A case of amyotrophic lateral sclerosis with intermediate ATXN-1 CAG repeat expansion in a large family with spinocerebellar ataxia type 1.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, with a genetic contribution to its pathogenesis [1]. It has been demonstrated that poly-Q intermediate expansions of ATXN-2 (SCA2) and ATXN-1 (SCA1) are a genetic risk factor for the disease [2, 3], even though the latter finding was not confirmed in another study [4]. The relationship between the two SCAs and ALS is further supported by the evidence that typical SCA1 or SCA2 patients may develop signs and symptoms of motor neuron (MN) degeneration [5–8]. Finally, a report showed the coexistence, in the same SCA2 family, of ALS bearing intermediate poly-Q expansions and SCA2, with a full expansion [9]. Here, we describe a patient with ALS, carrying an intermediate ATXN-1 poly-Q expansion, who belonged to a large SCA1 family. A 47-year-old worker (IV-19, Fig. 1) was referred with a history of progressive weakness of the right hand. His family history was positive for SCA1 (Fig. 1), but he never showed signs or symptoms of ataxia. The neurological examination showed weakness and muscular atrophy in both upper limbs, with fasciculations, cramps and brisk reflexes in both upper and lower limbs. Speech, swallowing, and respiratory function were normal. Sensory function was within normal range. An extensive biochemical and immunological work-up, including a CSF analysis, was negative. A brain and spine MRI demonstrated a bilateral corticospinal tract hyperintensity. EMG showed diffuse polyphasic MUPs, fibrillation potentials and PSWs in all limbs. Nerve conduction studies were normal. A genetic screening (SOD1, C9orf72, FUS, TARDPB, angiogenin) was negative. Analysis of ATXN-1, showed in the patient IV-9, intermediate CAG expansions in both alleles (33/33) with no CAT interruptions. A clinical diagnosis of ALS was made. The progression rate (DFS) was calculated following Kimura et al. [10] and gave a value of 3.33, indicating a rapidly progressing disease. Ten months after diagnosis, he died because of a myocardial infarction. We clinically examined and performed genetic testing in three other members of this family (IV-12, IV-18 and IV-24; Fig. 1). IV-18 was the proband’s brother. When he was 30 years old, unsteadiness when walking, truncal titubation and slurred speech occurred. Genetic testing revealed an expanded CAG repeat of 33/54 in ATXN-1. At the age of 45, he developed a severe cerebellar ataxia, proximal and distal muscle atrophy with marked weakness, brisk reflexes in all four limbs, anarthria and dysphagia, atrophy of the tongue with fasciculations. He died at the age of 46 years because of a respiratory failure. The other two SCA1 members of the family (IV-12 and IV-24) showed, respectively, a clinical onset at age of 41 and 32 with an ataxic-spastic phenotype but without lower MN signs or symptoms. Genetic testing revealed expanded ATXN-1 CAG repeats of 30/49 for IV-12 and 28/51 for IV-24. In this report, we have described a SCA1 family in which a member, bearing an intermediate ATXN-1 repeats, was affected by a clinically-definite ALS. There is only another report describing, in a SCA2 family, the co-existence of SCA and ALS in two members [9]. Note that the R. Spataro (&) V. La Bella ALS Clinical Research Center, Bio.Ne.C., University of Palermo, via G La Loggia 1, 90129 Palermo, Italy e-mail: rossellaspataro@libero.it