|
|
|
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.
|
|
|