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Ataxia with oculomotor apraxia type 2

A clinical, pathologic, and genetic study

From the Department of Neurological Sciences (C. Criscuolo, P.M., F.S., F.B., G.D.M., A.F.), Federico II University, Naples; Department of Experimental Medicine and Pathology (L.C., M.P.) and Department of Neurology and ORL-Polo Pontino (F.P., C. Casali), La Sapienza University, Rome; Molecular Medicine and Neurology, IRCCS Bambino Gesù Hospital (S.D., F.M.S.), Rome; Molecular Neurogenetics-IRCCS C. Mondino, Pavia-San Raffaele Pisana Rome (G.S.G., C. Casali); Telethon Institute of Genetics and Medicine (C. Criscuolo, S.B.), Naples; Department of Neurology (L.G.), City Hospital, Rovereto (TN); and Department of Neurological and Visual Sciences, Section of Neurology (N.R.), University of Verona, Italy.

Address correspondence and reprint requests to Dr. Chiara Criscuolo, Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, Via Pansini 5, I-80131, Napoli, Italy; e-mail: sky569{at}libero.it

Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients.

Objective: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families.

Methods: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations.

Results: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation).

Conclusions: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 25 issue to find the title link for this article.

*These authors contributed equally to this work.

Supported by grants from Istituto Superiore di Sanità and the Italian Ministry of Health (Ricerca corrente, strategica) to F.M.S., Italian Ministry of Education, University and Research (PRIN prot. 2004065878 to C.C. and L.C.), and from FIRB to A.F. Supported by Telethon–Italy (grant no. GGP05226 to C.C. and L.C.).

Disclosure: The authors report no conflicts of interest.

Received June 24, 2005. Accepted in final form January 11, 2006.

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