Eur. Neurol. 14: 328-339 (1976)

Chromosome Abnormalities in Neurological Diseases D. V assilopoulos University Department of Human Genetics (Director: Prof. A. E. H. E mery ), Western General Hospital, Edinburgh

Key Words. Chromosome abnormalities • Neuromuscular diseases • Multiple sclerosis • Neoplasms • Various neurological diseases Abstract. The current status of research into chromosomal abnormalities in neu­ rological diseases is reviewed. The only possible association between chromosome aberration and neurological disorder is found in ataxia telangiectasia and in tum­ ours of the nervous system. In the remaining diseases reviewed, no specific associa­ tion was confirmed. This was expected to some extent, since the majority of these diseases (spinal muscular atrophies, muscular dystrophies, etc.) are due to single gene defects.


Received: October 1,1975; accepted: October 27, 1975.

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There is much evidence to suggest a relationship between chromosome abnormalities and disorders of the nervous system, but the exact mecha­ nism of this relationship is still unknown. There are two approaches to this problem. The first is to consider neurological features of the ‘cytoge­ netic syndromes’. The second is to detect possible chromosome abnor­ malities in neurological diseases. The first approach is confusing because many clinical syndromes associated with chromosome abnormalities have similar neurological presentations (table I). In addition, more specific neurological abnormalities have been de­ scribed in association with different chromosome aberrations. For exam­ ple, ‘arhinencephaly’, has been reported as the main neurological abnor­ mality in T8 short arm deficiency syndrome’ [71] and ‘13-15 trisomy’

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Table I. Chromosomal abnormalities associated with recognised clinical syndromes; from E mery [18] Chromosomal abnormality


CNS manifestations

Trisomy 21 or D/G translocation, etc.


mental retardation hypotonia

Trisomy 13


motor and mental re­ tardation-microcephaly

Trisomy 18


motor and mental retardation



mental retardation epilepsy



mental retardation microcephaly


de Grouchy’s

mental retardation

21 q- (G deletion syndrome 1)



22q- (G deletion syndrome II)

hypotonia retarded development

[50], There is also much support from pathological features in chromo­ some syndromes. Recently, two more articles described abnormal features in pathological examination of Down’s syndrome patients. C olon [13] re­ ported that the number of neurones in the cerebral cortex of patients with Down’s syndrome is about 50°/o of the normal and the nuclear volume is about 1.5 times larger, and P adilla [55] described various types of struc­ tural abnormalities in the fibrillar neuronal organisation in Down’s as well as in Patau’s syndrome. Many clinical characteristics have also been described in Down’s, Patau’s, Edward’s, cri-du-chat, and in other chro­ mosome syndromes. The sex chromosomes also have an important role in the structure and function of the nervous system. Recently W right [68] and W right and L auder [69] reported that the nerve conduction velocity is considerably lower in XYY, XXYY and other sex chromosome syn­ dromes than in healthy individuals. Cerebral malformations have been also described in XYY syndrome [10]. One third of the cases of XXXXY

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motor and mental re­ tardation-microcephaly

Trisomy 22


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people are hypotonic [64], In addition, XXY patients (Klinefelter’s syn­ drome) have slight mental retardation. As the number of X chromosomes increases, mental retardation becomes more obvious illustrating further evidence of the relationship between sex chromosomes and the nervous system. Although a study of neurological manifestations in chromosome ab­ normalities is very useful for the cytogeneticist, it does not help the clini­ cal neurologist. For this reason, some of the chromosome abnormalities in neurological diseases have been summarised. The aim of this article is to review the current status of some relevant research in this field.

Spinal Muscular Atrophies

Muscle Diseases Muscular Dystrophies It is of great interest that muscular hypotonia is a feature of many se­ vere chromosomal defects (table I). However, no studies have been made of the lower motor neurone and muscle in these conditions. It is possible that some of these syndromes would show signs of either neuropathy or myopathy. R uffie et al. [60] reported a case of an 11-year-old boy who suffered from a severe myopathy and who seemed to have abnormal G group chromosomes, but the same chromosome abnormality was also found in other members of his family who were absolutely normal. Three women with ovarian dysgenesis (XO sex chromosome constitution Turner’s syndrome) who suffered from Duchenne muscular dystrophy have been described [66].

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There are few references to chromosome abnormalities in spinal mus­ cular atrophies. H akansson [22] described a case of Werdnig-Hoffmann’s disease with a peculiar dicentric chromosome in the 6-12 group. In the same case one third of the cells lacked one chromosome in the 19-20 group. Several years later, B onasegla and M ontevecchi [7] re­ ported two cases of Wolfhart-Kugelberg-Welander’s syndrome with chro­ mosome abnormalities. In the first case 1/29 cells examined was consid­ ered to have 45 chromosomes, and in the second case 2/35 cells had 45 chromosomes. Recently, K unze et al. [37] described a mosaicism in the sex chromosomes (XO/XY) in a child with a progressive type of spinal muscular atrophy.

