|Providing new hope to families facing the
debilitating aspects of lysosomal storage diseases.
|An Overview of Lysosomal Storage Diseases and the GM2 Gangliosidosis
John G. (Jack) Keimel
February 24, 2007
where she shows traces of her workings apart from the beaten path; nor is there any
better way to advance the proper practice of medicine than to give our minds to the
discovery of the usual law of Nature by careful investigation of cases of rarer forms of
From a letter written by William Harvey in 1657
Research Incentive from the "Big Picture"
In 1908, Sir Archibald Garrod, in an address to the Royal College of Physicians of London, described a
small group of four benign disorders* that appeared to follow Mendel’s laws of inheritance and named
them “inborn errors of metabolism.” Since this initial grouping, over 500 disorders have been
attributed to point defects in metabolism and included in this general classification. (Scriver 2001) In
line with Garrod’s original observation, the majority of these disorders are caused by single-gene
defects that are transmitted in an autosomal recessive manner, but now also include disorders caused
by autosomal dominate, X-linked recessive, or mitochondrial genetic mutations (Clarke 2002). The
grouping of “inborn errors of metabolism” are generally defined as those diseases being caused by
metabolic disturbances associated with deficiencies of catalytic or transport proteins.
Each of these individual diseases is caused by a distinct genetic defect, and it is anticipated that
therapeutic solutions will need to specifically respond to the genetic mutation or to the uniquely
associated metabolic disturbance. It is highly unlikely that a “magic bullet”** therapeutic solution will
be found for all “inborn errors of metabolism,” or even subclasses of these diseases. Because of the
infrequent occurrence of the individual diseases, a specific therapeutic solution for one disease may
have relatively limited benefit for society as a whole, and with this perspective, efforts to find cures for
these diseases are primarily motivated by academic curiosity or the moral conviction of a particular
researcher. Many research institutions and medical corporations hold this limiting perspective and
have little financial incentive for investing in cures for these individual diseases, or in general, cures
that do not require repeated application with an ongoing revenue stream. It is indeed true that each of
the diseases associated with “inborn errors of metabolism” occur infrequently and are generally
classified as rare, but taken as a whole, these diseases represent a large portion of chronic diseases
around the world, especially those afflicting children (Clarke 2002). The opportunity then is to
understand the aspects of these diseases that are in common and to identify research or technology
that can be leveraged across these diseases to make the individual therapeutic solutions more
economically achievable. A solution for an individual disease could thereby have much broader
implications. Finding a solution for an individual disease may not only benefit the small group of
patients afflicted, but could provide direction for cures in the broader class of diseases.
Adjustments in diet or environment is an option for patients with a small number of these metabolism
diseases, such as phenylketonuria (PKU), and other therapeutic options are also already in clinical
practice for a limited number of the other diseases that primarily afflict the body’s systemic systems.
Unfortunately, dietary restrictions or systemic therapies are not effective options for many patients with
inborn errors of metabolism that affect the central nervous system. A sub-classification of inborn
errors of metabolism that have major central nervous system implications is lysosomal storage
diseases (LSDs). There are no available therapies for patients suffering from the neurological aspects
of these diseases.
Today, an improved understanding of the genetic basis for LSDs is enabling both a means for early
diagnosis and advancements in central nervous system focused therapy. These advancements are
providing new hope to patients and parents of children afflicted with these devastating
neurodegenerative conditions. This disease overview provides a focused review of one of the LSDs,
GM2 gangliosidosis, also called Hexosaminidase A Deficiency or Tay Sachs Disease, including the
clinical manifestation of the disease, the associated substrate that fails to be catabolized, and the
enzyme deficiency that cause this disease. Also included is a short perspective on the options for
future treatment of the neurological aspects of this disease.
Read more on Lysosomal Storage Diseases
* Initial diseases of “inborn errors of metabolism” included by Sir Archibald Garrod were alkaptonuria, cystinuria,
pentosuria, and albinism.
** Magic bullet is a translation of the German word Zauberkugel, used by Dr Paul Ehrlich in reference to his search for
a cure for syphilis. From about 1938, this term has taken the meaning of a drug that will provide a perfect cure.