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Lysosomal Storage Disorders or LSDs

Introduction

  

Though storage disorders are rare, collectively the incidence is 1:6000 in Western countries while in India this may be higher due to ethnical variation.

Our study of nearly 1000 children with developmental regression, hepatosplenomegaly, neuroregression and skeletal dysplasia shows that 35% of such children may have storage disorder. It is likely that every year almost 6000 to 8000 children are born with storage disorders in India, most of which remain undiagnosed due to lack of awareness, limited option for treatment and facility of diagnosis. Although with recent availability of enzyme replacement therapy for disorders like MPS, Fabry, Gaucher, NPD and Pompe diseases there is a growing interest among clinicians to diagnose these cases at an early age.

At FRIGE’s IHG, we have the facility to investigate large number of lysosomal enzymes which are specific for various lysosomal storage disorders.


Clinical Features

When to suspect a child with LSDs?

Children with dysmorphic features, failure to thrive, regression of learned skills, corneal clouding, hepatosplenomegaly, cherry red spot, hearing loss, neuroregression, skeletal dysplasia, respiratory distress with muscular myopathy and cardiomegaly are at the high risk of storage disorder and need further study of enzymes.

Which investigation to do for LSDs?

There is no common screening test except plasma chitotriosidase which is markedly elevated in children with Gaucher disease and Niemann Pick A/B type diseases, qualitative and quantitative analysis for GAG from urine for MPS and I cell screen from plasma for I-cell disease. However final confirmation is needed by lysosomal enzyme study either from leucocytes, plasma or fibroblasts.

Storage Disorder

Enzyme Deficiency

Clinical Features

SPHINGOLIPIDOSIS & LIPIDOSIS

Niemann-Pick disease, Type A 

Sphingomyelinase

Neuropathic, foamy histiocytes in bone marrow, acute neuropathic progressive loss of motor and intellectual capacity early in life, hepatosplenomegaly, cherry-red macula, commonly fatal in infancy

Niemann-Pick disease, Type B

Sphingomyelinase

Similar to Niemann-Pick disease, Type A but  non-neuropathic and age of onset is slightly older

Niemann-Pick disease, Type C

Depressed cholesterol esterification and abnormal filipin staining; Sphingomyelinase may be depressed but not absent.

Psychomotor symptoms occurring in first year or 2 of life. Vertical supranuclear ophthalmoplegia; hypertonic limbs and loss of coordination; organomegaly common, neonatal hepatitis and/or jaundice; mixed expression due to greater or lesser secondary liver involvement such that milder forms may be considered as described below as subacute.

Gaucher’s disease

β-glucosidase

Type 1—Chronic non-neuropathic: hepatosplenomegaly, Gaucher cells, anemia, bone pain and lytic lesions, striking elevation of angiotensin converting enzyme. Most frequently occurring storage disease with the highest incidence in Ashkenazi Jews.

 

β-glucosidase

Type 2—Infantile acute neuropathic, rapidly degenerative central nervous system manifestations, peripheral symptoms similar to type 1 but greatly exaggerated, death usually occurs by 1 year of age.

 

β-glucosidase

Type 3—Subacute neuronopathic; similar to type 2 except later onset and a milder course eventually causing death in early childhood.

Krabbe disease

Galactosylceramide β-galactosidase

A number of forms are recognized, differing largely in age of onset and severity of symptoms, progressive psychomotor retardation, globoid cells in central nervous system, spastic quadriparesis, hypertonicity, hyperthermia, elevated cerebrospinal fluid protein.

Metachromatic leukodystrophy (MLD)

Arylsulphatase A

Several closely related disorders with differing ages at onset from 1 year of age well into adulthood, peripheral neuropathy, intermittent pain in arms and legs with eventual difficulty sitting, gait disturbance, absence of deep tendon reflexes, plantar flexion of feet. Adult form—slowly progressive dementia; often confused with nonorganic psychoses.

Fabry disease

a-galactosidase

Severe pain in extremities; angiokeratoma on buttocks and around navel; tortuous, dilated conjunctival and retinal venules; neuropathy; hypertension; myocardial ischemia. Female carriers may show manifestations.

