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Neurologic and Psychiatric Manifestations in a Family With a Mutation in Exon 2 of the Guanosine Triphosphate–Cyclohydrolase Gene
Heidi Hahn, MD;
Melissa R. Trant, MS;
Michael J. Brownstein, MD, PhD;
R. Andrew Harper, MD;
Sheldon Milstien, PhD;
Ian J. Butler, MD
Arch Neurol. 2001;58:749-755.
ABSTRACT
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Objective To investigate the range of clinical features to correlate genotypic
and phenotypic manifestations in hereditary progressive and/or levodopa-responsive
dystonia due to a defect in the guanosine triphosphate–cyclohydrolase
(GCH1) gene.
Design and Setting A large family from Texas was studied in an ambulatory setting by clinicians
in genetics, neurology, and psychiatry using structured interviews and examinations.
Patients The family was selected after neurometabolic investigations of a young
boy (proband) with foot dystonia and fatigue and his father, who had a long
history of anxiety and depression. Results of metabolic studies showed decreased
levels of metabolites of biopterin and biogenic amines in cerebrospinal fluid.
Subsequently, a novel mutation (37–base pair deletion) in exon 2 of
the GCH1 gene was demonstrated in 11 family members.
There was no observed female sex bias, but there was a wide variability of
motor dysfunctions in family members. Approximately 50% had clinical deafness
and a similar number had significant psychiatric dysfunction, including depression
and anxiety.
Conclusion Study of additional families with hereditary progressive and/or levodopa-responsive
dystonia using modern molecular methods will be necessary to confirm the neuropsychiatric
spectrum of this disorder, in which important clinical features may be unrecognized
and thus inappropriately managed.
INTRODUCTION
FOLLOWING recognition that some patients with a clinically variable
dystonic movement disorder (autosomal dominant hereditary progressive dystonia1) responsive to levodopa (levodopa-responsive dystonia2) had a single gene disorder with mutational defects
in the guanosine triphosphate (GTP)–cyclohydrolase I (GCH1) gene,3 there has been considerable
interest in understanding genotypic-phenotypic correlations using molecular
methods.4, 5
Guanosine triphosphate–cyclohydrolase I (GCH1) is the rate-limiting
enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin
(BH4), the natural cofactor for 3 aromatic amino acid monooxygenases.
These are tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting
enzymes in dopamine (DA) and serotonin (5-HT) biosynthesis, respectively,
and phenylalanine hydroxylase, which is involved in phenylalanine metabolism.
Mutations in the GCH1 gene have been identified in
the following 3 clinically different neurometabolic disorders: (1) autosomal
dominant hereditary progressive and/or levodopa-responsive dystonia2 that is characterized by childhood-onset dystonia
with sustained clinical responsiveness to low doses of levodopa; (2) autosomal
recessive GCH1-deficient hyperphenylalaninemia6
presenting in the first 6 months of life with a severe neurologic disorder
(psychomotor retardation, convulsions, truncal hypotonia, and limb hypertonia);
and more recently, (3) compound heterozygote mutations of the GCH1 gene with a neurologic disorder intermediate in severity between
the above disorders.7 Biochemical studies of
patients and families with recessive mutations of the GCH1 gene (homozygous or compound heterozygous) have demonstrated severe
or moderately severe defects in BH4metabolism that correlate with
the severity of neurologic symptoms, low biogenic amine metabolite levels
in cerebrospinal fluid (CSF), and partial responsiveness to neurotransmitter
precursors (levodopa and 5-hydroxytryptophan) and cofactor administration.
Patients with autosomal dominant levodopa-responsive dystonia have a dystonic
movement disorder without mental retardation or convulsions. Biochemically,
they have a milder defect in biogenic amine and BH4metabolism (based
on results of CSF studies) than patients with the recessive form of the disease.
With levodopa administration, the responsiveness of the motor dysfunctions
in these patients is dramatically improved. A recent report documented that
autosomal dominant levodopa-responsive dystonia is a disorder with a high
degree of penetrance. The expressivity of this disorder, however, shows marked
interfamilial and intrafamilial variability.4
In this study, we investigated the neurologic and biochemical as well
as molecular variables in members of a large Texas family with an unusual
frequency of neurologic and psychiatric symptoms. The starting point of the
investigation was a young boy (the proband) with variable foot dystonia and
fatigue, and his father, who had a long history of anxiety and depression.
