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Die genetischen Probleme der Schizophrenien. Nebst vorläufiger Mitteilung der Ergebnisse in einem Schweizer Isolat (mit 3 Stammbaumskizzen)
- E. Hanhart
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- Journal:
- Acta geneticae medicae et gemellologiae / Volume 14 / Issue 1 / January 1965
- Published online by Cambridge University Press:
- 01 August 2014, pp. 13-40
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- January 1965
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The so-called endogenous psychoses, i. e. the manic-depressive pychosis and the schizophrenias have still to be treated like functional characters, as their probably existing somatic bases are still unknown. It may be granted that these two groups are genetically different, though there are — particularly in isolates — hereditary types of psychoses mixed with both manic-depressive and schizophrenic symptoms. According to the data of twin research, schizophrenias and cyclic psychoses have no common genetic background.
The very high concordance of monozygotic twins for schizophrenia is liable to prove the high importance of genetic factors, while it does not exclude accessorial environmental influences in its etiology.
A simple recessive inheritance, which seemed to be outruled by most authors, appears now to be possible according to Garrone (1962). Other authors (Slater, Böök) pleaded for irregular dominance of major genes with or without single accessory genes, and others even for an unspecific polygenic origin.
The term “ schizoid ” is vague and does not correspond to a satisfactorily clear conception either clinically or genetically. It may be the incomplete expression of a disposition to schizophrenia and more often that of a recessive gene in heterozygotic state or an incompletely dominant gene. Schizoid features which have been observed twice in children with trisomy-22 are not likely to have anything to do with schizophrenic psychoses.
Most probably the schizophrenias are heterogenic, but not with regard to clinical variations such as hebephrenia, catatonia, dementia simplex or paranoides. At any rate, we should not rely too much on the empirical hereditary prognosis.
The study of the occurrence of schizophrenia in isolates has the advantage that we have to do mostly with one and the same biotype and that we are able to trace the presumable genes throughout 8 and more generations. On the other hand the number of character-bearers is numerically limited.
In an isolate of eastern Switzerland with about 400 individuals of a highly inbred and fertile population, the frequency of schizophrenia is at least 1.75%. There are accumulations of the trait in some families and collateral lines. The oldest cases of presumable schizophrenics go back a hundred years; the more recent ones were or are interned in the two Cantonal asylums. The diagnoses in their records were controlled by prominent Swiss psychiatrists. Among the parents and sibs of those schizophrenics only a few can be judged as “ schizoid ” at a psychopathic degree.
The parental consanguinity of our propositi is about three times higher than the average of this population, which also contains 3.5% of undifferentiated oligophrenia being low-grade in 1%. The frequency of both schizophrenia and oligophrenia does not account at all for the relatively high number of 5 so-called “ Pfropf-schizophrenias ” (i. e., combinations of schizophrenias with inborn mental deficiency); however, Larsson and Sjögren found the same in a Swedish isolate.
While the 14 cases of sure or most probable schizophrenia in our isolate do not clearly show a monomeric recessive inheritance (since Weinberg's sibmethod gives a =10.4% and Bernstein's a priori-method a P = 3.0%), the undifferentiated oligophrenia of all degrees most probably depends on one specific simple recessive gene. It is not unlikely after all that the schizophrenias be inherited in the same way in this population, provided there is a considerably reduced manifestation of a mutated autosomal gene.
Ueber einfache Rezessivität bei Mikrocephalia vera, spuria et combinata und das herdweise Vorkommen der Mikrocephalia vera in Schweizer Isolaten
- E. Hanhart
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- Journal:
- Acta geneticae medicae et gemellologiae / Volume 7 / Issue 4 / October 1958
- Published online by Cambridge University Press:
- 01 August 2014, pp. 445-524
- Print publication:
- October 1958
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According to the results found in literature Microcephaly — better Micrencephaly — is a syndrom with a very heterogenous pathogenesis which often remains unclarified. Its etiology, though occasionally purely exogenous, seems to be mostly hereditary in the sense of monomeric recessivity, as the experiences, so far rather scanty, of research in families and in twins show.
The so-called Microcephalia vera is to be considered identical with this mono-recessive form.
