Screening of ARHSP-TCC Patients Expands the Spectrum of SPG11 Mutations and Includes a Large Scale Gene Deletion

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing. (C) 2008 Wiley-Liss, Inc.

Agence Nationale pour la Recherche (France)

Agence Nationale de la Recherche de la France (ANR)

Verum foundation (Germany)

Verum foundation (Germany)

Groupement d`Interet Scientifique - Institut des Maladies Rares (France)

Groupement d`Interet Scientifique - Institut des Maladies Rares (France)[A04180DS/A04139DS]

Association Strumpell-Lorrain

Association Strumpell-Lorrain

ISS (Istituto Superiore di Sanita)

ISS (Istituto Superiore di Sanita)

IRCCS-Fondazione Don Gnocchi

IRCCS-Fondazione Don Gnocchi

ISS, Fondazione Mariani ONLUS and Telethon Italy[GGP06188]

ISS, Fondazione Mariani ONLUS and Telethon Italy

EUROSPA

EUROSPA

[PRIN-2006063820]