr) in exon 6 of the PSAP gene, respectively.

Specification and guideline for technical aspects and scanning parameter settings of neonatal lung ultrasound examination.

Lung ultrasound (LUS) is now widely used in the diagnosis and monitor of neonatal lung diseases. Nevertheless, in the published literatures, the LUS images may display a significant variation in technical execution, while scanning parameters may influence diagnostic accuracy. The inter- and intra-observer reliabilities of ultrasound exam have been extensively studied in general and in LUS. As expected, the reliability declines in the hands of novices when they perform the point-of-care ultrasound (POC US). Consequently, having appropriate guidelines regarding to technical aspects of neonatal LUS exam is very important especially because diagnosis is mainly based on interpretation of artifacts produced by the pleural line and the lungs. The present work aimed to create an instrument operation specification and parameter setting guidelines for neonatal LUS. Technical aspects and scanning parameter settings that allow for standardization in obtaining LUS images include (1) select a high-end equipment with high-frequency linear array transducer (12-14 MHz). (2) Choose preset suitable for lung examination or small organs. (3) Keep the probe perpendicular to the ribs or parallel to the intercostal space. (4) Set the scanning depth at 4-5 cm. (5) Set 1-2 focal zones and adjust them close to the pleural line. (6) Use fundamental frequency with speckle reduction 2-3 or similar techniques. (7) Turn off spatial compounding imaging. (8) Adjust the time-gain compensation to get uniform image from the near-to far-field.

Synthesis and Biological Evaluation of a Depsipeptidic Histone Deacetylase Inhibitor via a Generalizable Approach Using an Optimized Latent Thioester Solid-Phase Linker.

We describe the synthesis of Xyzidepsin, a depsipeptidic analogue of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy. Our latent thioester solid-phase linker was synthesized in 92% yield (three steps). Chemoselective conditions unmasked the thioester functionality and cyclized the depsipeptidic macrocycle. An IC50 value of 0.50 µM ± 0.05 was obtained for U937 cells. This synthetic route, well-suited to SAR, represents a generalizable route toward all manner of analogues, including structures with acidic and basic amino acids.

A Case Report on Chikungunya Virus-Associated Encephalomyelitis.

Chikungunya is a rerising alphavirus infection that has resulted from enhanced vector competence. Alphaviruses are divided into arthritogenic viruses (old world) and encephalitogenic viruses (new world) including equine encephalitis viruses. Chikungunya is a dengue-like illness characterized by acute febrile polyarthralgia, arthritis, malaise, body ache, rash, headache, and nausea. The illness is self-limiting. The neurological manifestations are uncommon and incorporate meningoencephalitis, myelitis, Guillain-Barre syndrome, cranial nerve palsies, myelopathy, and neuropathy; MRI abnormalities in patients with encephalopathy from India have been reported in the form of multiple punctuate white matter lesions that are more prominent on diffusion-weighted MRI than on T2 or T1. Here, we present an intriguing case of chikungunya encephalomyelitis who presented to our tertiary care hospital with quadriparesis and urinary retention. He was treated with 5 doses of intravenous immunoglobulin along with supportive care with which he showed partial recovery.

Lysosomal Storage Disorders in Indian Children with Neuroregression Attending a Genetic Center.

OBJECTIVE: To study the etiology of neuroregression in children having deficiency of the lysosomal enzymes. DESIGN: Review of medical records. SETTING: Specialized Genetic Center. PARTICIPANTS: 432 children aged 3 mo-18 y having regression in a learned skill, selected from 1453 patients referred for diagnostic workup of various Lysosomal storage disorders (LSDs). METHODS: Plasma chitotriosidase, quantitative and qualitative glycosaminoglycans, and mucolipidosis-II/II screening followed by confirmatory enzyme study using specific substrate was carried out; Niemann-Pick disease Type-C was studied by fillipin stain method on skin fibroblasts. RESULTS: Total 309 children (71.5%) were diagnosed with different lysosomal storage disorders as the underlying cause of neuroregression. Plasma chitotriosidase was raised in 82 of 135; 64 (78%) of these had various LSDs. 69 out of 90 cases showed high excretion of glycoaminoglycans, and 67 (97.1%) of these were confirmed to have enzyme deficiency for various mucoplysaccharide disorders. While 3 of 90 children with positive Icell screening had confirmed mucolipidosis II/III disease. Among all, glycolipid storage disorders were the most common (50.2%) followed by mucopolysaccharidosis (MPS) (21.7%) and sulphatide degradation defect (17.5%). Neuronal ceroid lipofucinosis1 and 2 (7.4%), mucolipidosis-II/III (1%), Sialic acid storage disorder (1%), Niemann-Pick disease type-C (1%) and Fucosidosis (0.3%) were observed with less frequency. Most common phenotypes in all subjects were cherry red spot (18.5%), hepatosplenomegaly (17.9%), coarse facies (15%), seizures (13.1%) and skeletal abnormalities (12.14%). CONCLUSIONS: Lysosomal storage disorders are considered to be one of the common causes in children with regression in learned skill, dysmorphic features and cherry red spot. Among these, glycolipid storage disorders are the most common, followed by mucopolysaccharidosis.