Juvenile, Westphal Variant, or Akinetic-rigid" HD

(Golden Nuggets of Information compiled by Phil Hardt 12/13/01)

National Institute of Neurological Disorders and Stroke (NINDS) http://www.ninds.nih.gov/health_and_medical/pubs/huntington_disease-htr.htm# Some individuals develop symptoms of HD when they are very youngbefore age 20. The terms "early-onset" or "juvenile" HD are often used to describe HD that appears in a young person. A common sign of HD in a younger individual is a rapid decline in school performance. Symptoms can also include subtle changes in handwriting and slight problems with movement, such as slowness, rigidity, tremor, and rapid muscular twitching, called myoclonus. Several of these symptoms are similar to those seen in Parkinson's disease, and they differ from the chorea seen in individuals who develop the disease as adults. These young individuals are said to have "akinetic-rigid" HD or the Westphal variant of HD. People with juvenile HD may also have seizures and mental disabilities. The earlier the onset, the faster the disease seems to progress. The disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years. Individuals with juvenile HD usually inherit the disease from their fathers. These individuals also tend to have the largest number of CAG repeats. The reason for this may be found in the process of sperm production. Unlike eggs, sperm are produced in the millions. Because DNA is copied millions of times during this process, there is an increased possibility for genetic mistakes to occur. To verify the link between the number of CAG repeats in the HD gene and the age at onset of symptoms, scientists studied a boy who developed HD symptoms at the age of two, one of the youngest and most severe cases ever recorded. They found that he had the largest number of CAG repeats of anyone studied so far--nearly 100. The boy's case was central to the identification of the HD gene and at the same time helped confirm that juveniles with HD have the longest segments of CAG repeats, the only proven correlation between repeat length and age at onset. ****************************************************************************************** Chapter 4 - YOUNG PEOPLE AT RISK Facing the reality - a balanced view Learning that you are at risk Some common reactions Marrying someone at risk Whether or not to plan children Responsibility for a parent Other practical problems http://www.ninds.nih.gov/health_and_medical/pubs/huntington_disease-htr.htm#

Facing the reality - a balanced view Being at risk to HD obviously presents a number of difficulties, but perhaps the basic one is learning to live with the knowledge realistically, Some people experience a kind of see-saw effect; on some days they feel sure that they will get HD, and on others they are sure they won't. Either extreme distorts reality. If you are too pessimistic, you live in continual dread and are unable to plan a career or a rewarding relationship, or cultivate interests. You may also be constantly looking for symptoms and the smallest accidents take on a different meaning. Being too optimistic, on the other hand, may lead to denial and irresponsibility, such as not telling your partner and having children without making the decision rationally. This can lead to misery later on. The more knowledge you have about the disease, then the more you are able to view your situation realistically and plan your life accordingly. Being prepared for both getting it, and not getting it, can mean that you can enjoy a satisfying life which is not destroyed if you are unfortunate enough to get HD. This is, of course, easier said than done, but a positive attitude can be helped by remembering that you are not alone, that keeping it to yourself makes it worse, and that even after the onset of the disease life can have meaning and happiness. Learning that you are at risk However you learn that you are at risk to HD, you are going to worry about the possible consequences, but the manner in which you were told will to some extent affect your outlook. If your parent developed HD early on, you may have grown up with its constant presence so that you are never actually told about HD - though the knowledge is around. You may have been subjected to the stresses of living with HD from an early age and though this may have had a profound effect on you, knowledge of the disease does not come as a shock. If you are a little older when your parent is diagnosed, then again the knowledge of its effects comes gradually. You may experience great sorrow at a loved parent changing physically and mentally until perhaps roles are reversed and the child cares for the parent. It needs to be remembered that not all people suffering from HD are affected in the same way. If there is one aspect of the disease that you find particularly distressing in your parent it does not mean that you would suffer in a similar way. Seeing a dependant parent may also make you fearful for your own future and possible loss of independence, a thought which is difficult to live with. Where this is no evidence of HD in the family, perhaps because a parent is at risk but has not shown any symptoms, it can be a great shock for a teenager suddenly to be told the facts of the disease. It may seem at first to disrupt completely all your plans for a career, marriage and the way you want to live your life. However you learned about HD, you will have a number of anxieties about the future. Perhaps you may even be worried about your present health - whether in fact you could already be showing symptoms. You may be concerned that you look like or have a similar personality to your parent with HD and irrationally fear that you are therefore more at risk. These are common and very understandable anxieties which can be dealt with if brought out into the open and discussed, but can be overwhelming if kept to yourself. Knowledge of the real facts of

the disease, rather than the belief in some of the myths that surround it, leads to a realistic assessment of your situation. For instance having a parent who is at risk, puts you in a different position from those whose parent is already affected, and this may influence your outlook. An appointment with a neurologist or geneticist organized by your family doctor would give you the chance to ask questions and clarify the information you have already received.