Low CSF levels of metabolites of DA (homovanillic acid [HVA]), 5-HT (5-hydroxyindoleacetic
acid [5-HIAA]), norepinephrine (NE) (3-methoxy-4-hydroxy phenylethylene glycol
[MHPG]), and tetrahydrobiopterin (neopterin and biopterin) were measured in
both subjects. Molecular analysis demonstrated a heterozygous mutation in
the GCH1 gene in both subjects. Other members of
their large Texas family were invited to participate in these studies. A total
of 11 members (8 male and 3 female) were identified as having a mutation in
exon 2 of the GCH1 gene. All members with this mutation
underwent a detailed neurologic and psychiatric history and examination to
delineate the spectrum of neurologic and psychiatric manifestations in this
single family with this unique mutation in the GCH1
gene (Table 1).
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Table 1. Neurologic and Psychiatric Manifestations in Family With Guanosine
Triphosphate-Cyclohydrolase Deficit*
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SUBJECTS AND METHODS
SUBJECTS
Once the proband and his father were identified, this large Texas family
of more than 70 members was recruited after formal consent was obtained and
after review of the clinical and molecular protocols by an institutional review
board of the University of Texas–Houston Medical School. Paternal and
maternal family members were of English Quaker origins from Pennsylvania.
The family recognized that Parkinson disease was common in older members and
that psychiatric manifestations, including anxiety, depression, obsessive-compulsive
traits, and eating disorders, were present in family members. Once a mutational
deletion (37 base pairs [bp]) was demonstrated in exon 2 of the GCH1 gene in several family members, the family underwent systematic
evaluation, and the 11 genetically affected members were enrolled in a detailed
study of personal, medical, social, and family history by a genetic counselor
(M.R.T.), with a standardized neurologic and psychiatric assessment by a board-certified
neurologist (I.J.B.) and psychiatrist (R.A.H.), respectively. A complete pedigree
was obtained (Figure 1), and none
of the family members carrying the gene mutation was born of a consanguineous
union. Informed consent was obtained and most patients were examined (and
videotaped) at home. All subjects underwent a clinical psychiatric interview.
A psychiatrist board certified in general as well as child and adolescent
psychiatry conducted this interview (R.A.H.). The interview screened for major
psychiatric disorders and was adapted from the questions on the Schedule for
Affective Disorders and Schizophrenia8 and
the Schedule for Affective Disorders and Schizophrenia for School-age Children.9 Further symptoms were obtained from subjects who responded
positively to the screening questions to determine if they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
criteria for a particular psychiatric disorder.10
Each subject also received the Mini-Mental State Examination11
to screen for cognitive difficulties. Coded samples of venous blood were obtained
for genomic DNA preparation from peripheral leukocytes using a standard method
(Puregene kits; Gentra Systems, Minneapolis, Minn). Member III:1 did not wish
to be studied.
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Figure 1. Pedigree of the Texas family studied.
Squares indicate male members; circles, female members; solid filled shapes,
individuals with gene mutation; dotted shapes, individuals undergoing testing
who had negative findings for mutation; and slashed shapes, deceased family
members. Arrow indicates proband.
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BIOGENIC AMINES AND PTERIN METABOLITES
Samples of CSF obtained at lumbar puncture were collected on ice and
stored at -80°C until analyzed. Samples were collected in the morning
in glass tubes (2 mg of ascorbic acid per milliliter of CSF), and concentrations
of neurotransmitter metabolites HVA, 5-HIAA, and MHPG were determined by means
of a modification of a gas chromatography–mass spectroscopy procedure.12 Total CSF neopterin and biopterin levels (oxidized
plus reduced forms) were determined by means of high-performance liquid chromatography
with fluorescence detection after oxidation as previously described.13
MUTATION DETECTION
For mutational analysis, exons 1 through 6, including splice junctions,
were amplified from genomic DNA using polymerase chain reaction (PCR) analysis.
Primer sequences used for amplification of exons were the same as those reported
previously.14 At first, a combined single-stranded
conformational polymorphism (SSCP) and heteroduplex analysis approach was
used under optimized conditions for a subset of DNA samples of family members.
The DNA samples were amplified in PCR buffer containing 2.2-mmol/L magnesium
chloride and  -phosphate 32–labeled deoxycytidine-5'-triphosphate
for 35 cycles at 95°C for 45 seconds, 58°C for 1 minute 30 seconds,
and 72°C for 45 seconds. Products were diluted 1:3 in a stop solution
and denatured at 95°C for 10 minutes, and 2.5 µL was loaded on the
gel. The gel formulation was as follows: 6% acrylamide:Bis(2.6% cross-linking)
10% glycerol at room temperature, 45W. Heteroduplexes were identified at the
bottom of the gels, and SSCPs were identified from the single-stranded region.
