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Alexandra Dürr, MD, PhD; Agnès Camuzat, BS; Emilie Colin, BS; Chantal Tallaksen, MD, PhD; Didier Hannequin, MD; Paula Coutinho, MD, PhD; Bertrand Fontaine, MD, PhD; Annick Rossi, MD; Roger Gil, MD; Christophe Rousselle, MD; Merle Ruberg, PhD; Giovanni Stevanin, PhD; Alexis Brice, MD

Arch Neurol. 2004;61:1867-1872.

Background  Hereditary spastic paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic paraplegia. Atlastin1 mutations have been identified in 8 families so far.

Objectives  To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years.

Patients and Methods  We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients.

Results  We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 ± 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations.

Conclusions  This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A.

Author Affiliations: Département de Génétique, Cytogénétique et Embryologie (Drs Dürr, Brice, and Stevanin), and INSERM U289, Hôpital Salpêtrière AP-HP, Paris, France (Drs Dürr, Camuzat, Colin, Tallaksen, Ruberg, Stevanin, and Brice); Département de Neurologie et INSERM EMIU9906, CHU de Rouen, Rouen, France (Dr Hannequin), Departamento de Neurologia, Hospital S. Sebastiao, Santa Maria da Feira, Portugal (Dr Coutinho); Fédération de Neurologie, Hôpital Salpêtrière, Paris (Drs Fontaine and Brice); Service de Génétique Clinique, CHU de Rouen, Rouen (Dr Rossi); Clinique Neurologique, CHU La Miletrie, Poitiers (Dr Gil); and Service de Pédiatrie, Centre Hospitalier Lyon-Sud, Lyon, France (Dr Rousselle).

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