Some common reactions Some young people feel very angry with fate, God, their parents or anyone else they can think of to blame. This is not surprising, as the disease has no sense of fairness. There are those who try bargaining: "If I'm good ... If I have children ... If I don't have children ... If I don't marry ...etc., I won't get HD". None of this, of course, has any affect and is not helpful except in relieving one's feelings. The temptation to blame parents is also strong, and it is wise to remember that parents themselves may be feeling guilty. They may or may not have known about HD when they decided to have children. If they didnt know, they may be blaming their own parents for this; if they did know, they may well have taken the risks into consideration and still thought it was worthwhile for their own and their children's sake. A frank discussion and explanation is the obvious approach to the problem, but children and/or parents may find this difficult and it may take time to fully understand each other's feelings. You may also be worried that even if your friends know about HD they may not understand the pressure you are under or that they will treat you differently. You may feel that boy- or girlfriends will be discouraged and you will never meet anyone who wants to marry you, which also brings out the problem of exactly when, in terms of a relationship, is the right time to tell someone. If you are already engaged or married, the problem could be how much to share the knowledge with your partner and how the relationship will be affected. There is no easy answer except perhaps that the information has to be shared whatever its consequences. To keep such a secret would place an enormous burden on you, and the fact that there is something hidden is bound to cause difficulties with your partner. You may choose to limit the number of people you tell, but those close to you really need to know. Even of the knowledge should cause a breakdown in a relationship, it is better to establish early on that your future partner or friend cannot cope with the implication of the disease, rather than at a crisis later. Not having been given the facts can lead to bitterness in husband or wife and greater likelihood of rejection. Sharing your anxieties with other people can help you to see that some of these worries are normal in all young people whilst others are peculiar to HD. Such understanding and reassurance can help.

Marrying someone at risk Thinking of marrying someone at risk can pose problems. If you have never seen or even heard of HD, you may try to ignore the risks and possible consequences. Some of you will feel so frightened that you break off the relationship almost immediately without going further into the subject. Learning the real facts and weighing up the risks and what they mean to you, against the quality of the relationship, is the only

way a proper decision can be taken. If you understand the implications and can work out plans for the possibility that your partner both may and may not get HD, then your marriage can be happy and a success whatever happens. After careful consideration, however, you may feel that you do not want to risk having to care for an ill person, or you may particularly want children without having to put them at risk too. It is difficult to reject someone for reasons that are just a possibility in the future, but unless you are convinced that you can live with the thought or the fact of HD, then it is better and kinder in the long run to decide against the marriage early on. Whether or not to plan children Perhaps the greatest problem that young people at risk have to face is the issue of having children. If you do not want to have the sort of predictive test which was discussed in Chapter 2, the decision has to be taken in the dark. Some people feel strongly that they should not burden a future generation with the risk of HD and therefore decide not to have any children. Others feel equally strongly that they want to lead as normal a life as possible, which includes having children, and that the risk is worth taking. We should perhaps remind ourselves that not every couple who plans a child will conceive. Overall about 1 couple in 10 cannot conceive and this is nothing to do with HD. Those that feel that their lives will be incomplete without children may consider some of the following: IVF (in vitro fertilization);AID (artificial insemination by donor);fostering (couples at risk to HD are not usually allowed to adopt); becoming a social aunt or uncle; limiting family size to one or two children; having children early so that if the parent should get HD the children would be at a reasonable age by then. Pre-natal testing has already been discussed in Chapter 2. Whatever the outcome, the decision is not easily arrived at and needs a lot of discussion between the two people involved. It is a good idea to seek information and the chance to discuss your personal situation with someone who is knowledgeable in the field. You can be referred by your doctor to a genetic counselor who will see you, or you and your partner, by appointment. The counselor will be able to answer your other questions. This could be a good opportunity for you to talk about your anxieties and perhaps sort out any conflicting or questionable information you have already been given. Some genetic counselors offer further appointments so that you have the chance to go over again any information you are not sure about, and ask questions which have occurred to you in the interval or which you forgot to ask the first time. Your own doctor or a clinic will be able to help you with family planning whether permanent (sterilization) if you are completely certain about the decision not to have children, or temporary until you are ready to make your decision. You may still feel that you would like to talk more to someone outside the family, if so ask to see a Social worker, either from your own Local Services Department or from the hospital where your genetic counselor is based or where one of your family is being treated. Responsibility for a parent Some young people are faced with the dilemma of how far they should be involved in the care of a sick parent. This problem is not, of course, unique to HD, though it may become one earlier than in other families. The question of care is discussed in

