Case 26-2006 — A 19-Year-Old Woman with Difficulty Walking
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《新英格兰医药杂志》
Presentation of Case
Dr. Roy N. Alcalay (Neurology): A 19-year-old right-handed woman was referred to the neurology clinic because of slowly worsening difficulty walking and painful spasms in her legs and arms. When the patient was eight years of age, her teacher noticed that her left shoe was disproportionately worn on its outer side. Her physician noted inversion of the left foot and made a diagnosis of poliomyelitis. Tendon-transplantation surgery was performed on the left ankle in an attempt to correct the inversion. After the operation, the patient had mild clumsiness of the left leg and ankle, and another operation was performed the next year.
Approximately two years later, painful spasms began in her left foot. Neurologic evaluation led to a diagnosis of cerebral palsy. During the next six years, the spasms progressed to involve her left arm and then her right leg; the symptoms were worse in the evening than during the day. At the age of 16 years, the patient was able to play field hockey during the day but was hardly able to walk by nightfall.
During the four months before the visit to the neurology clinic, her symptoms worsened. She was typically asymptomatic in the morning, but pain, stiffness, and cramping of her feet, legs, thighs, hands, and arms developed by midday and worsened toward evening. Spasms in both legs, in the left more than in the right, caused her feet to bend down and turn in at the ankle, forcing her to stop walking. She felt a burning sensation in the feet, which was somewhat alleviated by removing her shoes. Spasms also occurred in her neck, forcing her head to the right. Tremors occurred in her arms and legs, predominantly at night, preventing her from sleeping. At bedtime, she became anxious and irritable. There was no decline in her cognitive functioning or academic progress, although the worsening of her gait from afternoon onward interfered with her ability to walk from room to room on the college campus.
The patient had been born in India after a full-term pregnancy and was delivered by cesarean section because of a nuchal cord. The cognitive and motor milestones were normal. Her parents were both Indian. Her father had leg pains and cramping without a gait disturbance, and a maternal cousin was dyslexic. Her one sister was healthy. The patient had moved with her family to the United States two years before the visit to the neurology clinic.
During the afternoon appointment in the clinic, general physical, mental-status, and cranial-nerve examinations were normal. Her muscle bulk was normal. There was dystonic posturing of her left foot, which was persistently held in plantar flexion with inversion at the ankle. There was dystonic posturing of her left hand, which was persistently held in palmar flexion at the wrist, with the fingers flexed at the metacarpophalangeal joint and extended at the interphalangeal joints. Similar, but milder, dystonic posturing was seen in her right foot and intermittently in her right hand, and there was intermittent twisting of her head to the right. All these dystonic postures and movements were intensified with voluntary movements of the affected limb and during walking. There was no weakness or sensory abnormality. The deep-tendon reflexes were ++ and symmetric. The plantar responses were flexor. Her gait was slow, effortful, and clumsy. Slit-lamp examination, serum ceruloplasmin levels, and positron-emission tomography (PET) of the head performed after the intravenous injection of 18F-fluorodeoxyglucose (18F-FDG) were normal.
Diagnostic procedures were performed.
Differential Diagnosis
Dr. Nagagopal Venna: When I examined this 19-year-old woman, she had had 11 years of persistent, slowly worsening, often painful, twisting involuntary movements, which began in her left foot, gradually spread to all her limbs and to her neck, intensified in severity, and caused substantial disability, particularly in walking. The movements were not accompanied by an alteration of sensation or strength in the limbs and trunk or of speech. Intermittent emotional instability and depression occurred, without psychosis, seizures, or cognitive impairment. Her neurodevelopmental history was unremarkable. There was no history of similar movements in family members.
The Movements
The involuntary movements of this patient are characteristic of a movement disorder known as dystonia,1 reviewed in this issue of the Journal.2 The movements are repetitive, slow, and twisting, accompanied by and superimposed on a more persistent component of distorted postures of the affected body parts. The foot, a frequent target, assumes plantar flexion (pes equinus, toe-walking) and plantar flexion with inversion (equinovarus), the hand is flexed at the wrist and extended at the fingers, and the neck is forcefully turned to the side (torticollis). Although dystonic movements typically begin and are most apparent in the distal parts of the limb, large twisting movements affecting the entire limb may eventually develop. When the trunk is involved, kyphoscoliosis, lordosis, or even bow-like arching of the back (opisthotonos) can result. A feature that defies accurate verbal description is that these movements are dynamic, fluctuate, and vary greatly in severity and location with sleep, rest, and voluntary action. They are typically dampened by sensory stimuli, such as touching the affected body part, and abate during sleep, whereas anxiety and scrutiny typically exacerbate them. Walking worsens the dystonia, impairing the gait. Dystonia may be confounded by a superimposed rapid, rhythmic tremor (dystonic tremor).
Dystonia can be categorized as focal, segmental, multifocal, and generalized in form.2 Some focal dystonias such as those that first appear in the lower limbs develop into segmental, multifocal, and generalized syndromes, whereas cervical dystonias tend to remain focal. All clinical forms of dystonia may have many causes, except hemidystonia, which is usually caused by a recognizable contralateral focal brain lesion.
