Some Reflections on the Genetics of Mental Disorder by INGRAM F. ANDERSON. M.B.B.Ch.(RancL) Department of and Clinical Genetics Unit, Johannesburg General Hospital.

"Heredity, the only one of the Gods whose real Whereas psychiatric genetics previously name we know . . . brings gifts of strange tem- appeared to be an empiric exercise and its peraments . . and impossible desires." — applications in mental disease were thought Oscar Wilde. to denote a state of irreversibility, it now A study of aberrant mental mechanisms provides a point of vantage for research and involves consideration of the interaction of therapeutic application. Thus a genetically the soma, psyche and multiform environ- determined biochemical disturbance may not ment. Such a vast field cannot be surveyed only point the way to new means of diag- critically or even adequately in a disserta- nosis but offers possibilities of correction at tion of this nature. The title of the paper is the molecular level. thus employed advisedly: "some" because With these introductory remarks it will be the scope is necessarily limited, "reflections" propitious to pass on to a consideration of because here are mirrored my thoughts and (A) Mental Deficiency and (B) The Psychoses. those of others which may not be true images, "genetics" indicates etiologic restric- (A) MENTAL DEFICIENCY. tion and "mental disorder" is used in the broad sense. About one out of every thousand whites in The average medical-man, like the man in this country is in a mental asylum because the street, has very little occasion to come of mental deficiency. The problem comprises up against cases of mental abnormality. The elements of considerable philosophic and latter are locked away early — out of harm's social importance; it provokes the question

) of why people are different and what deter-

2 way, out of society's way, out of medicine's

1 mines their individuality; it limelights the

0 way . . . However most of the major ad-

2 paradox of human rights and raises the vances in genetics and especially in cyto- d polemic aspects of eugenics as these reflect e t genetics in the last few years have evolved in the mirror of human ecology. a

d against this very background and notably (

r within its parameters, as exemplified in the Almost half of the institutionalised cases e h case of mongolian idiocy. The recent splurge are simple oligophrenics. So-called simple s i l of spiders across the erstwhile neatly-lined mental deficiency involves the genetics of b

u pages of the medical journals has seemed to intelligence. The latter is a tenuous entity, P many to represent the soap-bubble interest dependent on multifactorial inheritance and it e h of a narrow speciality. On the contrary, the is safe to say that its precise nature remains t

y implications have been widespread and a matter of controversy. One reads in the b diverse, and have impinged upon the whole book of Job: d e t broad structure of medical-biology.

n "But where shall Wisdom be found? a It is noteworthy that the layman has al-

r And where is the place of understanding? g

ways been aware of an hereditary component Man knoweth not the price thereof; e c in mental illness, as evidenced by everyday Neither is it found in the land of the living. n The deep sayeth it is not in me e statements such as, "There's madness in X's c

i And the sea sayeth it is not with me. l family. Comes through the father's side it It cannot be gotten for gold, r e does!" The medical world has been tardy in Neither shall silver be weighed for the price d thereof. n accepting such a situation and only in the u Whence then cometh Wisdom? last few decades has it given concrete for- y And where is the place of 'understanding? ..." a mulation to the concept. The current explo- w

e sion of activity and interest in human gene- For our purposes, we note that the simple t a tics has again focussed attention on the moron has no distinctive characters and sta- G domain of the . tisically lies at the negative end of the t e n i b a