Chapter 5, but it needs repeating that you have to consider very carefully the immediate and long-term effects on you before you commit yourself to looking after a mother or father however much you may love them. This may be right for some people but not for others. You can be under considerable pressure from others, even from your well parent who depends on you to take over at times, but a social worker will help sort out what services are needed, what are available, and what help from you is reasonable given your own feelings and circumstances. Other practical problems Other important worries about HD are in relation to insurance, employment, mortgage and so on. Where you have to make a medial statement it is wise to include information about HD as otherwise any documents, such as an insurance policy, could be invalid if it were proved that you knowingly gave false information. Where you give permission for a medical reference which includes family illnesses, your doctor will have to give the relevant details. It is an unfortunate fact that you can be adversely affected in these matters by being at risk to HD, but not necessarily so, and it is worth shopping around various insurance companies to get the terms. Some jobs will need medical references where health is an important factor. Employers may be prejudiced, but this could largely be through ignorance and a frank discussion about the disease may be helpful. Where no medical recommendation is required, it is up to you whether or not you tell your employer that you are at risk. ****************************************************************************************** DIAGNOSIS AND DISCUSSION: JUVENILE-ONSET HUNTINGTON'S DISEASE Molecular Testing The 5' region of the Huntington's disease (HD) gene on the short arm of chromosome 4, which contains a polymorphic trinucleotide (CAG) repeat, was amplified by polymerase chain reaction (PCR) and the sizes of the two alleles were measured by denaturing polyacrylamide electrophoresis against M13mp18 as size standard (5). The results are shown in Figure on the right. The patient in this case report has one normal-sized allele and one abnormally expanded allele with 68 CAG repeats. In contrast, a normal control has two alleles in the normal size range (<36 CAG repeats). Approximately 99% of patients with a clinical diagnosis of Huntington's disease have an expanded allele with 36 or more CAG repeats (7). Discussion Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and behavioral dysfunction. The hallmark of the disorder is involuntary choreiform and athetotic movements, hence it is also known as Huntington's chorea. Within the last four years, great advances have been made in understanding the molecular genetics of HD. In 1993, a novel gene containing a polymorphic CAG trinucleotide repeat was cloned and HD patients were found to have expansions of this CAG repeat (6). Normal individuals have alleles with up to 35 CAG repeats, while affected HD patients almost always have an allele with 40 or more CAG repeats. Alleles containing from 36 to 39 repeats showed "reduced

penetrance," meaning that only some individuals with such alleles will show clinical symptoms within their expected lifespans (8, 9). The presented case describes onset of HD before the third decade of life. Such juvenile-onset cases of HD are differentiated from classic adult-onset HD cases by a number of clinical, pathological and genetic features. Juvenile HD patients typically do not present with chorea, but instead with rigidity or seizures (2). With progression of disease, classic uncontrolled, choreoathetotic movements do develop. Behavioral, cognitive or psychiatric difficulties are prominent, as seen in this patient, who presented with a decline in school performance and is currently being treated for psychosis. Although degeneration and atrophy in the caudate and putamen are seen in juvenile HD patients as in adult-onset HD patients, a more widespread pattern of neurodegeneration is usually seen both radiologically and neuropathologically. Neuronal loss in the Purkinje and granule cells of the cerebellum is common, as is atrophy of the dentate nucleus, globus pallidus, hippocampus and neocortex (3). An interesting genetic feature of HD is anticipation, which may be defined as worsening disease severity in successive generations. Thus, in some cases offspring of affected HD patients have been found to present at an earlier age than their affected parent and to have their disease progress more rapidly than that of the affected parent. For HD, a strong parental bias for this effect has been shown, with paternal transmission of the HD gene mutation found to be statistically more likely to produce anticipation (1). The molecular explanation for anticipation lies in the instability of the causal CAG repeat expansion. Research has shown that there is a correlation between the length of the mutant CAG repeat expansion and the age of onset and age of death in HD (4, 10). Further expansion of the CAG repeat occurs much more frequently with paternal transmission than maternal transmission of the HD CAG repeat mutation. Thus, this increased tendency to further expansion upon paternal transmission accounts for the observation that about 90% of juvenile HD patients have inherited their disease repeat from an affected father. The presented case, which shows paternal transmission of HD, exemplifies this, with the patient inheriting a 68 CAG repeat allele- an increase of 11 from the father's 57 CAG repeats. REFERENCES Andrew, S. E., Y. P. Goldberg, B. Kremer, H. Telenius, J. Theilmann, S. Adam, E. Starr, F. Squitieri, B. Lin, M. A. Kalchman, R. K. Graham, and M. R. Hayden (1993). The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet 4: 398-403. Byers, R. K., and J. A. Dodge (1967) Huntington's chorea in children. Report of four cases. Neurology 17: 587-96. Byers, R. K., F. H. Gilles, and C. Fung (1973). Huntington's disease in children. Neuropathologic study of four cases. Neurology 23: 561-9.

