Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype-phenotype correlation and penetrance of the mutations. METHODS: A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives. RESULTS: In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo. CONCLUSIONS: In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype-phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism.

A crosslinguistic study of the relationship between grammar and lexical development.

The relationship between grammatical and lexical development was compared in 233 English and 233 Italian children aged between 1;6 and 2;6, matched for age, gender, and vocabulary size on the MacArthur Communicative Development Inventories (CDI). Four different measures of Mean Length of Utterance were applied to the three longest utterances reported by parents, and to corrected/expanded versions representing the 'target' for each utterance. Italians had longer MLUs on most measures, but the ratio of actual to target MLUs did not differ between languages. Age and vocabulary both contributed significant variance to MLU, but the contribution of vocabulary was much larger, suggesting that vocabulary size may provide a better basis for crosslinguistic comparisons of grammatical development. The relationship between MLU and vocabulary size was non-linear in English but linear in Italian, suggesting that grammar 'gets off the ground' earlier in a richly inflected language. A possible mechanism to account for this difference is discussed.