RICERCA ITALIANA     

Ataxias with oculomotor apraxia: clinical and genetic study

Università degli Studi di Roma "La Sapienza"

Abstract

Hereditary autosomal recessive cerebellar ataxias (ARCAs) are rare diseases. The most common is Friedreich's ataxia (FA) that accounts for 30-40% of the cases in Caucasian populations. Other aetiologies, including ataxia telangiectasia (A-T), autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with vitamin E deficiency, are less frequent. A subgroup of ARCA associated withoculomotor apraxia but different from A-T has been identified (Aicardi et al., 1988; Barbot et al., 2001). Based on linkage studies, ataxia with oculomotor apraxia recently was found to encompass at least two types, type 1 (AOA1) (Moreira et al., 2001a) and type 2 (AOA2) (Bomont et al., 2000; Nemeth et al., 2000). AOA1, located to 9p13, is characterized by the association of CA with cerebellar atrophy on MRI, frequent choreic movements at onset which regress with the course of the disease, oculomotor apraxia, severe peripheral neuropathy, occasional mild mental retardation, hypercholesterolaemia and hypoalbuminaemia (Bomont et al., 2000; Tachi et al., 2000; Moreira et al., 2001a; Shimazaki et al., 2002; Le Ber et al., 2003; Tranchant et al., 2003). The defective gene, aprataxin gene (APTX), mapped to 9p13, was found to code for a new histidine-triad protein, named aprataxin, possibly involved in DNA single strand break repair (Date et al., 2001; Moreira et al., 2001b). In 2000, Nemeth and colleagues, and Bomont and colleagues independently reported linkage to 9q34 of autosomal recessive >>>

Principal Investigator

Carlo CASALI Universita' degli Studi di ROMA

Research Objectives

This project is aimed at collecting and characterizing genetically a large series of patients with Autosomal Recessive Cerebellar Ataxia (ARCA) after the recent identification of two new disease entities AOA1 and AOA2 and the mutated genes, APTX and SETX, respectively (Le Ber et al., 2003; Le Ber et al., 2004). The clinical presentation includes cerebellar ataxia and oculomotor apraxia (Ataxia with ocumototor apraxia, AOA). The actual prevalence is still unknown. While AOA1 is only relatively frequent among childhood onset patients (Le Ber et al., 2003), AOA2 is probably the most frequent form of ARCA in adults after Friedreich's ataxia (10% of ARCA) (Le Ber et al., 2004). Available data show that AOA2 is present in Europe (Moreira et al., 2004). For example an initial attempt at identifying patients suitable for genetic analysis of SETX gene in the existing series at the UO1, 2 and 3, gave encouraging results. Many individuals have been identified with ocular apraxia and/or elevated alpha fetoprotein, a laboratory marker of AOA2. The APTX gene has been shown to be causative of AOA1 in 2002 (Moreira et al., 2002), while SETX mutations have only been reported in march 2004 in AOA2 patients (Moreira et al., 2004). As a consequence little is known about the prevalence of mutated genes in the Italian poplulation of ataxic patients and about the different allele variants associated with the disease. Our study is aimed at adressing some of these questions.
For that >>>

First Results

Recruitment of a large series of patients with AOA1 (15-20 individuals) and AOA2 (20-30 individuals)
Detailed information about the clinical presentation, disease course, ecc.
Acquisition of electrophysiologic and neuroimaging data
Oculographic study
Bank of DNA from patients and their relatived
Bank of lymphoblastoid linesResults of the mutational analyses of APTX and SETX genes in the Italian population
Possible identification of novel mutations and founder effect in restricted poulations
Genetic counseling and molecular diagnosis for subjects at risk, healthy carriers and prenatal diagnosis
Epidemiologic data (prevalence; frequency of the mutated genes at the heterozygote state)
Reappraisal a posteriori of the clinical features of AOA1 and 2 in genetically confirmed patients; validation of clinical criteria for diagnosis
Assessment of inter and intrafamilia variability
Qualitative and quantitative evaluation of oculomotor apraxia
Qualitative and quantitative description of cerebellar and extracerebellar atrophy also for diagnostic purposes
Phenotype-genotype correlation for different mutations
Result of funcional studies in lymphoblastoid cell lines

Timescale

24 months

National and international background

Hereditary autosomal recessive cerebellar ataxias (ARCAs) are rare diseases. The most common is Friedreich's ataxia (FA) that accounts for 30±40% of the cases in Caucasian populations. Other aetiologies, including ataxia telangiectasia (A-T), autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with vitamin E deficiency, are less frequent. A subgroup of ARCA associated withoculomotor apraxia but different from A-T has been identified (Aicardi et al., 1988; Barbot et al., 2001). Oculomotor apraxia was described initially in children affected by congenital oculomotor apraxia as the inability to generate volitional horizontal saccades with a characteristic compensatory headthrusting and synkinetic blinking (Cogan, 1953). It is better described as intermittent saccade failure rather than a true apraxia (Harris et al., 1996; Shawkat et al., 1996). A-T is characterized by an early age at onset, the association of cerebellar ataxia (CA), oculomotor apraxia, telangiectasias, recurrent infections, cancers and markedly elevated a-foetoprotein (AFP) level. The patients usually become wheelchair-bound in their early teens (Woods et al.,1992; Stankovic et al., 1998). The ATM gene codes for a protein involved in DNA double strand break repair (Stavitsky et al., 1995; Laake et al., 2000; Campbell et al.,2003). Approximately 10% of A-T patients have mutations causing a milder phenotype (`A-T variants') that differs from the typical phenotype by a later age at onset, a longer >>>