Duyao, M., C. Ambrose, R. Myers, A. Novelletto, F. Persichetti, M. Frontali, S. Folstein, C. Ross, M. Franz, M. Abbott, J. Gray, P. Conneally, A. Young, J. Penney, Z. Hollingsworth, I. Shoulson, A. Lazzarini, A. Falek, W. Koroshetz, D. Sax, E. Bird, J. Vonsattel, E. Bonilla, J. Alvir, J. Bickham Conde, J.-H. Cha, L. Dure, F. Gomez, M. Ramos, J. Sanchez-Ramos, S. Snodgrass, M. de Young, N. Wexler, C. Moscowitz, G. Penchaszadeh, H. MacFarlane, M. Anderson, B. Jenkins, J. Srinidhi, G. Barnes, J. Gusella, and M. MacDonald (1993) Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet 4: 387-92. Goldberg, Y. P., S. E. Andrew, L. A. Clarke, and M. R. Hayden (1993) A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington disease. Hum Mol Genet 2: 635-6. Huntington's, Disease, Collaborative, Research, and Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971-983. Kremer, B., P. Goldberg, S. E. Andrew, J. Theilmann, H. Telenius, J. Zeisler, F. Squitieri, B. Lin, A. Bassett, E. Almqvist, and et al. (1994) A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats [see comments]. N Engl J Med 330: 1401-6. Nance, M. A. (1996). Huntington disease--another chapter rewritten. Am J Hum Genet 59: 1-6. Rubinsztein, D. C., J. Leggo, R. Coles, E. Almqvist, V. Biancalana, J. J. Cassiman, K. Chotai, M. Connarty, D. Crauford, A. Curtis, D. Curtis, M. J. Davidson, A. M. Differ, C. Dode, A. Dodge, M. Frontali, N. G. Ranen, O. C. Stine, M. Sherr, M. H. Abbott, M. L. Franz, C. A. Graham, P. S. Harper, J. C. Hedreen, M. R. Hayden, and et al. (1996) Phenotypic characterization Of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet 59: 16-22. Snell, R. G., J. C. MacMillan, J. P. Cheadle, I. Fenton, L. P. Lazarou, P. Davies, M. E. MacDonald, J. F. Gusella, P. S. Harper, and D. J. Shaw (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet 4: 393-7. Contributed by Wolfgang T. Hofgrtner MD, Albert R. La Spada, MD, PhD, and Jonathan F. Tait, MD, PhD. ************************************************************************************************ Online Mendelian Inheritance in Man (OMIM)

http://life.nthu.edu.tw/~g854229/INHERITANCE

Welcome to OMIM(TM), Online Mendelian Inheritance in Man. This database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by NCBI, the National Center for Biotechnology Information. The database contains textual information, pictures, and reference information. It also contains copious links to NCBI's Entrez database of MEDLINE articles and sequence information. In 2 families with Huntington disease linked to the short arm of chromosome 4, Sax et al. (1989) demonstrated remarkable intrafamilial variability. In 1 family, affected persons of 3 generations showed a 50-year variation in age of onset. The member with the latest onset (at age 67) died at age 91 with autopsy-confirmed HD. The next generation had hypotonic chorea beginning in the fourth decade with death in the fifth. In the third generation, a rigid patient, inheriting the illness from an affected father, had onset at age 16, while her sibs had chorea beginning in the third decade. In the second family, several members had cerebellar signs as well as chorea and dementia; MRI and CT showed olivopontocerebellar and striatal atrophy. Whether these phenotypes are the result of different allelic genes at the HD locus or of unlinked autosomal modifying loci is unknown. Kerbeshian et al. (1991) described a patient with childhood-onset Tourette syndrome who later developed Huntington disease. Ridley et al. (1988) found that while the mean age of onset in offspring of affected mothers did not differ greatly from that in their mothers, the distribution of age of onset in the offspring of affected fathers fell into 2 groups; the larger group showed an age of onset only slightly younger than that in their affected fathers, and a smaller group had, on average, an age of onset 24 years younger than that of their affected fathers. Analysis of the grandparental origin of the Huntington allele suggested that while propensity to anticipation could be inherited for a number of generations through the male line, it originated at the time of differentiation of the germ line of a male who acquired the Huntington allele from his mother. Ridley et al. (1988) suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of 'genomic imprinting,' that is, in the mechanism by which the parental origin of alleles is indicated (Reik et al., 1987; Sapienza et al., 1987). Adams et al. (1988) also found that the offspring of affected males had significantly younger onset than did offspring of affected females, and a trend suggested an excess of paternal descent among juvenile-onset cases. Ridley et al. (1991) showed that the age of onset varies between families and between paternal and maternal transmission and that rigidity is associated specifically with very early onset, major anticipation, paternal transmission, and young parental age of onset. Major anticipation was defined as an age of onset of the proband more than 15 years less than that in the affected parent. They proposed that age of onset depends on the state of methylation of the HD locus, which varies as a familial trait, and as a consequence of 'genomic imprinting' determined by parental transmission. They

further suggested that young familial age of onset and paternal imprinting occasionally interact to produce a major change in gene expression, that is, the earlyonset/rigid variant. In 2 families with Huntington disease linked to the short arm of chromosome 4, Sax et al. (1989) demonstrated remarkable intrafamilial variability. In 1 family, affected persons of 3 generations showed a 50-year variation in age of onset. The member with the latest onset (at age 67) died at age 91 with autopsy-confirmed HD. The next generation had hypotonic chorea beginning in the fourth decade with death in the fifth. In the third generation, a rigid patient, inheriting the illness from an affected father, had onset at age 16, while her sibs had chorea beginning in the third decade. In the second family, several members had cerebellar signs as well as chorea and dementia; MRI and CT showed olivopontocerebellar and striatal atrophy. Whether these phenotypes are the result of different allelic genes at the HD locus or of unlinked autosomal modifying loci is unknown. Kerbeshian et al. (1991) described a patient with childhood-onset Tourette syndrome who later developed Huntington disease. *********************************************************************************************** International HD Association