Lack of familiarity with the manifestations of dystonia often leads to an incorrect diagnosis. The movements of dystonia differ from those of the more familiar syndrome of chorea, which are quick, jerky, nonrhythmic, and unsustained. Athetosis refers to more or less continuous, slow, writhing, squirming movements of the limbs or trunk. These two types of movement are fused often enough to warrant the term choreoathetosis. The variability of the movements and the seemingly bizarre postures may lead to a misdiagnosis of psychogenic disorder. When the postural distortions of the limbs and trunk become more or less fixed, they are mistaken for primary orthopedic deformities, as they were in this patient.
Dystonia is recognized on the basis of observation of the play of movement and the posture of the limbs, trunk, head, face, and neck at rest, during the maintenance of posture by the limbs, and during skilled movement. Study of the patient while he or she is standing, walking naturally, walking on the outer edges of the feet (stress gait), and running may reveal the full extent of the dystonia. Examination of patients or videos of patients' movements are the indispensable tools for identifying dystonias. Electromyography is rarely needed except to differentiate dystonia from rare disorders that mimic it such as stiff-person syndrome, neuromyotonia (Isaac's syndrome), and myotonia. The electromyographic hallmark of dystonia is sustained simultaneous contraction of the agonistic and antagonistic muscles and abnormal activation of adjacent and distant muscles.
Causes of Dystonia
Even after making a diagnosis of dystonia, determining the cause is often difficult because of the similar clinical picture, bewildering number of possible causes, and the lack of a known cause in many forms of the disorder2 (Table 1). The cause may be obvious in patients with affected family members or may be strongly suspected because of some unique or distinctive clinical feature or in relation to the patient's race or ethnic group. More often, systematic thinking, treatment trials, and observation are required to determine the cause. A pragmatic approach is to look for treatable and "not-to-be-missed" diagnoses and to reserve extensive investigation until after these have been ruled out. Imaging studies can be useful in narrowing the differential diagnosis.
Table 1. Differential Diagnosis of Dystonia in This Patient.
Dr. P. Ellen Grant: Many forms of secondary dystonia are associated with characteristic findings on brain magnetic resonance imaging (MRI) or computed tomography, although MRI scans are typically normal on visual inspection in the primary dystonias. Subtle structural differences in the brain on volumetric MRI analysis and differences in brain organization on diffusion tensor imaging and in spatiotemporal responses on functional MRI have emerged in some forms of primary dystonia,3,4 but these techniques are not currently available in routine practice. In this patient, brain MRI was not performed.
Dr. Venna: As a first step, dystonias can be separated into primary and secondary forms (Table 2).
Table 2. Clinical Characteristics of Dopa-Responsive Dystonia.
Secondary Dystonias
Among secondary dystonias,5 tardive dystonia caused by the use of psychotropic drugs should be considered in all cases, even though this complication is less common than choreoathetotic tardive dyskinesia.6 The culprit drugs have a common mechanism of interfering with brain neurotransmitters; most of them are neuroleptic agents, but antiemetic metoclopramide is an easily overlooked cause. The dystonia emerges slowly after prolonged exposure and may persist long after the drug is stopped. The movements are most prominent in the face, oromandibular muscles, and the neck, but they can be generalized to and indistinguishable from primary dystonias. The patient's history should be probed, since the exposure may be long forgotten. Despite this patient's emotional problems, she had no history of the use of such medications.
When dystonia is a manifestation of cerebral palsy, the movement disorder is most prominent in the legs and is frequently associated with abnormal developmental milestones, spasticity, and seizures. Dystonia is often too readily attributed to cerebral palsy, as it was in this patient, missing the rare but more treatable causes.
In many inborn errors of metabolism, dystonia is only a fragment of the phenotype among other neurologic and systemic signs, but dystonia may be the cardinal manifestation in some cases.2,7,8 Many cases of inborn errors of metabolism have characteristic appearances on MRI and key laboratory markers. Dystonia in childhood is a major manifestation of pantothenate kinase–associated neurodegeneration, and it is one of many complex movement disorders that appear in patients with Fahr's disease. In this patient, the normal physical and neurologic examinations, apart from the dystonia, render all these conditions unlikely.
Wilson's Disease
Wilson's disease should be included in the differential diagnosis of any persistent movement disorder of unknown cause, because early diagnosis and treatment are critical. Focal or multifocal dystonia may be prominent. The detection of golden-brown pigmentation at the outer rim of the cornea (Kayser–Fleischer rings) on clinical or slit-lamp examination and a low level of ceruloplasmin are key to the diagnosis. Results of MRI may be normal early in the patient's course, but later on, characteristic lesions of the basal ganglia may appear. A slit-lamp examination was performed in this patient, and the results were normal, as was her serum ceruloplasmin level.
Mitochondrial Disorders
Inherited failure of mitochondrial energy metabolism is increasingly being recognized as a fundamental mechanism of many puzzling neurologic diseases in children and less commonly in adults. Generalized dystonia is being recognized in the widening spectrum of neurologic phenotype, especially in association with Leber's hereditary optic neuropathy and pyruvate dehydrogenase complex.9,10,11 Tests for elevated serum lactate and pyruvate levels and MRI of the brain are useful in the diagnosis of these disorders.
Primary Dystonias
Most chronic progressive focal, multifocal, or generalized dystonias, uncomplicated by other neurologic abnormalities, structural lesions, or multisystem disorders, are now being recognized as inherited, thanks to modern neurogenetic research; these dystonias are currently designated DYT1 to DYT15.12 The features of this case suggest a primary dystonia (Table 1).
