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Glycogen Storage Disease (GSD)
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This is the general name given to a group of inborn errors of metabolism that are
characterized by the accumulation of a poly-glucose molecule called glycogen. Usually
glycogen is synthesized and stored in the human body (in the liver, kidneys, muscles
etc.) as a reserve of sugar. When required, in situations where there is a lack
of sugar/food, the body breaks the glycogen down to glucose and uses it for energy.
In the glycogen storage diseases there is a malfunction of the synthesis or disintegration
of the glycogen, and as a result accumulation and high concentration of glycogen
in tissues such as liver and/or muscle. At the same time there are frequent episodes
of hypoglycemia (low blood glucose levels) and a lack of glucose and energy supplied
to muscle and brain.
Many enzymes are involved in the normal process of the synthesis and breakdown of
glycogen, and there are more than 11 types of GSDs according to the specific enzyme
that is not functioning along the metabolic chain of glycogen metabolism. The clinical
picture in each type may be different.
The following are the types that are common among Jews:
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GSD-1a: Von Gierke disease
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The basic defect resides in glucose-6-phosphatase.
Hypoglycemia (low blood glucose level), especially at night, is the major problem.
Children with this disease require continuous feeding at night to prevent the severe
nocturnal hypoglycemia.
With such treatment survival to adulthood, previously rare, is now the norm.
Failure to thrive is a problem in 90% of these children; renal stones appear in
65% of the cases, and 25% of the patients may develop renal failure.
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In addition the liver is enlarged. There may be high blood lipid levels (hyperlipidemia),
which may lead to xanthoma formation. High blood levels of uric acid (hyperuricemia)
have been observed in a considerable number of patients and in some cases arthritis
has developed as a result of clinical gout.
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The gene for the disease
G6Pase
Location
The long arm of chromosome 17q21.
Patient and Carrier testing among North African Jews
Among Jews, most of the affected children have been found to be of North African
origin. Mutations in the gene have also been found in other groups (Jews and non-Jews),
but they are rare in these groups. The carrier frequency in the healthy North African
Jewish population is between 1:30 and 1:40. There is 1 major mutation known today
that causes this disease in North African Jews: this is 4455delT (a deletion of
nucleotide T at position 4455 of the gene). Therefore it has been suggested that
as an initial diagnostic test of patients of North African origin, testing of this
mutation will replace the previously used diagnostic procedure of liver biopsy.
The mutation 4455delT is responsible for most of the cases of GSD-3 in Israel and
therefore it may also be useful for carrier screening in couples without a family
history of GSD. However, the relatively good prognosis of this type of GSD does
not yet justify general population screening. In Jews of other ethnic groups, carriers
cannot be identified. If carrier testing is nevertheless considered, it is advisable
to perform tests only in couples where both partners are of full or partial North
African origin.
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GSD-3: Cori disease
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This disease is similar to but relatively milder than GSD-1a. The liver is enlarged.
The age of onset may vary from childhood until adulthood in correlation to the severity
of the clinical findings. In almost all cases liver functions remain within the
normal range. In this condition also there may be high blood lipid levels (hyperlipidemia),
but to a lesser degree. Nowadays patients generally survive to adulthood. In Israel
this is the most common type of GSD (75% of GSD patients in Israel have GSD-3)
The gene for the disease
AGL
Location
The short arm of chromosome 1q21.
Patient and Carrier testing among North African Jews
Among Jews, most of the affected children have been found to be of North African
origin. Mutations in the gene have also been found in other groups (Jews and non-Jews),
but they are rare in these groups. The carrier frequency in the healthy North African
Jewish population is between 1:30 and 1:40. There is 1 major mutation known today
that causes this disease in North African Jews: this is 4455delT (a deletion of
nucleotide T at position 4455 of the gene). Therefore it has been suggested that
as an initial diagnostic test of patients of North African origin, testing of this
mutation will replace the previously used diagnostic procedure of liver biopsy.
The mutation 4455delT is responsible for most of the cases of GSD-3 in Israel and
therefore it may also be useful for carrier screening in couples without a family
history of GSD. However, the relatively good prognosis of this type of GSD does
not yet justify general population screening. In Jews of other ethnic groups, carriers
cannot be identified. If carrier testing is nevertheless considered, it is advisable
to perform tests only in couples where both partners are of full or partial North
African origin.
