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Benign hereditary chorea
R e v i e w Article
Benign Hereditary Chorea P a t r i c i a G. W h e e l e r , M D * , D a v i d D. W e a v e r , M D * , a n d W i l l i a m B. D o b y n s , M D t
Benign hereditary chorea is an uncommon inherited form of childhood chorea that can be mistaken for much more serious disorders, such as Huntington disease. The clinical manifestations of this condition are reviewed, emphasizing the differential diagnosis, treatment modalities, and evaluation of childhood chorea. Wheeler PG, Weaver DD, Dobyns WB. Benign hereditary chorea. Pediatr Neurol 1993;9:337-40.
Introduction Benign hereditary chorea (BHC) is an inherited neurologic disorder that consists of childhood-onset, nonprogressive chorea generally without other manifestations. Other names used for this disorder include benign familial chorea and benign hereditary nonprogressive chorea. Inheritance is autosomal dominant, although a few families with apparent autosomal-recessive inheritance have been reported [ 1-3]. Perhaps the major significance of this condition is the risk of misdiagnosis which, in the past, has resulted in prolonged hospitalizations, invasive diagnostic procedures, and even surgery.
Clinical Manifestations Age of Onset and Development. The age of onset of BHC ranges through most o f childhood and may be divided roughly into 3 age groups: early infancy [1,4,5], at about 1 year of age [6-8], and during late childhood or early adolescence [7,9,10]. The most common time of onset is about 1 year of age, usually as the child is beginning to walk [6]. Within families, the age of onset in affected siblings tends to be similar but not identical [3,7]. Some of the variation in age of onset may be related to the severity of chorea and observer bias. For example, it may be difficult to distinguish between active, poorly coordinated movements in toddlers and mild chorea. Alternatively, earlier detection of chorea may occur if it has been recognized in older siblings or other relatives. Affected children often have delay in walking [4,5] and may present to a physician because of delayed motor
From the *Department of Medical and Molecular Genetics; Indiana University School of Medicine; Indianapolis, Indiana; and tDivision of Pediatric Neurology;University of Minnesota Medical School; Minneapolis, Minnesota.
development. These children are usually described as clumsy and have frequent falling episodes. The latter can lead to scarring of the knees and shins as was described by Sadjadpour and Amato [4]. One child was so unsteady that he was wheelchair-bound until age 9 years, at which time he was finally able to walk on his own [11]. Another individual had to use crutches to avoid falls [12]. Chorea. The choreic jerks observed in BHC can involve any part of the body, including the face, tongue, neck, torso, arms, and legs. The jerks vary greatly in frequency and severity among affected persons, including individuals from the same family [6]. Some individuals have infrequent jerks that they do not recognize and are only identifiable by an experienced examiner [6]. Others are so severely affected that they cannot hold a cup without spilling the contents [12]. In all families reported, the intensity and frequency of the movements tend to worsen with stress or excitement, while disappearing entirely during sleep [1,6-8]. Soon after the initial onset of chorea, movements may appear to progress in severity and intensity for a short time; however, they subsequently reach a plateau with no future progression. In several families, a few individuals have actually reported improvement over time [6,8]; however, real improvement must be differentiated from attempts by the patient to mask the movements by engaging in voluntary activities or by converting an involuntary movement into a voluntary one [13]. The ability to suppress chorea for short periods has been reported [6].
Intelligence Intellectual function is typically normal in individuals with BHC, although affected persons from several families have had low-average I.Q. scores [4,6,7]. In one family in whom both affected and unaffected individuals were tested, affected individuals had I.Q. results averaging 10 points lower than their unaffected relatives [14]. The lowered scores on intelligence tests may be due in part to lack of education and poor family circumstances as described by Haerer et al. [6]. Another possible explanation for below-average results on cognitive tests in affected individuals is that these children are often the object of ridicule by peers [1,8,15,16] which may lead to
Communications should be addressed to: Dr. Wheeler; Department of Medical and Molecular Genetics; IB 130; Indiana University Medical Center; 975 West Walnut Street; Indianapolis, IN 46202-5251. Received May 7, 1993; accepted June 11, 1993.
Wheeler et al: Benign Hereditary Chorea 337
early termination of formal education, as was reported by Bird et al. [8].
this region [181. Thus, BHC does not appear t~ be al~ allele of Huntington disease.