A mutation in the gene encoding the protein torsin A, which is expressed in the dopaminergic neurons but is of unknown function, is responsible for DYT1, an autosomal dominant generalized form of dystonia, often referred to as dystonia musculorum deformans or idiopathic torsion dystonia. This mutation accounts for 90 percent of childhood-onset dystonia in the Ashkenazi Jewish population and about 50 percent in other populations; the penetrance is about 30 percent, and the onset of symptoms occurs before the age of 26 years. The clinical picture of our patient is consistent with this phenotype, and she could be tested for this mutation. PET was performed after the intravenous injection of 18F-FDG to look for patterns of abnormal hypermetabolism that have been reported in affected persons who are carriers of the gene for DYT1, and the result was normal.
Dopa-Responsive Dystonia
Dopa-responsive dystonia is an inherited metabolic disorder (now classified as DYT5) that results in dopamine deficiency in the basal ganglia, unaccompanied by neuronal degeneration. A key feature of this disorder is that the neurologic function is dramatically restored in a sustained manner by means of orally administered dopaminergic therapy.13,14,15 Many clinical features of this case point to this diagnosis.
Girls and women are affected two to four times as often as boys and men; the onset usually occurs in childhood but may rarely occur as late as the sixth decade. The incidence is estimated to be between 0.5 and 1 per million persons, but frequent misdiagnosis probably renders this an underestimate. The typical clinical features are exemplified in this case (Table 2). Dystonia begins in the foot and spreads to other limbs and the trunk. Dramatic diurnal variation in symptoms is characteristic and is a distinctive and powerful clinical clue in this case; however, it is not invariable, and its absence should not rule out the diagnosis. In untreated patients, the dystonia and gait disorder gradually worsen during the first two decades after their onset, as in this patient, and bradykinesia may emerge. Postural tremors in the arms tend to appear in the fourth decade. Psychiatric manifestations are common in dopa-responsive dystonia, with a high incidence of recurrent major depression and obsessive–compulsive tendencies in patients older than 20 years.16 This patient had emotional instability and depression, particularly during periods of personal or academic stress and intercurrent medical illness. Because syndromes associated with this disease are so exquisitely reversed by simple and specific treatment,17 awareness of the variations of the disease and possible misdiagnoses is helpful (Table 3).
Table 3. Misdiagnosis in Patients with Dopa-Responsive Dystonia.
Therapeutic response to levodopa is an important diagnostic test. It is good clinical practice to give a therapeutic trial in any chronic dystonic-movement disorder of unknown causes. Most patients respond within days to small doses (50 to 100 mg) of levodopa, and the degree of relief from the dystonia and the improvement in gait are dramatic (Video Clips 1 and 2, available with the full text of this article at www.nejm.org). Some patients require doses of up to 600 mg per day, but lack of improvement at this dose makes the diagnosis unlikely. A remarkably consistent feature is that the response to levodopa is maintained indefinitely over a period of years with a low incidence of dyskinesias and the dreaded on–off effect, which are the rule in Parkinson's disease.18 Levodopa may restore neurologic functioning, even in patients who have been wheelchair-bound for many years.19 Although most patients have a dramatic response to levodopa, some patients also respond to anticholinergic agents.20 Psychiatric symptoms may also improve with levodopa and may be treated with selective serotonin-reuptake inhibitors without aggravating the dystonia.
In this patient, her normal birth and perinatal and developmental history, the lack of emergence of sensory, motor, or intellectual dysfunction during many years of increasing symptoms of dystonia, and the absence of systemic abnormalities and exposure to neuroleptic drugs strongly point to primary dystonia. The pronounced diurnal variation in the symptoms lead to the diagnosis of dopa-responsive dystonia. A therapeutic trial with levodopa would be the diagnostic test of choice. Genetic testing for the disorder is also available and could be performed.
Dr. Nagagopal Venna's Diagnosis
Dopamine-responsive dystonia (DYT5).
Discussion of Diagnostic Testing
Dr. Alcalay: Carbidopa and levodopa in combination were started at low doses (25 and 100 mg, respectively, twice a day). The patient reported marked improvement in her symptoms within 24 hours, and on the second night she was able to sleep without pain for the first time in years. On the evening of the third day after beginning therapy, excited by the resolution of her symptoms, she went jogging and was surprised that she was able to run with ease.
Dr. Katherine B. Sims: Additional testing was performed in this patient to confirm the diagnosis. Two biochemical-pathway defects have been identified in patients with dopa-responsive dystonia,14,21,22,23,24 autosomal dominant guanosine triphosphate cyclohydrolase 1 (GTPCH1) deficiency25 and autosomal recessive tyrosine hydroxylase deficiency.26 Tyrosine hydroxylase deficiency is generally more severe and has an earlier onset than GTPCH1 deficiency; the symptoms include tremor, myoclonus, spastic tetraparesis, psychomotor retardation, or a combination of these,27 and there is no diurnal variation. Our patient's clinical features thus suggest GTPCH1 deficiency.
Biochemical Pathways
GTPCH1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (Figure 1), a critical cofactor for the synthesis of dopamine, serotonin, and norepinephrine and in the hepatic metabolism of phenylalanine to tyrosine, and in other pathways.28,29 A deficiency of dopamine presumably underlies the movement disorder seen in dopa-responsive dystonia and explains the remarkable response to dopamine-agonist therapy.
Figure 1. Synthesis and Catabolism of the Neurotransmitters Catecholamine and Indolamine.
