Ataxia with Isolated Vitamin E Deficiency and Retinitis Pigmentosa Takayoshi Shimohata, MD,*t Hidetoshi Date, PhD,? Hideaki Ishiguro, MD,' Takashi Sizuki, MD,' Hiroki Takano, MD,t Hajime Tanaka, MD,t Shoji Tsuji, M D , t and Kohichi Hirota, MD'

We read with great interest the report of Yokota and col- leagues' describing Friedreich-like ataxia with retinitis pig- mentosa caused by the His'"'G1n mutation of the a-tocopherol transfer protein (a-TTP) gene, because we also recently found a novel missense mutation of the a -TTP gene in a patient with retinitis pigmentosa as well as ataxia.

The proband was a 57-year-old woman who was born of a consanguineous marriage. On physical examination, she ex- hibited ataxia, dysarthria, bilateral sensorineural deafness, hy- poreflexia, muscular atrophy of extremities, decreased proprio- ceptive and vibratory sensations, and retinitis pigmentosa. Brain magnetic resonance imaging revealed marked dilatation of the cisterna magna, a finding that has also been reported in a Japanese family with idiopathic vitamin E deficiency.2 Laboratory data revealed an extremely low serum vitamin E concentration (1.7 pg/ml; normal, 7.5-14.1 pg/ml). Al- though three of the proband's siblings suffered from similar symptoms, her 5 1 -year-old sister exhibited neither retinal change nor dilatation of the cisterna magna. The sister's se- rum vitamin E concentration was higher than that of the proband (4.2 pg/ml), because by chance, she had been tak- ing 200 mgiday a-tocopherol since she was 20 years old.

High-molecular-weight genomic DNA was extracted from peripheral blood leukocytes of two affected and two unaf- fected family members. The a-TTP gene was amplified by the polymerase chain reaction and subjected to direct nucle- otide sequence analysis as described by Ouahchi and col- l eague~.~ We found a single nucleotide alteration in the third of thc five coding exons of the a-TTP gene. The results re- vealed that the affected members were homozygous for a thymine-to-cytidine transition at nucleotide 566 of the a -TTP cDNA that results in substitution of proline (CCT) for leucine (CTT) at codon 183. The two unaffected mem- bers were heterozygous for the mutation. Because analysis of the a-TTP gene of 100 unrelated Japanese subjects did not reveal this mutation, these findings indicate that the L e ~ ' ~ - ~ P r o mutation is likely to be the pathogenic mutation.

Our report emphasizes the importance of serum vitamin E screening in patients with spinocerebellar degeneration re- sembling Friedreich's ataxia, particularly if the clinical fea- tures include retinitis pigmentosa or dilatation of the cisterna magna, since this neurological disorder can be arrested by appropriate supplementation with vitamin E.

*Department o f Neurology, Akita Red Cross Hospital, Akita, and 'Department of Neurology, Clinical Neuroscience Branch, Brain Researcb Institute, Niigata Uniuersig, Niigata, Japan

Rejerences 1. Yokota T, Shiojiri T, Gotoda T, et al. Friedreich-like ataxia with

retinitis pigmentosa caused by the His'"'Gln mutation of the a-rocopherol transfer protein gene. Ann Neurol 1997;41:826- 831

2. Aoki K, Washimi Y, Fujimori N , et al. Familial idioparhic vita-

min E deficiency associated with cerebellar atrophy. Clin Neurol 1990;30:966-971

3. Ouahchi K, Arira M, Kayden H, et al. Ataxia with isolated vi- tamin E deficiency is caused by mutations in the a-tocopherol transfer protein. Nat Genet 1995;9: 141-145

Surgical Treatment of Hypothalamic Hamartoma S. M. Sisodiya,' S. L. Free,? and S. D. Shorvont

Although the demonstration of effective treatment for epi- lepsy associated with a hypothalamic hamartoma (HH) in one patient by Kuzniecky and colleagues' is very welcome, most patients reported on in the literature have failed to be- come seizure-free whether interventional treatment was di- rected against HH or neocortical epileptogenic foci.2 Al- though diencephalic lesions may generate gelastic seizures (that may secondarily generalize), and apparently focal dys- geneses may be intrinsically epileptogenic, most patients with HH have multiple seizure types. Munari and associates3 showed that some nongelastic seizures in one patient with HH may have non-HH, neocortical origin, even if these foci develop secondarily and are not visible on routine inspection of volumetric magnetic resonance images (MRI). Apparently focal cerebral dysgeneses are often associated with locally ex- tensive occult cerebral structural changes*; widespread struc- tural changes detected only by quantitation of MRI may have biological significance in patients with epilepsy, being associated with poor outcome after focal surgical re~ect ion.~ We propose that some HH patients may do well after focal rescctioii whereas others do not because the latter have addi- tional structural changes not visualized on MRI, as has been demonstrated in 2 patients by quantitative analysis.6

To determine whether the presence of additional quanti- tative abnormalities of cerebral structure in patients with HH is a biological cause of the heterogeneous response to surgery, a prospective study of quantitation of preoperative MRI data would be required. This analysis is relatively simple and is performed on preoperative MRI data, which are prerequisite for surgery. Although Kuzniecky and colleagues demon- strated elegantly the value of single-photon emission com- puted tomography, this technique is not available for all pa- tients, whereas MRI data are easily transmitted. Since few centers are likely to see sufficient patients to undertake a pro- spective study and to minimize operator variability in perfor- mance of quantitative analysis, we offer to perform quanti- tative analysis on volumetric MRI data acquired by any center from patients with HH being considered for surgery. Correlation of MRI quantitation results with surgical out- come would test the hypothesis of biologically important heterogeneity of cerebral structures associated with HH. This might in the future assist clinicians, enabling the rational provision of interventional treatment to patients most likely to benefit and avoiding exposing patients likely for biological reasons to do badly to possible morbidity.

Annals of Neurology Vol 43 No 2 February 1997 273