http://www.huntington-assoc.com/huntin.htm
JUVENILE HUNTINGTON'S DISEASE In approximately ten percent of cases, HD affects children or adolescents. Children most often inherit the disease from their fathers (adult-onset HD is inherited from both parents with the same frequency). The symptoms of the juvenile form, or Westphal variant, of HD are somewhat different from adult-onset HD. Initial symptoms usually involve slow, stiff and awkward walking and talking, choking, clumsiness and falling. Later, the child may become slow to respond and performance at school may become erratic. The course of the juvenile form is generally more rapid than the adult-onset. *********************************************************************************************** HD Society of Canada

http://www.hsc-ca.org/abouthd.html
What Is Juvenile HD? In hereditary diseases, such as Huntington's, earlier than average onset of symptoms usually means more severe disease. There is usually a shorter course and a greater variety of symptoms. Children with HD show a disorder of movement and posture somewhat different than the usual HD adult, a disorder of mental function, and often a convulsive disorder or tendency to epileptic seizures, something almost never seen in HD adults. The earlier the disease onset, the more likely the child is to be very rigid

and very different in appearance form the majority of adult cases. Clinical symptoms differ between early onset and adult onset HD. In 1969, it was determined that children with HD, both boys and girls, were much more likely to have an affected father than an affected mother. Through research and observation, we are learning more about this rare form of HD each day. For more information, the booklet Living with Juvenile Huntington Disease is available from HSC. ********************************************************************************************** JERRYS LIGHTHOUSE

http://table.jps.net/cgi-bin/cgiwrap/wuf/toc
Neurology 1999 Jan 15;52(2):392-4 Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC Department of Neurosciences, Park Nicollet Clinic, St. Louis Park, MN 55426, USA. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. A patient with juvenile Huntington's disease (HD) of probable maternal inheritance is reported. The expanded IT-15 allele was only detected with the use of modified PCR and Southern transfer techniques, which showed a CAG trinucleotide repeat expansion of approximately 250 repeats-the largest CAG expansion reported within the huntingtin gene. This case emphasizes the Need for communication between the diagnostic laboratory and the clinician to define the molecular genetics of unusual cases. [Juvenile HD is associated with a CAG count of greater that 49 and Paternal inheritance. Here is a large variation. --Jerry 02/06/99]

Mov Disord 1998 Nov;13(6):920-8 Neurophysiological abnormalities in the Westphal variant of Huntington's disease. Topper R, Schwarz M, Lange HW, Hefter H, Noth J Department of Neurology, Technical University of Aachen, Germany. The Westphal variant of Huntington's disease (HD) is a distinct clinical entity of HD characterized by a rigid-hypo kinetic syndrome and is often associated with a juvenile onset of disease. Definite genetic differences between the subtypes of HD have not been delineated so far. Here we present the results of a battery of neurophysiological tests including somatosensory-evoked potentials, blink reflexes, long-latency reflexes, And measurement of saccadic velocities in a Westphal HD patient. Although quantitative assessment of his motor performance showed a severe hypo kinetic syndrome resembling Parkinson's disease, the results of somatosensory-evoked potentials and blink reflexes were indistinguishable from results obtained in hyperkinetic HD patients. Long-latency reflexes, however, which are typically absent in hyper-kinetic HD patients, were retained in this patient. It is concluded that

neurophysiology in HD patients is not a mere reflection of the patient's symptomatology but can give insight into the underlying pathophysiological process. [Wuf, the lighthouse dog, marks his territory by urinating. A psychologist marks his territory by establishing protocols and policies. Your territory is "the best interests of your child and family." Start with the yellow pages to get the nearest Helix or other DNA lab. ]

Am J Hum Genet 1997 Nov;61(5):1163-1168 Laboratory Policies and Practices for the Genetic Testing of Children: A Survey of the Helix Network. Wertz DC, Reilly PR Summary: In order to discover whether laboratories have policies regarding the testing of unaffected children, we surveyed all laboratories registered with Helix, a national network of DNA diagnostic laboratories. Of 186 laboratories asked to respond anonymously to a four-page questionnaire, 156 (84%) replied. A screening question removed 51 laboratories that provided no clinical services. Of the remaining 105, 92% said that their requisition forms asked the person's age. Substantial minorities had policies for the testing of minors for late-onset disorders (46%), for carrier status for recessive disorders (33%), or for disorders for which the test offers no medical benefit within 3 years (33%). Most laboratories are responsive to parental requests. For 12 of 13 late-onset disorders, the majority of laboratories that offered testing had had requests to test children. The majority had tested healthy children, <12 years of age, for eight disorders. Approximately 22% had tested children, <12 years of age, for Huntington disease. Majorities had received requests to test healthy children for carrier status for 10 of 15 recessive or X-linked disorders and had tested children, <12 years of age, for 6 of these disorders, including cystic fibrosis, hemophilia A, fragile X syndrome, and Duchenne muscular dystrophy. Approximately 45% of the laboratories occasionally had provided tests directly to consumers. In view of the possibility that the harms of presymptomatic diagnoses of children sometimes may outweigh the benefits, our results suggest a need for consistent laboratory policies designed for the best interests of the child and the family. [In the US, the duration of juvenile HD is less. This could be due to the excessive use of prescription drugs. --Jerry 02/20/99]

