This model is consistent with familial cases of ALS and FTLD, were TDP-43 is predominantly mutated in the C-terminal, prion-like domain (5– 8) that regulates tissue-specific gene expression, transcriptional repression and alternative splicing, and is essential for binding to ribonucleoproteins involved in microRNA and mRNA biogenesis, as well as RNA turnover (9, 10, 12, 13).
Other factors, such as vascular BM-derived co-factors for amyloid scaffolding, might also be important in vascular specificity of PrP amyloid both in the Tg44 mouse model and in humans with familial prion disease related to expression of mutated truncated PrP.
Altogether, these data emphasize a less deterministic model with a role for familial and other environmental factors operating at different developmental time periods.
To assess the hypothesis of no familial association, we compared the likelihood of the sporadic model without familial components with that in which parameters for both parent-offspring and sib-sib were estimated.
Similarly to our childhood cases, spontaneous joint buckling with falls followed by clinical amelioration over 2 years has been recently described in an equine model of familial narcolepsy with cataplexy (Ludvikova et al., 2012).
Chr13q32 was originally identified to be linked with familial KC in Ecuadorian families, under an autosomal dominant model [ 90].
When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected.
4 Perturbation of DA recycling impairing intracellular DA content and synaptic plasticity has been previously observed in experimental mouse models carrying specific gene mutation associated with familial PD. 5– 7 Most cases of PD occur sporadically and are idiopathic, but causal or predisposing genes have been identified in familial cases.
