Lysosomal Storage Disorders:

Lysosomal storage diseases (LSDs) are a group of approximately 41 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomal storage diseases result when a specific organelle in the body's cells – the lysosomes do not function properly.

They are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or so-called mucopolysaccharides. Individually, LSDs occur with incidences of less than 1:100.000, however, as a group the incidence is about 1:5000 - 1:10.000. Most of these disorders are autosomal recessively inherited, however a few are X-linked recessively inherited, such as Fabry disease and Hunter syndrome (MPS II). In India, prevalence of LSD’s in not known but with our experience MPs, NPD, Tay-Sach’s and Gaucher’s are the most common one. In high suspected group of children the incidence of LSDs is up to 30% at FRIGe-Genetic centre. This indicates that these diseases are not uncommon but under-diagnosed in India.

The lysosome is the cell’s recycling center because it processes unwanted material into substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival. Lysosomal disorders are triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome doesn’t function normally, excess products destined for breakdown and recycling are stored in the cell.

Like other genetic diseases, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome.

Lysosomal storage diseases affect mostly children and they often die at a young and unpredictable age, many within a few months or years of birth. Many other children die of this disease following years of suffering from various symptoms of their particular disorder. The symptoms of lysosomal storage disease vary, depending on the particular disorder and other variables like the age of onset, and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness and/or blindness enlarged livers (hepatomegaly), enlarged spleens (splenomegaly), pulmonary and cardiac problems. Skeletal dysplasia and neuralegression. At our centre we carry out extensive study for various LSD’s, which can be viewed in Biochemical investigations.

Plasma Chitotriosidase Study:

Evidence and recent data have shown that plasma Chitotriosidase is markedly elevated in Gaucher disease, moderately raised in Niemann- Pick A/B and mild elevated in various LSD’s. Therefore study for Chitotriosidase is the key for neonatal screening for Gaucher’s & NPD-A/B.

Chitotriosidase (ChT) is an enzyme that is selectively activated in tissue macrophage. It is found to be raised in Gaucher (GD), Niemann Pick typeA/B (NPD) and other lysosomal storage disorders (LSDs). This makes ChT the potential screening test for certain LSDs. Twenty healthy children in the age range of 10 days to 5 yrs and 129 children in the age range of 2.5 months to 13 yrs with regression of milestones, skeletal dysplasia, neuroregression and hepatosplenomegaly were selected for plasma ChT followed by confirmative diagnosis carried out by specific Lysosomal enzyme study from the leukocytes or fibroblasts. Plasma ChT was 55.21±20.81 nmol/ml/hr in twenty healthy age matched controls. Raised ChT level was observed in 43 of 129 children [33.33%] ranging from 213.74 to 23511.40 nmol/ml/hr. and 20 of these children (46.51%) found to have Morquio-B, Sly Syndrome, Metachromatic Leukodystrophy [MLD], GM1 & GM2 Gangliosidosis, NPD-A/B, GD and Krabbe disease. Marked elevated ChT was observed in all cases of GD and NPD A and B (4000 to 23,511 nmol/ml/hr). Whereas 13 of 86 children (15.11%) with normal ChT (61.33±18.45 nmol/ml/hr) had confirmed LSDs like Morquio B, Pompe, MLD, Sandhoff and NPD-C. It can be concluded from present study that moderately raised activity of ChT can be utilized as a positive predictive test for certain LSD's. Those with marked elevated ChT have confirmed GD or NPD-A/B making it a specific diagnostic test for this group of diseases.( Unpublished work at FRIGE)

MPS by Electrophoresis:

Urine screen and electrophoresis for Heparan, Chondroitin and Dermatan sulfate are the diagnostic clue to confirm various MPs by Leucocyte study for specific lysosomal study enzymes. This will curtail the need to do unnecessary enzyme study.

I-Cell Screening:

Many children with MPs, I-Cell, Thyroid disorders and Sialic Acid storage disorders look alike. Therefore, primary screening for I-cell disease from plasma prevents unnecessary investigations and provide useful clue to the clinician for further investigations.

Mucolipidosis type II (ML-II) or I–cell disease is a rare autosomal recessive lysosomal storage disorder. This occurs due to deficiency of lysosomal transporter enzyme (phosphotransferase) with the birth incidence of 1:3,50,000.

As a result, affected cells show dense inclusion filled with complex storage material. It is this property of ML that give rise to heterogeneous phenotype of an affected child mainly involving skeletal system. Diagnosis of the disorder can be made biochemically by estimating several lysosomal enzymes from serum or by studying characteristic pattern of lysosomal enzyme deficiencies from the fibroblast. Though there is no treatment option available, prenatal diagnosis is the only choice after index case confirmation.