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Infantile ceroid lipofuscinoses


Clinical signs

The neuronal ceroid lipofuscinoses (CLNs) are a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Clinically, the neuronal ceroid lipofuscinoses are characterized by progressive blindness, seizures, dementia, and proteolipid pigment deposits in lysosomes in neurons and other cell types.

There are several subtypes of CLN distinguished by age at clinical onset and storage-body appearance. Each type is caused by a different CLN gene. The most common types are CLN1 - 3.

One type, CLN6, is relatively frequent in families living in Costa Rica, Pakistan and Portugal. The carrier rate among healthy individuals in these risk groups is between 1:25 - 1:50.

Inheritance pattern

All types: Autosomal recessive.

When both parents are carriers, the child will only be affected if he or she inherits two abnormal genes - one from the mother and one from the father.

Penetrance

Complete.

Associated features that can be demonstrated in tests performed during pregnancy

There are no definitive signs that are detectable during the pregnancy, and only DNA tests can confirm the diagnosis.

In all cases it is important to refer the couple for genetic counseling, to which they should bring all data, including the results of other tests performed during the pregnancy such as alpha-fetoprotein, nuchal translucency, etc.

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.

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, affected relatives of partners, consanguinity between the parents, if present, etc., and is established within genetic counseling.

Molecular genetic information

The gene for the disease

Various CLN genes (CLN1 - 8).

The CLN6 gene encodes the linclin protein and is located on chromosome 15q21-23.

Genetic testing

Diagnostic testing

For CLN6: Among patients with suspected Ceroid lipofuscinosis from the risk groups, a direct test can be performed to identify the mutation in the gene by testing for the common mutations. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal recessive diseases.

In other types the gene that seems to be involved needs to be sequenced.

Carrier testing

In Costa Rican families 2 mutations have been found to cause neuronal ceroid lipofuscinosis: G123D and E72TER. In Pakistani families a different mutation is found: 1-bp ins,316C. In families from Portugal the 460delATC mutation is common.

In these risk groups the carrier rate in the healthy population varies between 1:25 and 1:50.

In view of this, it is very important to ascertain the carriers among pregnant women from these risk groups, and it is advisable to examine first the partner with the greater chance that the mutation will be identified.

See also: "Introduction to population DNA screening for autosomal recessive diseases such as Cystic fibrosis and others".

Carrier status testing in relatives of patients with Infantile ceroid lipofuscinosis It is important that relatives of patients with Infantile ceroid lipofuscinosis 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.

Fetal testing

Same as the diagnostic test.

Prenatal diagnosis 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 be considered within genetic counseling.
 
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