Hereditary causes of chorea in childhood

Hereditary Causes of Chorea in Childhood Katherine D. Mathews Chorea and athetosis are rare presenting symptoms in childhood. Chorea can be a presenting symptom in a number of hereditary diseases, including neurodegenerative diseases, paroxysmal diseases, and metabolic diseases. In these situations, family history, associated symptoms, and other physical findings will often enable a correct diagnosis. Benign childhood chorea is probably a genetically heterogeneous group of disorders, generally without other symptoms. Clinical aspects of these disorders are reviewed here. © 2003 Elsevier Inc. All rights reserved.

HOREA CAN be defined as involuntary, continuous, brief movements that flow from body part to body part. Athetosis is a slower form of chorea. In childhood, chorea is most often due to a nongenetic factor, such as Sydenham's chorea (rheumatic fever), systemic lupus etythematosis, drug effect, or static acquired encephalopathy. Rarely, though, an inherited disease presents with childhood chorea. This article discusses some of these diseases. They have been classified into neurodegenerative diseases, metabolic diseases, paroxysmal diseases, and benign hereditary chorea, a disease or group of diseases of unknown cause.

C

NEURODEGENERATIVE DISORDERS The neurodegenerative disorders are unlikely to present with chorea as a primary symptom in childhood. However, chorea or similar movements can be seen at some point in the disease process. Huntington's Disease

Clinical Huntington's disease (HD), an autosomal-dominant disorder, is among the most common of the inherited choreas but is a rare cause of chorea in childhood. HD typically presents in mid-adulthood with psychiatric/emotional symptoms (depression, aggression), cognitive impairment, and movement disorder, including chorea. It is progressive and leads to death 10 to 20 years after diagnosis. Between 1% and 12% of HD patients become symptomatic in before age 20 years] -4 Onset can

From the Departments of Pediatrics and Neurology, University of lowa, Iowa City, IA. Address reprint requests to Katherine D. Mathews, Associate Professor, Departments of Pediatrics and Neurology, University of Iowa, Iowa City, IA 52242. © 2003 Elsevier Inc. All rights reserved. 1071-9091/03/1001-0004530.00/0 doi:10.1053/spen.2003.0000 20

occur any time during childhood; the most severely affected children show developmental impairment in infancy. 4 Childhood HD is inherited from the father in 75% to 80% of cases, and the child may be affected before the parent exhibits symptoms. First symptoms in childhood are nonspecific; a family history is usually the initial clue to diagnosis. Presenting symptoms can include any of the following: behavior problems, developmental delay or regression, seizures, rigidity, tremor, cognitive decline, myoclonus, ataxia, and chorea. Initial symptoms tend to cluster; for example, rigidity, bradykinesia, and tremor occur together, producing a Parkinsonian phenotype ("Westphal variant") that is more common in children than in adults 5 and actually is a more common presentation in childhood than chorea. 4 The youngest children axe most likely to have seizures as part of the presentation, and, overall, seizures occur in 30% to 40% of patients with childhood-onset HD. 2 Facial hypokinesis is often a prominent physical finding. The course of HD in childhood, like that in adulthood, involves progressive motor and cognitive disability and premature death. There is some evidence that cognition is better preserved in those with childhood onset compared with patients with onset of motor symptoms in adulthood. 6 Brain imaging (computed tomography [CT] scanning and magnetic resonance imaging [MRI]) in advanced cases shows severe atrophy of the caudate nucleus and generalized brain atrophy. In children, increased proton density and T2weighted signal abnormality in the putamen and caudate are seen early in the disease (Fig 1). 7,8 Pathologically, cellular loss is greatest in the candate and putamen in brains of children dying of HD. 9 The glubus pallidus shows gliosis without neuronal loss.