Chromosome Abnormalities in Neurological Diseases


Myotonic Disorders Myotonic dystrophy. Some years ago there was much discussion about the chromosome constitution in myotonic dystrophy. F itzgerald [19] and F itzgerald and C aughey [20] reported an additional small acrocen­ tric chromosome in a number of cells in 5 of 7 patients with myotonic dystrophy. These authors postulated the existence of a supernumerary chromosome in this disorder. E berle and Becker [17] examined 866 cells of ten patients with myotonic dystrophy and found that 30 cells (3.5%) had a 47-chromosome constitution. According to these authors, the additional chromosome was randomly distributed. J ackson [29] using a statistical evaluation concluded that some observed abnormalities in 393 cells from eight patients ‘could have been expected by chance alone’. M utton and G ross [52] in a preliminary report described an unusually high frequency of chromatid and isochro­ matid gaps and breakage in 2 of 12 patients with myotonic dystrophy. B owen et al. [8] reported that there is a significant excess of cells con­ taining additional atypical chromosome elements in the affected group (13 patients) in comparison with the control group (14 subjects). These authors suggested that this phenomenon could be the result of a genetic abnormality or of some uncontrolled environmental factor or the result of some ‘nonspecific’ therapeutic agents that have been administered to the patients. The same authors [9] described a balanced translocation be­ tween two nonhomologous chromosomes of the D group in a 44-year-old patient and also in five other members of his family. The dystrophic mother of the patient and another affected relative had a normal kary­ otype so the authors concluded that the association of D translocation and myotonic dystrophy was fortuitous. Thus, although chromosome abnor­ malities have been described in some patients with myotonic dystrophy, in the majority of the cases there is apparently no significant chromosome abnormality. Myotonia congenita. In an examination of chromosomes from seven cases of myotonia congenita (Thomsen’s disease) by M ularek et al. [51] no numerical or structural chromosome abnormalities were found.

There is also controversy about chromosome abnormalities in multiple sclerosis. K oulicher [36] first described abnormalities interpreted as

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Multiple Sclerosis


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D/G translocation in a group of nine patients with multiple sclerosis, four of whom (unrelated) had a familial incidence of the disease. K honakarian et al. [35] reported an increased frequency of hyperploid and hypo­ ploid cells with chromosome fragmentation in patients with multiple scle­ rosis. On the other hand C azullo et al. [11] found no significant abnor­ malities neither in number nor in structure of chromosomes in patients with familial incidence of multiple sclerosis. Two more papers reported that there is no evidence of chromosome abnormalities in multiple scle­ rosis. Recently K aminskaya et al. [34] found some abnormalities in the number as well as in the structure of chromosomes but they concluded that these abnormalities did not correlate with any clinical parameter and did not exceed the level of chromosome abnormality in the cultures of blood leucocytes of normal subjects. Also W right and B ates [70] found no differences in the frequency of structural aberrations and sug­ gested that the differences previously described could be the result of some technical factors. Congenital Malformations Many chromosome abnormalities have been described as a cause of various types of congenital malformations of the CNS. Sorsby [65] re­ ported that a kind of translocation may be an aetiological factor of anencephaly. K abarity et al. [33] reported that in a 9-month-old infant with micropseudoanencephaly and meningoencephalocele, the chromosome analysis revealed a 44,XX,D-E/45,XX,D-E-t (DqEq) mosaicism.

Since the development of new chromosome techniques, many studies have been performed on the incidence and nature of chromosome abnor­ malities in nervous system neoplasms. The majority of these investigations were attempts to determine the chromosome constitution of the neoplastic cells themselves, and to try to relate these to the clinical and pathological manifestations of the tumour. The results of this approach are summar­ ised in table II. In addition, there are a number of case reports of chro­ mosomal aberrations in neoplasms. A condition of much interest mainly because of its possible relation­ ship to an increased incidence of malignant disease is ‘ataxia telangiecta-

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Chromosome Abnormalities in Neurological Diseases


Table II. Chromosome constitution of the neoplastic cells of the NS Type of tumour

Chromosomal abnormalities




V* of cells diploid Zi hypo- or hyperploid 9

C -, A±

14, 67, 49

D —, A —, C ±



A + , E —, D +

42, 45, 49


V* of cells diploid % hypo- or hyperploid

E-.B + , G —, D —

42, 44, 61,49


2/3 diploid

Gliomas Astrocytic Oligodendro Ependymomas

Neurinomas Meningiomas


1/3 hyper- or hypoploid

D —, B —

diploid-hypoand hyperploid

E —, G —

46, 49

33 % diploid 60% hypoploid 7% hyperploid

G—, C ± D±

72, 43, 47

large variability (a lot of triploid cells)

