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Health - Lysosomal storage disorders

May 2013
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Lysosomal storage disorders (LSDs) are a large heterogeneous group of more than fifty genetically inherited metabolic disorders characterized by lysosomal malfunctions in body's cells. Most of them are rare types caused by autosomal recessive inheritance. However, a few are X-linked and recessive.

Though known as pediatric disorders, late on-setting adult forms have been recognized. Certain ethnic groups have an increased carrier frequency for specific disorders. Pompe, Gaucher, Niemann-Pick, Tay-Sachs, Sandhoff, Krabbe, Hermansky-Pudlak, Chediak-Higashi, Griscelli and Fabry disorders are the more known conditions.

What is lysosomal storage disorder?

The lysosomal body is a specialized organelle in the cell which by enzymatic activity breaks down and recycles unwanted materials in the cell. In certain inherited disorders resulting from different gene mutations, there is deficiency or absence of the lysosomal enzyme activity leading to storage and accumulation of substances destined for breakdown and recycling. The supposition of these disorders has been broadened to include deficiency, absence or defect in certain crucial proteins. These proteins are required for post-translational modifications, activator functions and intracellular trafficking between the lysosomal body and other intracellular components.

Classification of lysosomal storage disorders

Considering the type of defect in degradation on molecular basis, lysosomal storage disorders are classified as follows:
  • non-enzymatic lysosomal protein defects,
  • transporters and structural proteins defects,
  • lysosomal enzyme protection defects,
  • post-translational processing defects,
  • neuronal ceroid lipofuscinoses (NCLs),
  • polypeptide degradation defects and
  • defects in lysosomal trafficking. 

Symptoms and manifestations

These storage disorders vary in degree of intensity in respect to the type of afflicting disorder and the age of onset. Moreover, the clinical manifestations of a particular type may vary widely among the affected patients. In severe forms of the disorder there may be total debility and even death. In untreated cases, there is gradual progressive increase in the intensity of symptoms and morbidity.

The clinical manifestations of lysosomal storage disorders are:
  • developmental delay, 
  • impaired mobility, 
  • ataxia and hypotonia, 
  • spasticity and hypertonia, 
  • convulsions and seizures, 
  • peripheral neuropathy, 
  • impaired vision and hearing, 
  • corneal clouding, 
  • enlargement of the liver, spleen and heart, 
  • lung and heart disorders, 
  • bone abnormalities, 
  • dementia and intellectual disability and
  • neuromuscular disorders.

Testing, screening and diagnosis

If a patient has one or more of the symptoms, tests may be conducted to rule out lysosomal storage disorder. To arrive at a definitive diagnosis enzyme assay and enzymatic activity measurement is done. Skeletal radiography is performed to find evidence of bone and cartilage malformations. Ultrasonography is performed to identify cardiomegaly, splenomegaly and hepatomegaly. To find evidence of cardiac involvement, echocardiography is performed. Ophthalmologic, hearing and ear Screening are performed to find evidence of lysosomal storage disorders. Peripheral blood smear test may be carried out to look for presence of anomalies in white blood cell vacuoles. Urine is tested for increased presence of oligosaccharides and glycosaminoglycans. Molecular analysis and molecular genetic testing (MGT), though rarely used, helps in carrier and prenatal testing.

Treatment trends

Recent research efforts have opened up many new therapeutic possibilities and options like enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction therapy and molecular chaperone therapy.

Enzyme replacement therapy (ERT)

Enzyme replacement therapy has been found to be safe and promising. However, for central nervous system manifestations ERT has been largely ineffective. To overcome the difficulty in penetrating the blood-brain barrier, active clinical trials are evaluating the efficacy of intrathecal enzyme delivery.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation with bone marrow or umbilical cord blood cells have been found to be effective in preventing the progression when performed early in the course of the disorder. Combination  therapy with hematopoietic stem cell transplantation and ERT has been found to be superior in results compared to separate treatments.

Substrate reduction therapy

Experiments and trials are going on substrate reduction therapy process to reduce the accumulated storage material. Substrate storage reduction therapy addresses the failure of the metabolic pathway and the accumulation of the substrate. If the level of substrate storage is reduced, the residual degradative activity may be sufficient to reduce and prevent substrate accumulation and storage.

Molecular chaperone therapy

One of the latest pharmacological process in the treatment of lysosomal storage disorder is molecular chaperone therapy. Chaperones are minute molecules which can penetrate blood brain barrier. Once the chaperones enter the central nervous system, they attach to the defective enzyme to make it functional. There are some limitations to molecular chaperone therapy as it is effective only in certain of the disorders. Research and clinical trials are currently going on to improve the efficacy and dosage management of molecular chaperone therapy for the treatment of this storage disorder.

Reference:
1.Mirella Filocamo and Amelia Morrone. Lysosomal storage disorders: Molecular basis and laboratory testing. Hum Genomics. 2011 Mar;5(3):156-69.
2.Orna Staretz-Chacham, MD, Tess C. Lang, BS, Mary E. LaMarca, BA, Donna Krasnewich, MD, PhD, Ellen Sidransky, MD. Lysosomal Storage Disorders in the Newborn. Pediatrics. 2009 April; 123(4): 1191–1207.
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