Tay Sach disease

Hexosaminidase A

Early motor weakness psychomotor deterioration after 1 year of age, progressive deafness, blindness, startle response, red macula.

Sandhoff disease

Hexosaminidase A and B

Similar to Tay-Sachs but with mild peripheral neuropathy and organomegaly.

GM1 gangliosidosis

β-galactosidase

Type 1—Severe mental retardation, seizures and muscle hypotonicity apparent in first few months of life, dysostosis multiplex, foam cells in marrow.

 

β-galactosidase

Type 2—Regression of normal motor development apparent after age 1, seizures and rapidly progressive spasticity after first symptoms apparent, mild dysostosis multiplex.

MUCOPOLYSACCHARIDOSIS

Hurler syndrome  
(MPS IH)

 

Progressive mental and physical debilitation beginning at age 1, corneal opacities, coarse facies, gingival hyperplasia, dysostosis multiplex, stiff joints (claw-hands), dwarfing, organomegaly.

Scheie syndrome  
(MPS IS)

 

A mild form of MPS IH with corneal opacity, mild or absent mental retardation, claw-hand deformity, aortic stenosis.

Hunter syndrome (MPS II)

Iduronate sulfatases

Dysostosis multiplex essentially the same as in MPS IH, mental retardation in the severe forms (syndrome runs gamut from severe to mild). Lack of corneal clouding; there is a longer life span of even the severest form.

Sanphilippo syndrome

Heparan N-sulphatase

Behavioral problems progressing to severe mental retardation, comparatively mild or nonexistent connective tissue abnormalities, pronounced hirsutism. Type a is the most common of the Sanfilippo’s syndromes.

Sanfilippo syndrome 
(MPS III B)

a-N-acetylglucosaminidase

Indistinguishable clinically from MPS III A.

Sanfilippo syndrome  
(MPS III C)

a-glucosaminide-N-acetyltransferase

Indistinguishable clinically from MPS III A.

Sanfilippo syndrome  
(MPS III D)

N-acetylglucosamine-6-sulfate sulfatase

Indistinguishable clinically from MPS III A.

Morquio disease  
(MPS IVa)

Galactosamine-6-sulfate sulfatase

Pronounced skeletal anomalies with small stature (short-trunk dwarfism), short neck, prominent lower ribs, odontoid anomalies, normal intellect.

Morquio disease 
(MPS IVb)

β-galactosidase

Mild form of IVa, spondyloepiphyseal dysplasia, short stature, cloudy corneas, normal intellect.

Maroteaux-Lamy disease 
(MPS VI)

Arylsulfatase B

Severe-mild dysostosis multiplex, gross corneal opacity, retardation of growth, normal intellect, cardiomyopathy.

Sly disease  
(MPS VII)

β-glucuronidase

Mild mental retardation, somewhat coarse facies, gingivitis, organomegaly, sometimes with corneal clouding.

DISORDERS OF UNDEFINED GLYCOPROTEIN AND/OR LIPID STORAGE PRODUCTS

Fucosidosis

a-fucosidase

Type 1—Frequent respiratory infections, progressive psychomotor retardation, dysostosis multiplex (“Hurler-like”), thick skin with hypersecretion of sweat with elevated salinity, cardiomegaly.

Fucosidosis

a-fucosidase

Type 2—Distinguished from type 1 by its milder clinical presentation and absence of unusual sweating; lesions (angiokeratoma) can be present.

Mannosidosis

a-mannosidase

Mild hepatosplenomegaly, mild radiologic bone changes, psychomotor retardation, nerve deafness.

Mucolipidosis I(ML I) 
(sialidosis)

Neuraminidase and after beta-galactosidase deficiency

Type I—(Normomorphic) Cherry-red spots of the macula, myoclonus and normal intelligence.

 

Neuraminidase

Type II—(Dysmorphic) Dysostosis multiplex, mental retardation, myoclonus, cherry-red spots of the macula, both infantile and juvenile onset.

