Neurology -- Correspondence for Schulte et al., 60 (9) 1529-1532

Correspondence published:

Neurophysiological findings in SPG4 are variable, dependent on the type of spastin mutation: Tohru Matsuura, Ichiro Yabe, Hidenao Sasaki (17 December 2003)

Neurophysiological findings in SPG4 are variable, dependent on the type of spastin mutation 17 December 2003

Tohru Matsuura,
Molecualr and Human Genetics
One Baylor Plaza, 905E, Houston, TX 77030,
Ichiro Yabe, Hidenao Sasaki
Send Correspondence to journal:
Re: Neurophysiological findings in SPG4 are variable, dependent on the type of spastin mutation

tohrum{at}bcm.tmc.edu Tohru Matsuura, et al.

We read with interest the article by Schulte et al [1] describing the electrophysiological characteristics of SPG4, the most frequent autosomal dominant form of hereditary spastic paraplegia (AD- HSP). The SPG4 gene named spastin maps to chromosome 2p and a variety of mutations have been identified. Most mutations are missense, nonsense, frameshift and splicing point mutations. The authors found that despite indistinguishable clinical presentation between the two groups, nerve conduction studies are almost normal in SPG4 (five families), whereas most non-SPG4 AD-HSP patients (seven families) show delay in central (CMCT) or peripheral motor conduction (PMCT) time, or both.
The German group has recently reported one SPG4 family with a large genomic deletion ranging from exons 13 to 16. [2] This first indicates that mutations (e.g. genomic rearrangement) undetectable by conventional PCR-based sequencing underlie the disease. This family showed abnormal findings of motor evoked potentials (MEP) and CMCT by transcranial magnetic stimulation (TMS), while the other family with a nonsense mutation (1299delG in exon 9) was not different from controls. The clinical course was similar between these two pedigrees, including age of onset and severity of symptoms.
We studied four affected individuals from a large Japanese AD-HSP family linked to the SPG4 locus (maximum lod score 3.53) [3], where no mutation was detected in the 17 coding exons or their splice sites, or 5’ and 3’ untranslated regions of spastin.[4] The deletion of exons 13 to 16 was also excluded. Neurophysiological findings in all the four patients consistently showed normal CMCT and MEP in thenar muscles by TMS, and normal somatosensory evoked potentials after median and tibial nerve stimulation. However, MEP in tibialis anterior muscles (TA) was of significantly lower magnitude with polyphasic waves, while CMCT to TA was normal. We did not detect any abnormalities in PMCT.
Additional SPG4-linked families without identifiable mutations are described elsewhere. [5] Although the authors did not exclude the possibility that electrophysiologically abnormal patients categorized as “non-SPG4” might have other spastin mutations [1], we have to be cautious in interpreting their data and recognize SPG4 mutations other than those reported previously, restricted to respective exons or their surrounding regions. The variable clinical expression and incomplete penetrance is already noted in SPG4. The aforementioned data suggest that electrophysiological findings in SPG4 are also variable despite similar clinical presentation, dependent on the type of mutation. Further investigations are required to explore other type of mutations and delineate the genotype-phenotype correlation.
References
1. Schulte T, Miterski B, Bornke C, Przuntek H, Epplen JT, Schols L. Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. Neurology 2003;60:1529-1532.
2. Bonsch D, Schwindt A, Navratil P, et al. Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. J Neurol Neurosurg Psychiatry 2003;74:1109-1112.
3. Matsuura T, Sasaki H, Wakisaka A, Hamada T, Moriwaka F, Tashiro K. Autosomal dominant spastic paraplegia linked to chromosome 2p: clinical and genetic studies of a large Japanese pedigree. J Neurol Sci 1997;151:65-70.
4. Yabe I, Sasaki H, Tashiro K, Matsuura T, Takegami T, Satoh T. Spastin gene mutation in Japanese with hereditary spastic paraplegia. J Med Genet 2002;39:e46.
5. Svenson IK, Ashley-Koch AE, Gaskell PC, et al. Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet 2001;68:1077-1085.