American Journal of Medical Genetics 39:l-3 (1991)
Huntington Disease and Childhood-Onset Tourette Syndrome Jacob Kerbeshian, Larry Burd, Cindi Leech, and Anne Rorabaugh Child Evaluation and Treatment Program, Medical Center Rehabilitation Hospital (L.B., C.L.), and Department of Neuroscience, University of North Dakota School of Medicine (J.K., L.B., A.R.), Grand Forks, North Dakota
brothers are ages 39 and 33. Recently, one brother has begun to experience behaviors consistent with a cyclic mood disorder, according to history provided by the father. E.T.’s mother died at age 46 years after a long illness. Her symptoms started approximately 15 years before her death. These included frequent headaches, an awkward gait that was wide-based and stiff-legged, infrequent eye movment, and frequent holding of the head forward with rubbing of the face with her hands. She KEY WORDS: tics, HD, dementia, tourette was quite apathetic and extremely withdrawn in the 6 syndrome years prior to her death. During the final 3 years of her life she was in a state hospital. Her father reported that she was given a diagnosis of “Lou Gehrig’s disease.” The INTRODUCTION validity of this diagnosis is uncertain. This woman’s Tourette syndrome (TS) has a n onset before age 21 records are not available for review. The patient’s uncle years, with a waxing and waning course of multiple on the maternal side was hospitalized with a diagnosis motor and phonic tics. These tics are temporarily sup- of schizophrenia and died from heart difficulties a t age pressible and are not due to other medical conditions 36 years. The uncle went to autopsy, and it was not (DSM-111-R 1987). Huntington disease (HD) is also a though that he had findings of HD. The patient’s materdyskinetic disorder, which has both a juvenile and a n nal grandmother died at age 24 years in the midst of a n adult onset. The chorea is accompanied by a dementing influenza epidemic. We did not have these records for process. review. Both syndromes are thought to be due to basal ganglia E.T. reported the onset of his movements to be before dysfunction. Alterations in dopaminergic neuro- age 10 years. He has had considerable difficulty since transmission have been implicated in both HD and TS. then, with severe motor and phonic tics. These have had The gene for HD has been localized to chromosome 4. a waxing and waning course, tending to disappear for a There is speculation that TS may be localized to a spe- while only to reappear again. They involved eye blinkcific genetic locus or multiple loci [Comings, 1990; Pauls ing, throat clearing, shoulder jerking, and other simple and Leckman, 19871. The cooccurrence of childhood- motor and phonic tics. The movements are suppressible onset TS and adult onset HD has not to our knowledge both on observation and by E.T.’s report. The movebeen reported previously. In that significant efforts are ments steadily proliferated and intensified over the underway to locate a candidate gene for TS and the gene years and became the source of a great deal of distress. for HD is known, study of individuals with both disor- He has been treated in the past for both alcohol and ders may be of considerable interest. substance abuse, including stimulant abuse. In the past 10 years, the patient has been on multiple CLINICAL REPORT medications, including clonidine, haloperidol, chlorE.T. first presented for evaluation a t age 26 years with diazepoxide, and thioridazine, all without relief of his concerns about a long-standing movement disorder with symptoms. Earlier, on physical examination, the patient a fluctuating course. E.T. was one of 4 sibs. A sister is 41 was a thin, 40-year-old, well developed, somewhat unyears old and the patient is 43 years. Two younger kempt man. Mental status examination indicated that he was oriented to person, place, and time. He knew the names of the president and of the president’s wife. He Received for publication February 2,1990; revision received July could name the presidents back to Johnson. He was able 5, 1990. to recall 2 of 3 objects a t 5 min. He could repeat 7 Address reprint requests to Larry Burd, Child Evaluation and Treatment Program, Medical Center Rehabilitation Hospital, 1300 numbers forward and 3 numbers backward. He had difficulty with simple calculations; he was unable to calcuSouth Columbia Road, Grand Forks, ND 58202.
A 40-year-oldman with childhood-onset Tourette syndrome (TS)developed Huntington disease (HD). We believe this to be the first reported case of childhood-onset TS with adult onset HD. Discovery of other cases with both disorders may provide clues to the pathophysiology of both conditions.
0 1991 Wiley-Liss, Inc.
