Rett syndrome: the Swedish Genealogic Research Project. New data and present position.

Using the genealogical method on both classical and atypical cases of Rett syndrome (RS) the assumption that atypical RS are true variants of the classical or nuclear group of RS was investigated. Also common ancestry, common geographical origins, and consanguinity were investigated. The pedigrees of 96 classical and 32 atypical ("forme fruste") RS individuals were examined. None of the RS females was born to first-cousin couples, but 7.3 +/- 1.9% of the classical and 6.6 +/- 3.2% of the atypical RS females had grandparents who were consanguineous. Eleven or 34% of the atypical RS females and 49 or 51% of the classical RS females could be traced to the same small, separate "Rett area". Furthermore, no less than 6 (19%) of the atypical and 28 (29%) of the classical RS females had originated in the same homestead as another RS female examined by us. Nineteen of the explored pedigrees of RS females belonged to 8 pedigrees. The pedigrees contained a mixture of typical and atypical forms of RS indicating that many or most of the variants of RS and the classical types have a common genetic background. The data gathered suggest that transmission starts with a premutation that can result over generations in a full mutation giving rise to RS. Both the X-chromosomes and an autosome pair of chromosomes may be involved.

Rett syndrome: presumptive carriers of the gene defect. Sex ratio among their siblings.

The live-born full siblings of 121 presumptive carriers of Rett syndrome belonging to eight pedigrees were examined as to sex ratio at birth. A total of 394 such siblings born in the period 1757-1966 were identified. 183 (46.4%) of them were male and 211 (53.6%) female, i.e., significantly fewer than in the average Swedish population (p = 0.03) were male. Our findings support the existence of one or more lethal alleles causing Rett syndrome.

Rett syndrome, classical and atypical: genealogical support for common origin.

AIMS OF THE STUDY: By using genealogical methods in atypical females with Rett syndrome (RS) we looked for support for the assumption that atypical RS cases are true variants of classical RS. SUBJECTS: We selected from the Swedish national RS series the "milder" RS cases, 10 years of age and older, fulfilling the criteria for the "forme fruste" (FF) type of RS. For 32 FF cases we were able to carry out complete genealogical analyses on 61 parental lines. The pedigrees contained details of about 3200 ancestors. COMMON GEOGRAPHICAL ORIGINS: Eleven (34%) of the FF females could be traced to a previously defined "Rett area" and no fewer than six females had their origin in the same homestead as another previously examined classical RS patient. ANCESTRY: In four pedigrees, two each contained one FF and two classical RS and two each contained one FF and one classical RS, all 10 being descendants of the same four couples who lived several generations ago. CONSANGUINITY: Consanguinity in four grandparents (6.6% (SD 3.2%)) is probably a higher frequency than in the average Swedish population and supported our findings from a series of classical RS. TRANSMISSION: The data indicate that transmission starts with a premutation that over generations can result in a full mutation giving rise to RS. Both the X chromosomes and a pair of autosomes may be involved. CONCLUSION: Many, or most, atypical FF cases are true variants of RS.

Rett syndrome: potential gene sources--phenotypical variability.

A previous genealogic study on classical Swedish Rett syndrome (RS) females documented an increased rate of common ancestry, with a high percentage originating generations ago in the same homestead. The present study, an a priori test of the first study, examines an additional 20 RS females, who were consecutively traced. Of these, no fewer than 10/19 (53%) originated from earlier defined "Rett areas": 11/19 (58%) could even be traced to the same homestead. In two clusters, each consisting of three RS females, all six subjects were descendants of the same two couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4/37), i.e. significantly more frequently than in the average Swedish population (1%). The results of this second study confirm all points of the first. A clinical analysis of cases with common ancestral origin underlines the phenotypical variability which is often seen in interrelated RS females. We conclude that RS can appear in either its classical form or as a variant. Our genealogical data may indicate transmission starting with a premutation that over generations can result in a full mutation, probably when the parents have the premutation in a homozygous form.

Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden.