GTPCH1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4). Tetrahydrobiopterin has a central role as cofactor in the metabolic pathways, including the synthesis of the biogenic amine dopamine, in the hepatic metabolism of phenylalanine to tyrosine, and in the production of the serotonin precursor 5-hydroxytryptophan (5-HTP). The downstream consequences of GTPCH1 deficiency, therefore, include alterations in a number of pathways that are important in biologic and neurologic homeostasis and function. A deficiency of dopamine presumably underlies the movement disorder seen in dopa-responsive dystonia and can explain the remarkable response to dopa-agonist replacement in patients. The multiple metabolic consequences, secondary to GTPCH1 deficiency, may explain the more complex phenotype often seen in dopa-responsive dystonia and beyond that explained by simple dopamine deficiency. PTS denotes pyruvoyl-tetrahydropterin synthase, GFRP-GTPCH feedback regulatory protein, SPR sepiapterin reductase, DHPR dihydropteridine reductase, NOS nitric oxide synthase, qBH2 quinoid dihydropterin, NO nitric oxide, 5-HTP 5-hydroxytryptophan, PCD pterin, COMT catechol-o-methyltransferase, AADC aromatic L-amino acid decarboxylase, B6 pyridoxine, 3-O MD 3-O-methyldopa, 5-HIAA 5-hydroxy-3-indole acetic acid, NE norepinephrine, DOPAC dihydroxyphenylacetic acid, HVA homovanillic acid, EPI epinephrine, DHPG dihydroxyphenyl glycol, MHPG 3-methoxy,4-hydroxyphenolglycol, and VMA vanilmandelic acid.
In this case, after the therapeutic trial of levodopa and carbidopa, further confirmatory testing was performed by biochemical assay. Although GTPCH1 deficiency, and the resultant deficiency of the tetrahydrobiopterin cofactor, presumably results in decreased phenylalanine hydroxylase activity, serum phenylalanine levels are not usually elevated in patients with dopa-responsive dystonia.22 However, an oral phenylalanine-loading study will increase the requirement for phenylalanine-hydroxylase activity, and this pharmacologic stress will unmask a partial tetrahydrobiopterin deficiency and lead to elevation of serum phenylalanine levels.30,31 In this patient, the phenylalanine-loading study produced an elevated level of serum phenylalanine and an elevated phenylalanine:tyrosine ratio (Figure 2).
Figure 2. Phenylalanine-Loading Test.
After oral administration of 100 mg of phenylalanine per kilogram of body weight, serum phenylalanine levels in a normal person peak at 400 μmol per liter or less, those in a patient with dopa-responsive dystonia and sepiapterin deficiency (DRD/SR) at 800 μmol per liter, and those in our patient at greater than 800 μmol per liter.
Molecular Genetics
The gene that encodes the 32-kD GTPCH1 protein, GCH1, is located on chromosome 14q22.1.32,33 More than 100 mutations in the coding region of this gene have been identified in patients with the dopa-responsive dystonia phenotype (Figure 3).34 Many of these patients have no family history of dopa-responsive dystonia. There appears to be a high rate of sporadic mutation, but incomplete and sex-specific penetrance has also been characterized: the clinical phenotype is expressed in only about 15 percent of men and 45 percent of women carrying GCH1 mutations.35 This patient was eager to proceed with genetic testing. We identified a two-nucleotide deletion in exon 6 of the GCH1 gene (E6 del GT635–636). This specific mutation has not been reported in the literature or in GCH1 databases but is presumed to be pathologic, since it is predicted to cause a frameshift that results in protein truncation and alteration in function or stability or both.
Figure 3. Mutations in the GCH1 Gene Associated with Dopa-Responsive Dystonia.
The genomic organization and location of mutations in the human GCH1 gene on chromosome 14q22.1-q22.2 show that this patient carries a 2-bp deletion in exon 6 (del GT635–636), which predicts a translational frameshift and the production of a truncated protein. Red indicates a deletion, and blue exons.
Genetic Counseling
Because of the incomplete penetrance and apparently high rate of sporadic mutation, many patients, such as this one, have no family history of dystonia. Identification of the specific DNA mutation allows testing of asymptomatic family members who are at risk for inheritance of the mutation. In this case, genetic counseling included a comprehensive discussion of the variant penetrance even in those who do carry the DNA mutation as well as of the broad phenotypic variability that can be seen both within and among families. The decision to offer genetic testing to asymptomatic family members is controversial. It may be warranted when early intervention might have a positive effect on the medical outcome by facilitating active management of the disease or therapeutic intervention. Genetic testing allows for prenatal testing, and the availability of in vitro fertilization-preimplantation testing and embryo selection should be discussed if family members seek such information in prenatal counseling. Family members of this patient have not chosen to undergo testing.
Dr. Alcalay: Follow-up neurologic examinations during the next three years revealed that she was pleased with the restoration of normal mobility. She functions with only a trace of dystonia of the left foot and left hand and a nearly natural gait. She occasionally needs to increase the dose of levodopa during intercurrent illnesses and periods of emotional stress.
Anatomical Diagnosis
Dopamine-responsive dystonia caused by a mutation (E6 del GT635–636) in the GCH1 gene.
Dr. Sims reports having received fees for serving on the Fabry Advisory Board (Genzyme). No other potential conflict of interest relevant to this article was reported.
Source Information
From the Neurology Service (N.V.), the Pediatric Neurology Service (K.B.S.), and the Department of Pediatric Radiology (P.E.G.), Massachusetts General Hospital; and the Departments of Neurology (N.V., K.B.S.) and Radiology (P.E.G.), Harvard Medical School.