Molecular Genetics and Pathophysiology HD was localized to chromosome 4p in 1983 by linkage mapping, and was one of the earliest disSeminars in Pediatric Neurology, Vol 10, No 1 (March), 2003: pp 20-25

HEREDITARY CHOREA IN CHILDHOOD

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important to remember that whereas there is a correlation between repeat length and age at onset and symptoms at onset, for any single individual knowledge of the repeat length does not allow prediction of age at onset of symptoms. Repeat length varied from 48 to 250 in a large series of children deemed symptomatic before age 18. 4 Like other polyglutamine repeat diseases (eg, Kennedy's disease, spinocerebellar ataxia type 1), the HD mutation results in a gain of function that is toxic to specific cells. 13

Diagnostic Testing and Ethical Considerations

Fig 1. Brain MRI on a 9-year-old girl with early symptomatic Huntington disease. The T2-weighted image shows caudate atrophy and increased signal intensity from the putamen bilaterally.

eases to be mapped using polymorphic genetic markers.l° It took 10 years to identify the causative mutation, a variable-length polyglutamine (CAG) repeat in exon 1 of the gene IT15, which encodes the protein huntingtin. The repeat has -<35 copies in the normal population. 11 There is an inverse relationship between length of repeat expansion and age of onset. Patients with typical adult-onset disease have 36 to 40 repeats, whereas the most severely affected young children have as many as 250 repeats. This repeat expansion underlies the clinical phenomenon of anticipation, the general pattern of progressively earlier onset of symptoms in successive generations. Patients with nonchoreic motor onset, such as rigidity, have longer average repeat lengths (55_+14) compared to those with choreic onset (45 _+4), and had younger average age at onset (27 vs 42 years). 5 Although CAG repeat length plays a major role in determining age at onset and type of motor presentation, it is likely that other genetic and nongenetic factors are also operative. 5'12 It is

The diagnosis of HD is considered in a child with unexplained progressive neurological disorder, particularly those affecting movement, tone, cognition, and behavior. A family history of HD is often the first clue to the diagnosis. When family history is unknown (eg, when a child is adopted), typical findings on MRI can be helpful. Diagnosis is confirmed by sending blood for DNA analysis, a test readily available through commercial laboratories. Several issues must be considered before performing DNA testing on a child (issues that also apply to DNA testing on other nontreatable, generally adult-onset neurodegenerative disorders): • Is testing the child going to impact other family members? For example, if an at-risk parent does not want to know whether he or she inherited the mutation, testing the child may yield undesired information. In this case, the benefits of knowing the child's diagnosis (eg, avoidance of other testing) need to be weighed against the family impact. • If the child inherited the mutant allele (ie, will develop HD), are the current symptoms definitely caused by HD? Sometimes a child will have symptoms that may or may not be related to HD. For example, behavior problems are a common complaint in the general population. Behavior problems may be an early sign of HD, but HD very rarely causes behavior problems in isolation. If a child at risk for HD has behavior problems but no other definite signs or symptoms, then demonstrating that he or she inherited the mutant allele says nothing about the cause of the current problems. It may be many years before the child develops clear HD. In this case, testing was presymptomatic.

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KATHERINE D. MATHEWS

• Will there be undesired impact on the child's insurability, schooling, or vocational options? • What benefits will come from testing? The most common medical benefit in cases where there is a clear decline in function is the avoidance of further unnecessary diagnostic testing. In addition, some families want a definite diagnosis (whereas other families prefer not to know). Guidelines for predictive molecular testing for HD were developed by representatives of the International Huntington Association and the World Federation of Neurology and were published in 1994. One of these guidelines is that presymptomatic testing be performed only on individuals who have reached the "age of majority," and then only after they receive counseling about the implications of the test result. Reasons for this recommendation include concerns about the following: • The right of each individual to decide for himself or herself whether or not he or she wants this information (as opposed to having a parent, guardian, or physician make that decision for him or her) • Impact on insurability • Potential misuse of information by employers and others • Lack of treatment or prevention of symptoms • Lack of information about the impact of having this knowledge on the individuals psychosocial development. Because of these issues, reputable laboratories generally require some sort of assurance that the child undergoing DNA testing for HD is symptomatic. Treatment is currently supportive and symptomatic. Genetic counseling should be offered to the family. There is hope that novel therapies, such as fetal striatal transplantation, will ameliorate symptoms and slow disease progress, but this work is in its infancy. ~4 DentatorubraI-Pallidoluysian Atrophy Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal-dominant neurodegenerative disorder that has been reported most commonly in Japan. ~5 Like HD, it is caused by a trinucleotide (CAG, polyglutamine) repeat expansion and shows anticipation with correlation between the size of the repeat and the age at onset of disease. ~6'17 The clinical phenotype is variable and has overlap with