Our data may be divided in four groups:
Group I comprises 35 cases of verified or almost sure M. vera in 23 sibships. The diagnosis are mainly assured by clinical data and photos and in 4 cases by post mortems, 3 of them having been most carefully examined under the guidance of brain-anatomists like C. v. Monakow, M. Minkowsky and E. Grünthal whose publications in detail are referred to here. The Sex-Ratio in our cases (17 male and 18 female) is practically 1:1, therefore deviating considerably from that found in Japan and even more from that found in England and in Holland.
The application of Weinberg's sib-Method to our thoroughly studied, non-selected series gives the percentage of 24,2 ± 6,2 largely corresponding with the theoretical expectation for the assumption of simple recessivity.
A parental consanquinity was only found in 10 families though even the IV. - V. Canonical degree was also considered twice and though about a third of our patients originate from isolates. The number of I. and II. cousin-marriages occur but three times each (together 26%). Further, 1 case of incest between father and daughter is described.
The main complications in our cases of M. vera are epileptic fits and fits of excitement with aggressive tendencies. An encephalocele was found only once and other states of dysraphy nowhere prevailed; neither did cerebral tumors, phacomatosis and other systematised nervous affections, as well as mongoloid idiocy, disturbances of metabolism and somatic malformations. Also psychoses were not above the average in the kinships concerned.
General spasticity, a symptom found regularly in their cases by other authors was only met with in a minority of our cases. Possibly there may exist heterogenity in M. vera, which phenotipically manifests itself by the presence or absence of general spasticity.
Since in Switzerland by far not all cases of M. are interned, the frequency of M. vera is difficult to ascertain. About half of our patients died in early childhood and maybe many die through abortions, the gene involved being semilethal.
Growth and life-span can rarely be normal even in high-grade microcephalic idiots. Most of them, however, are undersized, exceptionally real dwarfs.
Among the non microcephalic sibs of our patients we found a considerable number of feebleminded and bordeline cases, showing — but not always — a lessened head-circumference. In the parents of our microcephalics, however, only exceptionally an intellectual deficiency was stated, more frequently as a matter of fact a lessened head-circumference. The very heterozygotes are not at all always characterised physically and mentally or even in one respect.
Our three other groups seem to refer to a secondary microcephaly and therefore are restricted to isolated cases. In one kinship a microcephalic boy is first cousin of an idiot with hydrocephaly. In another kinship with apparently simple recessive deaf-mutism and idiocy one patient shows microcephaly. In a third family with four sibs of clincally diagnosed cases of diffuse cerebral sclerosis each affected member was also microcephalic; here we have to deal probably — as the parents are II. cousins — with a particular specific simple recessive gene.
Die Schweizer Fälle von Splenohepatomegalie (Niemann-Pick) Ein Beitrag zur genetischen Abgrenzung der Phospatid-Lipoidosen
- E. Hanhart
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- Journal:
- Acta geneticae medicae et gemellologiae / Volume 5 / Issue S1 / July 1956
- Published online by Cambridge University Press:
- 01 August 2014, pp. 294-318
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- July 1956
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In this paper a counterpart is given to the data of our investigation about the incidence of infantile amaurotic idiocy (Tay-Sachs) in Switzerland, published here in 1954. The term «the-saurismose» is rather unclear and had to be critisised by Letterer. The diagnose of all lipidosis is more difficult than of any other genetic character, as neither a thorough clinical and histological examination nor the chemical analysis of the brain and the big abdominal organs (spleen, liver etc.) is sufficient; it ought always to be completed by the modern histochemical method at least if we want to separate the M. Niemann-Pick from the M. Tay-Sachs. The quarrel between the « unitarists » and the « dualists » concerning the independence of these two phosphatid-lipidosis does not seem to be ended definitely by chemical analysis of the affected organs. Undoubtfully these two very similar diseases must have many common traits in their pathogenesis. This does not mean, however, that they do not depend on 2 different genes, may be working at the same pheno-genetical chain (Klenk), perhaps there is a pseudo-allely, which as a matter of fact can hardly ever become proved in men. This author showed that the M. Niemann-Pick is regularly characterised by a high percentage of sphingomyelin whilst in the M. Tay-Sachs the gangliosids prevail. But recently this difference is regarded to hold only quantitatively. Therefore we have to look for genetical proofs of the independence of these two lipidosis. An observation of van Bogaert in his famous pedigree of the family Mi. and another less convincing of Driessen show that among the children of the same parents cases of both these lipidosis can appear. Since both these families are of Russian respectively Polish-Jewish origin, coming from a not very big area in which these lipidosis were found relatively very often, these two instances also could be explained by mere coincidence.
