What’s new on CLN8 in Latin America?
F. Pesaola, I.A. Cismondi, N. Guelbert, R. Kohan, M.N. Carabelos, G. Alonso, P. Pons, A.M. Oller-Ramírez, I. Noher de Halac
Center for the Study of Inborn Errors of Metabolism (CEMECO), Children´s Hospital, Medical Science Department,
Universidad Nacional de Córdoba, Córdoba, Argentina, 5014, E-mail: email@example.com; firstname.lastname@example.org
Traslational Program: NCLs in South America
The NCL program at Children’s Hospital
(Córdoba, Argentina) was initiated in 2003 as a
Translational Research Program for the
detection of different NCL forms in Latin
NCL families from Latin America for their willingness to help us.
National Council of Research and Technology (CONICET, Argentina)
Science and Technology Secretary (SECyT), Universidad Nacional de Córdoba,
Electron Microscopy Center, Universidad Nacional de Córdoba, Argentina.
Batten Disease Support and Research Association, USA.
References: FP, fingerprints; CB, curvilinear bodies; GRODs, granular osmiophilic deposits.
Age of onset 3y 4-6y 5-10y
Initial symptoms Psycho-
Yes Yes Yes
Myoclonus Yes Yes No
Yes Yes Yes
Yes Yes Yes
Visual failure ? Yes No
Light microscopy No
Electron microscopy FP, CB and
FP, CB and
Age at death 12y Generally,
What is our next step?
We aim to investigate the cell biology of the CLN8 lipoprotein
studying the metabolic pathway/s involved and the interacting
factors that participate in its functionality. We seek to find out
new useful biomolecules to follow up the natural history of the
disease and potential treatment outcomes.
Biomarkers: what are their uses?
A biomarker is a measurable
characteristic that reflects the severity
or presence of some disease state. It
can be an endogenous molecule like a
gene, protein or lipid, a specific cell or
an exogenous substance that is
introduced into the subject under
study. Biomarkers can help in early
diagnosis, disease prevention, drug
target identification, drug response, to
examine organ function, to evaluate
the risk or progression of a disease, or
the susceptibility of the disease to a
What is the status of the CLN8-
CLN8 mutations, mainly in Finland, underlay Progressive Epilepsy
with Mental Retardation Syndrome (red). In other countries,
mutations in that gene cause variant Late Infantile forms (blue).
Now it was found one index family in Argentina: one new mutation
and new polymorphisms were described in this gene, with still
Where is CLN8 in the World today?1
Child with seizures,
Suspiction of other NCL types
Skin biopsy for
Clinical suspiction Normal PPT1 and TPP1 enzymes
What is the diagnostic strategy?2
How we did to diagnose the first CLN8 child in Latin America under
our Traslational Program?
Wild type CLN8
1. In vitro cultured neurons
2. Experiments: mouse model and human
The CLN8 protein is located in
the RER. It would be related to
lipid metabolism. The cell
pathways conducing from gene
mutations to disease remain
NEURONAL CELL IN
Where is the disease in the cell?3
CLN8 -/- mouse
We screened out the CLN8 gene in the blood
DNA from 15 Late Infantile children that
remained with no molecular characterization
of the disease in spite of having excluded
mutations in most of the other NCL genes.
A severe mutation, c.1A>G, p.Met1Val, was
found. It was considered pathogenic because
of its deleterious nature.
What is new in molecular biology?
The new c.1A>G mutation of Argentina is expected to produce severe pathological changes of
the membrane protein CLN8 involving the complete lack of expression and absence of CLN8
protein in the cell.
CLN8 gene with known