SPG6 is an autosomal dominant (AD) form of hereditary spastic paraplegia (HSP), a clinically and genetically heterogeneous group of neurodegenerative diseases mainly characterized by progressive spasticity in the lower limbs [1]. Four different nucleotide changes have been reported in the NIPA1 gene (Supplementary Table 1) [2].

We analyzed the five coding exons of the NIPA1 gene by direct sequencing in 110 index cases of ADHSP families originating from France (n = 98), other European countries (n = 11) and Israel (n = 1). All index patients were previously excluded for known mutations in the spastin gene (SPG4) by denaturing high-performance liquid chromatography. Considering the usually early onset of SPG3A [3, 4], only patients with onset before the age of 10 years (n = 76 index cases) were tested for SPG3A mutations by direct sequencing. No mutations were identified.

We only found one index case (FSP-747-3) with a mutation in SPG6/NIPA1: the G106R missense mutation at nucleotide c.316 (G>C). SPG6 is therefore a rare cause of ADHSP in Caucasians (<1%). All patients in family FSP-747 for whom DNA was available (n = 5) were heterozygous for this mutation that segregated with the disease and was not found in unaffected individuals and spouses (Supplementary Fig. 1). The G106R missense mutation was previously reported in five families of Chinese, Brazilian/Portuguese, and British origin (Supplementary Table 1). Interestingly, the G106R mutation in this gene is caused by two different nucleotide changes at a CpG dinucleotide suggesting the existence of a hot spot for recurrent mutations as recently shown in SPG3A [5]. The c.316G > C nucleotide change detected in the French kindred was only found in one family from China, arguing against a recent common founder effect [6]. A different nucleotide change (G>A) at the same position has been reported in three families from Great Britain, China, and Brazil/Portugal (Supplementary Table 1).

The mean age at onset of our SPG6 patients was 17.5 ± 11.3 years (8–37). The phenotype was similar to former reports. The disease started with stiffness in the legs and consisted of mild to moderate spastic gait and moderate to severe functional impairment on examination (Table 1). In addition, urinary problems and impaired vibration sense at the ankles were noted in two patients each. Brain magnetic resonance imaging, nerve conduction velocities, and needle electromyography were normal in patient II/5. This patient had no response to motor-evoked potentials, indicating a major dysfunction of the central motor pathway to the lower limbs, and also had a delayed response to somatosensory-evoked potentials in the cordonal posterior pathways. Interestingly, four patients had mild memory deficits after six or more years of disease duration. This has not yet been reported in SPG6. A neuropsychological evaluation (digit span, Rey’s figure, Grober and Buschke test, verbal fluency) in patient II/5 showed an impairment of executive functions and memory recalls, suggestive of an attention deficit and dysfunction of encoding or retrieval processes.

Table 1 Clinical characteristics of six patients in family FSP-747 carrying the G106R mutation in the NIPA1 gene

In summary, nucleotide 316, where this mutation occurred, appears to be a hot spot for recurrent mutations in SPG6. However, this form of ADHSP was found in less than 1% of our families.