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Glycogen Storage Disease (GSD)


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:

GSD-1a: Von Gierke disease

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.
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.

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.

GSD-3: Cori disease

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.

GSD-4: Adult polyglucosan body disease

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.

GSD-7: Tauri disease

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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