that of HD. In children, the phenotype is generally dominated by progressive myoclonus epilepsy and cognitive impairment. Chorea, ataxia, and psychiatric symptoms tend to be more common in patients with onset in adulthood; however, there is significant clinical overlap between age groups. 17-19 MRI shows diffuse atrophy of the cerebrum, brainstem, and cerebellum along with diffuse white matter changes. 2°'21

Spinocerebellar Ataxias The spinocerebellar ataxias (SCAs) are an everincreasing group of progressive, autosomal-dominant disorders with cerebellar ataxia as the dominant feature. DRPLA is often included in this group of disorders. The SCAs usually develop in adulthood, but can occur in early childhood. Although ataxia is the defining symptom in all of these diseases, other neurological signs and symptoms, including chorea, myoclonus, spasticity, peripheral neuropathy, cognitive decline, retinopathy, ophthalmoparesis, and seizures, may o c c u r . 22-24 The SCAs with known genetic mutation are all trinucleotide repeat expansions and show anticipation. 24 Chorea-Acanthocytosis Chorea-acanthocytosis is a rare autosomal-recessive disorder caused by mutation of a recently identified gene for the protein chorein on 9q21.25 Affected individuals have chorea and other dyskinesias (particularly involving the face, mouth, and tongue), psychiatric disorders, cognitive decline, seizures, and axonal polyneuropathy. The symptoms typically begin in young adulthood, but can begin in childhood. Laboratory findings include acanthocytes seen on peripheral blood smear and a mildly elevated creatine kinase level. Acanthocytes may be difficult to find, and should be sought repeatedly. Brain MRI findings are similar to those in HD, with caudate atrophy and increased T2weighted signal from the caudate and putamenY. 26 BENIGN HEREDITARY CHOREA Benign hereditary chorea (BHC) is a rare autosomal-dominant condition. It can begin anytime during childhood, but usually occurs between age 1 and 2 years. The chorea is nonprogressive. The very early onset and lack of progression differentiate BHC from HD and other neurodegenerative

HEREDITARY CHOREA IN CHILDHOOD

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Table 1. Paroxysmal Choreoathetoic Disorders Affecting Children

Inheritance Genetic map location Age at onset (years) Provoking events Aura Duration of attack Frequency Treatment Associated conditions

Paroxysmal nonkinesigenic dyskinesia (PNKD or PDC}40-42

Paroxysmal kinesigenic choreoathetosis (PKC)43

Infantile convulsions and paroxysmal chroeoathetosis (ICCA)44

Autosomal dominant 2q

Autosomal dominant 16q13-q22.1

Autosomal dominant Pericentromeric 16q

<20

<20

<20

Alcohol, caffeine, hunger, stress, fatigue ->5 minutes to hours

Sudden movement, startle, hyperventilation Tingling sensation, tightening, <5 minutes

-< Several times/day Benzodiazepines; gabapentin 46 Migraine; dystonia, dysarthria, dysphagia

