Sandhoff Disease Presented by: Megan Frantz History Sandhoff

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Sandhoff Disease

• Presented by
• Megan Frantz

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History

• Sandhoff disease is named for Konrad Sandhoff, a
  German chemist who first described Sandhoff in
  Life Science in 1968.
• Sandhoff, like its near twin Tay-Sachs, is a
  progressive neurological autosomal recessive
  genetic disorder that appears in three forms
  Classic Infantile, Juvenile and Late Onset or
  Chronic Sandhoff.

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What is Sandhoff Disease?

• Sandhoff disease is a rare, genetic, lipid
  storage disorder resulting in the progressive
  deterioration of the central nervous system.
• It is caused by a deficiency of the enzyme
  beta-hexosaminidase, which results in the
  accumulation of certain fats (lipids) in the
  brain and other organs of the body.
• Sandhoff disease is a severe form of Tay-Sachs
  disease--which is prevalent primarily in people
  of Eastern European and Ashkenazi Jewish
  descent--but it is not limited to any ethnic
  group.
• Onset of the disorder usually occurs at 6 months
  of age.

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What are the symptoms?

• Neurological symptoms may include motor weakness,
  startle reaction to sound, early blindness,
  progressive mental and motor deterioration,
  macrocephaly (an abnormally enlarged head),
  cherry-red spots in the eyes, seizures, and
  myoclonus (shock-like contractions of a muscle).
• Other symptoms may include frequent respiratory
  infections, doll-like facial appearance, and an
  enlarged liver and spleen.

5
What is Sandhoff Disease. (2007) National Tay
Sachs Allied Diseases Assoc. lthttp//www.ntsad.o
rg/S02/S02sandhoff.htmgt. Date accessed 11 April
2008.
6
Cherry red spot
Haynie, J.M. Retinal Manifestations of Systematic
Disease. (2006) Pacific University College of
Optometry lthttp//www.opt.pacificu.edu/ce/catalog/
web020/haynie_retinal.htmlgt. Date accessed 11
April 2008.
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Classic Infantile Sandhoff

• Classic Infantile Sandhoff is the most common
  form of this rare disease and is characterized by
  very little to no Hexosaminidase-A (Hex-A) and
  Hexosaminidase-B (Hex-B) enzyme activity.
• Motor weakness begins in the first 6 months of
  life and is progressive.
• Death usually occurs at about 3 years of age.

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Juvenile Sandhoff Disease

• Individuals who have low levels of Hex-A and
  Hex-B, have a slower onset of symptoms and
  progression of disease, compared to those with
  Classic Infantile Sandhoff.
• Within each form of Sandhoff disease, there is a
  range of severity and each persons experience
  with the disease is distinctive.
• In children with Juvenile Sandhoff, Hex-A enzyme
  activity is extremely low but not as low as in
  children with Classical Infantile Sandhoff.
• Children with the Juvenile form of the disease
  usually develop symptoms around 5 years of age.
  Though the course of the disease is slower, end
  stages generally occur in late adolescence.
• Death usually occurs within the first 15 years
  due to other complications, such as respiratory
  infection.

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Late-Onset Sandhoff Disease

• Late-Onset Sandhoff disease is a rare form of
  Sandhoff disease
• Because only a low level of Hex-A and Hex-B is
  functional in patients with Late-Onset Sandhoff,
  the symptoms typically presents in adolescence,
  with dysarthria, proximal (trunk) muscle
  weakness, tremor and ataxia. Muscle cramps,
  especially in the legs at night, and
  fasciculations (muscle twitching) are common.
• Late-Onset Sandhoff differs from the juvenile
  form primarily in its impact of intelligence,
  which is minimal in patients with Late-Onset
  Sandhoff.

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What is a ganglioside?

• Gangliosides are acidic glycosphingolipids they
  contain oligosaccharides with terminal, charged
  N-acetyl neuraminic acids (NANA).
• Depending on the number of NANA sugars,
  gangliosides are designated M, D, T, Q (e.g., GM2
  ).
• Glycosphingolipids, or glycolipids, are composed
  of a ceramide backbone with a wide variety of
  carbohydrate groups (mono- or oligosaccharides)
  attached to carbon 1 of sphingosine.

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Synthesis of glycosphingolipids

• Glycosphingolipids are synthesized by
  membrane-bound glycosyltransferases which exist
  as multienzyme complexes.
• Synthesis reactions occur in the Endoplasmic
  Reticulum and Golgi apparatus.
• The first step in their synthesis is the
  condensation of a molecule of palmitoyl-CoA with
  the amino acid serine to form 3-ketosphinganine,
  catalyzed by the enzyme 3-ketosphinganine
  synthase.
• The ketone group is reduced to an alcohol by the
  enzyme 3-ketosphinganine reductase, resulting in
  sphinganine.
• The sphinganine is acylated by fatty acyl-CoA to
  yield N-acylsphinganine.
• The palmitoyl group can then be oxidized to a
  double bond to form ceramide.
• Ceramide can combine with phosphatidylcholine to
  form sphingomyelin, which is the major lipid
  component of the myelin membrane, or it can add
  glucosyl groups onto the alcohol to form
  glycosphingolipids, which are important in
  cell-cell recognition and intracellular
  communications.