2
Kerbeshian et al.
late how many nickels there are in a dollar or how many nickels there are in four dollars. He was able to subtract $1.25 from $5.00 accurately, and he interpreted proverbs and similarities appropriately, but concretely. Cranial nerve examination showed full visual fields. The optics discs were normal. There was no evidence of Kayser-Fleischer rings. He had very impaired saccades and very abnormal optokinetic nystagmus and was unable to maintain forced eye closure for more than 2-3 sec. He was able to protrude his tongue for only 10 sec, and he had difficulty maintaining arm extension. The rest of the cranial nerve examination was remarkable only for a moderate dysarthria. Motor examination showed normal strength. Tone was normal. Rapid alternating movements were moderately decreased bilaterally. Reflexes were 3 + in all limbs, and the plantar responses were flexor. During the motor examination, choreiform movements were noted in all limbs, the trunk, and the face as well a s mild to moderate dystonic posturing of the arms and legs. The patient had a n irregular, somewhat wide-based gait, with superimposed choreiform movements in all limbs. He was able to tandem walk with difficulty. He had mild dystonic posturing during examination of his gait. Sensory examination was normal. Chromosome studies of peripheral blood demonstrated a karyotype of 46,XY/46,XY,fra(16)(q22)in 12% of the cells analyzed. The presence of these fragile sites on autosomes has been reported in phenotypically normal individuals, and the clinical significance of these sites is presently unknown. The impression on physical examination was that the patient has a movement disorder with all the classic features of HD, including abnormal eye movements, abnormal fine motor coordination, and involuntary movements characterized by choreiform movements of all limbs, trunk, and face. He also has abnormal vocalizations, which are a feature of HD because of abnormal diaphragmatic contractions but are also seen in tic disorders. Neuropsychological consultation was consistent with a subcortical dementia. Comparison of his computed tomography (CT) scans 3 years apart found progressive atrophy of the caudate. Neurocanthocytosis was considered, but laboratory results were negative. His has been a relentlessly progressive condition, with severe dementia and incapacitating chorea now rendering this man unable to care for himself. More recently, age 43 years, he was placed in a nursing home for demented patients with HD. He has been seen by 3 neurologists, all of whom have made a diagnosis of HD.
DISCUSSION The issue of whether this patient may have had 2 movement disorders, TS followed by HD, or one movement disorder with HD presenting as TS, is particularly difficult. Confirmation of the diagnosis of HD likely will await autopsy. Brooks et al. [19871 have noted that the symptoms of early-onset HD may be frequently overlooked. The childhood onset of symptoms in HD ranges from 1%to 10% [Stevens, 1976; Oliver, 19701. Hayden and Beighton [1982] found that fewer than 5% of 2,699 cases they reviewed had begun before age 20 years. In our patient it appears that TS symptoms were the
earliest presentation of his movement disorder. This had a characteristic waxing and waning course. It was in the patient’s early adult life and during the stress of army life with substance abuse that his HD symptoms came to the fore. In this patient the early onset of tic symptoms, his ability to suppress these movements, and the waxing and waning course argue against HD being responsible for his early abnormal movements. The 25 year span between onset of his motor symptoms and severe dementia also argues against HD being the appropriate diagnosis for his childhood movement disorder. On average, patients with HD live between 10 and 20 years from symptom onset [Kurtzke, 1975; Burch, 19751. E.T. does have a marked dementia a t this time, which is not characteristic of TS but has been reported [Guinon, 1886, 1887; Chabbert, 18931. The idea that there may be a hereditary degeneration associated with TS has been discussed by Shapiro et al. 119881, who have suggested that this is a rare occurrence. There are examples of the cooccurence of chorea and tics [Creak and Guttmann, 19351. Neuroacanthocytosis is another such example [Spitz et al., 19851.HD in adult patients with adult onset of motor and phonic tics has been previously reported [Sacks, 1982; Tolosa and Pena, 1988; Kurlan et al., 19891. The pathophysiological basis for these 2 movement disorders is interesting. Both are on a continuum in the dopaminergic system of the basal ganglia. Carbamazepine, which enhances presynaptic release of dopamine by striatal neurons, has been reported to cause tics in a patient with HD, which resolved when the drug was discontinued [Kurlan et al., 19891. HD is associated with atrophy of the cadaute, which has been observed and documented by CT scans in this patient. It is of considerable interest that a patient with both HD and TS symptoms had a t autopsy the expected