Next, PCR products with SSCP and heteroduplex variants were subcloned in the
PCR 2.1 vector (Invitrogene, Carlsbad, Calif) and sequenced using an automatic
DNA sequencer (Applied Biosystems 370A, Foster City, Calif) and a commercially
available kit (Taq Dye Deoxy Terminator Cycle Sequencing kit; Perkin Elmer,
Norwalk, Conn). A 37-bp deletion was identified by sequencing of the coding
and complementary strands. Subsequently, all genomic DNA samples from individuals
of the family were amplified with the primer set for exon 2 (5'-GTA
ACG CTC GCT TAT GTT GAC TGT C-3' and 5'-ACC TGA GAT ATC AGC AAT
TGG CAG C-3'), and the PCR products underwent electrophoresis on a 3%
agarose gel.
RESULTS
PATIENTS
Eleven subjects were determined to have the mutation and agreed to take
part in the clinical family study (Figure
1). Neurologic, psychiatric, and other medical manifestations of
these family members are summarized inTable
1. Ages at evaluation ranged from 10 to 73 years. Six subjects had
a motor disorder, and 6 had psychiatric manifestations, with 3 of these having
a combination of motor and psychiatric manifestations. Only 2 subjects were
considered clinically unaffected. Deafness was clinically apparent in 6 subjects
but was not evaluated by audiometry. Results of DNA mutational analysis were
conveyed to those subjects who requested this on their consent form. Genetic
and medical counseling was given. In several patients, levodopa treatment
was recommended and initiated after appropriate consultation with local physicians.
Levodopa in combined with carbidopa (Sinemet tablets) was administered to
6 subjects with subjective (eg, fatigue) and objective symptoms (eg, dystonia
and parkinsonism). Improvement was observed in all 6, with the usual dose
being 2 to 3 tablets (25 mg carbidopa–100 mg levodopa tablet) daily.
Antidepressants (usually fluoxetine hydrochloride) were administered to 4
subjects.
BIOGENIC AMINES AND PTERIN METABOLITES
The proband (IV:5) and his father (III:3) had low CSF levels of HVA,
5-HIAA, and MHPG metabolites, compared with age-matched control subjects (Table 2). Levels of neopterin and biopterin
in CSF were also markedly decreased in the proband and his father, whereas
all metabolite levels were normal in the unaffected sister (IV:6) of the proband
(Table 2).
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Table 2. Biogenic Amine Metabolite and Biopterin Levels in Cerebrospinal
Fluid in a Family With Guanosine Triphosphate–Cyclohydrolase Deficit*
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MUTATIONAL ANALYSIS
The proband and his father were heterozygous for an SSCP variant in
exon 2 that was not present in related family members (data not shown). Sequencing
analysis of exon 2 of the proband demonstrated a 37-bp deletion mutation in
1 allele of the GCH1 gene (Figure 2A). With the use of PCR-based screening with the primer
set for exon 2 (Figure 2B), the
deletion was detected in 11 individuals in the family. The deletion shifts
the translational reading frame of the GCH1 gene
at amino acid 138 and predicts a premature stop codon at position 160 (Figure 2C).
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Figure 2. Analysis of the mutation of the
guanosine triphosphate–cyclohydrolase (GCH1)
gene. A, Sequence profile of the wild-type (wt) allele and that of the mutated
(del) allele of the proband. The deleted 37 base pairs (bp) in exon 2 of the GCH1 gene are boxed in the wt sequence and marked with
an arrow in the del allele. B, Polymerase chain reaction analysis of genomic
DNA samples from individuals of the family (shown are III:3, IV:5, and IV:6
of the family pedigree). The primer set for exon 2 was used. The wt gene and
the del gene migrate as a 315- and 278-bp band, respectively. Pedigree symbols
are explained in the legand to Figure 1. C, Predicted translational reading
frames of wt and del alleles of affected individuals. The 37-bp deletion in
exon 2 leads to a shift of the reading frame, which results in a premature
termination codon after amino acid 159. In boldface type are the deleted DNA
sequence (marked in the wt allele) and the predicted amino acid sequence resulting
from the deletion.