Variants and Related Disorders
Incidence
Additional manifestations that may represent variants of BHC have been described in two families. The first was a family with both BHC and intention tremor [17]. In this family, intention tremor may have been a mild expression of the BHC phenotype. Another variant was observed in a family who had two siblings affected with both BHC and sensorineural hearing loss [2]. There are several additional reports of a condition that is very similar to BHC, and characterized by progressive chorea without apparent intellectual deterioration. In one family with a history of BHC, progression was described in only a single individual. It allegedly began after he suffered minor head trauma at 18 years of age [15]. In another family, onset of chorea occurred in the early to mid teens and the choreiform movements increased progressively in all affected family members. Chorea was severe enough to prevent affected persons from holding jobs, but apparently did not affect survival because two family members, ages 67 and 75 years, had experienced chorea for 50 and 65 years, respectively; no signs of dementia or other progressive symptoms were reported [9]. Although the condition in the latter family could be a variant of BHC, we suspect that it is an entirely separate disorder. Genetics
In most reported families, the inheritance of BHC is clearly autosomal dominant based on observation of vertical transmission, including several instances of male-tomale transmission [5,8,10,13,15]. Both incomplete penetrance (in which an unaffected individual has had both an affected parent and an affected child [6,9]) and variable expressivity have been observed [6]. Harper estimated the penetrance of BHC to be 100% in males and 75% in females based on the patients reported [1]. Three families have been reported in whom affected siblings have had unaffected parents and grandparents [2,3,7]. These observations may be explained by autosomal-dominant inheritance with incomplete penetrance, germ line mosaicism, or possibly autosomal-recessive inheritance of a phenocopy. Germ line mosaicism occurs when unaffected parents have affected children because one parent possesses a clone of germ cells with the mutation that causes the condition. Because DNA analysis for BHC is not available, this type of transmission cannot be proved. Prenatal diagnosis is also unavailable for BHC because the cause is unknown, and BHC has not been linked to any DNA markers. The major feature of BHC is the presence of chorea; therefore, the possibility has been raised that BHC could possibly be allelic to Huntington disease. Linkage studies between BHC and locus D4S10 (Huntington disease locus) using the G8 probe excluded the BHC gene from
338 PEDIATRICNEUROLOGY Vol.9 No. 5
Although the true incidence of BHC is unknown. Harper estimated it to be about 1:500,000 based on the number of affected individuals reported in Wales 111. It is likely that the actual incidence is higher than this because of incomplete ascertainment especially for mildly affected individuals, and in more severely affected patients in whom inaccurate diagnoses are made. Differential D i a g n o s i s and Diagnostic Studies
The differential diagnosis of chorea in childhood is extensive, including both inherited (Table 1) and noninherited (Table 2) causes. To establish the cause of chorea, an extensive evaluation is often required, especially for recent onset or progressive chorea. Appropriate tests may include cranial magnetic resonance imaging (MRI), streptolysin antigen (Sydenham chorea), thyroid function studies, parathyroid hormone assay, serum electrolytes, lumbar puncture, plasma amino acids, urine organic acids, serum ceruloplasmin and slit-lamp examination (Wilson Table 1. Inherited causes of chorea in childhood* Metabolic
Abetalipoproteinemia(Bassen-Kornzweig;AR) Glutaric aciduria (AR) Lesch-Nyhandisease (XR) Phenylketonuria (untreated; AR) Porphyria, acute intermittent (AD) Nonprogressive
Benign hereditary chorea (AD) Familial paroxysmalchoreoathetosis(AD) Hereditary essential myoclonus(AD) Progressive Ataxia-telangiectasia (AR) Ataxia without telangiectasia (AR?) Chorea-acanthocytosis(AD/AR) Friedreich ataxia (AR) Hallervorden-Spatzdisease (AR) Huntington disease,juvenile-onset (AD) Incontinentiapigmenti (XR) Pelizaeus-Merzbacherdisease (XR) Wilson disease (AR) Remit~ng Familial remitting chorea, nystagmus,and cataracts (AR?) * Adapted from Lockman[19]. Abbreviations: AD = Autosomaldominant AR = Autosomalrecessive XR = X-linkedrecessive
