Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
Arch Neurol. 2004-12-01; 61(12):
DOI: 10.1001/archneur.61.12.1867
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1. Arch Neurol. 2004 Dec;61(12):1867-72.
Atlastin1 mutations are frequent in young-onset autosomal dominant spastic
paraplegia.
Dürr A(1), Camuzat A, Colin E, Tallaksen C, Hannequin D, Coutinho P, Fontaine B,
Rossi A, Gil R, Rousselle C, Ruberg M, Stevanin G, Brice A.
Author information:
(1)Département de Génétique, Cytogénétique et Embryologie, and INSERM U289,
Hôpital Salpêtrière AP-HP, Paris, France.
Comment in
Arch Neurol. 2004 Dec;61(12):1842-3.
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.
DOI: 10.1001/archneur.61.12.1867
PMID: 15596607 [Indexed for MEDLINE]