DISORDERS PRESUMED TO INVOLVE MULTIPLE STORAGE PRODUCTS

Mucolipidosis II (ML II) 
(I-cell disease)

UDP-N-acetylglucosemia: 
glycoprotein N-acetylglucosaminyl-phosphotransferase

Early onset of Hurler-like symptoms (often noted at birth), gingival hyperplasia, thoracic deformities, hepatosplenomegaly.

Mucolipidosis III (ML III) 
(pseudo-Hurler polydystrophy)

UDP-N-acetylglucosemia: 
glycoprotein N-acetylglucosaminyl-phosphotransferase

Mild variant of ML II; slowly progressing Hurler-like features, particularly claw-hand deformity; mild growth and mental retardation; joint stiffness with reduced mobility.

Multiple sulfatase deficiency 
(MSD)

Deficiency of all lysosomal sulfatases to greater or less degrees (arylsulfatase A less than arylsulfatase B).

Similar to infantile metachromatic leukodystrophy but with the skeletal anomalies of muccopolysaccharidosis, hepatosplenomegaly, thickening of the skin, ichthyosis.

Schindler disease

alpha-N-Acetylgalactosaminidase (?-galactosidase B)

Onset at about 1 year followed by development delay, and thereafter, psychomotor retardation, cortical blindness, spasticity, decorticate posturing.

GLYCOGEN STORAGE DISORDERS

Pompe disease 
(Type II GSD)

alpha-Glucosidase
(acid maltase)

Though glycogen storage is ubiquitous to nearly all tissues, cardiomegaly and hypotonia are the most life-threatening of the sequelae. There are multiple forms of the disease which give rise to infantile through adult presentation.

Types of Disorders

SCREENING FOR VARIOUS LSDs

 

I-Cell Screening

Mucolipidosis II

Plasma chitotriosidase

Gaucher’s or NPD A/B

MPS Screening

 

Azure A Spot Test

MPS I to VII

GAG Quantitative analysis

MPS I to VII

GAG Qualitative analysis

(MPS electrophoresis)

MPS I to VII

 

 

ENZYMES

DISORDERS

Mucopolysaccharidosis

 

a-iduronidase

Hurler Syndrome, MPS I

a-idurnoate sulphatase

Hunter Syndrome, MPS II

Heparan N sulphatase

Sanfilippo Syndrome, MPS IIIA

N- acetyl- a- D- glucosaminidase

Sanfilippo Syndrome, MPS IIIB

β-galactosidase-6-sulphate-sulphatase

Morquio Syndrome, MPS IVA

β-galactosidase

Morquio Syndrome, MPS IVB

Arylsulphatase B

Maroteaux-Lamy Syndrome, MPS VI

β-glucuronidase

Sly Syndrome, MPS VII

Glycoproteins degradation

a-fucosidase

Fucosidosis

a--mannosidase

Mannosidosis

Glycolipids and lipids

β-galactosidase

GM1 gangliosidosis

β-hexosaminidase (Total)

GM2 gangliosidosis (Sand hoff disease)

β-hexosaminidase (A)

GM2 gangliosidosis (Tay Sach disease)

Sphingomyelinase

Niemann Pick disease A/B (NPD A/B)

Β-glucosidase

Gaucher’s disease

Sulphatides

Arylsulphatase A

Metechromatic Leukodystrophy (MLD)

Β-galactocerebrosidase

Krabbe disease

Glycogen Storage

a-1-4-glucosidase (With-without acarbose)

Pompe disease, GSD II

Debrancher Enzyme

Cori disease, GSD III

Globotriaosylceramide

a-galactosidase

Fabry’s disease

Defects in protein degradation

Tripeptidyl peptidase I (TPP I)

Late Infantile Ceroid Lipofuscinosis II, NCL II

Palmitoyl-protein thioesterase (PPT)

Infantile Ceroid Lipofuscinosis I, NCL I

Defects in degradation of triglycerides and cholesteryls ester

Acid lipase

Wolman disease

Defects in lysosomal transporters

Sialic acid

Sialic Acid storage disorder

Defects in lysosomal trafficking proteins

NPC 1

Niemann Pick disease type C (NPC)

ENZYME PANELS FOR LSDs

FRIGE also offers different panel study for LSDs:

Enzymes in the NEURODEGENERATIVE (and other) screens which can be assayed initially on plasma:

