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Biochemical and molecular genetic studies have shown that PME of the Unverricht-Lundborg type is unrelated to myoclonic epilepsy with ragged-red fibres (MERRF),9 an epilepsy which also belongs to the PME

gene.8

group. The existence of high consanguinity in almost all MM families, together with their circumscribed origin from Mediterranean countries, suggests that a small number of mutations account for most MM cases. Similarly, on the basis of genealogical and population data, it is likely that only one or very few mutations are responsible for BM in Finland. Whether BM and MM are caused by a single mutation or whether a spectrum of mutations exists will only be determined when the gene is mapped and cloned. DNA from patients and families with both diseases should facilitate identification of the EPM1gene. This work might also benefit from the analysis of allelic association between the disease gene and 21q 22.3 markers, since only a few mutations seem to be involved. Moreover, our findings have immediate implications for genetic counselling. Once the EPMI gene is cloned and its protein product characterised, insights into neuronal homoeostasis might follow. The metabolic pathways whose abnormalities underlie other, more frequent, non-mendelian epilepsies might then be identified. We thank Dr J. Roger, Dr M. Baldy-Moulinier, Dr P. Jallon, Dr C. Remy, Mauguieres, Dr C. Messina, Dr G. Rubboli, Dr R. Pantieri, Dr A. Toscano, Dr M. Koskiniemi, Dr P. Sistonen, Dr R. Norio, and Dr J. Feingold for generously placing their extensive clinical and technical expertise at our disposal, and for collection of families. This work was supported by I’Association Francaise contre la Myopathie, le Centre National pour la Recherche Scientifique, l’Institut National de la Santé et de la Recherche Medicale, the Academy of Finland, the National Institutes of

De-novo mutation in hereditary motor and sensory neuropathy type I

Isolated

of

hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) have been thought to be most frequently autosomal recessive. We have found that a recently discovered duplication in chromosome 17, responsible for most cases of autosomal dominant cases

H MSN I, is present as a de-novo mutation in 9 out of 10 sporadic patients. This finding has important implications for genetic counselling of isolated patients with HMSN I. Lancet 1992; 339: 1081-82.

Dr F.

Health, and the Folkhàlsan Institute of Genetics.

REFERENCES 1.Berkovic SF, Anderman F,

Carpenter S, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med

1986; 315: 296-305. 2. Marseille Consensus Group. Classification of progressive myoclonus epilepsies and related disorders. Ann Neurol 1990; 28: 113-16. 3. Genton P, Michelucci R, Tassinari CA, Roger J. The Ramsay-Hunt syndrome revisited: Mediterranean myoclonus versus mitochondrial encephalomyopathy with ragged-red fibers and Baltic myoclonus. Acta Neurol Scand 1990; 81: 8-15. 4. Elridge R, Iivanaienen M, Stern R, Koerger I, Wilder BJ. "Baltic" myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet 1983; ii: 838-42. 5. Lehesjoki AE, Koskiniemi M, Sistonen P, et al. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc Natl Acad Sci USA 1991; 88: 3696-99. 6. Patterson D. Report of the second international workshop on human chromosome 21 mapping. Cytogen Cell Genet 1991; 58: 168-74. 7. Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 1984; 36: 460-65. 8. Lehesjoki AE, Koskiniemi M, Pandolfo M, et al. Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora disease. Neurology (in press). 9. Tassinari CA, Michelucci R, Forti A, et al. Ramsay-Hunt syndrome and MERRF: two unrelated conditions as demonstrated by mitochondrial DNA study. Neurology 1991; 41 (Suppl 1): 281. ADDRESSES:

INSERM

U249,

CNRS

UPR8402,

34060

Montpellier, France (A Malafosse, MD, P. Labauge, MD); Department of Medical Genetics, University Helsinki, 00290 Helsinki, Finland (A. E Lehesjoki, MD, A de la Chapelle, MD); Centre St Paul, 13009 Marseille, France (P. Genton, MD, Ch. Dravet, MD); Service de Neurophysiologie Clinique, HIA Val-de-Grâce, 75005 Paris (G. Durand, MD); Department of Neurology, University of Bologna, Bellaria Hospital, Bologna, Italy (C. A. Tassinari, MD, R Michelucci, MD). Correspondence to Dr A. Malafosse, Laboratoire de Médecine Expérimentale, Institut de Biologie, Bvd Henri IV, 34060 Montpellier, France.

Hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) is a slowly progressive demyelinating motor-sensory polyneuropathy, beginning in childhood.1 The prevalence of HMSN I is the highest of all inherited neuromuscular disorders.2 Inheritance is autosomal dominant in most families, but autosomal recessive transmission has also been reported.3 To differentiate between these modes of inheritance is essential for genetic counselling, and may be important for prognosis because of reported differences in severity.33 Although the possibility of an autosomal dominant de-novo mutation is acknowledged by most investigators, isolated cases are most frequently thought to be autosomal recessive.3,4 Recently, we and others reported the presence of a DNA duplication in chromosome 17p 11.2 in autosomal dominant HMSN I families.s°6 In 1 patient, the duplication was shown to be a de-novo mutation. In this study, we have investigated whether duplication is an exceptional finding in isolated cases of HMSN I. 10 patients (4 males, 6 females, aged 10-33 years) and their parents gave informed consent to take part in our study. These patients were selected on the basis of a previous diagnosis of sporadic HMSN I, and met the following criteria: distal weakness and wasting predominantly in the legs; motor nerve conduction velocity (MNCV) of the median nerve < 30 m/s or MNCV of the peroneal nerve < 15 m/s; and abnormalities on nerve biopsy examination (completed in 8 patients) consistent with HMSN I (loss of large and small diameter fibres, segmental demyelination and remyelination, and classic onion bulbs). All 20 parents were normal on neurological examination. Blood sampling, together with DNA isolation, restriction, Southern blotting, and hybridisation, were done by standard procedures. 6 ug DNA was digested by EcoRand hybridised with single copy fragments of the chromosome 17p probes VAW409R3 and VA W412R3 (obtained from Dr D. F. Barker, University of Utah School of Medicine, Salt Lake City, USA), leaving all individuals homozygous for a 20 kb and 45 kb fragment, respectively. Probe E3.9 (obtained from Dr T. J. M Hulsebos, Academic Medical Center, Amsterdam, the Netherlands) was used as reference for DNA loading. This probe detects a 39 kb EcoRl

1082

VAW412R3/E3.9 and VAW409R3/E3.9 ratios (%). A. In affected

(.)

and unaffected controls

(0) B.

fragment on chromosome 22. Hybridisation signals on the filters were quantified by a phosphor imager (Molecular Dynamics, Sunnyvale, California, USA), and the VAW409R3/E3.9 and ratios were calculated. 15 affected and 22 unaffected controls originated from five families in which the duplication has been shown previously.s The ratios in affected

VAW412R3/E3.9

controls, sporadic patients, and parents

were

expressed

as

percentages of mean values in unaffected controls, which were set at 100%. Logistic-regression analysis combining the two ratios resulted in complete separation of affected and unaffected controls (figure, A). The duplication was present in 9 of the 10 sporadic patients, and absent in all parents (figure, B).

The presence of the duplication was confirmed by finding three VAW409R3-CA repeat alleles6 in 3 patients and an MspI dose difference in 4 further patients. These abnormalities were not found among parents. In 2 patients with the duplication, these methods did not allow any conclusion to be drawn because of lack of heterozygosity. In all cases, paternity was confirmed with the hypervariable probe P9 (heterozygote frequency 0-95).’ Our results indicate that a de-novo mutation is by far the most frequent cause of sporadic cases with typical HMSN I. This finding contradicts previous assumptions. Dyck has suggested that the mutation is transmitted autosomal dominantly to isolated HMSN I patients,1 and others have believed that most isolated cases are autosomal recessive.3,4 This assumption was supported by the observation that sporadic cases, similar to those reported in sibships, were more severely affected than autosomal dominant cases.3 In our sporadic patients, clinical severity was greater than in 19 age and sex matched patients from 6 families with the duplication (median neurological disability score 30 vs 20 [95% CI of the difference 1 to 16]). A possible explanation may be differences in selection procedures, since scores were not significantly different from the index patients in the six families (median score 31 5,95% CI of the difference -13 to

12).

Absence of the duplication does not necessarily imply autosomal recessive inheritance, since other autosomal dominant HMSN I types and X -linked HMSN are found.99 Our results show, however, that testing for the duplication

In

sporadic patients (.) and their parents (

De-novo mutation in hereditary motor and sensory neuropathy type I.

Isolated cases of hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) have been thought to be most frequently ...
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