Neurofibromatosis type 1 (NF1) is a genetic disease with an extremely wide range of manifestations. As yet, the individual course of NF1 cannot be predicted, and it is uncertain to what extent the disorder is associated with increased mortality. In order to gain insights into these aspects, we have conducted a 12-year follow-up study of 70 adult NF1 patients in the city of Göteborg, Sweden, whereby life expectancy, mortality, causes of death and the prognostic value of clinical findings were investigated. Clinical examinations were made, and all available records, including medical files, death certificates, and autopsy reports were scrutinized. The survival in the NF1 cohort was compared to that in the general Swedish population. Twenty-two deaths occurred in the NF1 group, whereas 5.1 deaths were expected in the general Swedish population (p = < 0.001). The mean age at death was 61.6 years. Malignancy was found in 12 (55%) of the deceased (soft tissue sarcomas in 3, and carcinomas in 9). Severe complications related to NF1 were seen in 27%. Hypertension was significantly associated with increased mortality, as 10 out of 12 (83%) patients with hypertension died during the observation period. NF1 was associated with increased mortality due to malignancy and NF1-related complications.

Rett syndrome: a search for gene sources.

A series of 77 Swedish females with classical Rett syndrome were genealogically traced as far back as possible, in most cases to 1720-1750, or 7-10 generations. Details were collected concerning approximately 8,000 ancestors. Common ancestry was seen in 2 pairs of females with Rett syndrome. Thirty-nine of the 77 Rett females were traced to 9 small and separate rural areas, and 17 pairs even came from the same farm or homestead. The common origin was found equally often among descendants of the father as of the mother. In 9 cases, the father came from one and the mother from another of the 9 specific "Rett areas." These observations, combined with the finding of a raised rate of consanguineous marriages in the paternal as well as in the maternal ancestry, point to a genetic transmission. Analyses of parental ages at birth and of birth order gave normal results.

Neurofibromatosis in Gothenburg, Sweden. IV. Genetic analyses.

The genetic analysis undertaken here shows that the direct (i.e. proband) method for calculating risk figures is not readily applicable to von Recklinghausen neurofibromatosis (NF-1); the selection of available sibling groups for analysis becomes biased in various ways, primarily because of the wide phenotypic variation of the disease. However, indirect methods of analysis confirm that NF-1 shows autosomal dominant inheritance with full penetrance. The existence of an unusually high mutation frequency is also confirmed. In this study it is estimated to be between 4.3 x 10(-5) and 6.5 x 10(-5). However, in contrast to the findings of others, among sporadic cases, both their distribution within sibships and parental ages at delivery did not differ from random distributions. An assessment of the degree of severity of NF-1 and comparisons of the sporadic cases with the familial cases produced no evidence of any clinical somatic differences between the two groups, likewise for psychiatric evaluations of the two groups. Apart from 2 cases with non-NF-1 segmental forms of NF, it was not possible to distinguish alternative forms of NF among the sporadic cases. A pair of monozygotic twins with NF-1 is discussed with reference to the nature and localization of their respective tumours, which are not identical, indicating the influence of factors beyond the mutant NF-1 gene itself on the manifestations of the disease. In a genealogical study involving about 3,000 ancestors of patients from Gothenburg with known NF-1, families with common ancestors were not found, nor was it possible to demonstrate a tendency to clustering in one geographical area or isolated locality.

Traditional views and new perspectives on the genetics of mild mental retardation.

Normal intelligence and mild mental retardation are generally assumed to be determined by additive polygenes. This old and basic theory is challenged by findings from modern population studies. The discrepancies concern frequency of mild mental retardation, sex ratio, and additional somatic handicaps in populations with mild mental retardation.

The biological origin of mild mental retardation. A critical review.

The prevailing theory that normal intelligence and mild mental retardation are determined by multiple additive genes is critically reviewed in the light of findings from recent population studies. Discrepancies between theoretical concepts and reported data are noted, particularly those concerning frequency of mild mental retardation, sex ratio, and additional somatic and psychiatric handicaps in populations with mild mental retardation.