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Dr. Roy N. Alcalay (Neurology): A 19-year-old right-handed woman was referred to the neurology clinic because of slowly worsening difficulty walking and painful spasms in her legs and arms. When the patient was eight years of age, her teacher noticed that her left shoe was disproportionately worn on its outer side. Her physician noted inversion of the left foot and made a diagnosis of poliomyelitis. Tendon-transplantation surgery was performed on the left ankle in an attempt to correct the inversion. After the operation, the patient had mild clumsiness of the left leg and ankle, and another operation was performed the next year.
Approximately two years later, painful spasms began in her left foot. Neurologic evaluation led to a diagnosis of cerebral palsy. During the next six years, the spasms progressed to involve her left arm and then her right leg; the symptoms were worse in the evening than during the day. At the age of 16 years, the patient was able to play field hockey during the day but was hardly able to walk by nightfall.
During the four months before the visit to the neurology clinic, her symptoms worsened. She was typically asymptomatic in the morning, but pain, stiffness, and cramping of her feet, legs, thighs, hands, and arms developed by midday and worsened toward evening. Spasms in both legs, in the left more than in the right, caused her feet to bend down and turn in at the ankle, forcing her to stop walking. She felt a burning sensation in the feet, which was somewhat alleviated by removing her shoes. Spasms also occurred in her neck, forcing her head to the right. Tremors occurred in her arms and legs, predominantly at night, preventing her from sleeping. At bedtime, she became anxious and irritable. There was no decline in her cognitive functioning or academic progress, although the worsening of her gait from afternoon onward interfered with her ability to walk from room to room on the college campus.
The patient had been born in India after a full-term pregnancy and was delivered by cesarean section because of a nuchal cord. The cognitive and motor milestones were normal. Her parents were both Indian. Her father had leg pains and cramping without a gait disturbance, and a maternal cousin was dyslexic. Her one sister was healthy. The patient had moved with her family to the United States two years before the visit to the neurology clinic.
During the afternoon appointment in the clinic, general physical, mental-status, and cranial-nerve examinations were normal. Her muscle bulk was normal. There was dystonic posturing of her left foot, which was persistently held in plantar flexion with inversion at the ankle. There was dystonic posturing of her left hand, which was persistently held in palmar flexion at the wrist, with the fingers flexed at the metacarpophalangeal joint and extended at the interphalangeal joints. Similar, but milder, dystonic posturing was seen in her right foot and intermittently in her right hand, and there was intermittent twisting of her head to the right. All these dystonic postures and movements were intensified with voluntary movements of the affected limb and during walking. There was no weakness or sensory abnormality. The deep-tendon reflexes were ++ and symmetric. The plantar responses were flexor. Her gait was slow, effortful, and clumsy. Slit-lamp examination, serum ceruloplasmin levels, and positron-emission tomography (PET) of the head performed after the intravenous injection of 18F-fluorodeoxyglucose (18F-FDG) were normal.
Diagnostic procedures were performed.
Differential Diagnosis
Dr. Nagagopal Venna: When I examined this 19-year-old woman, she had had 11 years of persistent, slowly worsening, often painful, twisting involuntary movements, which began in her left foot, gradually spread to all her limbs and to her neck, intensified in severity, and caused substantial disability, particularly in walking. The movements were not accompanied by an alteration of sensation or strength in the limbs and trunk or of speech. Intermittent emotional instability and depression occurred, without psychosis, seizures, or cognitive impairment. Her neurodevelopmental history was unremarkable. There was no history of similar movements in family members.
The Movements
The involuntary movements of this patient are characteristic of a movement disorder known as dystonia,1 reviewed in this issue of the Journal.2 The movements are repetitive, slow, and twisting, accompanied by and superimposed on a more persistent component of distorted postures of the affected body parts. The foot, a frequent target, assumes plantar flexion (pes equinus, toe-walking) and plantar flexion with inversion (equinovarus), the hand is flexed at the wrist and extended at the fingers, and the neck is forcefully turned to the side (torticollis). Although dystonic movements typically begin and are most apparent in the distal parts of the limb, large twisting movements affecting the entire limb may eventually develop. When the trunk is involved, kyphoscoliosis, lordosis, or even bow-like arching of the back (opisthotonos) can result. A feature that defies accurate verbal description is that these movements are dynamic, fluctuate, and vary greatly in severity and location with sleep, rest, and voluntary action. They are typically dampened by sensory stimuli, such as touching the affected body part, and abate during sleep, whereas anxiety and scrutiny typically exacerbate them. Walking worsens the dystonia, impairing the gait. Dystonia may be confounded by a superimposed rapid, rhythmic tremor (dystonic tremor).
Dystonia can be categorized as focal, segmental, multifocal, and generalized in form.2 Some focal dystonias such as those that first appear in the lower limbs develop into segmental, multifocal, and generalized syndromes, whereas cervical dystonias tend to remain focal. All clinical forms of dystonia may have many causes, except hemidystonia, which is usually caused by a recognizable contralateral focal brain lesion.
Lack of familiarity with the manifestations of dystonia often leads to an incorrect diagnosis. The movements of dystonia differ from those of the more familiar syndrome of chorea, which are quick, jerky, nonrhythmic, and unsustained. Athetosis refers to more or less continuous, slow, writhing, squirming movements of the limbs or trunk. These two types of movement are fused often enough to warrant the term choreoathetosis. The variability of the movements and the seemingly bizarre postures may lead to a misdiagnosis of psychogenic disorder. When the postural distortions of the limbs and trunk become more or less fixed, they are mistaken for primary orthopedic deformities, as they were in this patient.
