ACID MALTASE DEFICIENCY AMD

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ACID MALTASE DEFICIENCY (AMD)

• BY AMANDA PFAFF
• LYCOMING COLLEGE SCHOLARS PRESENTATION

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ACID MALTASE DEFICIENCY also known as

• Glycogen Storage Disease Type II
• Type II Glycogenosis
• Pompes Disease

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DEFINITION OF AMD...

• Acid maltase deficiency is a heterogeneous
  autosomal recessive disease caused by a
  deficiency of lysosomal alpha-glucosidase,
  leading to a characteristic accumulation of
  glycogen in lysosomes.

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Terms with which we must be familiar...

• Heterogeneous
• Autosomal
• Recessive
• Lysosome

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HISTORY OF AMD

• In 1932, Pompe and Putschar first described AMD
  in infants.
• Engel and Dale subsequently described the later
  onset or adult form of AMD
• In 1959, Sant Agnese described the diagnostic
  criteria for infantile AMD.
• In 1963, Hers discovered the primary deficiency
  of lysosomal acid alpha-glucosidase.

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INTERESTING FACTS ABOUT AMD...

• AMD is not confined to the human species
• also occurs in the Lapland dog
• in cats, sheep, and cattle

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OTHER FACTS ABOUT AMD...

• The severity of AMD is largely correlated with
  residual acid alpha-glucosidase activity.
• People with AMD have at least one deleterious
  mutation in each of their 2 alpha-glucosidase
  alleles
• leads to a partial or complete loss of the enzyme
  protein and/or catalytic function

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ACID MALTASE ENZYME

• Acid maltase (or acid alpha-glucosidase) degrades
  glycogen in the lysosomes and free tissue.
• Acid maltase also hydrolyzes alpha 1-4 and 1-6
  glycosidic linkages in maltose, isomaltose, and
  glycogen.

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THE STRUCTURE OF GLYCOGEN
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GLYCOGEN

• Resides primarily in the muscle tissue.
• It is an important fuel for muscles, especially
  type II muscle fibers.
• Its most important function is glycolysis.
• Under anaerobic conditions, glycogen is the main
  energy source for muscle contraction.

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HOW DOES GLYCOGEN GET INTO THE LYSOSOMES?

• Most cell types self-digest parts of cells as a
  normal lysosomal function.
• As a result, glycogen and other cell components
  get into the lysosomes.

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NORMAL ACID MALTASE FUNCTION

• In people not affected with AMD, acid maltase
  breaks down glycogen in the lysosomes.

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ACID MALTASE FUNCTION IN AMD

• Reduced activity of acid maltase.
• Leads to abnormal accumulation of glycogen in the
  lysosomes, skeletal muscle, and free tissues.

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GENETICS OF AMD

• The acid maltase gene (GAA gene) is located on
  the q arm of chromosome 17.
• The GAA gene contains 20 exons and is
  approximately 20 kilobases long.

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COMMON MUTATIONS IN AMD

• The 3 types of mutations that occur in patients
  with AMD are missense, nonsense, and frameshift.
• 3 common mutations of the GAA gene are
• deletion of exon 18 (Dexon 18)
• a single base pair deletion (DT525)
• a base substitution in intron 1 (-13T to G)

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DELETION OF EXON 18

• Dexon 18 is the most frequent mutation in AMD
  with an incidence of 10 in 78 alleles (0.13
  frequency).
• It is not restricted to certain phenotypes, but
  it is more frequent in Dutch populations.
• A patient homozygous for Dexon 18 has the
  infantile form of AMD with no acid maltase
  activity.
• Dexon 18 paired with the base substitution (-13T
  to G) manifests the juvenile or adult form o fAMD
  with 10-20 acid maltase activity.

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SINGLE BASE PAIR DELETION DT525

• The DT525 occurs in exon 2.
• DT525 is also a common mutation within the Dutch
  population.
• Homozygotes for DT525 present the infantile form
  of AMD with complete deficiency of acid maltase.

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BASE SUBSTITUTION IVS1 (-13T TO G)

• The IVS1 (-13T to G) mutation is frequent among
  adults with AMD, but it is not found in the
  infantile form.
• IVS1 (-13T to G) is a mild mutation
• it allows acid maltase synthesis and function at
  20-40 of the normal level.

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THREE CLINICAL FORMS OF AMD

• The 3 different phenotypes of AMD are related to
  the different mutations in the acid maltase gene.
• Infantile Juvenile
  Adult

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INFANTILE FORM OF AMD

• Shortly after birth, the infant develops severe
  hypotonia.
• Enlargement of the heart, liver, and tongue
  occurs due to massive glycogen accumulation.
• There is marked limb weakness with a reduction of
  acid maltase levels in the muscle.
• Rapid progression of the disease leads to death
  before 2 years of age, usually due to cardiac or
  respiratory failure.

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JUVENILE FORM OF AMD

• Symptoms begin in infancy or early childhood, but
  the decline is much slower.
• AMD is restricted to skeletal muscle with no
  cardiac involvement.
• Weakness of trunk and proximal limbs is slowly
  progressive.
• Patients can survive for many years, but death
  due to respiratory failure usually occurs before
  age 30.

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ADULT FORM OF AMD

• Symptoms usually begin in the thirties or
  forties.
• The first symptom is weakness of the limb and
  girdle muscles with slow deterioration.
• As with the juvenile form, there is no cardiac
  involvement.
• Death from respiratory failure occurs years after
  onset.

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TREATING AMD

• Mobilizing glycogen in tissues
  through epinephrine injections.
• Mobilizing glycogen with ephedrine and glucagon.
• Administering oral acid maltase prepared from
  bacteria and human placenta.
• Limiting carbohydrate intake.

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DIAGNOSING AMD

• Diagnosis requires laboratory studies of acid
  maltase levels in
• muscle, lymphocytes, fibroblasts, and urine
• Muscle biopsies and skin biopsies are also
  performed.

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The End
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THANK YOU...

• Dr. Gabriel--project supervisor
• Bhavin Desai
• Kimberly Bunting
• Lycoming College Scholars Council