striatal changes but also lesions in the medial thalamus [Sacks, 19821. In a patient with Hallervorden-Spatz disease, who also had chorea, myoclonus, tics, compulsive movements, and Tourette-like phonic tics, changes in the globus pallidus, substantia nigra, and corpus callosum axons have been reported [Sacks, 19821. HD is a low-frequency condition, estimated at 1 per 18,000 [McKhann, 19791. Assuming a n equal distribution between males and females, the frequency of HD in males would also be 1 per 18,000. In North Dakota children, the prevalence of TS in boys was estimated to be 1 per 1,000 [Burd et al., 19861. Comings [19901 has estimated a prevalence for boys as high as 1per 100. The probablity of a chance cooccurrence for the 2 conditions would thus range from 10- x 5.6 x 10- ( = 5.6 x 10to 10- x 5.6 x 10- ( = 5.6 x 10- 7 ) . The chance cooccurrence of these 2 conditions would approximate 6 per 100,000,000 to 6 per 10,000,000. Although the presence of both TS and HD in our patient does not necessarily point to a common or related primary etiology, there still may be a pathophysiologic relationship between the expression of TS and HD. If the HD gene and the putative TS gene channel into similar biochemical pathways, one might predict that someone with a typical childhood onset of TS might have a n earlier onset of symptoms of HD. Our patient’s HD symptoms started while he was in
Huntington Disease a n d Tourette Syndrome the army, a t a n unusually early age for HD. Kurlan et al. [1989] also reported a woman who by age 25 years had developed severe HD. An alternative hypothesis is that exposure to stimulants and other drugs of abuse might have kindled the earlier emergence of HD in our patient. Conversely, assuming complementary pathophysiology between TS and HD, one could predict a particularly severe course of TS in someone with the HD gene. Our patient’s tic symptoms were severe. The apparent mutual exacerbation of TS and HD symptoms in our patient would be of interest if one could identify a potential pathophysiologic hypothesis for these events. The brains of victims with HD have been found to have elevated levels of the biosynthetic enzyme 3-hydroxyanthranilate oxygenase. This enzyme is particularly present in the striatum, which exhibits the most prominent nerve cell loss in HD [Schwarcz et al., 19881. The immediate product of this enzyme, quinolinic acid, a metabolite of tryptophan, is also likely to be at increased levels in the striatums of victims of HD. Quinolinic acid demonstrates a spectrum of neurotoxicity similar to that of other excitotoxins, such as kainic acid [Schwarcz et al., 1988; Davies et al., 1988; Coyle, 19831. Excitotoxins cause repeated depolarization of neurons, resulting in neuronal swelling and degradation. The action of kainic acid has been shown to be localized in dendrites and cell bodies, sparing axons with dendrites and cell bodies originating in nuclei a t a distance from the concentration of the excitotoxin. A concentration of the excitotoxin quinolinic acid in the striatum would be expected to lead to a depletion of inhibitory GABAergic neurons in cell bodies in the striatum, resulting in less opposition to neurotransmission by nigrostriatal dopaminergic neurons synapsing in the striatum. One result could be the expression of HD symptomatology. Comings 119903 has proposed a candidate gene for TS to be the gene leading to elevated levels of the enzyme tryptophan oxygenase. Elevated levels of tryptophan oxygenase would result in a shift of typtophan metabolism from the serotonin pathway to the kynurenine pathway. There would be a subsequent increase in levels of quinolinic acid, which is the further metabolic product of kynurenine. As has been noted, quinolinic acid has activity a s a neuroexcitant and a neurotoxin. Excitation, depletion without degradation, and recovery of inhibitory GABAergic neurons in the striatum as triggered by perhaps fluctuating activity of quinolinic acid could result in varying levels of opposed neurotransmissin by dopaminergic neurons. The result could be the waxing and waning of dopaminergic-triggered tics. In our patient, one could hypothesize that a genetic diathesis for TS was expressed by levels of quinolinic acid increasing gradually, resulting first in TS and later in the expression of the HD diathesis as there occurred a n accumulated loss of striatal GABAergic neurons. Another alternative is that our patient’s childhood-onset TS was a phenocopy and the first sign of his HD due to a neuroexcitatory and neuronal damageidepletion process, such as the action of quinolinic acid on the dendrites and cell bodies in the striatum. With the passage of time and the accumulation of striatal neuronal dam-
3
age, one would begin to see the more characteristic choreiform and dementing symptoms of HD. Study of other individuals with both TS and HD may help to support or refute our speculations and shed further light on the relationship between these disorders a t the level of pathophysiology and perhaps a t the level of genetic etiology.