Dystonia is recognized on the basis of observation of the play of movement and the posture of the limbs, trunk, head, face, and neck at rest, during the maintenance of posture by the limbs, and during skilled movement. Study of the patient while he or she is standing, walking naturally, walking on the outer edges of the feet (stress gait), and running may reveal the full extent of the dystonia. Examination of patients or videos of patients' movements are the indispensable tools for identifying dystonias. Electromyography is rarely needed except to differentiate dystonia from rare disorders that mimic it such as stiff-person syndrome, neuromyotonia (Isaac's syndrome), and myotonia. The electromyographic hallmark of dystonia is sustained simultaneous contraction of the agonistic and antagonistic muscles and abnormal activation of adjacent and distant muscles.
Causes of Dystonia
Even after making a diagnosis of dystonia, determining the cause is often difficult because of the similar clinical picture, bewildering number of possible causes, and the lack of a known cause in many forms of the disorder2 (Table 1). The cause may be obvious in patients with affected family members or may be strongly suspected because of some unique or distinctive clinical feature or in relation to the patient's race or ethnic group. More often, systematic thinking, treatment trials, and observation are required to determine the cause. A pragmatic approach is to look for treatable and "not-to-be-missed" diagnoses and to reserve extensive investigation until after these have been ruled out. Imaging studies can be useful in narrowing the differential diagnosis.
Table 1. Differential Diagnosis of Dystonia in This Patient.
Dr. P. Ellen Grant: Many forms of secondary dystonia are associated with characteristic findings on brain magnetic resonance imaging (MRI) or computed tomography, although MRI scans are typically normal on visual inspection in the primary dystonias. Subtle structural differences in the brain on volumetric MRI analysis and differences in brain organization on diffusion tensor imaging and in spatiotemporal responses on functional MRI have emerged in some forms of primary dystonia,3,4 but these techniques are not currently available in routine practice. In this patient, brain MRI was not performed.
Dr. Venna: As a first step, dystonias can be separated into primary and secondary forms (Table 2).
Table 2. Clinical Characteristics of Dopa-Responsive Dystonia.
Secondary Dystonias
Among secondary dystonias,5 tardive dystonia caused by the use of psychotropic drugs should be considered in all cases, even though this complication is less common than choreoathetotic tardive dyskinesia.6 The culprit drugs have a common mechanism of interfering with brain neurotransmitters; most of them are neuroleptic agents, but antiemetic metoclopramide is an easily overlooked cause. The dystonia emerges slowly after prolonged exposure and may persist long after the drug is stopped. The movements are most prominent in the face, oromandibular muscles, and the neck, but they can be generalized to and indistinguishable from primary dystonias. The patient's history should be probed, since the exposure may be long forgotten. Despite this patient's emotional problems, she had no history of the use of such medications.
When dystonia is a manifestation of cerebral palsy, the movement disorder is most prominent in the legs and is frequently associated with abnormal developmental milestones, spasticity, and seizures. Dystonia is often too readily attributed to cerebral palsy, as it was in this patient, missing the rare but more treatable causes.
In many inborn errors of metabolism, dystonia is only a fragment of the phenotype among other neurologic and systemic signs, but dystonia may be the cardinal manifestation in some cases.2,7,8 Many cases of inborn errors of metabolism have characteristic appearances on MRI and key laboratory markers. Dystonia in childhood is a major manifestation of pantothenate kinase–associated neurodegeneration, and it is one of many complex movement disorders that appear in patients with Fahr's disease. In this patient, the normal physical and neurologic examinations, apart from the dystonia, render all these conditions unlikely.
Wilson's Disease
Wilson's disease should be included in the differential diagnosis of any persistent movement disorder of unknown cause, because early diagnosis and treatment are critical. Focal or multifocal dystonia may be prominent. The detection of golden-brown pigmentation at the outer rim of the cornea (Kayser–Fleischer rings) on clinical or slit-lamp examination and a low level of ceruloplasmin are key to the diagnosis. Results of MRI may be normal early in the patient's course, but later on, characteristic lesions of the basal ganglia may appear. A slit-lamp examination was performed in this patient, and the results were normal, as was her serum ceruloplasmin level.
Mitochondrial Disorders
Inherited failure of mitochondrial energy metabolism is increasingly being recognized as a fundamental mechanism of many puzzling neurologic diseases in children and less commonly in adults. Generalized dystonia is being recognized in the widening spectrum of neurologic phenotype, especially in association with Leber's hereditary optic neuropathy and pyruvate dehydrogenase complex.9,10,11 Tests for elevated serum lactate and pyruvate levels and MRI of the brain are useful in the diagnosis of these disorders.
Primary Dystonias
Most chronic progressive focal, multifocal, or generalized dystonias, uncomplicated by other neurologic abnormalities, structural lesions, or multisystem disorders, are now being recognized as inherited, thanks to modern neurogenetic research; these dystonias are currently designated DYT1 to DYT15.12 The features of this case suggest a primary dystonia (Table 1).