disease), peripheral blood smear (chorea-acanthocytosis), electron microscopy of leukocytes (Hallervorden-Spatz disease and neuronal ceroid-lipofuscinoses), and chromosome breakage studies (ataxia-telangiectasia and ataxia without telangiectasia). To help in limiting the number of tests performed, it is useful to answer several questions regarding a child who presents with chorea: (1) When did the chorea begin (i.e., acute or chronic)? (2) Have the movements progressed? (3) Are any other neurologic symptoms present? (4) Is there a history in the family of movement abnormalities? (5) Is the child taking any medication that might cause choreic movements (e.g., phenothiazines)? and, Table 2. Noninherited causes of chorea in childhood*
Autoimmune/Inflammatory
Henoch-Sch6nlein purpura (anaphylactoid purpura) Systemic lupus erythematosus Endocrine and Metabolic
Addison disease Beriberi Chorea gravidarum Cerebral lipidoses Hypematremia Hypocalcemia Hypoglycemia Hypomagnesemia Hyponatremia Hypoparathyroidism Polycythemia Thyrotoxicosis Vitamin B 12 deficiency in infants
Infectious Diptheria Encephalitis Neurosyphilis Pertussis Sydenham chorea (poststreptococcal infection) Typhoid fever
Neoplasms Any that involve the basal ganglia
Perinatal Cerebral palsy Kernicterus Physiologic chorea of the newborn
Tox& Carbon monoxide Isoniazide Lithium Mercury Oral contraceptives Phenothiazine Reserpine Scopolamine Vascular
Cerebral infarction involving the basal ganglia Posthemiplegic chorea * Adapted from Lockman [19].
(6) Is there a report of recent head trauma or infectious disease? The answers to these questions can direct the investigation and limit the necessary tests. If the chorea were chronic and stable or the family history indicated that the chorea was benign, few tests may be needed. In BHC, all tests are normal, including neurophysiologic tests (e.g., electroencephalograms, electromyograms) [20]. Cranial computed axial tomography and MRI also are normal [21]. A few studies have demonstrated that positron emission tomography (PET) has potential to delineate some types of chorea, such as that caused by Huntington disease or chorea-acanthocytosis [22]. One study did find some PET abnormalities on a patient reported to have BHC, but she had progressive chorea with onset occurring in her twenties and thus most likely had either a variant of BHC or an entirely separate disorder [23]. Another study using PET in patients with classic BHC reported no abnormalities [24]. It is also important to consider any medication a child may be taking as a potential cause of chorea. Among the more commonly used medications that have been reported to cause chorea are antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, ethosuximide) and stimulants (e.g., amphetamine, methylphenidate, pemoline, aminophylline, theophylline, caffeine) [25]. Treatment
The chorea observed in BHC has proved difficult to control. Some improvement has occurred with the use of haloperidol, chlorpromazine, and prednisone [ 11,16,17]. Although it may diminish chorea, haloperidol has been associated with tremor, akasthisia, and depression which have led to its discontinuation in some patients [16,21]. Chlorpromazine resulted in improvement in 2 children [17], but the drug was not helpful in another [7]. High doses of prednisone were used to treat asthma in 1 child with BHC [11] and unexpectedly resulted in reduction of the chorea which returned to its previous intensity when the dose was lowered. Two persons in one family reported improvement of chorea with alcohol, although this was believed to be due to the ability of ethanol to reduce stress which, as mentioned previously, tends to exacerbate the chorea [16]. A wide variety of treatments has been unsuccessful in controlling choreic movements, including numerous medications and physical and psychologic therapies [12,16]. Medications that did not result in reduction in chorea included procyclidine [3], phenobarbital [7], scopolamine [7], diazepam [7], phenothiazine [6], resperine [6], clonazepam [1], tetrabenazine [1,9,15], and phenytoin [12]. Conclusions
The diagnosis of BHC is one of exclusion. Necessary for this diagnosis is the presence of nonprogressive chorea beginning in childhood without other neurologic ab-