S JOURNAL OF THE SOUTH AFRICAN LOOPEDIC SOCIETY 1 y b d e c u d o r p e R Gaussian distribution of intelligence. In con- On the smallest time scale are events at trast to this somewhat ubiquitous entity, the dynamic intracellular level. Interest here great strides have been made in our under- centres on the chromosome constitution. In standing of two definitive types of mental man each cell contains 46 chromosomes: 22 defect, namely, mongolism and phenylketo- pairs of autosomes and a pair of sex-chromo- nuric oligophrenia. somes. In 1959 Lejeune and his co-workers discovered that the mongol possesses an ex- (1) Mongolism. tra autosome — a state of aneuploidy (i.e. an abnormal number of chromosomes). Basically It is convenient to discuss this in terms of two mechanisms underlie the chromosomal a collocation of the three time factors in the aberrations in mongolism: non-disjunction biologic picture. On the largest scale is Evo- and translocation. Non-disjunction is the lution, with Man the result of a long line of common type. During meiosis there is failure ancestors and himself the potential ancestor of separation of two homologous chromo- of a long line of descendants. The interest somes. Thus one daughter cell will come to here is historic. When Langdon-Down pub- contain both components of an autosome pair lished his classic paper on "An Ethnic Clas- and the other cell neither. The former, after sification of ", in 1866, he described fertilisation will be trisomic (i.e. it will have Mongolism for the first time, characterising three instead of two of a certain chromo- the mongol as, "... a representative of the some, in this case number 21 on the Denver great Mongolian race". Crookshank in 1931 classification), and will have a diploid num- added the hypothesis that these cases were ber of 47. This situation is seen typically derived from Mongolian ancestors and fur- with older mothers and may be related to ther that they represented an atavistic return mechanical factors operating in an old ovary towards the orang-utang. There is no scien- with "old" ova. Less commonly translocation tific validity for this idea and the anomaly occurs. This involves the breakage of two can be readily recognised in the Mongol race non-homologous chromosomes and an ex- itself. Because of this confused inference change of fragments between them. The attendant on the name, the designation Lang- greater part of chromosome 21 becomes don- has been preferred by attached to one or other fragment leading to

) many. a normal diploid number of 46, but in fact 2

1 there exists a virtual trisomy 21. In addition 0 On the intermediate time-scale we consider 2

translocation allows of the formation of a

d the individual as such — his life history.

e carrier state and the defect may therefore be t Mongolism exceeds all other morbid condi- a perpetuated through several generations. In d tions of severe mental retardation in number, (

essence then, whatever the mechanism, an r constituting some 5 to 10% of asylum in- e additional chromosome is overtly or occultly h mates. There are approximately 125 mongols s

i present. A great many genes — each con- l at the institution at Witrand. The incidence b trolling specific metabolic processes — lie u in the population is nearly one in every 600

P a'on^ its length. However, the relationship

e births. As a comparative measure it is salu- of the cytology to either the biochemistry or h t tory to note that the incidence of hyperten- to the remains obscure. It is impor- y sive disease is 5%, of all forms of congenital b

tant to realise that the mongol is abnormal

d heart disease about 1%, while myelomatosis

e from the moment of conception. A degree of t accounts for 3 per 100,000 of the population. n developmental irreversibility is attendant at a ι r birth and must therefore be more or g

The child with mongolism is usually born e less ineffective, there is no rationale for the c into a normal family with parents and n use of thyroid extract, alpha glutavite, sicca- e siblings ofjten above average intelligence. An c

i cell therapy (injection of dried foetal brain l

enormous j psycho-social problem is at once r cells) or large doses of vitamin E. e generated \ and cannot be elaborated upon d n here. Apart from the mental subnormality, (2) Phenylketonuria. u

mongols jexhibit extensive physical ab- y a normality,, proneness to infection being quite A somewhat brighter vista is revealed w

e a feature. The advent of the era when we look to the inborn error of meta- t a has seen a rise in the mean survival age of bolism, phenylketonuria. This is the G