May be 100/day Carbamazepine or phenytoin 47

conditions. There is marked variation in severity even within a family, and like most movement disorders, the movements are worsened by stress or fatigue. Although there is controversy regarding this entity as a discrete genetic disease, 27 at least two families have reportedly exhibited a linkage to chromosome 14q. 28"29 In one of these families, the movement disorder abated as the children reached adulthood. A few of the affected individuals in these families had other neurological disorders along with the chorea. These included ataxia, psychiatric disease, and dystonia. In all patients, earlyonset chorea was the predominant symptom. 29 CT scan, MRI, and positron emission tomography findings are normal. The diagnosis is established by family history, exclusion of other causes, and the benign course of the disorder. 3° A recently described autosomal-dominant variant of this disease has been termed "familial dyskinesia and facial myokymia. ''28 Affected family members exhibit perioral movements along with the choreiform movements of the extremities. Aside from some progression in continuity of movements, the disease is nonprogressive.

PAROXYSMAL DYSKINESIAS The paroxysmal dyskinesias result in episodic abnormal movements of variable duration. There is

Sudden movement, stress, excitement Feeling of muscle tension? <5 minutes Variable, may be 100/d ay Carbamazepine or phenytoin Benign neonatal seizures

Choreoathetosis and spasticity (CSE)45

Autosomal dominant ip

Exercise, stress, fatigue, and alcohol

- 2 0 minutes <5 times/day ? Spasticity during and between attacks

often some sort of provoking stimulus. Between episodes, patients generally exhibit no physical findings related to the diagnosis. Patients retain a normal level of consciousness during an attack and can recall the attack. Several different clinical classification systems have been developed for these disorders, based on the duration of attack or the nature of provocation. 31'32 More recently, specific genetic localization or specific genes complement the clinical classification. These disorders are discussed in greater detail elsewhere in this volume. Four syndromes with known genetic localization are summarized in Table 1.

METABOLIC DISORDERS THAT CAN INCLUDE CHOREA Very rarely, the phenotype of untreated phenylketonuria 33 can include minor chorea. Also rarely, the neurological manifestations of Wilson's disease include chorea. This is almost always associated with liver disease in childhood. 34

Glutaric Aciduda Type 1/GlutaryI-CoA Dehydrogenase Deficiency Glutaric aciduria type 1 (GA1) is an autosomalrecessive disorder with 2 distinct patterns of presentationY Most commonly (--75%), a previously healthy infant develops an acute encephalopathy

24

KATHERINE D. MATHEWS

that variably includes lethargy, seizures, and abnormal tone in the setting a viral illness. The usual acute diagnosis is viral encephalitis. This is followed by motor abnormalities, including spasticity, chorea, athetosis, and dystonia, often with relatively preserved cognitive function. The less common presentation is that of gradually progressive developmental delay with extrapyramidal features. Macrocephaly is seen in 70% of affected infants. A characteristic finding on CT is a widened operculum and temporal lobe atrophy. 36'37 MRI shows increased signals in the basal ganglia 35'3s in addition to temporal atrophy. The diagnosis is suggested by abnormal excretion of glutaric acid in the urine; however, this finding can be intermittent. The acylcarnitine profile is abnormal in some individuals. The definitive diagnosis is made by demonstrating decreased glutaryl-CoAdehydrogenase activity in skin fibroblasts. 35 Treatment with riboflavin, carnitine, and dietary restriction is recommended.

In states where

newborn

screening

automated tandem mass spectrometry, be

diagnosed

Nonetheless, to d a t e . 39

before

the

onset

includes GA1 will

of symptoms.

treatment has had limited success

Lesch-Nyhan Disease Lesch-Nyhan disease is an X-linked recessive condition resulting from a lack of hypoxanthineguanine phosphoribosyl-transferase activity. The phenotype is distinctive, with spasticity, choreoathetosis, mental retardation, self-injurious behavior, and self-mutilation seen in all patients. The motor disability is greater than the cognitive disability in most cases, and the movement disorder may precede the spasticity. The diagnosis is suggested by a marked increase in uric acid in blood and excessive excretion of uric acid in urine. Hematuria and crystalluria may be presenting symptoms in infancy.

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