Wheeler et al: Benign Hereditary Chorea 339
normalities. The presence of a family history of nonprogressive chorea is not essential for this diagnosis, but it certainly helps. It is necessary to consider the diagnosis of BHC in any child who presents with chorea. The importance of doing so is illustrated by the diagnoses that have been, in the past, incorrectly ascribed to BHC patients. These diagnoses include Huntington disease [8,15,21], cerebral palsy [1,7], infantile paralysis [4], epilepsy [12J, Sydenham chorea [8], familial cerebellar ataxia [1], and functional ataxia [121]. Furthermore, some BHC patients have undergone prolonged evaluations and hospitalizations in attempts to diagnose and treat their condition [l]. One affected individual even had his toes amputated in an unsuccessful attempt to aid him in walking [1 ]. References
[1] Harper PS. Benign hereditary chorea: Clinical and genetic aspects. Clin Genet 1978;13:85-95. [2] Damasio H, Antunes L, Damasio AR. Familial nonprogressive involuntary movements of childhood. Ann Neurol 1977; 1:602-3. [3] Nutting PA, Cole BR, Schimke RN. Benign, recessively inherited choreo-athetosis of early onset. J Med Genet 1969;6:408-10. [4] Sadjadpour K, Amato RS. Hereditary nonprogressive chorea of early o n s e t - A new entity. Adv Neurol 1973;1:79-91. [5] Deonna TH, Voumard C. Benign hereditary (dominant) chorea of early onset. Helv Paediatr Acta 1979;34:77-83. [6] Haerer AF, Currier RD, Jackson JF. Hereditary nonprogressive chorea of early onset. N Engl J Med 1967;276:1220-4. [7] Chun RWM, Daly RF, Mansheim BJ Jr, Wolcott GJ. Benign familial chorea with onset in childhood. JAMA 1973;225:1603-7. [8] Bird TD, Carlson CB, Hall JG. Familial essential ('benign') chorea. J Med Genet 1976;13:357-62. [9] Sehady W, Meara RJ. Hereditary progressive chorea without dementia. J Neuro! Neurosurg Psychiatry 1988;51:295-7. [10] Refsum S, Sjaastad O. Hereditary nonprogressive involuntary movements with early onset and intention tremor, without dementia. Acta Neurol Scand 1972;51(Suppl):489-91.
340
PEDIATRIC NEUROLOGY
Vol. 9 No. 5
[111 Robinson RO, Thomett CEE. Benign hereditary ch~,rca I~,~: sponse to steroids. Dev Med Child Nearol 1985:27:81=I 2t. [12] Sleigh G. Lindenbaum RH. Benign (non-paro,,ysmal! lamilial chorea. Paediatric perspectives. Arch Dis Child 1981:5~:616-2 I. [13] Burns J. Neuhauser G, Tomasi L. Benign hereditat5 nonpn~gressive chorea of early onset: Clinical genetics of the syndrome and report of a new family. Neuropaediatrie 1976:7:431 :~ [14] Leli DA, Furlow TW Jr, Falgout JC. Bcnign familial cholca: An association with intellectual impairment. J Neurol Neurosur,,.,!,Psychiatr} 1984;47:471-4. [15] Behan PO, Bone I. Hereditary chorea without dementia. J Neurol Neurosurg Psychiatry 1977;40:687-91. [161 Loosmore SJ, Wood K. Benign hereditary chorea- ~, case report, Br J Psychiatry 1988; 152:131-4. [17] Pincus JH, Chutorian A. Familial benign chorea with intention tremor: A clinical entity. J Pediatr 1967:70:724-9. [181 Quarrell OWL Youngman S, Saffarazi M, Harper PS. Absence of close linkage between benign hereditary chorea and the locus D4S10 (probe G81. J Med Genet 1988;25:191-4. [19] Lockman LA. Movement disorders. In: Swaiman KI:. Wright FS, eds. The practice of pediatric neurology. St. Louis: CV Mosby. 1982;287-308. [20] Stapert JLRH, Busard BLSM, Gahreels FJM, Renier WO. Colon EJ, Verhey FILM. Benign (nonparoxysmal) familial chorea of early onset: An electroneurophysiological examination of two families. Brain Dev 1985:7:38-42. [211 Rice E, Terrence C. Computerized tomography in hereditary nonprogressive chorea. Arch Neurol 1979;36:249-50. [22] Hosokawa S, Ichiya Y, Kuwabara Y, etal. Positron emission tomography in cases of chorea with different underlying diseases. J Neural Neurosurg Psychiatry 1987;50:1284-7. [23] Suchowersky O, Hayden MR, Martin WRW, Stoesst A J, Hildebrand AM, Pate BD. Cerebral metabolism of glucose in benign hereditary chorea. Mov Disord 1986; 1:33-44. [24] Kuwert T, Lange HW, Langen KJ, et al. Normal striatal glucose consumption in two patients with benign hereditary chorea as measured by positron emission tomography. J Neurol 1990;237:80-4. [25] Padberg GW, Bmyn GW. Chorea --- Differential diagnosis. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology, vol 5 (49): Extrapyramidal disorders. New York: Elsevier, 19861 551-2.