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COMMENT
Torsion dystonia is clinically characterized by early, exercise-induced
or spontaneous intense and sustained muscle contractions of trunk and extremity
muscles with torsional components. Age of onset is in the first 2 decades
of life. Clinicians in the 1950s observed dramatic clinical improvement in
some patients with torsion dystonia when they were treated with modest doses
of an anticholinergic medication, trihexyphenidyl hydrochloride.15
With the advent of levodopa administration for Parkinson disease, clinicians
observed a similar dramatic improvement in approximately 5% to 10% of children
with torsion dystonia such that a trial of levodopa is now empirically recommended
in all children with torsion dystonia.2 Further
clinical features observed in such patients include ataxia, choreoathetoid
and spastic-type cerebral palsy states, and parkinsonism, often with worsening
of motor symptoms toward the end of the day.1
Earlier studies emphasized the prominent diurnal fluctuations of the motor
disorder, the continuing therapeutic response to levodopa, and clustering
in families, although a pattern of recessive or dominant inheritance with
variable penetrance was clinically difficult to determine.
Previous investigators documented low levels of HVA and biopterin metabolites
in CSF from patients with torsion dystonia responsive to levodopa.16 Given the familial nature of the disorder and advances
in understanding the role of BH4 in aromatic amino acid hydroxylation
and biogenic amine metabolism, molecular biologists allied with clinicians
were subsequently able to demonstrate mutations underlying this disorder.
Mutations were detected in the rate-limiting enzyme of BH4 biosynthesis,
GCH1, causing a dominantly inherited disorder with variable penetrance.3 Compound heterozygote mutations of the GCH1 gene cause severe psychomotor delay and dystonia responsive to
levodopa.7 Mutations have also been found in
the gene for tyrosine hydroxylase, which is the rate-limiting enzyme in DA
biosynthesis. These mutations cause a recessive disorder with decreased levels
of DA and NE metabolites.17
By means of biochemical and molecular methods, we characterized 11 members
of a large Texas family heterozygous for a deletion mutation in exon 2 of
the GCH1 gene. We observed a marked intrafamilial
phenotypic variability in GCH1 heterozygotes. Dystonia
was present in 2 patients (IV:5 and IV:21). Obvious parkinsonism was observed
only in 1 patient (II:3), whose father (I:1, the great-grandfather of the
proband of the study) died of parkinsonian-related complications. Late-afternoon
fatigue was observed in 3 patients (IV:5, II:1, and III:3), which improved
in all 3 with administration of moderate doses of levodopa. Tremor was observed
in 3 patients (II:1, II:3, and IV:21) and torticollis in 2 patients (father
and son, III:12 and IV:21, respectively), and in 3 patients (II:3, III:12,
and IV:21) there was a cerebral palsy–like state (flexion of hips and
legs affecting gait and posture). Extensor plantar responses (possible striatal
toe18) were present in 3 patients (II:3, III:12,
and II:5), ataxia in 2 patients (II:3 and II:5), and definite brisk deep tendon
reflexes in 1 patient (III:12). In the patient with obvious Parkinson disease
(II:3), dyskinetic features improved after a reduction in his dose of levodopa.
Although the various phenotypic motor features of levodopa-responsive dystonia
with parkinsonism have been recognized for many years,19
only with the advent of molecular techniques has it been possible to define
phenotypically the motor manifestations with certainty in GCH1-deficient patients
and families.20 A recent study of 5 families
with levodopa-responsive dystonia4 demonstrated
marked variation in expressivity, even between affected members of the same
kindred. In our study we have demonstrated that there is indeed a marked intrafamilial
variability in motor manifestations in levodopa-responsive dystonia with parkinsonism
due to a specific new mutation in the GCH1 gene.
