201
Case Report
REVISTA PAULISTA DE MEDICINADarie r’s dise ase : a ne w paradigm
for ge ne tic studie s in psychiatric disorde rs
Institute of Psychiatry, School of Medicine, Universidade de São Paulo, São Paulo, Brazil
a b s t r a c t
CO N TEX T: O ne strategy fo r identifying susceptibility genes fo r co
m-mo n diso rders is to investigate Mendelian diseases, co segregating with these co mmo n disease pheno types.
CASE REPO RT: A family with seven members is described, in which three members present Darier’s disease and depressio n. This ap-parent co seg reg atio n, if true, wo uld suppo rt the hypo thesis that in so me pedig rees, a g ene fo r mo o d diso rder may be lo cated o n chro mo so me 1 2 .
KEY W O RDS: Darier’s disease. Depressio n. Psychiatry. G enetics.
• Q uirino Co rdeiro Júnio r • Daniela Meshulam W erebe • Ho mero Vallada
INTRODUCTION
Darier’s disease (fo llicular kerato sis) is an auto -so mal do minant genetic di-so rder, characterized by kerato tic plates o n the skin. There are descriptio ns o f ne uro psychiatric manife statio ns such as me ntal deficiency, epilepsy, psycho sis and mo o d diso rders in p atie nts with this d e rm ato lo gic al d ise ase .1 The
prevalence o f Darier’s disease is estimated at 1 per 100,000 inhabitants, with an incidence o f 4 new cases per millio n, o ver 10 years. The gene which causes the disease was recently identified o n chro mo so me 12 (12q23-q24.1).
CASE REPORT
A 22 year-o ld male patient, with a histo ry o f Darier’s disease since the age o f 18, started to present a lack o f interest in his activities, lo w self-esteem, so cial iso latio n, terminal inso mnia and depressed mo o d. Within a few weeks the sympto ms go t wo rse, and he also develo ped audito ry hallucinatio ns and delusio nal ideas that were co ngruent to his mo o d, i.e. he believed that his neighbo rs wanted to kill him because he was a despicable human being. Apparently, these psychiatric sympto ms were no t asso ciated with the wo rsening o f his dermato lo gical sympto ms.
He was treated with sertraline at a do se o f 150 mg and 2 mg o f risperido ne per day, with full remis-sio n o f the psychiatric manifestatio ns. The patient had no previo us psychiatric diso rder, o r any histo ry o f abno rmal psycho so cial behavio r. He had had fo ur years o f primary scho o l educatio n, and he had been wo rking
202
as an o ffice assistant since the age o f 18.
Additio nally, his father also presented Darier’s disease and sho wed recurrent majo r depressio n but witho ut psycho tic sympto ms. Ano ther family member, o ne o f the patient’s sisters, also had Darier’s disease and recurrent majo r depressio n witho ut psycho tic sympto ms. The patient’s mo ther and his o ther three siblings presented neither a dermato lo gical disease no r any psychiatric diso rder (Figure 1).
DISCUSSION
Since the 19th century, psychiatrists have o
bserved that so me psychiatric diso rders, like schizo -phrenia o r manic-depressive illness, seem to be mo re p re vale nt in s o m e fam ilie s . This s p e c ulative inheritance co mpo nent has been co nfirmed by fam-ily, twin and ado ptio n studies, with the next step being to identify its gene(s).
One o f the strategies used fo r identifying sus-ceptibility genes fo r co mmo n diso rders (also called co mplex diso rders because they are very likely to be e tio lo gic ally he te ro ge ne o us ) is to s tud y the ir co segregatio n with a Mendelian diso rder. A success-ful example in psychiatry was the disco very o f a Mendelian cause o f Alzheimer’s disease, lo cated o n chro mo so me 21 (mutatio ns at the APP lo cus), due to the o bservatio n that Do wn syndro me patients sho w similar Alzheimer neuro patho lo gical features.
The family described abo ve presents co -o ccur-rence o f depressio n and Darier’s disease in so me o f its members. Po ssible interpretatio ns fo r this asso -ciatio n are:
1. This pheno meno n co uld o ccur because the gene o f Darier’s disease also predispo ses to wards de-pressio n (also called the pleio tro pic effect). There are previo us repo rts o f depressio n and suicidal be-havio r in patients with Darier’s disease. In additio n, skin and brain are o riginated fro m the ecto derm, sharing the same embryo nic o rigin. Therefo re, it can b e spe culate d that the de fe ct in ce llular ad he sio n e xp re sse d in the skin and b rain is pro mo ted b y an alteratio n o n the same gene. Ho wever, the o nly systematic study o f Darier’s disease co ncluded that there was no statistically significant asso ciatio n with psychiatric diso rders.1
2. Darier’s disease, as a chro nic dermato lo gical dis-o rder, cdis-o uld prdis-o mdis-o te depressive illness as a psy-cho lo gical stresso r. Ho wever, Craddo ck, et al.2
repo rted that tho se patients with bo th diso rders do no t relate their depressive sympto ms to the der-mato lo gical disease, and apparently the sympto ms
o f each diso rder develo p at different times. The fam ily p re se nte d in this re p o rt c o nfirm s the o bservatio n fo und in Craddo ck, et al.2 In additio n,
Burge & Wilkinso n1 did no t find a higher prevalence
o f depressio n in patients with Darier’s disease. 3. The asso ciatio n between these diseases co uld also
be by chance, with no true bio lo gical asso ciatio n, caused o nly because depressio n is a very preva-lent diso rder in the general po pulatio n, reaching up to 13% o f peo ple during their life times. But in a study with a family with co segregatio n between affective diso rders and Darier’s disease, Craddo ck et al.2 demo nstrated that the pro bability o f this
as-so ciatio n o ccurring by chance was very lo w.