J Neurol Neurosurg Psychiatry 1993 Jan; 56(1):98-100 Duration of illness in Huntington's disease is not related to age at onset. Roos RA, Hermans J, Vegter-van der Vlis M, van Ommen GJ, Bruyn GW Department of Neurology, Academic Hospital, Leiden, The Netherlands. The age at onset and duration of illness were studied in patients with Huntington's disease in the Leiden Roster which at 1 July 1990 contained 2787 patients. Of 1106

patients, 800 deceased and 306 alive, the age at onset was known. The median duration was 16.2 (range 2-45) years. In contrast to the current opinion, the median duration was independent of the age of onset. The median duration in juvenile Huntington's disease was 17.1 years, which is much longer than reported in the literature, and comparable with the categories for the age of onset of 20-34 and 35-49 years. Only in the group where onset was over 50 years of age was the median duration somewhat shorter (15.6 years), which can be ascribed to unrelated causes of death. As age of onset and duration of illness are not related, at least two mechanisms to determine the clinical course have to be postulated: one for age of onset and another for duration of illness. Duration was shorter for males, especially for those with an affected father.

Too Much Too Young From New Scientist, 20 February 1999. By: Janet Fricker "In many cases, we have no real idea of the side effects different drugs produce in children," says Richard Cooke, director of the research unit at the Royal College of Paediatrics and Child Health in London. "If randomized control trials have not been performed, it is impossible to tell whether symptoms are part of the patient's condition or an effect of the drug." Fourty years ago, dozens of children in the US died of a condition known as grey baby syndrome after taking a new antibiotic. The drug, chloramphenicol, had been used to treat blood infections in adults, but had never been tested on children. Doctors did not realise until too late that children's immature livers were incapable of clearing it from their bodies, and toxic levels quickly built up in their bloodstream. Astonishingly, children still face similar risks today. The vast majority of drugs have never been tested on children, forcing doctors to prescribe them "off label"-outside the conditions for which they were licensed. They have to gamble on a child being able to cope with the dosage they prescribe. This also means that liability for the outcome rests with them or their health authority, rather than the drugs company. "Every paediatrician and GP caring for children faces this problem on a daily basis," says Vas Novelli, a consultant in paediatric infectious diseases at Great Ormond Street Hospital in London. "Each is expected to weigh up the pros and cons of using an unlicensed medication, knowing full well that they are taking on the responsibility themselves for any major problems that may occur." "Recent advances in biomedical research have not been translated into advances in child health," says Tim Westmoreland, a Washington lobbyist working with the Elizabeth Glaser Pediatric Aids Foundation in Santa Monica. "For years, doctors and parents have been put in the untenable position of [either] ignoring drugs that are effective in adults or exposing children to drugs of unknown safety."

In 1997 in Britain, a House of Commons health committee on the needs of young people expressed astonishment at this situation. Since then, however, nothing has been done to remedy it. "The present lack of resources and capacity of the workforce to improve knowledge and practice of paediatric drugs is nothing short of a national disgrace," says Al Aynsley-Green, the director of clinical research and development at Great Ormond Street. In the US, an estimated 80 per cent of prescription drugs are not licensed for use in children, according to a 1996 report in Pediatrics (vol 98, p 18). And the National Institute of Child Health and Human Development in Bethesda, Maryland, estimates that only 5 of the 80 drugs most frequently used in infants are licensed for paediatric use. However, the situation is set to change with the Food and Drug Administration's 1997 Modernisation Act, which comes into force on 1 April this year. The act will force drugs companies to provide the FDA with information on the paediatric use of any medicine that may offer children better treatment than existing therapies, or will be widely used by children. Life-threatening The legislation is long overdue, and doctors in Europe are hoping it will encourage similar action there. On both sides of the Atlantic, there has been a string of tragedies resulting from giving children pharmaceuticals that have not been tested on them. In the 1980s, a drug called verapamil was widely used for the treatment of certain heart conditions in children. The drug was approved by the FDA after safety and efficacy tests in adults only. Between 1983 and 1987, reports emerged of lifethreatening adverse reactions, including heart attacks that required resuscitation. The drug is no longer recommended for use in children. More recently, adverse effects have been reported in children taking cisapride, which helps gut contractions and is given every year to thousands of young children who regurgitate their food. Some children who were given unsuitably high doses suffered dangerous heart problems. The manufacturer now plans to test the drug in children. "In many cases, we have no real idea of the side effects different drugs produce in children," says Richard Cooke, director of the research unit at the Royal College of Paediatrics and Child Health in London. "If randomised control trials have not been performed, it is impossible to tell whether symptoms are part of the patient's condition or an effect of the drug." If a drug is not licensed for children, a doctor will often estimate a suitable dose by extrapolating according to body weight from the recommended adult dose. But children are not simply miniature adults--they react to chemicals quite differently. For a start, the way the kidney excretes substances changes in the first few years after birth, with different mechanisms maturing at different times. Because of this, the proportion of a drug that stays in the bloodstream depends on the age of a child.