the mongol. paradigm of a genetically determined en- t e n i b a December, 1962 JOURNAL OF THE SOUTH AFRICAN LOOPEDIC SOCIETY S 1 y b d e c u d o r p e R zyme-block. It is transmitted as a single mental disintegration. The same basic pro- autosomal recessive, the homozygous state cess is believed to underlie the endogenous being necessary for phenotypic expression. psychoses, but it is far more subtle, as yet The enzyme, phenylalanine hydroxylase, is elusive and cannot be so elegantly demon- at fault and there follows failure of oxidation strated. It is central to the understanding of of the essential amino-acid, phenylalanine, to the etiogenesis of these psychoses to appreci- tyrosine. Various intermediate products ac- ate the remarkable shift in emphasis implicit cumulate proximal to the block and act in the foregoing statements. For, whereas deleteriously on the nervous system causing such mental diseases have been attributed to profound mental subnormality. Treatment traumatic psychological experiences, which takes the form of a phenylalanine-low diet, cause a disturbed and maladjusted psyche, and if commenced immediately after birth, it is now postulated that there is a primary offers a reasonable chance of preventing the genetic error underlying and indeed creating mental disturbance. Although the heterozy- a disruption at the intracellular level: an im- gotes are mentally and physically quite nor- balance in internal neuronal metabolic mal, they can be detected by means of blood milieu. Without elaborating on the detailed tests (the phenylalanine-load test) and this biochemistry and in broad terms, mental fact can be utilised in eugenic counseling. mechanisms depend upon the interaction of Finally, very simple tests are available for four (or more) endogenous neurohormones, diagnosis and have been employed routinely adrenalin, nor-adrenalin, acetylcholine and in many maternity centres overseas. This serotonin. A delicate state of homeostasis logical application in preventive medicine between these substances is a pre-requisite could be profitably employed in this country. for mental normality — imbalance is believed to underlie the genesis of the psychoses con- (B) THE PSYCHOSES. sidered here. Interestingly enough, many of Whereas the mental defective lies outside the drugs used as therapeutic agents have our conceptional world and symbolises all been found to act upon and interfere with the the horror of mute animalism in man, the biochemical patterns of the aforementioned psychotic may be regarded as a rather neurohormones and have thus furnished fur- interesting eccentric with whom one can still ther evidence for the indictment of these ) latter substances in the etiology of the psy- 2 maintain a somewhat narrow contact and 1 choses. Professor Hurst is a strong advocate 0 communication. 2

for the employment of such therapeutic d e Professor L. A. Hurst stands uniquely and agents as the monoamine oxidase inhibitors t a eloquently in relation to in South (e.g. iproniazid) and the chemically unrelated d (

Africa as the protagonist of the hereditary substance, imipramine in the pin-pointing of r e discipline in this field. His researches, dis- the peccant chemical sequences. While much h s ciples and numerous publications on the sub- i remains to be propounded and still more re- l b ject testify cogently to his dynamic influence mains to be clarified, it is apparent that the u

P in a school formerly dominated solely by the kaleidoscopic conundrum of the endogenous

e environmentalists. He has moreover suc-

h psychoses has assumed a new colour and for- t ceeded in impregnating a matrix of genetic mat in terms of basic genetic concepts and y b precepts not only into the crude clay of his the elaboration of the latter in the direction d e own speciality, but into the ground-substance of enzyme chemistry, neurochemistry and t n of related medical divisions. neuropsychopharmacology. a r g

The endogenous psychoses have been e c shown by the work of F. J. Kallmann in While these "reflections" have been rather n e America and Eliot Slater in Britain, to be terse and incomplete, they do highlight the c i l emergent fact of an operative genetic com-

determined on an autosomal hereditary basis. r e The genetic mechanism is single recessive in ponent in many forms of mental disorder. d Armed with this evidence our knowledge n Schizophrenia and irregular dominant in u Manic Depressive psychosis. One has illus- can be translated into practical application y a trated in the case of phenylketonuria how a in the form of eugenic counseling. A clinic w for the provision of this service to the com- e mutant gene, via the enzyme-block hypo- t a thesis, creates a disturbance of cellular munity has been inaugurated at the Johan- G