A mutation in the gene encoding the protein torsin A, which is expressed in the dopaminergic neurons but is of unknown function, is responsible for DYT1, an autosomal dominant generalized form of dystonia, often referred to as dystonia musculorum deformans or idiopathic torsion dystonia. This mutation accounts for 90 percent of childhood-onset dystonia in the Ashkenazi Jewish population and about 50 percent in other populations; the penetrance is about 30 percent, and the onset of symptoms occurs before the age of 26 years. The clinical picture of our patient is consistent with this phenotype, and she could be tested for this mutation. PET was performed after the intravenous injection of 18F-FDG to look for patterns of abnormal hypermetabolism that have been reported in affected persons who are carriers of the gene for DYT1, and the result was normal.
Dopa-Responsive Dystonia
Dopa-responsive dystonia is an inherited metabolic disorder (now classified as DYT5) that results in dopamine deficiency in the basal ganglia, unaccompanied by neuronal degeneration. A key feature of this disorder is that the neurologic function is dramatically restored in a sustained manner by means of orally administered dopaminergic therapy.13,14,15 Many clinical features of this case point to this diagnosis.
Girls and women are affected two to four times as often as boys and men; the onset usually occurs in childhood but may rarely occur as late as the sixth decade. The incidence is estimated to be between 0.5 and 1 per million persons, but frequent misdiagnosis probably renders this an underestimate. The typical clinical features are exemplified in this case (Table 2). Dystonia begins in the foot and spreads to other limbs and the trunk. Dramatic diurnal variation in symptoms is characteristic and is a distinctive and powerful clinical clue in this case; however, it is not invariable, and its absence should not rule out the diagnosis. In untreated patients, the dystonia and gait disorder gradually worsen during the first two decades after their onset, as in this patient, and bradykinesia may emerge. Postural tremors in the arms tend to appear in the fourth decade. Psychiatric manifestations are common in dopa-responsive dystonia, with a high incidence of recurrent major depression and obsessive–compulsive tendencies in patients older than 20 years.16 This patient had emotional instability and depression, particularly during periods of personal or academic stress and intercurrent medical illness. Because syndromes associated with this disease are so exquisitely reversed by simple and specific treatment,17 awareness of the variations of the disease and possible misdiagnoses is helpful (Table 3).
Table 3. Misdiagnosis in Patients with Dopa-Responsive Dystonia.
Therapeutic response to levodopa is an important diagnostic test. It is good clinical practice to give a therapeutic trial in any chronic dystonic-movement disorder of unknown causes. Most patients respond within days to small doses (50 to 100 mg) of levodopa, and the degree of relief from the dystonia and the improvement in gait are dramatic (Video Clips 1 and 2, available with the full text of this article at www.nejm.org). Some patients require doses of up to 600 mg per day, but lack of improvement at this dose makes the diagnosis unlikely. A remarkably consistent feature is that the response to levodopa is maintained indefinitely over a period of years with a low incidence of dyskinesias and the dreaded on–off effect, which are the rule in Parkinson's disease.18 Levodopa may restore neurologic functioning, even in patients who have been wheelchair-bound for many years.19 Although most patients have a dramatic response to levodopa, some patients also respond to anticholinergic agents.20 Psychiatric symptoms may also improve with levodopa and may be treated with selective serotonin-reuptake inhibitors without aggravating the dystonia.
In this patient, her normal birth and perinatal and developmental history, the lack of emergence of sensory, motor, or intellectual dysfunction during many years of increasing symptoms of dystonia, and the absence of systemic abnormalities and exposure to neuroleptic drugs strongly point to primary dystonia. The pronounced diurnal variation in the symptoms lead to the diagnosis of dopa-responsive dystonia. A therapeutic trial with levodopa would be the diagnostic test of choice. Genetic testing for the disorder is also available and could be performed.
Dr. Nagagopal Venna's Diagnosis
Dopamine-responsive dystonia (DYT5).
Discussion of Diagnostic Testing
Dr. Alcalay: Carbidopa and levodopa in combination were started at low doses (25 and 100 mg, respectively, twice a day). The patient reported marked improvement in her symptoms within 24 hours, and on the second night she was able to sleep without pain for the first time in years. On the evening of the third day after beginning therapy, excited by the resolution of her symptoms, she went jogging and was surprised that she was able to run with ease.
Dr. Katherine B. Sims: Additional testing was performed in this patient to confirm the diagnosis. Two biochemical-pathway defects have been identified in patients with dopa-responsive dystonia,14,21,22,23,24 autosomal dominant guanosine triphosphate cyclohydrolase 1 (GTPCH1) deficiency25 and autosomal recessive tyrosine hydroxylase deficiency.26 Tyrosine hydroxylase deficiency is generally more severe and has an earlier onset than GTPCH1 deficiency; the symptoms include tremor, myoclonus, spastic tetraparesis, psychomotor retardation, or a combination of these,27 and there is no diurnal variation. Our patient's clinical features thus suggest GTPCH1 deficiency.
Biochemical Pathways
GTPCH1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (Figure 1), a critical cofactor for the synthesis of dopamine, serotonin, and norepinephrine and in the hepatic metabolism of phenylalanine to tyrosine, and in other pathways.28,29 A deficiency of dopamine presumably underlies the movement disorder seen in dopa-responsive dystonia and explains the remarkable response to dopamine-agonist therapy.
Figure 1. Synthesis and Catabolism of the Neurotransmitters Catecholamine and Indolamine.