4. The gene respo nsible fo r Darier’s disease may be lo cated very clo se to the susceptibility gene fo r depressio n, in the same chro mo so me regio n. Therefo re, in a rare situatio n in which bo th genes are mutated (i.e. causing the diseases), they will always be transmitted to gether to the next genera-tio n (linkage pheno meno n). Investigating this last hypo thesis, Dawso n, et al.3 studied patients with
bo th Darier’s disease and bipo lar affective diso rder, and fo und an allelic asso ciatio n with the pancreatic p ho s p ho lip as e A2 ge ne ( PLA2A) . Ho we ve r, Jaco bsen, et al.4 sho wed that alteratio ns o n the gene
that co des the sarco plasmic/endo plasmic reticulum calcium-pumping ATPase (SERCA2) are implicated in the appearance o f Darier’s disease and neuro p-sychiatric manifestatio ns. Thus, they co ncluded that this gene sho uld have a pleio tro pic actio n, being respo nsible fo r bo th clinical manifestatio ns. In summary, the apparent co segregatio n in this family between Darier’s disease and depressio n, if true, co uld either be the result o f a gene co ntributing to mo o d diso rder, in the neighbo rho o d o f the Darier’s
Figure 1. Schematic representation of the family. The black circles and squares are the family members with Darier’s disease and depression.
203
disease lo cus o n chro mo so me 12, o r alternatively a mutatio n in the Darier’s disease gene resulting in a direct effect o n the b rain. Since depressio n is a co mmo n pheno type, it is mo st pro bably etio lo gically hetero geneo us, like o ther co mmo n diso rders such as
hypertensio n o r diabetes. Therefo re, the depressio n described abo ve co uld belo ng to a rare subtype o f depressive diso rders characterized by stro ng genetic susceptibility and presenting a Mendelian pattern o f inheritance.
r e s u m o
CO N TEX TO: Uma e stra té g ia p a ra id e ntific a r g e ne s d e susceptibilidade para do enças co muns é investigar a co -segregação entre essas enfermidades e algumas do enças mendelianas.
RELATO DO CASO: É descrita uma família co m sete membro s, do s
quais três deles apresentam depressão e do ença de Darier. Essa aparente co -segregação , se verdadeira, daria supo rte à hipó tese que, em algumas famílias, um gene relacio nado ao transto rno do humo r po deria estar lo calizado no cro mo sso mo 1 2 .
PALAV RAS-CH AV ES: Do ença de Darier. Depressão . Psiquiatria. G enética.
Quirino Corde iro Júnior, MD. Psychiatry resident, Department o f Psychiatry, Universidade de São Paulo , São Paulo , Brazil.
Danie la Me shulam We re be , MD. Psychiatrist, Head o f the Teaching Pro gram o f the Co nsultatio n Liaiso n Gro up, Department o f Psychiatry, Universidade de São Paulo , São Paulo , Brazil.
Home ro Vallada, MD, PhD. Asso ciate Pro fesso r, Department o f Psychiatry, Scho o l o f Medicine, Universidade de São Paulo , São Paulo , Brazil.
Source s of funding: No t declared Conflict of inte re st: No t declared Last re ce ive d: 27 June 2000 Acce pte d: 28 June 2000
Addre ss for corre sponde nce :
Instituto de Psiquiatria, Labo rató rio de Neuro ciências (LIM-27), Faculdade de Medicina da Universidade de São Paulo
R. Ovídio Pires de Campo s, 171 - Apto . 701 São Paulo /SP - Brasil - CEP 05403-010 E-mail: hvallada@ usp.br
p u b lis hin g in fo r m a t io n
1. Burge SM, Wilkinso n JD. Darier-Withe disease: a review o f the clinical features in 163 patients. J Am Acad Dermato l 1992;27:40-50.
2. Crad d o c k N, Owe n M, Burgan S, Kuriam B, Tho m as P, Mc Guffin P. Fam ilial Co s e g re g atio n o f m ajo r affe c tive d is o rd e r an d Da ri e r’s d i s e a s e ( ke ra to s i s fo l l i c u l a ri s ) . Br J Ps yc h i a try 1994;164:355-8.
REFERENCES
3. Dawso n E, Gill M, Curtis D, et al. Genetic asso ciatio n between alleles o f pancreatic pho spho lipase A2 gene and bipo lar affective diso rder. Psychiatr Genet 1995;5(4):177-80.
4. Jaco bsen NJ, Lyo ns I, Ho o gendo o rn B, et al. ATPA2 mutatio ns in Darier’s disease and their relatio nship to neuro psychiatric pheno types. Hum Mo l Genet 1999;8(9):1631-6.