D —, G —


sia’ (Louis-Bar syndrome). Some authors [27, 41] observed an increase of spontaneous chromosome breakage, whereas others [59, 62] have re­ ported a normal chromosome constitution. P feiffer [58] found 2 of 6 pa­ tients had some cells with chromosome abnormalities but could not corre­ late these with the abnormal IgA globulin levels. Recently, H a r n d en [24] confirmed the presence of the chromosome abnormalities in Louis-Bar syndrome but he suggested that these abnormalities may not occur in vivo, but as a result of chromosomal instability only manifested in vitro. This is in agreement with Hecht’s observation that the bone marrow cells have normal chromosome constitution. In addition to the frequently re­ ported chromosome instability, the D group, especially the chromosome 14, seems to be the most consistently vulnerable [12, 24, 28]. Recently, further evidence for the. involvement of chromosome 14 is provided by N elson et al. [53] who reported a case of a boy suffering from ataxia tel­ angiectasia in whom the chromosome analysis revealed a translocation between 14 and the X chromosome but no breaks were found.

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V assilopoulos

Other Diseases Chromosome abnormalities have been reported as the cause of a num­ ber of other neurological conditions but because of the limited space available, only a few of these will be mentioned. Sturge-Weber Syndrome There has been much discussion as to whether or not this condition may be a form of trisomy [21, 25, 26]. P atau et al. [56] considered that this syndrome is a kind of partial trisomy, but later this case was recog­ nised as a XYY individual. Essential Tremor A relationship between supernumerary sex chromosome syndromes and essential tremor, a usually familial condition [2, 3, 15], has been dis­ cussed, and there is little doubt now that essential tremor is a clinical component of supernumerary X or Y syndromes. Congenital Analgesia B ecak et al. [4, 5] who reported five cases (in three families) with a

congenital indifference to pain, found that four patients had a karyotype containing one or two extra chromosomes interpreted as belonging to the D (13-15) group. However P atau et al. [57] have described a similar 13-15 trisomy in which the clinical symptoms were completely different.

Senile and Presenile Dementias J acobs et al. [30-32] and H amerton et al. [23] reported a significant increase of hypoploid cells with age and suggested that this loss of chro­

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Speech Disorders Several authors have proposed the existence of ‘hérédité logopathique’ as a separate clinical entity [38, 39, 63], Recently, D ebray-R itzen et al. [16] reported serious disorders of language integration in three children with chromosome abnormalities. Duplication of the short arm of the chromosome 9 was demonstrated in one case, the second exhibited triso­ my 8 mosaicism, and a ring chromosome of unknown origin mosaicism was present in the third. The authors suggested that partial imbalance in karyotype may show itself as a disseminated lesion of the higher function and particularly in speech disorders.

Chromosome Abnormalities in Neurological Diseases


mosome material (especially in 6-X-12 group) might be a primary age change. N ielsen [54] reporting a statistically significant higher percen­ tage of hypoploid cells in female patients with senile dementia compared with age matched controls, suggested that the increased loss of chromo­ some material mainly from the X chromosome in these patients is ‘a basic part of the aetiology and pathogenesis of senile dementia’ B ergener and J ungklaass [6], in clinically and pathologically confirmed cases of Alzeimer’s disease, described chromosomal aneuploidia and the appearance of ‘unusually structured extra chromosomes.’

Conclusion In conclusion, it appears that the large number of studies in this field have failed to reveal any specific association of chromosomal abnormali­ ties with neurological disorders. This is not surprising since many of the disorders mentioned above (spinal muscular atrophies, muscular dystro­ phies) are single gene defects and so, presumably, the presence of differ­ ent chromosomal abnormalities in some of these cases is purely coinci­ dental. A possible exception to this is ataxia telangiectasia in which chro­ mosome 14 has been implicated. Perhaps the recent investigations of the chromosome constitution of tumour cells found within the nervous system might prove informative in elucidating further possible relationships of chromosomal abnormalities and neurological diseases.

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27 H echt , F.; K oler, R. D.; R igas, D . A.; D ahnke, G. S.; C ase, M. P.; T isdale ,

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Chromosome Abnormalities in Neurological Diseases


Dr. D. V assilopoulos, Department of Human Genetics, University of Edinburgh, Western General Hospital, Edinburgh EH4 211U (Scotland)

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Chromosome abnormalities in neurological diseases.

Eur. Neurol. 14: 328-339 (1976) Chromosome Abnormalities in Neurological Diseases D. V assilopoulos University Department of Human Genetics (Director...
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