Benign Hereditary Chorea P a t r i c i a G. W h e e l e r , M D * , D a v i d D. W e a v e r , M D * , a n d W i l l i a m B. D o b y n s , M D t
Benign hereditary chorea is an uncommon inherited form of childhood chorea that can be mistaken for much more serious disorders, such as Huntington disease. The clinical manifestations of this condition are reviewed, emphasizing the differential diagnosis, treatment modalities, and evaluation of childhood chorea. Wheeler PG, Weaver DD, Dobyns WB. Benign hereditary chorea. Pediatr Neurol 1993;9:337-40.
Introduction Benign hereditary chorea (BHC) is an inherited neurologic disorder that consists of childhood-onset, nonprogressive chorea generally without other manifestations. Other names used for this disorder include benign familial chorea and benign hereditary nonprogressive chorea. Inheritance is autosomal dominant, although a few families with apparent autosomal-recessive inheritance have been reported [ 1-3]. Perhaps the major significance of this condition is the risk of misdiagnosis which, in the past, has resulted in prolonged hospitalizations, invasive diagnostic procedures, and even surgery.
Clinical Manifestations Age of Onset and Development. The age of onset of BHC ranges through most o f childhood and may be divided roughly into 3 age groups: early infancy [1,4,5], at about 1 year of age [6-8], and during late childhood or early adolescence [7,9,10]. The most common time of onset is about 1 year of age, usually as the child is beginning to walk [6]. Within families, the age of onset in affected siblings tends to be similar but not identical [3,7]. Some of the variation in age of onset may be related to the severity of chorea and observer bias. For example, it may be difficult to distinguish between active, poorly coordinated movements in toddlers and mild chorea. Alternatively, earlier detection of chorea may occur if it has been recognized in older siblings or other relatives. Affected children often have delay in walking [4,5] and may present to a physician because of delayed motor
From the *Department of Medical and Molecular Genetics; Indiana University School of Medicine; Indianapolis, Indiana; and tDivision of Pediatric Neurology;University of Minnesota Medical School; Minneapolis, Minnesota.
development. These children are usually described as clumsy and have frequent falling episodes. The latter can lead to scarring of the knees and shins as was described by Sadjadpour and Amato [4]. One child was so unsteady that he was wheelchair-bound until age 9 years, at which time he was finally able to walk on his own [11]. Another individual had to use crutches to avoid falls [12]. Chorea. The choreic jerks observed in BHC can involve any part of the body, including the face, tongue, neck, torso, arms, and legs. The jerks vary greatly in frequency and severity among affected persons, including individuals from the same family [6]. Some individuals have infrequent jerks that they do not recognize and are only identifiable by an experienced examiner [6]. Others are so severely affected that they cannot hold a cup without spilling the contents [12]. In all families reported, the intensity and frequency of the movements tend to worsen with stress or excitement, while disappearing entirely during sleep [1,6-8]. Soon after the initial onset of chorea, movements may appear to progress in severity and intensity for a short time; however, they subsequently reach a plateau with no future progression. In several families, a few individuals have actually reported improvement over time [6,8]; however, real improvement must be differentiated from attempts by the patient to mask the movements by engaging in voluntary activities or by converting an involuntary movement into a voluntary one [13]. The ability to suppress chorea for short periods has been reported [6].
Intelligence Intellectual function is typically normal in individuals with BHC, although affected persons from several families have had low-average I.Q. scores [4,6,7]. In one family in whom both affected and unaffected individuals were tested, affected individuals had I.Q. results averaging 10 points lower than their unaffected relatives [14]. The lowered scores on intelligence tests may be due in part to lack of education and poor family circumstances as described by Haerer et al. [6]. Another possible explanation for below-average results on cognitive tests in affected individuals is that these children are often the object of ridicule by peers [1,8,15,16] which may lead to
Communications should be addressed to: Dr. Wheeler; Department of Medical and Molecular Genetics; IB 130; Indiana University Medical Center; 975 West Walnut Street; Indianapolis, IN 46202-5251. Received May 7, 1993; accepted June 11, 1993.
Wheeler et al: Benign Hereditary Chorea 337
early termination of formal education, as was reported by Bird et al. [8].
this region [181. Thus, BHC does not appear t~ be al~ allele of Huntington disease.