nesburg General Hospital under the aegis of

t chemistry ultimately manifesting in grave e n i b a JOURNAL OF THE SOUTH AFRICAN LOOPEDIC SOCIETY 1 S 2 y b d e c u d o r p e R Professor Hurst. Genetic advice is furnished (A) Simple oligophrenia is briefly alluded in a wide variety of circumstances, not least to against the polygenic background of in- of all in cases of mental disorder. Present telligence. The discoveries in the cytogene- policy is in line with similar clinics in Europe tics of mongolian idiocy are discussed arid it and America: the odds are stated, the gene- is noted that though the key to etiogenesis tics of a particular disease is explained and is now known, the door to the related bio- no attempt is made to influence parents as chemistry and pathology remains closed. to whether or not they should have children. Phenylketonuria is presented as the perfect However, the role of the counselor is not example of an inborn error of metabolism. entirely passive as one emphasised at the Heterozygotes for the condition can be de- recent Pretoria Congress on Genetics: tected by means of blood tests and this con- stitutes a step forward in terms of eugenic "With regard to the counselor, these counseling. Treatment with a low phenyla- very developments in cytologic and bio- lanine diet at birth offers chances of a happy chemical genetics have altered the milieu outcome. In view of the success of therapy, in which he acts, in as much as his prog- and ease of diagnosis, a plea is made for the nostications change in emphasis from pas- routine testing of all neo-nates (as practised sive empiricism to definitive understanding overseas). in terms of enzyme-blocks, protein de- rangements or cytopathogenetics. In addi- (B) Of the psychoses, manic depressive tion to mere advice, he is able to thrust psychosis and schizophrenia are shown to be back further the barriers of uncertainty genetically determined. Furthermore, the and to detect heterozygotes and late onset role of the neurohormones, acetylcholine, cases . . . Thus far from being an inactive nor-adrenalin, adrenalin and serotonin in advisor, the counselor, as I see it, converts brain is mentioned. Disturbance at to the status of active moderator." the genetic level leads to disturbance in the In conclusion, it is almost tautological to chemical homeostasis of the aforementioned stress that mental disorder constitues a for- substances, manifesting ultimately in mental midable challenge to the medical world and aberration. Many of the drugs used in the to society in general. Psychiatry has lagged treatment of these endogenous pyschoses a little behind the rapid progress made in have furnished further indictment of the part )

2 general medicine — having been snared in a played by the neurohormones in the genesis 1

0 network of classifications and bedevilled of mental illness. With entry into the realm 2 with nebulous concepts of "psyche-patho- of genes, molecules and atoms, our under- d e t logy". It is therefore all the more gratifying standing of the psychoses is placed on a fun- a damental and firm footing. d to see it caught up now on the giant tidal (

r wave of human genetics — physiologic gene- A Genetic Counseling Unit has been estab- e

h tics — and elevated from the esoteric depths

s lished at the Johannesburg General Hospital i l of conceptual thinking to the crest of eclectic, under the aegis of Professor L. A. Hurst. b concrete formulation and application. u Various problems of a medico-genetic nature P e SUMMARY. are dealt with, not least of all, those in the h t field of mental disorder. It is a happy augury y There appears to be a lack of appreciation that psychiatry, which has somewhat lagged b

d of the problem of mental disorder on the part behind the rapid progress made in general e t of both the medical profession and the lay- medicine, has attained a clear scientific ap- n a man. The ^urrent interest in proach with the incorporation of the basic r g

has seemed to many to be a somewhat nar- science of genetics into its discipline. e c row speciality. However, mental disorder and n e genetic research have in fact been mutually OPSOMMING. c i l

fructifying. Only recently has the hereditary r Dit lyk asof beide die mediese professie e component in mental illness been accorded d en die leek nie die erns van geestesgebreke n concrete status in the face of the former pre- u

vailing environmentalist doctrine. insien nie. Die huidige belangstelling in y

a mediese genetika word deur meer as een as w Consideration is given to examples within 'n baie beperkte rigting van spesialisasie e t the broader classifications of, (A) Mental De- a beskou. Geestegebreke en genetiese navor-