ENZYME

DISORDER

Arylsulphatase A

I-cell

a-fucosidase

Fucosidosis

β-glucuronidase

MPS VII

β-hexosaminidase  (Total)

Sand hoff disease

β-hexosaminidase  (A)

Tay Sach disease

a-mannosidase

Mannosidosis

Chitotriosidase

Gaucher and NPD also helpful indicator of other LSD

Enzymes in the NEURODEGENERATIVE (and other) screens which can be assayed initially on leucocytes

ENZYME

DISORDER

Arylsulphatase A

Metachromatic leukodystrophy

β-galactocerebrosidase

Krabbe disease

β-galactosidase

GM1 gangliosidosis

Palmitoyl protein thioesterase

Infantile neuronal ceroid lipofuscinosis (INCL)

Tripeptdyl peptidase I  

Late infantile  neuronal ceroid lipofuscinosis (cLINCL)

Dysmorphology Screen (Send a urine sample as well)

ENZYME

DISORDER

β-galactosidase

GM1 gangliosidosis

Arylsulphatase A

Multiple sulphatidosis

a-fucosidase

Fucosidosis

a-mannoaidase

Mannosidosis

a-neuraminidase

Sialidosis

β-galactosidase

Galactosialidosis

I-cell screen

I-cell (Mucolipidosis II)

β-glucuronidase

Sly Syndrome, MPS VII

+ Chitotriosidase

 

LIVER & SPLEEN SCREEN

ENZYME

DISORDER

β-glucosidase

Gaucher disease

Sphingomyelinase

Niemann Pick Disease A/B

β-galactosidase

GM1 gangliosidosis

a-fucosidase

Fucosidosis

a-mannosidase

Mannosidosis

a-neuraminidase

Sialidosis

I-cell Screening

I-cell (Mucolipidosis II)

β-glucuronidase

Sly Syndrome, MPS VII

+ Chitotirosidase

 

CHERRY RED SPOT AND NEUROREGRESSION SCREEN

ENZYME

DISORDER

β-hexosaminidase Total / A

GM2 gangliosidosis

Sialic acid (Total & Free): urine

Sialic acid storage disorder

β-glucosidase

Gaucher’s disease

Sphingomyelinase

Niemann Pick Disease (A / B)

β-galactosidase

GM1 ganglisidosis


Which samples are needed?

Most of the enzyme study is done from leucocytes, fibroblasts or plasma samples. It require about 5 – 8 cc blood in EDTA vial. We also request to send us 10-15 cc of urine and clear plasma as well for additional study.

Prenatal Diagnosis of Lysosomal storage disorders

Increased awareness, investigational facilities and available treatment option for various lysosomal storage disorders (LSDs) has generated the great deal of interest and hope to prevent and cure for this group of diseases. Postnatal confirmation and prenatal diagnosis (PD) is one of the important parts in counseling to the affected families for prevention of the disease with treatment option are either not available or beyond reach to the family. Various methods have been known and employed in the prenatal diagnosis of LSDs that include enzyme study from uncultured chorionic villus cells (CV), morphological study of CV sample for vacuoles, cultured chronic villus (CT) and/or amniotic fluid (AF) cells, electrophoresis of amniotic fluid for excretion pattern of various mucopolysaccharides, electroscopic ionization tandem mass spectrometry (Ramsay S et al., 2004) and mutation analysis using DNA from uncultured chorionic villous or amniotic fluid cells.

Though molecular study provides specific diagnosis of the LSDs, identification of the known mutation in an affected child is the prerequisite for confirmed prenatal diagnosis. This require database of common mutation observed in Indian population which is not known except for Ashkenazi Jewish population. Therefore, in most part of the world lysosomal enzyme study is prerequisite for prenatal diagnosis followed by mutation study as a confirmation where mutation is known.

At FRIGE, prenatal study has been undertaken with a view to establish the prenatal diagnosis of LSDs using enzyme study from CV, CT or AF and demonstrate the specialty of reliability of enzyme study in the prenatal diagnosis of LSDs. 

http://link.springer.com/article/10.1007%2Fs40556-014-0001-3