Lysosomal storage disorders

 3000 Children have these diseases in France. 250 to 400 new cases are detected every year.

RARE GENETIC DISEASES

The term “Lysosomal diseases” includes a group of approximately fifty child degenerative disorders that have a genetic dysfunction of the lysosome as a common trait .

In each of our cells, the role of the lysosome is to recycle substances (called metabolites) that come out of the cells functioning. In lysosomal diseases, for a genetic reason, the lysosome does not function properly. Metabolites progressively increase in the cells and subsequently in the tissue of the sick person.

TRANSMISSION

Apart from the Hunter disease and the Fabry disease that are hereditary disorders of the transmission metabolism related to the X chromosome, lysosomal diseases are transmitted following the autosomal recessive model. This means that both parents are healthy carriers of the disease. On each pregnancy there is 25% risk that these parents’ children will have the disease. The sick child carries a genetic patrimony with two deficient alleles. Boys and girls are equally affected.

SCREENING

The screening of the disease can only take place when there is a case known in the family.
In these circumstances, a prenatal diagnosis can be arranged for couples at risk

For the past few years, some of these disorders can benefit from specific treatments. Early diagnosis is crucial so that a therapeutic strategy can be put in place. Early intervention prevents the occurrence of definitive lesions.

CONSEQUENCES

Lysosomal storage disorders (LSD) include a number of diseases with a wide range of symptoms. They are specific multisystemic affections with a spectrum of clinical severity that range from extremely severe to mild forms. The most severe forms include neurological affections, which is the case for numerous pathologies leading to bedridden states.
The disease typically develops from deficiencies to definitive lesions which, depending on the pathology, affect various organs such as bones, heart, liver, spleen and brain.

Most of the time, the classical symptoms of the disease are absent at birth. These symptoms can become apparent only after a period of several month or several years or even at the adult age. 

Typical symptoms include a progressive and definitive impairment of the physical and mental states.

TREATMENTS

For the time being, therapeutic possibilities are limited to the following:

• Type I and III Gaucher disease (except pathologies with neurological consequences)
• Fabry disease
• Mucopolysaccharidosis Type I (MPS I, Hurler, Hurler/Scheie, Scheie syndrome)
• Mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome)
• Cystinosis
• Glycogenosis Type II (Pompe disease)
• Mucopolysaccharidosis Type II (MPS II, Hunter syndrom)

Results obtained with these treatments, all done by Enzyme Replacement Therapy (ERT) (apart from cystinosis) are very encouraging given the improvement of the general state of health and re-growth for adolescent treatment.
This treatment technique is based on the production of the deficient enzyme by gene therapy. The enzyme is injected by vein perfusion at regular intervals. This is a treatment for life.
Spine transplants have also been experimented; their success closely depends on the compatibility between donors and receivers. These transplants depend on heavy techniques, they are not without risk. When the transplants are successful, the progression of the disease and symptoms diminishes, however we have no evidence that this technique would relieve any previous brain damage.

Clinical trials are ongoing, giving hope for the following diseases :

• Type III Gaucher disease
• Gangliosidosis (for late forms)
• Niemann-Pick Type C disease (trials for the type B are about to start)
• Sanfilippo Syndrom

There will be more treatment avenues for the gene therapy on a long term basis. With the support of the Scientific Board of Management, the Society provides funding for several Research programmes in this domain. 
Along this action and with the support of the Medical Committee, VML looks for child relief through ongoing care. For example, in the case of a metachromatic dystrophy, oral feeding may become difficult. Spectacular improvement has been obtained with the introduction of a gastrostomy feeding port allowing enteral feeding. This way the child regains weight and is better equipped to fight the disease.
Hip dislocations are often noticed and abductions are often necessary; special equipment has to be made accordingly.

LIST OF LYSOSOMAL STORAGE DISORDERS

The usual classification is presented according to the nature of the substrate accumulated. As a matter of fact, we distinguish between Lipidosis, Mucopolysaccharidosis and Glycoproteinosis.  Respectively all three of the above are characterised by the accumulation of :

• Sphingolipidosis – in the case of Lipidosis 
• Glycosaminoglycans – in the case of Mucopolysaccharidosis
• Glycoproteins – in the case of Glycoproteinosis

This classification is completed by pathologies that are related to certain lysosomal proteins transporting or affecting the maturing of the targeting of groups of enzymes.

LIPIDOSIS

MULTIPLE SULFATASE DEFICIENCY (AUSTIN DISEASE)
FABRY
FARBER
GAUCHER
KRABBE
METACHROMATIC LEUCODYSTROPHY
NIEMANN-PICK
SCHINDLER
LANDING (GANGLIOSIDOSIS)
SANDHOFF (GANGLIOSIDOSIS)
TAY-SACHS (GANGLIOSIDOSIS)
CHEDIAK-HIGASHI SYNDROME

MUCOPOLYSACCHARIDOSIS

HURLER-HURLER/SCHEIE-SCHEIE (MPS I)

HUNTER (MPS II)

SANFILIPPO (MPS III)

MORQUIO (MPS V)
MAROTEAUX-LAMY (MPS VI)
SLY (MPS VII)
MPS IX 

ANOMALIES IN LYSOSOMAL TRANSFER

SALLA DISEASE (Sialic acid storage disease)
CYSTINOSIS 
DANON

OLIGOSACCHARIDOSIS AND GLYCOPROTEINOSIS

MUCOLIPIDOSIS TYPE II (I Cell)
MUCOLIPIDOSIS TYPE III
MUCOLIPIDOSIS TYPE IV

ASPARTYLGLUCOSAMINURIA

SIALIDOSIS

GALACTOSIALIDOSIS
FUCOSIDOSIS
MANNOSIDOSIS
 

PYCNODYSOSTOSIS

GLYCOGEN STORAGE DISORDER

SYNDROME TYPE II ( POMPE DISEASE)

CEROÏD LIPOFUSCINOSIS DISORDERS

PAPILLON-LEFEVRE’S SYNDROME