G ficiency and (B) The Psychoses.

sing het egter, gesamentlik baie vrugte af- t e n i b a December, 1962 JOURNAL OF THE SOUTH AFRICAN LOOPEDIC SOCIETY 3 S y b d e c u d o r p e R gewerp. Dit was maar onlangs wat die rol wat geopenbaar word in geestesafwykings. Baie oorerwing speel in geestesgebreke sy ware van die verdowingsmiddels, wat gebruik status bereik het, in vergelyking met omge- word vir die behandeling van hierdie psigo- wingsleer. ses, het verdere aanduiding verskaf van die rol wat neurohormone, in die veroorsaking Spesiale aandag word geskenk aan voor- van sielsiektes, speel. Met die toetrede tot beelde binne die wyer klasifikasie van, (A) die gebied van genes, molekules en atome, Swaksinnigheid (B) Sielsiekte. het ons begrip 'n vaste grondlegging gekry. (A) Daar word kortliks verwys na een- voudige oligofrenie, gesien teen die polige- 'n Genetiese Raadgewingseenheid is in die niese agtergrond van intelligensie. Uit die lewe geroep by die Johannesburg Algemene bespreking van die ontdekkings in die sito- Hospitaal onder die beskerming van Prof. genetika van mongoolse idiootheid is bemerk L. A. Hurst. Verskei probleme, van medies- dat die oorerflikheids oorsake nou bekend is, genetiese aard, word ondersoek; waaronder maar die verwante biochemie en patologie is ook probleme op die gebied van geestesge- nog onbekend. Fenielketonurie word voorge- breke. Dit is verblydend dat psigiatrie, wat hou as die perfekte voorbeeld van 'n aange- agtergeraak het by die snelle vooruitgang bore defek van metabolisme. Heterosigote vir van algemene medisyne, 'n suiwer weten- die toestand kan opgespoor word deur middel skaplike benadering geniet, met die insluiting van bloedtoetse en dit is reeds vordering in van die basiese wetenskap van genetika. eugeniese raadgewing. Behandeling met 'n REFERENCES. lae fenielalanien dieet met geboorte dui op 'n goeie prognose. Na aanluiding van die suk- 1. Opening Vistas in Psychiatry. L.A. Hurst. Wit- watersrand University Press, 1959. ses. van terapie en die vergemakliking van 2. Applications of Genetics in Psychiatry and diagnose, word 'n beroep gedoen vir die . L. A. Hurst. S.A. Jnl. of Lab. and Clin. roetine toetsing van alle pasgebore babas Med. 1958. 4/3. p.169. (soos oorsee gedoen word). 3. Converging Advances in Psychiatric Genetics and the Pharmacology of Psychotropic Drugs. L. A. (B) Van die sielsiektes word die manies- Hurst. Medical Proceedings 1961. 7/20. p. 417. 4. The Genetics of Mental Deficiency. I. F. Ander- depressiewe psigose en die gesplete persoon- son. The Leech. Oct. 1962.

) likheid geneties bepaal. Verder word die rol 5. Genetic Prognosis. I. F. Anderson. 2nd. Congress 2 van neurohormone, asetielkolien, nor-adrena- of S.A. Genetics Society, Pretoria. 1st October, 1

0 lien, adrenalien en serotonien in brein-fisio- 1962 (in the Press). 2 6. Phenylketonuria in a Mentally Defective Popula- d logie genoem. Steuring op die genetiese vlak e tion. I. F. Anderson, (in the Press). t lei tot steurings in die chemiese homeostase a 7. The Strategy of the Genes. C. H. Waddington. d George Allen and Unwin. Ltd., London. 1957.

( van die bogenoemde stowwe, wat uiteindelik r e h s i l b u P e h t y b d e t n a r g e c n e c i l r e d n u y a w e t a G t e n i b a JOURNAL OF THE SOUTH AFRICAN LOOPEDIC SOCIETY 1 S y b d e c u d o r p e R