The same applies to the liver, where enzyme systems that detoxify drugs mature at different times. Thus the ability of the body to break down drugs also varies with age. In addition, the proportion of water in the body changes dramatically during the first two years of life, which affects the concentration of a drug. Finally, children's ability to respond to a drug may be different. The organ upon which it is supposed to work may be immature, says Robert Ward, a paediatric pharmacologist at the University of Utah in Salt Lake City. Market forces There are two main reasons why pharmaceuticals companies are reluctant to test their drugs on children. First, there is not much money to be made. Children consume small quantities of drugs and are a small proportion of the market. Secondly, parents are generally reluctant to allow their children to take part in clinical trials. For example, this month the Public Health Laboratory Service in Britain announced that trials of a new children's meningitis vaccine had been delayed for up to a year because only half the 2000 volunteers needed had been recruited. In particular, they lacked recruits aged three to four. But in the US, drugs companies will soon have an incentive to overcome these difficulties. As part of the new Act, for 493 drugs that the FDA considers a priority, companies will be granted a six-month extension of their patents, in exchange for comprehensive paediatric data. This could be lucrative: a 1993 report estimated that for an average drugs company, each year of exclusivity is worth $100 million. However, this deal will not help with drugs whose patents have expired and that can now be produced by any company. Without market exclusivity, there would be no financial incentive for the original patent holders to do trials in children. Despite the lack of legislation in Britain, there is momentum for change. The Royal College of Paediatrics and Child Health is producing Medicines for Children, the first formulary with data on drugs prescribed for children. The dossier, due to be published in the spring, will provide information on how drugs should be used and their common complications. And last August, Aynsley-Green and four colleagues set up the British Forum for Use of Medicine in Childhood. Their aim is to improve research, development and training in paediatric pharmacology, and to make sure doctors get the information they need. Such action is desperately needed to prevent children being treated as what Harry Shirkey, former chairman of paediatrics at the Children's Hospital in Birmingham, Alabama, described 30 years ago as "pharmaceutical orphans."

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Neurology 1997 Oct;49(4):1048-1053 Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing Group. Nance MA, Hennepin County Medical Center, Minneapolis, MN, USA. http://www.medscape.com/server-java/MedLineApp?/membersearch/getdoc.cgi?ord=11&searchid=9&have_local_holdings_file=0& local_journals_only=1

Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing Group. Nance MA [Medline record in process] We reviewed 44 symptomatic children tested for CAG repeat expansions in the gene responsible for Huntington's disease (HD). Thirty-three patients had CAG repeat expansions, and 11 did not. No patient with a CAG repeat expansion had a negative family history of HD. Of the 15 patients presenting in the first decade, 12 had greater than 80 CAG repeats and a clinical profile at the time of the test that included two or more of the following: declining school performance, seizures, oral motor dysfunction, rigidity, and gait disorder. Three patients with smaller CAG repeat expansions had incomplete or atypical symptom profiles. Symptom patterns in patients presenting in the second decade were more varied but usually included behavioral and motor symptoms. Patients without CAG expansions had incomplete or atypical symptom profiles. We define the historical and clinical profiles of HD presenting in the first two decades and suggest that physicians exercise restraint in using a "diagnostic" gene test for HD in the evaluation of at-risk children with incomplete or atypical symptom profiles or no family history of HD, in whom test results are very likely to be normal or unrelated to the patient's symptoms.

Arch Neurol 1998 Jun;55(6):835-43 (ISSN: 0003-9942) Severity of cognitive impairment in juvenile and late-onset Huntington disease. Gomez-Tortosa E; del Barrio A; Garcia Ruiz PJ; Pernaute RS; Benitez J; Barroso A; Jimenez FJ; Garcia Yebenes J Department of Neurology, Fundacion Jimenez Diaz, Madrid, Spain. http://www.medscape.com/server-java/MedLineApp?/membersearch/getdoc.cgi?ord=42&searchid=5&have_local_holdings_file=0&local_journals_o nly=1

OBJECTIVES: To compare the severity of cognitive impairment among groups of patients with different age ranges at the onset of Huntington disease (HD) and to evaluate the variable influence of motor and cognitive deficits on functional disability across different ages at the onset of HD.