Variants and Related Disorders
Incidence
Additional manifestations that may represent variants of BHC have been described in two families. The first was a family with both BHC and intention tremor [17]. In this family, intention tremor may have been a mild expression of the BHC phenotype. Another variant was observed in a family who had two siblings affected with both BHC and sensorineural hearing loss [2]. There are several additional reports of a condition that is very similar to BHC, and characterized by progressive chorea without apparent intellectual deterioration. In one family with a history of BHC, progression was described in only a single individual. It allegedly began after he suffered minor head trauma at 18 years of age [15]. In another family, onset of chorea occurred in the early to mid teens and the choreiform movements increased progressively in all affected family members. Chorea was severe enough to prevent affected persons from holding jobs, but apparently did not affect survival because two family members, ages 67 and 75 years, had experienced chorea for 50 and 65 years, respectively; no signs of dementia or other progressive symptoms were reported [9]. Although the condition in the latter family could be a variant of BHC, we suspect that it is an entirely separate disorder. Genetics
In most reported families, the inheritance of BHC is clearly autosomal dominant based on observation of vertical transmission, including several instances of male-tomale transmission [5,8,10,13,15]. Both incomplete penetrance (in which an unaffected individual has had both an affected parent and an affected child [6,9]) and variable expressivity have been observed [6]. Harper estimated the penetrance of BHC to be 100% in males and 75% in females based on the patients reported [1]. Three families have been reported in whom affected siblings have had unaffected parents and grandparents [2,3,7]. These observations may be explained by autosomal-dominant inheritance with incomplete penetrance, germ line mosaicism, or possibly autosomal-recessive inheritance of a phenocopy. Germ line mosaicism occurs when unaffected parents have affected children because one parent possesses a clone of germ cells with the mutation that causes the condition. Because DNA analysis for BHC is not available, this type of transmission cannot be proved. Prenatal diagnosis is also unavailable for BHC because the cause is unknown, and BHC has not been linked to any DNA markers. The major feature of BHC is the presence of chorea; therefore, the possibility has been raised that BHC could possibly be allelic to Huntington disease. Linkage studies between BHC and locus D4S10 (Huntington disease locus) using the G8 probe excluded the BHC gene from
338 PEDIATRICNEUROLOGY Vol.9 No. 5
Although the true incidence of BHC is unknown. Harper estimated it to be about 1:500,000 based on the number of affected individuals reported in Wales 111. It is likely that the actual incidence is higher than this because of incomplete ascertainment especially for mildly affected individuals, and in more severely affected patients in whom inaccurate diagnoses are made. Differential D i a g n o s i s and Diagnostic Studies
The differential diagnosis of chorea in childhood is extensive, including both inherited (Table 1) and noninherited (Table 2) causes. To establish the cause of chorea, an extensive evaluation is often required, especially for recent onset or progressive chorea. Appropriate tests may include cranial magnetic resonance imaging (MRI), streptolysin antigen (Sydenham chorea), thyroid function studies, parathyroid hormone assay, serum electrolytes, lumbar puncture, plasma amino acids, urine organic acids, serum ceruloplasmin and slit-lamp examination (Wilson Table 1. Inherited causes of chorea in childhood* Metabolic
Abetalipoproteinemia(Bassen-Kornzweig;AR) Glutaric aciduria (AR) Lesch-Nyhandisease (XR) Phenylketonuria (untreated; AR) Porphyria, acute intermittent (AD) Nonprogressive
Benign hereditary chorea (AD) Familial paroxysmalchoreoathetosis(AD) Hereditary essential myoclonus(AD) Progressive Ataxia-telangiectasia (AR) Ataxia without telangiectasia (AR?) Chorea-acanthocytosis(AD/AR) Friedreich ataxia (AR) Hallervorden-Spatzdisease (AR) Huntington disease,juvenile-onset (AD) Incontinentiapigmenti (XR) Pelizaeus-Merzbacherdisease (XR) Wilson disease (AR) Remit~ng Familial remitting chorea, nystagmus,and cataracts (AR?) * Adapted from Lockman[19]. Abbreviations: AD = Autosomaldominant AR = Autosomalrecessive XR = X-linkedrecessive