ACKNOWLEDGMENTS This work was supported by the Medical Center Rehabilitation Hospital Foundation (Grand Forks, ND).
REFERENCES Brooks DS. Muruhv D. Janota I. Lushman WA (1987): Earlv-onset Huntington’s’ chorea: Diagnostic clues. Br J Psyihiatry 151:850-852. Burch PRJ (1975):Huntington’s disease: Types, frequency and progression. In Chase TN, Wexler NS, Barbeau A (eds): “Advances In Neurology: Huntington’s Disease.” New York: Raven Press, Vol23, pp 43-57. Burd L, Kerbeshian J, Wickenheiser M, Fisher W (1986):A Prevalence Study of Tourette Syndrome in North Dakota School-Age Children. J Am Acad Child Psychiatry 25:552-553. Chabbert L (1893): [Burd e t al., (198611: De La maladie des tics (tics, choree, hysterie: diagnostique). Arch Neurol 25:lO-41. Comings DE (1990): “Tourette Syndrome and Human Behavior.” Dua r k , CA: Hope Press. Coyle J T (1983): Neurotoxic action of kainic acid. J Neurochem 41:l-11. Creak M, Guttmann E (1935):Chorea, tics and compulsive utterances. J Ment Sci 81:834-839. Davis S, Roberts, Beal MF, Kowall NW, Swartz K J , Ferrante RJ, Martin J B (19881: Model of Huntington’s disease. Science 241:474-475. Guinon G (1887): Sur la maladie des tics convulsifs. Fkv Med (350-80. Guinon G (1887): Tics convulsifs et hysteria. Rev Med 7:509-519. Hayden MR, Beighton P (1982): Genetic aspects of Huntington’s chorea: Results ofa National Survey. Am J Med Genet 11:135-141. Kurlan R, Kersun J , Behr J, Leibovici A, Tariot P, Lichter 0,Shoulson I (1989): Carbamazebine-inducted tics. Clin Neuropharmacol 12:298-302. Kurtzke JF (1975): Hayden M Beighton (1982):Huntington’s disease: Mortality and morbidity data from outside the United States. In Chase TN, Wexler NS, Barbeau A (eds):“Advances in Neurology: Huntington’s Disease.” New York: Raven Press, Vol 43. p 57. McKhann GM (1979):Huntington’s chorea. In Bergsma D (ed):“Birth Defects Compendium.” New York: Alan E. Liss, Inc., p 531. Oliver J E (1970):Huntington’s chorea in Northhamptonsire. Br J Psychiatry 166:244-253. Pauls DL, Leckman JF (1987):The inheritance of Gilles de la Tourette syndrome and associated behaviors: Evidence for autosomal dominant transmission. N Engl J Med 315:1347-1348. Sacks 0 (1982): Acquired tourettism in adult life. In Friedhoff AJ, Chase T N (eds): “Advances i n Neurology: Gilles de l a Tourette Syndrome.” New York: Raven Press,Vol 35, pp 89-92. Schwarcz R, Okuno E, White R J , Bird ED, Whetsell WO J r (19881: 3-Hydroxyanthranilate oxygenase activity is increased in the brains of Huntington disease victims. Proc Natl Acad Sci USA 85:4079-4081. Shapiro AK, Shapiro ES, Young J G , Feinberg TC (1988):“Gilles de la Tourette Syndrome, 2nd ed.” New York: Raven Press. Spitz MC, Jankovic J, Killian J M (1985):Familial tic disorder, Parkinsonism, motor neuron disease and acanthocytosis. A new syndrome. Neurology 35:316-370. Steven DL (1976): Huntington’s chorea: A demographic, genetic and clinical study. MD thesis, University of London. Tolosa E, Pena J (19881: Involuntary vocalizations i n movement disorders. In Jankovic J , Tolosa E (eds): “Advances in Neurology: Facial Dyskinesia.” New York: Raven Press, Vol 49, pp 343-363.
