Mutations in the SPG3A gene cause the most frequent autosomal dominant (AD) type of pure hereditary spastic paraplegia (HSP) with very early onset [1, 2]. Here, we report a novel disease-associated mutation in the SPG3A gene in an immigrant South African Zulu family with ADHSP and atypical clinical characteristics. Individuals were clinically evaluated by two neurologists with a proven experience in HSPs (A.O., G.B.). The proband (Fig. 1a, II:3) was a 68-year-old male. He had had progressive walking disturbance from the age of 56 years and a hoist had been required from the age of 66 years. A recent neurological examination disclosed moderate disease severity (SPRS [3] score 35/52) and mild mental retardation (WAIS-R IQ [4] score 62). Furthermore, the patient reported urinary incontinence due to sphincter incompetence. Brain MRI showed a thin corpus callosum (TCC) without cerebellar involvement or white matter abnormalities (Fig. 1b). The spinal cord MRI demonstrated no abnormal signal intensity or atrophy. Similar clinical features, including a late-onset of the disease (55 ± 5.6 years, mean ± SD), mental impairment and the occurrence of TCC, were observed in the other family members (Table 1). After informed consent was given by participants, genomic DNA was isolated from blood samples and subject to linkage analyses at all currently known ADHSP loci (OMIM web site: http://www.ncbi.nlm.nih.gov/omim). HSP gene sequences were studied by direct sequencing. The PCR-RFLP method was used for segregation analysis as described previously [5]. Significant two-point lod scores were obtained at the microsatellite markers of the SPG3A region (Zmax = 4.11 for D14S269 at h = 0.0), while linkage to the other known ADHSP loci was excluded. Sequence analysis of SPG3A demonstrated a novel heterozygous change in exon 12 (c.1246 C[T), resulting in the change of amino acid arginine to cysteine at codon 416 (R416C). The PCR-RFLP analyses showed that all affected family members carried the mutation in SPG3A, while the unaffected members did not (Fig. 1). The mutation was absent in 400 control chromosomes from unrelated South African Zulu individuals. In addition, sequence analyses of the known genes causing HSP with mental retardation and TCC (SPG1, SPG7, SPG11, SPG15 and SPG21) showed no pathological nucleotide changes. We detected a novel R416C missense mutation in a South African Zulu family with ADHSP. The genetic variation fell on exon 12, in accordance with the literature indicating a frequency of 35% for SPG3A mutations in this exon [2], and the R416C amino acid change could exert its pathogenic effect by generating an aberrant secondary A. Orlacchio (&) P. Montieri C. Babalini F. Gaudiello G. Bernardi Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 64 Via del Fosso di Fiorano, 00143 Rome, Italy e-mail: a.orlacchio@hsantalucia.it
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