In previous studies of levodopa-responsive dystonia, investigators have
postulated that, based on clinical manifestations and rapid and persistent
responses to medications (anticholinergic agents and levodopa replacement),
the various motor manifestation of GCH1 deficiency are DA mediated.19, 21 In addition, the patients often show
decreased levels of 5-HT (5-HIAA)22 and NE
(MHPG)23 metabolites. By means of CSF analysis
in 2 heterozygous subjects of the family (the proband [IV:5] and his father
[III:3]), we were able to show that the mutation in the present study produced
a defect in cerebral DA as well as cerebral 5-HT and NE biosynthesis (Table 2). Psychiatrists have increasingly
implicated the role of 5-HT and NE in depressive and anxiety states.24 Using a standardized psychiatric interview process,
a board-certified psychiatrist (R.A.H.) determined that depressive manifestations
(requiring previous and current pharmacotherapy) were prominent in 4 patients
(IV:5, III:3, III:16, and III:17), anxiety was variably present in 6 patients
(IV:5, II:1, III:3, III:12, III:16, and III:17), and obsessive-compulsive
traits in 1 patient (III:12). In general, psychiatric manifestations have
been only occasionally mentioned in patients with levodopa-responsive dystonia
with parkinsonism.25 However, the psychiatric
manifestations (eg, depression and anxiety) of adult-onset Parkinson disease
have been increasingly recognized26, 27
and may have a similar neurochemical basis, given the known pathologic and
neurochemical defects in the locus ceruleus (NE) and raphe nuclei (5-HT) in
the brain regions of patients with Parkinson disease.28
Manifestation of juvenile-onset parkinsonism may not always be present
in the patient and may only become apparent in later decades. Therefore, the
differential diagnosis between degenerative Parkinson disease and levodopa-responsive
(genetic) dystonic parkinsonism without family history or a demonstrable genetic
defect is often a hard task for a clinician. The possibility of both conditions
being present in older individuals is certainly feasible and of prognostic
significance. In such patients, the decrements in DA functions with aging,
including DA transporter (presynaptic) and dopamine (D2) receptor
(postsynaptic) defects, as recently quantitated by means of positron-emission
tomography imaging,29 may be further exacerbated
by modest defects in DA synthesis in GTP1-deficient heterozygous and manifesting
carrier subjects. The recent demonstration of increased D2 receptor
density in the basal ganglia using carbon 11–labeled raclopride positron-emission
tomography imaging in asymptomatic and symptomatic patients with levodopa-responsive
dystonia is of interest, and presumed up-regulation of these receptors is
related to functional synaptic DA deficiency.16
This up-regulation in DA receptors may explain the initial therapeutic sensitivity
of patients with levodopa-responsive dystonia treated with even small doses
of levodopa.
Clinically detectable deafness of a mild to severe degree was apparent
in 6 heterozygous patients; however, the significance of this observation
is uncertain because deafness has not been a feature in previously described
patients with levodopa-responsive dystonia with parkinsonism and is rarely
associated with dystonia.30 Recently, an X-linked
form of dystonia-deafness syndrome was studied by means of mutational analysis
of a novel X-linked gene, deafness/dystonia peptide (DFN-1:DDP).31 The association of clinically apparent
hearing loss in 6 members of this family with a mutation in the GCH1 gene may warrant further clinical and molecular studies.
Previous investigators have demonstrated a sex-related bias with a female-male
ratio of 4.3 in patients with levodopa-responsive dystonia. Penetrance of GCH1 mutations was 2.3 times higher in women compared with
men.5 In the family described herein, 8 male
and 3 female subjects were affected, and there was no apparent segregation
by sex of motor and psychiatric manifestations (Table 1). Although we cannot explain this difference in sex bias
in the family, the specific mutation within a family may be an important determinant
for sex-related penetrance.5, 32
From a therapeutic viewpoint, management of the movement disorder(s)
component of levodopa-responsive dystonia with levodopa and a peripheral decarboxylase
inhibitor has to be one of the most satisfying in neurologic practice.33, 34 Levodopa may actually have a neurotrophic
and neuroprotective role.35, 36, 37
Thus, after the molecular identification of genetically affected individuals
who are asymmptomatic, administration of levodopa may also have a beneficial
role in disease prevention, particularly in later-onset parkinsonism. Levodopa
administered alone (as is currently advocated) may interfere with the uptake
of other aromatic amino acids (including phenylalanine, tyrosine, tryptophan,
and 5-hydroxytryptophan) into neurons and thus interfere with precursor availability
in neuronal synthesis of 5-HT.38 The impact
on impaired neuronal synthesis of 5-HT by levodopa administration may be further
exacerbated by the vulnerability of 5-HT biosynthesis by a reduction in active
cofactor levels in patients with the defective GCH1
gene.39 Potentially defective brain synthesis
of 5-HT could cause or exacerbate psychiatric conditions such as depression
or obsessive-compulsive traits.
The study of this large Texas family with a newly described and unique
heterozygous mutation in the GCH1 gene and with a
dominant pattern of inheritance and variable penetrance shows the wide intrafamilial
variability in clinical expression (phenotype) of this disorder. Although
the proband may have had a rather typical presentation with focal foot dystonia,
his history of muscle fatigue was sufficiently prominent to delay diagnosis.