Huntington Disease and Childhood-Onset Tourette Syndrome Jacob Kerbeshian, Larry Burd, Cindi Leech, and Anne Rorabaugh Child Evaluation and Treatment Program, Medical Center Rehabilitation Hospital (L.B., C.L.), and Department of Neuroscience, University of North Dakota School of Medicine (J.K., L.B., A.R.), Grand Forks, North Dakota
brothers are ages 39 and 33. Recently, one brother has begun to experience behaviors consistent with a cyclic mood disorder, according to history provided by the father. E.T.’s mother died at age 46 years after a long illness. Her symptoms started approximately 15 years before her death. These included frequent headaches, an awkward gait that was wide-based and stiff-legged, infrequent eye movment, and frequent holding of the head forward with rubbing of the face with her hands. She KEY WORDS: tics, HD, dementia, tourette was quite apathetic and extremely withdrawn in the 6 syndrome years prior to her death. During the final 3 years of her life she was in a state hospital. Her father reported that she was given a diagnosis of “Lou Gehrig’s disease.” The INTRODUCTION validity of this diagnosis is uncertain. This woman’s Tourette syndrome (TS) has a n onset before age 21 records are not available for review. The patient’s uncle years, with a waxing and waning course of multiple on the maternal side was hospitalized with a diagnosis motor and phonic tics. These tics are temporarily sup- of schizophrenia and died from heart difficulties a t age pressible and are not due to other medical conditions 36 years. The uncle went to autopsy, and it was not (DSM-111-R 1987). Huntington disease (HD) is also a though that he had findings of HD. The patient’s materdyskinetic disorder, which has both a juvenile and a n nal grandmother died at age 24 years in the midst of a n adult onset. The chorea is accompanied by a dementing influenza epidemic. We did not have these records for process. review. Both syndromes are thought to be due to basal ganglia E.T. reported the onset of his movements to be before dysfunction. Alterations in dopaminergic neuro- age 10 years. He has had considerable difficulty since transmission have been implicated in both HD and TS. then, with severe motor and phonic tics. These have had The gene for HD has been localized to chromosome 4. a waxing and waning course, tending to disappear for a There is speculation that TS may be localized to a spe- while only to reappear again. They involved eye blinkcific genetic locus or multiple loci [Comings, 1990; Pauls ing, throat clearing, shoulder jerking, and other simple and Leckman, 19871. The cooccurrence of childhood- motor and phonic tics. The movements are suppressible onset TS and adult onset HD has not to our knowledge both on observation and by E.T.’s report. The movebeen reported previously. In that significant efforts are ments steadily proliferated and intensified over the underway to locate a candidate gene for TS and the gene years and became the source of a great deal of distress. for HD is known, study of individuals with both disor- He has been treated in the past for both alcohol and ders may be of considerable interest. substance abuse, including stimulant abuse. In the past 10 years, the patient has been on multiple CLINICAL REPORT medications, including clonidine, haloperidol, chlorE.T. first presented for evaluation a t age 26 years with diazepoxide, and thioridazine, all without relief of his concerns about a long-standing movement disorder with symptoms. Earlier, on physical examination, the patient a fluctuating course. E.T. was one of 4 sibs. A sister is 41 was a thin, 40-year-old, well developed, somewhat unyears old and the patient is 43 years. Two younger kempt man. Mental status examination indicated that he was oriented to person, place, and time. He knew the names of the president and of the president’s wife. He Received for publication February 2,1990; revision received July could name the presidents back to Johnson. He was able 5, 1990. to recall 2 of 3 objects a t 5 min. He could repeat 7 Address reprint requests to Larry Burd, Child Evaluation and Treatment Program, Medical Center Rehabilitation Hospital, 1300 numbers forward and 3 numbers backward. He had difficulty with simple calculations; he was unable to calcuSouth Columbia Road, Grand Forks, ND 58202.
A 40-year-oldman with childhood-onset Tourette syndrome (TS)developed Huntington disease (HD). We believe this to be the first reported case of childhood-onset TS with adult onset HD. Discovery of other cases with both disorders may provide clues to the pathophysiology of both conditions.
0 1991 Wiley-Liss, Inc.