Our Swiss cases which all happened in families of non Jewish origin do not show sibs the one of whom had M. Tay-Sachs and the other M. Niemann-Pick, nor were combinations of both lipidosis observed. Unfortunately excepted one, namely that of Baumann, Scheidegger & Klenk, none of our cases has been examined with all the modern methods. These 3 specialists established the theory that we deal in the M. Niemann-Pick and M. Tay-Sachs with specific cellular dystrophies and not an overloading of the blood with certain lipids, as was supposed by Pick: For, all values of blood-chemistry, principally of the total amount of fatty acids as well as of cholesterol and of anorganical phospor used to be normal in the serum of those patients. The data published by U. Pfändler could become disguised as rare exceptions or consequences of alterations in a no more fresh serum. His conclusions with regard to the pathogenesis and the way of hereditary transmission cannot become adopted neither for the adult, nor for the infantile forms of Niemann-Pick.
The facts found by us and others clearly speak in favour of a simple-recessive transmission, at least for the infantile forms of M. Niemann-Pick, the same has been proved by us for M. Tay-Sachs. Videbaeks pedigree with parents of the 2 children with M. Niemann-Pic being first cousins, is not to be interpreted otherwise. Of our Swiss families with M. Niemann-Pick 3 contain each 2 fraternal and 3 isolated cases; parental consanguinity was found 4 times but not very close though 5 of these families come from isolates. The gene concerned therefore cannot be too rare. Like the other authors we did not observe secondary cases in collateral lines. The oldest of our patients reached the age of 3½ years. There is no higher incidence of other hereditary diseases, especially with regard to metabolism, in our 6 Swiss families.
From the clinical standpoint there is to mention that 4 of our 5 cases studied in detail showed the typical red spot in the region of the macula retinae; one case showed a complete atrophia nervi optici and another an atrophy of the temporal parts of the papilla nervi optici. In most cases a demencia or «imbecility » was noted, a fact which suggests the participation of the brain in the processus of the specific thesaurismosis. Unfortunately, however, the brain has but once been examined with the modern histochemical methods.
Über 27 Sippen mit infantiler amaurotischer Idiotie (Tay-Sachs)*
- E. Hanhart
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- Journal:
- Acta geneticae medicae et gemellologiae / Volume 3 / Issue 3 / September 1954
- Published online by Cambridge University Press:
- 01 August 2014, pp. 331-364
- Print publication:
- September 1954
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This paper is based on 45 cases in 27 families, all of which have been studied in Children Hospitals. In Switzerland almost all cases of infantile amaurotic idiocy (Tay-Sachs) have probably been collected, so that the stated 13 primary and 14 secondary cases may allow an estimation of the frequency of this character, which seems to oscillate temporarily. In the last 10 years no new cases have been observed.
All 24 autochthonus Swiss cases are from non-Jewish, mostly rural origin, in which Eastern Jews are not to be supposed as ascendants.
Our in all 27 families with TS make Slome's statistic of Jewish and non-Jewish cases in literature much more significant; the incidence of parental consanguinity is, as a matter of fact, nearly twice as high in families with non-Jewish origin.
There is no evidence of a milder and longer course of TS in non-Jewish families.
The mode of inheritance is, according to Slome, monohybrid autosomal recessive, though in remarkably many sibships there is an accumulation of cases. The reduction method, however, gives a percentage of 28,3 ± 6,2, coming quite near to the expectation of the Mendelian quarter.
The penetrance of the character is total, the expressivity generally very equal, with only a few deviations from the well—known clinical picture of TS.
The interfamiliar and intrafamiliar variability therefore is small. In not even one of the families studied have there been found other forms of lipoidosis, principally no cases of splenohepatomegalia Niemann-Pick. All available respective cases in Switzerland have been collected by the present author and will soon be published in these Acta. In none of these families with M. Niemann-Pick have cases of M. Tay-Sachs been seen. This fact is liable to prove that these clinically and anatomically very similar conditions derive from independent i. e. different mutations.
Modifying genes may account for the incidence of sibships in which all or almost all children died from M. TS.
Environmental influences do not seem to favour its manifestations.
If in the newer literature from the U.S.A. the Jewish cases of M. TS are still prevalent and if, as we heard, the concomitant manifestations occur fairly often in Israel, the origin may be sought in one at least 200 years old respective mutation in the Jewish population of a relatively restricted White-Russian era.