Pathophysiology of uld

The gene responsible for ULD was identified using a positional cloning approach . The disease-causing gene, named CSTB or EPM1, is a 674 base-pair gene that contains 3 exons and localizes to chromosome 21q22 . 3 . EPM1 encodes a previously known but unmapped cysteine protease inhibitor called cystatin B (CSTB) . The identification of two point mutations found in EPM1 proved that this gene was responsible for ULD To date, a total of eight different point mutations have been identified in EPM1 Some mutations affect conserved splice-site sequences and predict severe splicing defects Others lead to protein truncation, and yet others affect a conserved amino acid sequence critical for cathepsin (i e , the target proteases) binding However, these mutations within the transcriptional unit account for less than 10% of EPM1 alleles causing ULD More than 90% of patients have unstable expansion, described previously, of a dodecamer repeat (5'CCCCGCCCCGCG-3')-175 base-pairs upstream from the translation initiation codon of EPM1

In contrast to some neurodegenerative disorders caused by trinucleotide repeat expansions, there is no correlation between the number of repeats and clinical severity or age of onset in ULD patients It is suggested that once the dodecamer repeat expands beyond a critical threshold, EPM1 gene expression is reduced, leading to pathological and physiological consequences

CSTB functions as an intracellular protease inhibitor able to inhibit cathepsins (lysosomal proteases) . In humans, CSTB deficiency leads to neuronal cell loss . However, until recently, it was not clear if the cell loss was due to the EMP1 mutation or to toxic effects of phenytoin Recently, it was shown that epm1 knockout mice never treated with this drug demonstrate apoptotic cell death These data suggest that CSTB has a role in preventing apoptotic cell death in certain mammalian cells The mechanisms leading to apoptosis and atrophy observed in humans and mice deficient in CSTB are poorly understood One proposed mechanism is that cathep-sins, which are inhibited by CSTB, directly activate caspases leading to the initiation of apoptosis Another possible mechanism is that the deficiency in CSTB causes an increase in general proteolysis, thus targeting such unhealthy cells for apoptosis

How apoptosis could lead to the clinical picture of a hyperexcitable cortex that generates seizures and myoclonus is not clear It has been suggested that GABA neurons are particularly prone to damage in cstb-deficient mice In these animals, seizure-induced cell death may be responsible for the progressive nature of the disease It is also possible that the hyperexcitable cortex is caused by an enhancement of tryptophan metabolism in the central nervous system (CNS) along the serotonin and kynurenine pathways

Finally, it has been shown that, in ULD patients, the thalamostriatal dopaminer-gic system is dysfunctional In a small study, there was an improvement of myoc-lonus in patients receiving a dopamine agonist This observation may represent a different mechanism responsible for the clinical findings However, the exact mechanism leading to such deficiency remains to be elucidated


1 ULD is the most common progressive myoclonus epilepsy

2 . Seizures, ataxia, and stimulus-sensitive myoclonus are the hallmarks of this disease

3 . Seizures in ULD may be easily controlled with antiepileptic medica tions, and some patients never develop tonic-clonic seizures

4 Phenytoin is exquisitely toxic to neurons in ULD and should be avoided

5 . With appropriate treatment, most symptoms can be controlled, and life span may be normal

6 . In ULD there is an absence of storage material. Therefore, biopsies are negative (as opposed to the other PMEs with onset between childhood and late adolescence)

7. Expansion of a dodecamer repeat in the promoter region of the EPM1 gene is responsible for more than 90% of ULD cases .

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