2
Kerbeshian et al.
late how many nickels there are in a dollar or how many nickels there are in four dollars. He was able to subtract $1.25 from $5.00 accurately, and he interpreted proverbs and similarities appropriately, but concretely. Cranial nerve examination showed full visual fields. The optics discs were normal. There was no evidence of Kayser-Fleischer rings. He had very impaired saccades and very abnormal optokinetic nystagmus and was unable to maintain forced eye closure for more than 2-3 sec. He was able to protrude his tongue for only 10 sec, and he had difficulty maintaining arm extension. The rest of the cranial nerve examination was remarkable only for a moderate dysarthria. Motor examination showed normal strength. Tone was normal. Rapid alternating movements were moderately decreased bilaterally. Reflexes were 3 + in all limbs, and the plantar responses were flexor. During the motor examination, choreiform movements were noted in all limbs, the trunk, and the face as well a s mild to moderate dystonic posturing of the arms and legs. The patient had a n irregular, somewhat wide-based gait, with superimposed choreiform movements in all limbs. He was able to tandem walk with difficulty. He had mild dystonic posturing during examination of his gait. Sensory examination was normal. Chromosome studies of peripheral blood demonstrated a karyotype of 46,XY/46,XY,fra(16)(q22)in 12% of the cells analyzed. The presence of these fragile sites on autosomes has been reported in phenotypically normal individuals, and the clinical significance of these sites is presently unknown. The impression on physical examination was that the patient has a movement disorder with all the classic features of HD, including abnormal eye movements, abnormal fine motor coordination, and involuntary movements characterized by choreiform movements of all limbs, trunk, and face. He also has abnormal vocalizations, which are a feature of HD because of abnormal diaphragmatic contractions but are also seen in tic disorders. Neuropsychological consultation was consistent with a subcortical dementia. Comparison of his computed tomography (CT) scans 3 years apart found progressive atrophy of the caudate. Neurocanthocytosis was considered, but laboratory results were negative. His has been a relentlessly progressive condition, with severe dementia and incapacitating chorea now rendering this man unable to care for himself. More recently, age 43 years, he was placed in a nursing home for demented patients with HD. He has been seen by 3 neurologists, all of whom have made a diagnosis of HD.
DISCUSSION The issue of whether this patient may have had 2 movement disorders, TS followed by HD, or one movement disorder with HD presenting as TS, is particularly difficult. Confirmation of the diagnosis of HD likely will await autopsy. Brooks et al. [19871 have noted that the symptoms of early-onset HD may be frequently overlooked. The childhood onset of symptoms in HD ranges from 1%to 10% [Stevens, 1976; Oliver, 19701. Hayden and Beighton [1982] found that fewer than 5% of 2,699 cases they reviewed had begun before age 20 years. In our patient it appears that TS symptoms were the
earliest presentation of his movement disorder. This had a characteristic waxing and waning course. It was in the patient’s early adult life and during the stress of army life with substance abuse that his HD symptoms came to the fore. In this patient the early onset of tic symptoms, his ability to suppress these movements, and the waxing and waning course argue against HD being responsible for his early abnormal movements. The 25 year span between onset of his motor symptoms and severe dementia also argues against HD being the appropriate diagnosis for his childhood movement disorder. On average, patients with HD live between 10 and 20 years from symptom onset [Kurtzke, 1975; Burch, 19751. E.T. does have a marked dementia a t this time, which is not characteristic of TS but has been reported [Guinon, 1886, 1887; Chabbert, 18931. The idea that there may be a hereditary degeneration associated with TS has been discussed by Shapiro et al. 119881, who have suggested that this is a rare occurrence. There are examples of the cooccurence of chorea and tics [Creak and Guttmann, 19351. Neuroacanthocytosis is another such example [Spitz et al., 19851.HD in adult patients with adult onset of motor and phonic tics has been previously reported [Sacks, 1982; Tolosa and Pena, 1988; Kurlan et al., 19891. The pathophysiological basis for these 2 movement disorders is interesting. Both are on a continuum in the dopaminergic system of the basal ganglia. Carbamazepine, which enhances presynaptic release of dopamine by striatal neurons, has been reported to cause tics in a patient with HD, which resolved when the drug was discontinued [Kurlan et al., 19891. HD is associated with atrophy of the cadaute, which has been observed and documented by CT scans in this patient. It is of considerable interest that a patient with both HD and TS symptoms had a t autopsy the expected striatal changes but also lesions in the medial thalamus [Sacks, 19821. In a patient