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GSD-4: Adult polyglucosan body disease
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This disease involves the brain. The clinical signs only become evident at age 40
years and progress with age. The main problem is a combination of dementia and muscle
weakness, which is due to brain and spinal nerve malfunctioning and not to a primary
muscle problem. Some patients have a neurogenic bladder, which results in a contracted
bladder and urinary difficulties. In the neural cells there is an accumulation of
intracellular bodies. Only a few patients have been found with this disease in Israel
and they have been of Ashkenazi origin. The clinical picture in these patients is
relatively mild.
The gene for the disease
GBE
Location
Chromosome 3.
Patient and Carrier testing among Ashkenazi Jews
Among Jews, most of the affected children have been found to be of Ashkenazi origin.
The carrier frequency in the healthy Ashkenazi Jewish population is very low - between
1:170 and 1:200. There is 1 major mutation, T329S, known today that causes this
disease in Ashkenazi Jews. The relatively rarity of this type of GSD does not yet
justify general population screening.
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GSD-7: Tauri disease
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This disease mainly involves muscles. The clinical signs are muscle contractions
following physical training. There are usually no other problems. Only a few patients
have been found with this disease in Israel and they have been of Ashkenazi origin.
The clinical picture in these patients is relatively mild.
The gene for the disease
PFKM
Location
Chromosome 3.
Patient and Carrier testing among Ashkenazi Jews
Among Jews, most of the affected children have been found to be of Ashkenazi origin.
The carrier frequency in the healthy Ashkenazi Jewish population is very low - 1:250.
There are 2 major mutations known today that cause this disease in Ashkenazi Jews:
D5, responsible for 65% of cases of GSD-7, and DC-22, responsible for 26% of the
cases. The relatively rarity of this type of GSD does not yet justify general population
screening.
Inheritance pattern of these types of GSD
Autosomal
recessive.
Penetrance
Full
Associated features that can be demonstrated in tests performed during pregnancy
There are no specific ultrasound signs or associated defects.
What is the risk of recurrence in a subsequent pregnancy?
For a couple who has already had an affected child, the risk is 25% in every subsequent
pregnancy. This also applies to a couple where both partners have been found to
carry mutations for GSD. When only one parent carries the abnormal gene, there is
no risk that any of their offspring will have the disease; however, in such families
there is a 50% chance that the infant will be a carrier, but he himself will be
healthy, like the carrier parent.
The risk for more distant relatives depends on the degree of relationship between
the relatives and the affected individuals, the ethnic groups of their partners,
the presence of family members with GSD in the partners families, consanguinity between the parents, if present, etc.
The risk is established within
genetic counseling.
Molecular genetic information
Gene, Location: see above for each specific type.
Genetic testing
Diagnostic testing
A direct test can be performed to identify the mutation in the gene by testing for
the common mutations that are common in the specific GSD type and according to the
patients ethnic origin. See: Testing the disease-causing
gene for mutations that are common in a specific ethnic group - autosomal recessive
diseases.
Carrier testing
The options and limitations of carrier screening for the various GSDs are noted
above. Of all the types, the one that is offered for screening among Jews is GSD-1a,
with a carrier frequency of 1:100 among Ashkenazi Jews. The rest are either very
rare (GSD-4 and GSD-7) or relatively mild (GSD-3).
It is important that relatives of patients with GSD clarify which mutations are
present in the patient or parents in their family in order to ascertain that they
are included in the battery of mutations routinely tested for - otherwise it will
be necessary to expand the list of mutations tested for and/or examine the partner.
This will be discussed in genetic counseling.
See also: "Introduction to population DNA screening
for autosomal recessive diseases such as Cystic fibrosis and others".
Fetal testing
Same as the diagnostic test. See above for each specific type.
Prenatal
diagnosis (amniocentesis) can also be offered to each couple who has had
an affected child. The best way is after identifying the mutations in the parents,
but if these are not found, indirect linkage analysis can be performed. See:
Indirect testing for genetic markers in a family that has one or more patients -
when there is only one gene that can cause the disease - autosomal recessive diseases.
Preimplantation diagnosis (before the embryonic
cells implant in the uterine wall) can also be offered for this disease - this is
performed in special centers, and in special cases this can be considered within
genetic counseling.
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