Hereditary diffuse leucoencephalopathy with spheroids.

The clinical, genetic, and morphological features of a previously unknown progressive neuropsychiatric disease are presented. By genealogical investigation of the background of an uncharacteristic case of presumed organic psychosis, we traced 71 relatives from four generations. The anamnestic data showed various combinations of psychiatric symptoms (depression, anxiety, aggressiveness, and severe dementia), neurological symptoms (impaired balance with retropulsion, hyperkinesia, and epilepsy), and somatic symptoms (gastrointestinal disorders, arthritis, and gynaecological problems) in 17 (11 dead and 6 living) members of the family. Age at onset varied between 8 and 60 years. Some patients rapidly developed severe dementia and died a few months after the onset of symptoms, while in others the course was prolonged with dementia over several decades. The genetic interpretation indicated an autosomal dominant inheritance with possible full penetrance but widely variable expressivity. Morphological studies were performed on the central nervous system of four decreased family members (three siblings and their maternal uncle). The same type of widespread leucoencephalopathy was seen in the four autopsy cases. It was characterised by degeneration and loss of myelin sheaths and axons, occurrence of numerous neuroaxonal spheroids in the affected white matter, accumulation of lipid-laden macrophages, and gliosis. The bilateral, frontal, fronto-parietal, and temporal locations of the most pronounced, diffusely demarcated lesions corresponded fairly well to the symptoms of an organic psychosyndrome with its main substrate in the forebrain. For this new clinico-pathological entity, the name "hereditary diffuse leucoencephalopathy with spheroids" (HDLS) is proposed. As a working hypothesis, it is suggested that not only genetic, but also immunological and possible endocrine factors may contribute to the development of the disease.

Neurofibromatosis in monozygotic twins: a case report.

A case report is given of a pair of monozygotic twin girls with neurofibromatosis caused by a new mutation. The symptomatology was dominated by a neurofibrosarcoma on the leg of one twin and by a large plexiform neurofibroma on the neck of the other twin. Otherwise, the disease showed similar, although not identical or mirror-image distribution of subcutaneous neurofibromas and café-au-lait spots. The twins had identical HLA and blood group antigens and the same chromosome aberration. These case reports indicate that nonhereditary factors may influence the manifestations of neurofibromatosis. A review of the literature on monozygotic twins with neurofibromatosis is given.

Y-to-X chromosome translocation observed in two generations.

A family is reported in which the mother and two sons are carriers of a Y-X translocation. The distal segment of the short arm of the X chromosome appears to have been deleted to give place to a translocation of the distal part of the long arm of the Y chromosome. Apart from short stature the mother is essentially free of stigmata, while the sons show a combination of mental retardation, hypertelorism, simian creases, clinodactyly, scanty palmar lines, and dry fragile skin. The cases described are discussed against the background of the few known previously published cases.

The length of the Y-chromosomes in men examined by forensic psychiatrists.

The relative length of the Y-chromosome was investigated by a method of photometric scanning in 106 consecutive cases of men referred for forensic psychiatric examination and in 49 healthy controls. Comparison of both the mean value and the variance of the relative length of the Y-chromosome produced negative evidence for any association between the size of the Y-chromosome and mental disorder associated with criminality.

A man with presumptive Y/Y translocation, observed in a forensic psychiatric department.

A man charged with a sexual offence was found to have complex karyotype anomaly, including a Y-chromosome of aberrant structure. Other features were: very small stature, skeletal deformities and obscure neurological defects. There were no gross psychiatric symptoms, nor was there mental retardation. Q- and G-banding and photometric scanning of the chromosomes of the propositus and his three healthy brothers indicated that the aberrant Y-chromosome probably arose from a reciprocal translocation, which may be written: t(Y: Y) (qter leads to p11: : q11 leads to qter). Fibroblast cultures differed from the lymphocytes: in the former the majority of the cells lacked the abnormal Y-chromosome, their karyotype being 45,X0.