disease), peripheral blood smear (chorea-acanthocytosis), electron microscopy of leukocytes (Hallervorden-Spatz disease and neuronal ceroid-lipofuscinoses), and chromosome breakage studies (ataxia-telangiectasia and ataxia without telangiectasia). To help in limiting the number of tests performed, it is useful to answer several questions regarding a child who presents with chorea: (1) When did the chorea begin (i.e., acute or chronic)? (2) Have the movements progressed? (3) Are any other neurologic symptoms present? (4) Is there a history in the family of movement abnormalities? (5) Is the child taking any medication that might cause choreic movements (e.g., phenothiazines)? and, Table 2. Noninherited causes of chorea in childhood*
Autoimmune/Inflammatory
Henoch-Sch6nlein purpura (anaphylactoid purpura) Systemic lupus erythematosus Endocrine and Metabolic
Addison disease Beriberi Chorea gravidarum Cerebral lipidoses Hypematremia Hypocalcemia Hypoglycemia Hypomagnesemia Hyponatremia Hypoparathyroidism Polycythemia Thyrotoxicosis Vitamin B 12 deficiency in infants
Infectious Diptheria Encephalitis Neurosyphilis Pertussis Sydenham chorea (poststreptococcal infection) Typhoid fever
Neoplasms Any that involve the basal ganglia
Perinatal Cerebral palsy Kernicterus Physiologic chorea of the newborn
Tox& Carbon monoxide Isoniazide Lithium Mercury Oral contraceptives Phenothiazine Reserpine Scopolamine Vascular
Cerebral infarction involving the basal ganglia Posthemiplegic chorea * Adapted from Lockman [19].
(6) Is there a report of recent head trauma or infectious disease? The answers to these questions can direct the investigation and limit the necessary tests. If the chorea were chronic and stable or the family history indicated that the chorea was benign, few tests may be needed. In BHC, all tests are normal, including neurophysiologic tests (e.g., electroencephalograms, electromyograms) [20]. Cranial computed axial tomography and MRI also are normal [21]. A few studies have demonstrated that positron emission tomography (PET) has potential to delineate some types of chorea, such as that caused by Huntington disease or chorea-acanthocytosis [22]. One study did find some PET abnormalities on a patient reported to have BHC, but she had progressive chorea with onset occurring in her twenties and thus most likely had either a variant of BHC or an entirely separate disorder [23]. Another study using PET in patients with classic BHC reported no abnormalities [24]. It is also important to consider any medication a child may be taking as a potential cause of chorea. Among the more commonly used medications that have been reported to cause chorea are antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, ethosuximide) and stimulants (e.g., amphetamine, methylphenidate, pemoline, aminophylline, theophylline, caffeine) [25]. Treatment
The chorea observed in BHC has proved difficult to control. Some improvement has occurred with the use of haloperidol, chlorpromazine, and prednisone [ 11,16,17]. Although it may diminish chorea, haloperidol has been associated with tremor, akasthisia, and depression which have led to its discontinuation in some patients [16,21]. Chlorpromazine resulted in improvement in 2 children [17], but the drug was not helpful in another [7]. High doses of prednisone were used to treat asthma in 1 child with BHC [11] and unexpectedly resulted in reduction of the chorea which returned to its previous intensity when the dose was lowered. Two persons in one family reported improvement of chorea with alcohol, although this was believed to be due to the ability of ethanol to reduce stress which, as mentioned previously, tends to exacerbate the chorea [16]. A wide variety of treatments has been unsuccessful in controlling choreic movements, including numerous medications and physical and psychologic therapies [12,16]. Medications that did not result in reduction in chorea included procyclidine [3], phenobarbital [7], scopolamine [7], diazepam [7], phenothiazine [6], resperine [6], clonazepam [1], tetrabenazine [1,9,15], and phenytoin [12]. Conclusions
The diagnosis of BHC is one of exclusion. Necessary for this diagnosis is the presence of nonprogressive chorea beginning in childhood without other neurologic ab-