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The biosynthesis of globosides and GM
gangliosides.
Voet, D. Voet, J. Biochemistry, John Wiley
sons Danvers, MA, 2004, 3 ed., pp 977-978.
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Degradation of glycosphingolipids

• A series of acid hydrolases participate in the
  degradation of glycosphingolipids.
• Degradation of most substrates occurs by the
  stepwise activity of a series of hydrolases, with
  each step requiring the action of the previous
  hydrolase to modify the substrate, so that the
  substrate can be further degraded by the next
  enzyme in the pathway.
• If one step in the process fails, further
  degradation ceases and the partially degraded
  substrate accumulates.
• The GM2-activator binds GM2 and helps expose it
  to the surface of the membrane.
• The GM2-activator-GM2 complex can then bind
  hexosaminidase A, an aß dimer that hydrolyzes
  N-acetylgalactosamine from GM2 at the lipid-water
  interface.

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Hexosaminidase A

• The Hex A gene, located on chromosome 15, codes
  for the alpha subunit of the hexosaminidase A
  enzyme which is necessary for breaking down GM2
  gangliosides in nerve cells.
• When there is a mutation in the coding for beta
  subunit of the hexosaminidase A it does not
  function properly and leads to an accumulation of
  GM2 which is toxic and eventually causes cell
  death.
• Sandhoff is characterized by loss of function of
  both the alpha and beta subunit of hexosaminidase
  A enzyme.
• Within lysosomes, beta-hexosaminidase A forms
  part of a complex that breaks down a fatty
  substance called GM2 ganglioside.

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Hexosaminidase B

• Sandhoff is caused by a mutation in the Hex B
  gene on chromosome 5.
• The Hex B gene codes for part of two essential
  nervous system enzymes the beta subunit of
  hexosaminidase A and the beta subunit of
  hexosaminidase B.
• When there is a mutation in the coding for beta
  subunit of hexosaminidase A and the beta subunit
  of hexosaminidase B both enzymes do not function
  properly and lead to an accumulation of GM2 which
  is toxic and eventually causes cell death.
• Tay-Sachs is characterized by loss of function
  of only the alpha subunit of the hexosaminidase A
  enzyme.

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Treatment

• To date, there is no cure or effective treatment
  for Sandhoff disease.
• However, there is active research being done in
  many investigative laboratories in the U.S. and
  around the world exploring a range of therapeutic
  approaches primarily in a Sandhoff mouse model,
  an animal model for Sandhoff disease.
• For the first time in the history of the disease
  there currently are clinical trials testing the
  potential of a substrate reduction drug
  (miglustat) in all three forms of Sandhoff and
  Tay-Sachs, with the Late Onset trial having
  started in 2002. The uses of enzyme replacement
  therapy to provide the Hex-A and Hex B that is
  missing in babies with classic infantile or
  significantly reduced in children and adults with
  Sandhoff disease has been explored but presents
  serious obstacles.
• Stem cell transplantation using umbilical cord
  blood is an investigational procedure attempted
  with a small number of very young children, but
  to date there is not enough information for
  specific results about reversing or slowing
  damage to the central nervous system in this
  group with Sandhoff disease.

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Testing

• Since Sandhoff is a recessive genetic disorder,
  both parents must be carriers for Sandhoff
  disease in order to have a child with Sandhoff
  disease.
• Enzyme assay- Measurement of enzyme activity with
  particular substrate. The assay involves the use
  of an artificial hexosaminidase substrate,
  4-methylumbelliferyl-ß-D-N-acetylglucosamine,
  which yields a fluorescent product upon
  hydrolysis. Fluorescence of the product,
  indicates hexosaminidase activity.
• DNA analysis looks for particular or known
  mutations in the genome or genetic make up.
• Pre-implantation Genetic Diagnosis (PGD) - Tests
  early-stage embryos produced through in vitro
  fertilization (IVF) for the presence of a variety
  of genetic conditions. One cell is extracted from
  the embryo in its eight-cell stage and analyzed.
  Embryos free of conditions that would cause
  serious disease can be implanted in a woman's
  uterus and allowed to develop into a child.

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Simple serum assay reaction
Voet, D. Voet, J. Biochemistry, John Wiley
sons Danvers, MA, 2004, 3 ed., pp 977-978.
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Summary

• While Hex-A and Hex-B differ in the kinds of
  subunits they contain, both play a role in the
  degradation of GM2 gangliosides
• Individuals with Sandhoff are unable to degrade
  these GM2 gangliosides and the gangliosides
  accumulate in special compartments of the cells
  called lysosomes.
• Since the accumulation of GM2 gangliosides is at
  the root of Sandhoff disease, it is classified as
  a GM2 gangliosidosis to distinguish it from
  other lysosomal storage diseases

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Summary (cont.)

• The severity of Sandhoff disease depends on the
  amount of residual enzyme that is produced.
• Children with virtually no hexosaminidase
  activity will have the infantile (acute onset)
  form of the disease. The infantile form is the
  most severe and, unfortunately, the most common.
• Those born with a small amount of hexosaminidase
  activity will have the juvenile, subacute form.
• Those with still more activity will have a later
  onset adult (chronic) form of Sandhoff disease.
• The juvenile and adult forms of Sandhoff disease
  occur later and tend to be much more variable in
  their clinical features. The amount of residual
  enzyme, and therefore the clinical course, is
  determined by the specific mutation(s) in the
  ß-subunit of Hex-A.