omment ry Genetic Markers i n Huntington s Disease ELLIOT M . FROHMAN Irvine, and JOSEPH B. MARTIN, MD, PhD, Boston Huntington s disease i s a neurodegenerative disorder that i s inherited a s a n autosomal dominant trait It is typically expressed later i n a patient s adult years, when i t m a y have a l- ready been transmitted t o t h e patient s children. T h e clinical symptoms o f this disorder include a progressive dementia com- bined with extrapyramidal motor manifestations o f t h e cho- reoathetotic type. Huntington s disease ha s as i ts most prominent neuropathologic feature a notable atrophy o f t h e caudate nucleus, which i s accompanied by less severe degeneration in t h e p u - tamen, globus pallidus a n d t h e cerebral cortex. Studies have shown that patients with Huntington s disease have alterations i n striatal receptors f o r -y-aminobutyric acid (GABA), benzodiaze- pines, muscarinic cholinergics, cholecystokinin anddopamine. Such changes have been related t o some extent t o t h e loss o f local circuit cholinergic a n d GABAergic a s well as neu- rons that project from t h e striatum t o other portions o f t h e basal ganglia. A reduction in feedback inhibition o f dopaminergic cells i n t h e substantia nigra m a y lead t o augmented dopaminergic a c - tivity i n t h e striatum, a putative precondition i n t h e development of t h e choreoathetosis characteristic o f h e disease. Recently, a D N A sequence probe called G 8 h a s been identi- fied an d h a s been shown t o b e closely linked t o t h e Huntington s disease gene on chromosome 4 . This newmarker i s a 17.6-kilo- base o f N that after digestion with t h e bacterial restriction enzyme, Hind III c a n give rise t o o n e o f four frag- ments o r polymorphisms. These haplotypes a r e called A , B , C a n d D . T h e discovery o f t h e localization o f a restriction fragment length polymorphism linked t o t h e Huntington s disease gene constitutes t h e first use o f recombinant N technology t o locate a.gene without having a n y previous knowledge regarding gene location. T h e u s e o f this f o r t h e purpose o f prediction tests i n persons a t risk represents a great advance i n o u r ability t o unmask the predisposition t o a complex hereditary disease. Unfortu- nately, i n t h e u s e of t h e G 8 marker, t h e sequence i s not close enough t o t he gene s o that o n e haplotype invariably segregates with t he presence o f Huntington s disease. F o r this reason a n error rate d u e t o genetic recombination of 5 t o 1 0 occurs even when a sufficient number o f family members i s available f o r study. Ideally, both t h e grandparents a n d parents o f a person a t risk should b e available for analysis o f t h e G 8 marker. An addi- tional caveat i n t he u s e o f this marker f o r prediction testing in Huntington s disease i s that the onset of t h e disorder is late enough i n life that some o f t h e parents a n d grandparents will probably b e deceased. T h e u s e o f prediction testing involves t w o principal compo- nents: marker identification a n d pedigree analysis. I n t h e most elementary an d informative case, information i s available from three generations: t h e grandparents, t h e parents a n d t h e person a t risk. Prediction is more difficult when information from only t w o generations is available. A n additional confounder i n t he prediction test i s t h e possible error caused b y recombination between t h e marker an d t h e locus of t h e Huntington s disease gene. An example o f theprocess o f genetic analysis will illustrate t h e u s e f t h e probe. I n t h e best o f circumstances wherein t he gr;andparents a n d parents a r e alive, a n affected parent might have received t he Huntington s disease gene and t h e A marker haplo- type from o n e of t h e affected grandparents, theother grandparent a n d parent being unaffected a n d labeled B B a n d C C , respectively. I f t h e child also received an A marker, then in t h e absence o recombination this person a t risk would b e expected t o b e affected andhence labeled A C o r A B . I f t h e person a t risk were B C , then, also barring t h e possibility o f recombination, this person would b e expected t o b e normal. I t i s important t o point o u t that t h e A , B , C , haplotypes represent only labels f o r polymorphism. A n y o n e family m ay have with i t a n y o f t h e labels. Moreover, th e significance of such polymorphisms in t h e marking o f thedisease state concerns t he presence o f o n e o f these haplotypes i n conjunction with the affected person. It then b e - comes likely that, barring errors o f recombination, offspring with t h e disease-associated haplotype will b e afflicted with t h e disease. A t present additional markers ar e being generated t o flank and, ultimately, converge t h e Huntington s disease gene Th e addition o f these n e w markers serves t o increase heterozy- gosity a n d thereby provide more precise counseling because a greater pattern complexity allows u t o better distinguish between persons. T h e development o f a testing procedure f o r a disease that i s lethal, o f late onset a n d f o r which there i s n o current treatment is n o t without significantcontroversy. F o r instance, there is specu- lation that i n those w h o test positivethere will b e an escalated risk o f suicide, psychiatric substance abuse, divorce a n d employment problems, t o name just a few. T h e development o f these testing procedures, however, will begin t o assume greater importance when t h e prospects o f early diagnosis will contribute t o optimizing t h e potency o f forthcoming treatment stratagems. I n essence, these n e w findings represent a major advance toward t h e progression of steps that will lead t o t h e understanding, treatment a n d prevention o f hereditary disorders such a s disease. Finally, despite t h e considerable limitations o f t h e current testing procedures, there is confidence that over t h e next five t o t e n years, gene isolation techniques will become available that all suspected persons c a n b tested r e - gardless o f which relatives a r e available f o r pedigree analysis. GENERAL REFERENCES Harper P S , Safarazi M: Genetic prediction a n d family structure i n Huntington s disease. B r Me d J [Clin Res] 1985 Jun; 290:1929-1931 Martin J B : Genetic testing i n Huntington s disease Editorial Comment). An n Neurol 1984 Oct; 16:512-513 Wexler N S, Conneally PM Houseman D, e t a l : N polymorphism f o r Huntington s disease marks the.future. Arch Neurol 1985 Jan; 42:20-24 Whitehouse P J, Trifiletti RR, Jones BE , e t a l : Neurotransmitter receptor alter- ations i n Huntington s disease: Autoradiographic a n d homogenate studies with spe- cial reference t o benzodiazepine receptor complexes. An n Neurol 1985 Aug; 18:202-210 4 8 6 (Frohman EM Martin J B : Genetic markers i n Huntington s disease. West J M e d 1987 Oct; 147:486) From t h e 4 t h Year MD/PhD Program, Departments of Neurology, Anatomy a n d Neurobiology, University o f California, Irvine, California College ofMedicine ( M r Frohman), an d the Neurology Service, Massachusetts General Hospital, HarvardMedical School, Boston ( D r Martin). A t t h e time this article w a s written, M r Frohman wa s a student representative o n t h e California Medical Association s Advisory Panel o n Neurology. Reprint requests t o Elliot M . Frohman, MD/PhD Program, Dept o f Neurology, University o f California, Irvine, California College o f Medicine, Irvine, C A 92717.