DESIGN: Cross-sectional multidisciplinary evaluation of patients referred to our institution for care related to a possible diagnosis of HD. SETTING: The Huntington disease program in the Departments of Neurology and Genetics at the Fundacion Jimenez Diaz, Madrid, Spain. PARTICIPANTS: Seventy-one patients with Huntington disease were classified into 3 groups depending on age at onset of motor symptoms: juvenile onset, 25 years of age or younger (group 1, n = 15); adult onset, from 26 to 50 years (group 2, n = 43); and late onset, 51 years or older (group 3, n = 13). Age- and education-matched controls (n=50) were included to compare cognitive performance with patients in groups 1 and 3. MEASURES: Cognitive evaluation encompassed a wide neuropsychological battery to assess global cognitive functioning and visuospatial, prefrontal, and memory functions. Clinical data included motor and functional variables measured by using the Unified Huntington's Disease Rating Scale. Genetic analysis determined the number of CAG trinucleotide repeats. RESULTS: Patients in group 1 scored 2.9 points and patients in group 3 scored 4.2 points below their respective controls on the Mini-Mental State Examination. Patients in groups 1 and 3 were similarly impaired in verbal memory. Visual function was much more impaired in patients in group 3, and prefrontal functions were slightly worse in patients in group 1. Cognitive scores were correlated only with time of evolution for patients in group 2. Functional scores were not significantly different among the 3 groups, but 11 (85%) of the patients in group 3 were in stage I or II vs 10 (67%) of the patients in group 1. Total functional capacity correlated better with the Mini-Mental State Examination score for patients in group 3 and with motor deficits (akinesia) and prefrontal dysfunction for patients in group 1. The mean+/-SD CAG repeat length decreased from 59.9+/-12.6 for patients in group 1 to 46.2+/-3.5 for patients in group 2 and 41.7+/-2.6 for patients in group 3. Longer CAG repeats in the HD study population correlated with akinetic features but not with cognitive performance.

CONCLUSIONS: Despite the much greater genetic defect, cognitive status is slightly better preserved in patients with juvenile-onset HD. Cognitive impairment in patients with juvenile- and late-onset HD differs in the severity of visual and prefrontal deficits. Functional disability in patients with late-onset HD depends more on global cognitive status, while in patients with juvenile-onset HD, it is conditioned more by motor deficits and prefrontal dysfunction. ************************************************************************************************* Clinical Presentations of Huntington's Disease Abstract: Huntington's Disease Workshop, Houston, TX, Joseph Jankovic, M.D.) About 10% of HD cases have their onset before age 20, but the typical peak age at onset is in the 4th and 5th decade. Young-onset patients usually inherit the disease from their father while older- onset patients are more likely to inherit the gene from their mother. Juvenile HD (onset of symptoms before 20 years) typically presents with the combination of progressive parkinsonism, dementia, ataxia, and seizures. In contrast, adult HD usually presents with the insidious onset of clumsiness and adventitious movements which may be wrongly attributed to simple nervousness. Slowness of movement (bradykinesia) is usually evident in patients with the rigid form of HD, but when it coexists with chorea it may not be fully appreciated on a routine examination. While bradykinesia is most pronounced in the rigid-akinetic patients, it is also evident in patients with the typical choreic variety of HD. When bradykinesia predominates, the patients exhibit parkinsonian findings some of which may be subtle. Micrographia may be one manifestation of underlying parkinsonism; when chorea predominates the handwriting is characterized by macrographia. Bradykinesia in HD may be an expression of "post-synaptic parkinsonism" and possibly explains why a reduction in chorea with anti-dopaminergic drugs rarely improves overall motor functioning and indeed may cause an exacerbation of the motor impairment. The natural course and prognosis of HD is quite variable: duration of illness from onset to death is about 15 years for adult HD and 8 to 10 years for the juvenile variant. Clinical-pathological studies have demonstrated strong inverse correlation between the age at onset and the severity of striatal degeneration. A review of clinical and pathological data in HD patients showed that patients with juvenile-adolescent onset had much more aggressive progression of the disease than patients with onset in middle and late life. Progressive motor dysfunction, dementia, dysphagia, and incontinence eventually lead to institutionalization and death from aspiration, infection, and poor nutrition.

The Juvenile HD Handbook-A Guide for Physician's, Neurologist and Other Professionals The HDSA published "The Juvenile HD Handbook-A Guide for Physician's, Neurologist and Other Professionals" (and of course families) that was released this summer. It also has the video: Claudia's Challenge that can be ordered. This is an EXCELLENT resource on JHD. The cost for the guide is $6.00 and can be ordered by calling the HDSA at (800) 345-4372 and asking for Anita Mark-Paul at ext. 19. Or, you can send her an email at amarkpau@hdsa.org . **********************************************************

Huntington's and Me - A Guide for Young People

New from Alison Gray - the author of "Genes and Generations" - "Huntington's and Me - A Guide for Young People" is full of information, thoughts, feelings and strategies for coping. "You have nothing to lose but fear. Fear is a lack of understanding. Get the knowledge. As young people, we need discussion, love, understanding, and most importantly, support ..." Sara Available Now! "Huntington's and Me - A Guide for Young People" is published by the Huntington's Disease Association, Wellington, New Zealand and is available from our UK Head Office at the cost of 5.00 including post and package. To order simply click the link below, print out the order form and send with an enclosed cheque to the HAD: http://www.hda.org.uk/news/nw005.html

The Juvenile HD Caregivers Club has been opened up on Yahoo. You can join this discussion by clicking on the link below and following the instructions:

http://clubs.yahoo.com/clubs/juvenilehdcaregiverclub