GTPCH1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4). Tetrahydrobiopterin has a central role as cofactor in the metabolic pathways, including the synthesis of the biogenic amine dopamine, in the hepatic metabolism of phenylalanine to tyrosine, and in the production of the serotonin precursor 5-hydroxytryptophan (5-HTP). The downstream consequences of GTPCH1 deficiency, therefore, include alterations in a number of pathways that are important in biologic and neurologic homeostasis and function. A deficiency of dopamine presumably underlies the movement disorder seen in dopa-responsive dystonia and can explain the remarkable response to dopa-agonist replacement in patients. The multiple metabolic consequences, secondary to GTPCH1 deficiency, may explain the more complex phenotype often seen in dopa-responsive dystonia and beyond that explained by simple dopamine deficiency. PTS denotes pyruvoyl-tetrahydropterin synthase, GFRP-GTPCH feedback regulatory protein, SPR sepiapterin reductase, DHPR dihydropteridine reductase, NOS nitric oxide synthase, qBH2 quinoid dihydropterin, NO nitric oxide, 5-HTP 5-hydroxytryptophan, PCD pterin, COMT catechol-o-methyltransferase, AADC aromatic L-amino acid decarboxylase, B6 pyridoxine, 3-O MD 3-O-methyldopa, 5-HIAA 5-hydroxy-3-indole acetic acid, NE norepinephrine, DOPAC dihydroxyphenylacetic acid, HVA homovanillic acid, EPI epinephrine, DHPG dihydroxyphenyl glycol, MHPG 3-methoxy,4-hydroxyphenolglycol, and VMA vanilmandelic acid.
In this case, after the therapeutic trial of levodopa and carbidopa, further confirmatory testing was performed by biochemical assay. Although GTPCH1 deficiency, and the resultant deficiency of the tetrahydrobiopterin cofactor, presumably results in decreased phenylalanine hydroxylase activity, serum phenylalanine levels are not usually elevated in patients with dopa-responsive dystonia.22 However, an oral phenylalanine-loading study will increase the requirement for phenylalanine-hydroxylase activity, and this pharmacologic stress will unmask a partial tetrahydrobiopterin deficiency and lead to elevation of serum phenylalanine levels.30,31 In this patient, the phenylalanine-loading study produced an elevated level of serum phenylalanine and an elevated phenylalanine:tyrosine ratio (Figure 2).
Figure 2. Phenylalanine-Loading Test.
After oral administration of 100 mg of phenylalanine per kilogram of body weight, serum phenylalanine levels in a normal person peak at 400 μmol per liter or less, those in a patient with dopa-responsive dystonia and sepiapterin deficiency (DRD/SR) at 800 μmol per liter, and those in our patient at greater than 800 μmol per liter.
Molecular Genetics
The gene that encodes the 32-kD GTPCH1 protein, GCH1, is located on chromosome 14q22.1.32,33 More than 100 mutations in the coding region of this gene have been identified in patients with the dopa-responsive dystonia phenotype (Figure 3).34 Many of these patients have no family history of dopa-responsive dystonia. There appears to be a high rate of sporadic mutation, but incomplete and sex-specific penetrance has also been characterized: the clinical phenotype is expressed in only about 15 percent of men and 45 percent of women carrying GCH1 mutations.35 This patient was eager to proceed with genetic testing. We identified a two-nucleotide deletion in exon 6 of the GCH1 gene (E6 del GT635–636). This specific mutation has not been reported in the literature or in GCH1 databases but is presumed to be pathologic, since it is predicted to cause a frameshift that results in protein truncation and alteration in function or stability or both.
Figure 3. Mutations in the GCH1 Gene Associated with Dopa-Responsive Dystonia.
The genomic organization and location of mutations in the human GCH1 gene on chromosome 14q22.1-q22.2 show that this patient carries a 2-bp deletion in exon 6 (del GT635–636), which predicts a translational frameshift and the production of a truncated protein. Red indicates a deletion, and blue exons.
Genetic Counseling
Because of the incomplete penetrance and apparently high rate of sporadic mutation, many patients, such as this one, have no family history of dystonia. Identification of the specific DNA mutation allows testing of asymptomatic family members who are at risk for inheritance of the mutation. In this case, genetic counseling included a comprehensive discussion of the variant penetrance even in those who do carry the DNA mutation as well as of the broad phenotypic variability that can be seen both within and among families. The decision to offer genetic testing to asymptomatic family members is controversial. It may be warranted when early intervention might have a positive effect on the medical outcome by facilitating active management of the disease or therapeutic intervention. Genetic testing allows for prenatal testing, and the availability of in vitro fertilization-preimplantation testing and embryo selection should be discussed if family members seek such information in prenatal counseling. Family members of this patient have not chosen to undergo testing.
Dr. Alcalay: Follow-up neurologic examinations during the next three years revealed that she was pleased with the restoration of normal mobility. She functions with only a trace of dystonia of the left foot and left hand and a nearly natural gait. She occasionally needs to increase the dose of levodopa during intercurrent illnesses and periods of emotional stress.
Anatomical Diagnosis
Dopamine-responsive dystonia caused by a mutation (E6 del GT635–636) in the GCH1 gene.
Dr. Sims reports having received fees for serving on the Fabry Advisory Board (Genzyme). No other potential conflict of interest relevant to this article was reported.
Source Information
From the Neurology Service (N.V.), the Pediatric Neurology Service (K.B.S.), and the Department of Pediatric Radiology (P.E.G.), Massachusetts General Hospital; and the Departments of Neurology (N.V., K.B.S.) and Radiology (P.E.G.), Harvard Medical School.
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