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Clinical Genetic Study of 15 Families

Antonio Orlacchio, MD, PhD; Toshitaka Kawarai, MD; Antonio Totaro, BSc; Alessia Errico, MPhil; Peter H. St George-Hyslop, MD, FRCPC; Elena I. Rugarli, MD; Giorgio Bernardi, MD

Arch Neurol. 2004;61:849-855.

Background  Autosomal dominant hereditary spastic paraplegia (ADHSP) is mainly caused by mutations in the SPG4 gene, which encodes a new member of the AAA (adenosine triphosphatases associated with diverse cellular activities) protein family (spastin). Accumulation of genotype-phenotype correlation is important for better understanding of SPG4-linked hereditary spastic paraplegia.

Objectives  To perform a clinical and genetic study of families with ADHSP and to perform the functional analysis of the founder mutation discovered in the SPG4 gene.

Design  Genetic and clinical study.

Patients  Fifteen unrelated families with ADHSP originating from southern Scotland.

Main Outcome Measures  Clinical assessment, linkage analysis, haplotype study, expression of mutant spastin protein in cultured cells.

Results  Nine families with ADHSP were linked to the SPG4 locus at 2p21-p24. Sequence analysis of SPG4showed a novel N386S mutation in all 9 of these families. Expression of mutant spastin showed aberrant distribution in cultured cells. Haplotype analysis suggested the existence of a common founder. Clinical examination of the affected members carrying the mutation showed phenotypic variations including broad range of age at onset and disease duration and additional neurologic features such as mental retardation. Magnetic resonance imaging demonstrated unique features, including thin corpus callosum and atrophy of the cerebellum in 2 patients. Linkage and sequence analyses showed no evidence of linkage to the currently known ADHSP loci in the remaining 6 families.

Conclusions  A founder SPG4 mutation N386S was identified in the families with ADHSP originating from southern Scotland. Clinical investigation showed intrafamilial and interfamilial phenotypic variations. The genetic study demonstrated evidence of further genetic heterogeneity in ADHSP.

From the Laboratorio di Neurogenetica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy (Drs Orlacchio and Bernardi and Mr Totaro); Dipartimento di Neuroscienze, Università di Roma "Tor Vergata," Rome (Drs Orlacchio and Bernardi); Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario (Drs Kawarai and St George-Hyslop); Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network (Dr St George-Hyslop); and Telethon Institute of Genetics and Medicine, Naples, Italy (Ms Errico and Dr Rugarli).

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