Wheeler et al: Benign Hereditary Chorea 339
normalities. The presence of a family history of nonprogressive chorea is not essential for this diagnosis, but it certainly helps. It is necessary to consider the diagnosis of BHC in any child who presents with chorea. The importance of doing so is illustrated by the diagnoses that have been, in the past, incorrectly ascribed to BHC patients. These diagnoses include Huntington disease [8,15,21], cerebral palsy [1,7], infantile paralysis [4], epilepsy [12J, Sydenham chorea [8], familial cerebellar ataxia [1], and functional ataxia [121]. Furthermore, some BHC patients have undergone prolonged evaluations and hospitalizations in attempts to diagnose and treat their condition [l]. One affected individual even had his toes amputated in an unsuccessful attempt to aid him in walking [1 ]. References
[1] Harper PS. Benign hereditary chorea: Clinical and genetic aspects. Clin Genet 1978;13:85-95. [2] Damasio H, Antunes L, Damasio AR. Familial nonprogressive involuntary movements of childhood. Ann Neurol 1977; 1:602-3. [3] Nutting PA, Cole BR, Schimke RN. Benign, recessively inherited choreo-athetosis of early onset. J Med Genet 1969;6:408-10. [4] Sadjadpour K, Amato RS. Hereditary nonprogressive chorea of early o n s e t - A new entity. Adv Neurol 1973;1:79-91. [5] Deonna TH, Voumard C. Benign hereditary (dominant) chorea of early onset. Helv Paediatr Acta 1979;34:77-83. [6] Haerer AF, Currier RD, Jackson JF. Hereditary nonprogressive chorea of early onset. N Engl J Med 1967;276:1220-4. [7] Chun RWM, Daly RF, Mansheim BJ Jr, Wolcott GJ. Benign familial chorea with onset in childhood. JAMA 1973;225:1603-7. [8] Bird TD, Carlson CB, Hall JG. Familial essential ('benign') chorea. J Med Genet 1976;13:357-62. [9] Sehady W, Meara RJ. Hereditary progressive chorea without dementia. J Neuro! Neurosurg Psychiatry 1988;51:295-7. [10] Refsum S, Sjaastad O. Hereditary nonprogressive involuntary movements with early onset and intention tremor, without dementia. Acta Neurol Scand 1972;51(Suppl):489-91.
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[111 Robinson RO, Thomett CEE. Benign hereditary ch~,rca I~,~: sponse to steroids. Dev Med Child Nearol 1985:27:81=I 2t. [12] Sleigh G. Lindenbaum RH. Benign (non-paro,,ysmal! lamilial chorea. Paediatric perspectives. Arch Dis Child 1981:5~:616-2 I. [13] Burns J. Neuhauser G, Tomasi L. Benign hereditat5 nonpn~gressive chorea of early onset: Clinical genetics of the syndrome and report of a new family. Neuropaediatrie 1976:7:431 :~ [14] Leli DA, Furlow TW Jr, Falgout JC. Bcnign familial cholca: An association with intellectual impairment. J Neurol Neurosur,,.,!,Psychiatr} 1984;47:471-4. [15] Behan PO, Bone I. Hereditary chorea without dementia. J Neurol Neurosurg Psychiatry 1977;40:687-91. [161 Loosmore SJ, Wood K. Benign hereditary chorea- ~, case report, Br J Psychiatry 1988; 152:131-4. [17] Pincus JH, Chutorian A. Familial benign chorea with intention tremor: A clinical entity. J Pediatr 1967:70:724-9. [181 Quarrell OWL Youngman S, Saffarazi M, Harper PS. Absence of close linkage between benign hereditary chorea and the locus D4S10 (probe G81. J Med Genet 1988;25:191-4. [19] Lockman LA. Movement disorders. In: Swaiman KI:. Wright FS, eds. The practice of pediatric neurology. St. Louis: CV Mosby. 1982;287-308. [20] Stapert JLRH, Busard BLSM, Gahreels FJM, Renier WO. Colon EJ, Verhey FILM. Benign (nonparoxysmal) familial chorea of early onset: An electroneurophysiological examination of two families. Brain Dev 1985:7:38-42. [211 Rice E, Terrence C. Computerized tomography in hereditary nonprogressive chorea. Arch Neurol 1979;36:249-50. [22] Hosokawa S, Ichiya Y, Kuwabara Y, etal. Positron emission tomography in cases of chorea with different underlying diseases. J Neural Neurosurg Psychiatry 1987;50:1284-7. [23] Suchowersky O, Hayden MR, Martin WRW, Stoesst A J, Hildebrand AM, Pate BD. Cerebral metabolism of glucose in benign hereditary chorea. Mov Disord 1986; 1:33-44. [24] Kuwert T, Lange HW, Langen KJ, et al. Normal striatal glucose consumption in two patients with benign hereditary chorea as measured by positron emission tomography. J Neurol 1990;237:80-4. [25] Padberg GW, Bmyn GW. Chorea --- Differential diagnosis. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology, vol 5 (49): Extrapyramidal disorders. New York: Elsevier, 19861 551-2.