with Hallervorden-Spatz disease, who also had chorea, myoclonus, tics, compulsive movements, and Tourette-like phonic tics, changes in the globus pallidus, substantia nigra, and corpus callosum axons have been reported [Sacks, 19821. HD is a low-frequency condition, estimated at 1 per 18,000 [McKhann, 19791. Assuming a n equal distribution between males and females, the frequency of HD in males would also be 1 per 18,000. In North Dakota children, the prevalence of TS in boys was estimated to be 1 per 1,000 [Burd et al., 19861. Comings [19901 has estimated a prevalence for boys as high as 1per 100. The probablity of a chance cooccurrence for the 2 conditions would thus range from 10- x 5.6 x 10- ( = 5.6 x 10to 10- x 5.6 x 10- ( = 5.6 x 10- 7 ) . The chance cooccurrence of these 2 conditions would approximate 6 per 100,000,000 to 6 per 10,000,000. Although the presence of both TS and HD in our patient does not necessarily point to a common or related primary etiology, there still may be a pathophysiologic relationship between the expression of TS and HD. If the HD gene and the putative TS gene channel into similar biochemical pathways, one might predict that someone with a typical childhood onset of TS might have a n earlier onset of symptoms of HD. Our patient’s HD symptoms started while he was in
Huntington Disease a n d Tourette Syndrome the army, a t a n unusually early age for HD. Kurlan et al. [1989] also reported a woman who by age 25 years had developed severe HD. An alternative hypothesis is that exposure to stimulants and other drugs of abuse might have kindled the earlier emergence of HD in our patient. Conversely, assuming complementary pathophysiology between TS and HD, one could predict a particularly severe course of TS in someone with the HD gene. Our patient’s tic symptoms were severe. The apparent mutual exacerbation of TS and HD symptoms in our patient would be of interest if one could identify a potential pathophysiologic hypothesis for these events. The brains of victims with HD have been found to have elevated levels of the biosynthetic enzyme 3-hydroxyanthranilate oxygenase. This enzyme is particularly present in the striatum, which exhibits the most prominent nerve cell loss in HD [Schwarcz et al., 19881. The immediate product of this enzyme, quinolinic acid, a metabolite of tryptophan, is also likely to be at increased levels in the striatums of victims of HD. Quinolinic acid demonstrates a spectrum of neurotoxicity similar to that of other excitotoxins, such as kainic acid [Schwarcz et al., 1988; Davies et al., 1988; Coyle, 19831. Excitotoxins cause repeated depolarization of neurons, resulting in neuronal swelling and degradation. The action of kainic acid has been shown to be localized in dendrites and cell bodies, sparing axons with dendrites and cell bodies originating in nuclei a t a distance from the concentration of the excitotoxin. A concentration of the excitotoxin quinolinic acid in the striatum would be expected to lead to a depletion of inhibitory GABAergic neurons in cell bodies in the striatum, resulting in less opposition to neurotransmission by nigrostriatal dopaminergic neurons synapsing in the striatum. One result could be the expression of HD symptomatology. Comings 119903 has proposed a candidate gene for TS to be the gene leading to elevated levels of the enzyme tryptophan oxygenase. Elevated levels of tryptophan oxygenase would result in a shift of typtophan metabolism from the serotonin pathway to the kynurenine pathway. There would be a subsequent increase in levels of quinolinic acid, which is the further metabolic product of kynurenine. As has been noted, quinolinic acid has activity a s a neuroexcitant and a neurotoxin. Excitation, depletion without degradation, and recovery of inhibitory GABAergic neurons in the striatum as triggered by perhaps fluctuating activity of quinolinic acid could result in varying levels of opposed neurotransmissin by dopaminergic neurons. The result could be the waxing and waning of dopaminergic-triggered tics. In our patient, one could hypothesize that a genetic diathesis for TS was expressed by levels of quinolinic acid increasing gradually, resulting first in TS and later in the expression of the HD diathesis as there occurred a n accumulated loss of striatal GABAergic neurons. Another alternative is that our patient’s childhood-onset TS was a phenocopy and the first sign of his HD due to a neuroexcitatory and neuronal damageidepletion process, such as the action of quinolinic acid on the dendrites and cell bodies in the striatum. With the passage of time and the accumulation of striatal neuronal dam-
3
age, one would begin to see the more characteristic choreiform and dementing symptoms of HD. Study of other individuals with both TS and HD may help to support or refute our speculations and shed further light on the relationship between these disorders a t the level of pathophysiology and perhaps a t the level of genetic etiology.
ACKNOWLEDGMENTS This work was supported by the Medical Center Rehabilitation Hospital Foundation (Grand Forks, ND).
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