GENETICALLY INHERITED DISEASE

1. Von GIERKE disease
• Also known as GSDI – glycogen storage disease type
•
• An inherited disorder that builds up glycogen in body cells
• Organs and tissues - liver, kidneys and small intestines and thus
impairs their function
• Seen at 3-4 months of baby when they don’t take feed normally at
nights
• Frequency - 1 in 1,00,000 where GSDIa is dominant as compared to
GSDIb

2. Von GIERKE disease
Dr. Esther Shoba R
Assistant Profesor
Kristu Jayanti College

4. Etiology
• Mutation s in gene G6PC (GSDIa) and SLC37A4 (GSDIb)
• G6PC gene codes for Glucose - 6 – phophatase (enzyme present on
membrane of ER) together with
• SLC37A4 codes for - solute carrier family 37 member 4, which function
as glucose 6-phosphate translocase protein
• This two work together to break glucose -6-phosphate
• If glucose -6-phosphate is not broken down they convert to glycogen
an fat, this becomes toxic and damages organs and tissues (liver and
kidney)
• Atleast 85 mutations are reported in G6PC gene

6. SLC37A4 gene - solute carrier family 37 member 4
The SLC37A4 gene provides instructions for making a protein called
glucose 6-phosphate translocase
This protein transports the sugar molecule glucose 6-phosphate from the
fluid inside the cell to the endoplasmic reticulum, which is a structure
inside cells that is involved in protein processing and transport
At the membrane of the endoplasmic reticulum, glucose 6-phosphate
translocase works together with the glucose 6-phosphatase protein
(produced from the G6PC gene) to break down glucose 6-phosphate
If glucose 6-phosphate cannot get to the endoplasmic reticulum, it
cannot get broken down and glucose is not produced
More than 80 mutations

10. INHERITANCE PATTERN
• This condition is inherited in an autosomal recessive pattern, which
means both copies of the gene in each cell have mutations.
• The parents of an individual with an autosomal recessive condition
each carry one copy of the mutated gene, but they typically do not
show signs and symptoms of the condition.
• That is parents should be carriers

11. Symptoms
• Seen at 3-4 months of baby when they don’t take feed normally at nights
• Affected infants have low blood sugar that leads to seizures
• More of lactic acid, uric acid and excess amount to fats
• As they get older, children with GSDI have thin arms and legs and short
stature
• An enlarged liver may give the appearance of a protruding abdomen
• The kidneys may also be enlarged
• Delayed puberty because of abnormal development of the ovaries –
polycystic ovaries
• Adenomas (tumor) form in the liver, may be noncancerous (benign) or
cancerous (malignant)

12. Symptoms
• Researchers have described two types of GSDI, which differ in their signs
and symptoms and genetic cause
• These types are known as glycogen storage disease type Ia (GSDIa) and
glycogen storage disease type Ib (GSDIb)
• People with GSDIb have neutropenia (less WBC), so more infections,
inflammation of intestinal walls, inflammation of the gums (gingivitis),
chronic gum (periodontal) disease, abnormal tooth development, and
open sores (ulcers) in the mouth
• The neutropenia and oral problems are specific to people with GSDIb
and are typically not seen in people with GSDIa

13. LABORATORY DIAGNOSIS

14. LABORATORY DIAGNOSIS
• Molecular Genetics Tests
• Targeted variant analysis (14)
• Deletion/duplication analysis (22)
• Sequence analysis of select exons (2)
• Mutation scanning of the entire coding region (1)
• Sequence analysis of the entire coding region (39)

15. TREATMENT

16. Treatment - Gene therapy
Adenovirus- and adeno-associated virus (AAV)-mediated gene
therapies have been evaluated for GSD-Ia in these model systems.
adenoviral therapy produces only short term corrections and only
impacts liver expression of the gene
AAV-mediated therapy delivers the transgene to both the liver and
kidney, achieving longer term correction of the GSD-Ia disorder
Gene therapy for GSD-Ib in the animal model is still in its infancy,
although an adenoviral construct has improved the metabolic profile
and myeloid function.
Initial studies using Adeno associated virus (AAV) serotype 2–based
vectors expressing G6Pase-α to treat infant GSD-Ia in dogs or mice
showed suboptimal improvement
Adeno associated virus (AAV) serotype 8 vectors are also used

17. Treatment - Gene therapy
• Correct gene in vectors of feline immunodeficiency virus (FIV), a
nonprimate lentivirus and transduced in the liver of the murines
• these vectors are capable of integrating stably into hepatocyte cell
lines and adult murine livers and lead to long-term transgene
expression
• Single administration of FIV vectors containing the human G6Pase
gene to G6Pase-α−/− mice did not change the biochemical and
pathological phenotype
• However, a double neonatal administration protocol led to
normalized blood glucose levels, significantly extended survival,
improved body weight, and decreased accumulation of liver glycogen
associated with the disease