The immediate family of the proband recognized psychiatric disorders in family
members, and parkinsonism was determined to be relatively common in family
members. Furthermore, diurnal variation in motor manifestations was unusual
in the family, except for increased afternoon fatigue in several members and
increased foot dystonia in the afternoon in the proband. Variability of clinical
expression is not unusual in GCH1 deficiency. Furthermore, family members
may undergo initial evaluation by a clinical psychologist or psychiatrist
for fatigue states, depression, anxiety, and obsessive-compulsive manifestations
before the familial nature of a movement disorder is recognized.
From our observations of the clinical manifestions of the syndrome in
this family, the current terminology emphasizing dystonia, parkinsonism, and
levodopa responsiveness may be too restrictive. Even the criterion of levodopa
responsiveness may be overly restrictive, given the potential impact of a
deficit of BH4 cofactor on other hydroxylation steps. The combination
of neurologic and psychiatric consultation, biochemical (CSF) analysis, possibe
phenylalanine loading studies,40 and molecular
methods should enable a more precise diagnosis of these conditions and the
application of appropriate therapies.
AUTHOR INFORMATION
Accepted for publication August 28, 2000.
Supported in part by Clinical Research Center grant RR02588 at the University
of Texas–Houston Medical School (Dr Butler), and by grant 15956 from
Shriners Hospital for Children, Tampa, Fla.
From the Institute of Pathology, GSF Research Center of Environment
and Health, Neuherberg, Germany (Dr Hahn); the Division of Medical Genetics,
Department of Pediatrics (Ms Trant), the Division of Child Psychiatry, Department
of Psychiatry (Dr Harper), and the Division of Child Neurology, Department
of Neurology (Dr Butler), University of Texas–Houston Health Science
Center; and the Laboratory of Genetics, National Institute of Mental Health
(NIMH)–National Human Genome Research Institute, (Dr Brownstein), and
the Laboratory of Cellular and Molecular Regulation, NIMH (Dr Milstien), Bethesda,
Md.
Corresponding author and reprints: Ian J. Butler, MD, Department
of Neurology, PO Box 20708, Houston, TX 77225-0708.
REFERENCES
| |
1. Segawa M, Nomura Y. Hereditary progressive dystonia with marked diurnal fluctuation. In: Segawa M, ed. Hereditary Progressive Dystonia
With Marked Diurnal Fluctuation. New York, NY: Parthenon Publishing
Group Inc; 1993:3-19.
2. Nygaard TG, Wooten GF. Dopa-responsive dystonia: some pieces of the puzzle are still missing. Neurology. 1998;50:853-855.
FREE FULL TEXT
3. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused
by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994;8:236-242.
FULL TEXT
|
ISI
| PUBMED
4. Steinberger D, Weber Y, Korinthenberg R, et al. High penetrance and pronounced variation in expressivity of GCH 1 mutations
in five families with dopa-responsive dystonia. Ann Neurol. 1998;43:634-639.
FULL TEXT
|
ISI
| PUBMED
5. Furukawa Y, Lang AE, Trugman JM, et al. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations
in dopa-responsive dystonia. Neurology. 1998;50:1015-1020.
FREE FULL TEXT
6. Niederwieser A, Blau N, Wang M, Joller P, Atarés M, Cardesa-Garcia J. GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia
with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular
hypotonia. Eur J Pediatr. 1984;141:208-214.
FULL TEXT
|
ISI
| PUBMED
7. Furakawa Y, Kish SJ, Bebin EM, et al. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase
I gene mutations. Ann Neurol. 1998;44:10-16.
FULL TEXT
|
ISI
| PUBMED
8. Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry. 1978;35:837-844.
ABSTRACT
9. Chambers WJ, Puig-Antich J, Hirsch M, et al. The assessment of affective disorders in children and adolescents by
semi-structured interview: test-retest reliability of the Schedule for Affective
Disorders and Schizophrenia for School-age Children, Present Episode Version. Arch Gen Psychiatry. 1985;42:696-702.
ABSTRACT
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition. Washington, DC: American Psychiatric Association; 1994.
11. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state
of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
12. Seifert WE, Foxx JL, Butler IJ. Age effect on dopamine and serotonin metabolite levels in cerebrospinal
fluid. Ann Neurol. 1980;8:38-42.
FULL TEXT
|
ISI
| PUBMED
13. Sakai N, Kaufman S, Milstien S. Tetrahydrobiopterin is required for cytokine-induced nitric oxide production
in a murine macrophage cell line (RAW 264). Mol Pharmacol. 1993;43:6-10.
ABSTRACT
14. Ichinose H, Ohye T, Matsuda Y, et al. Characterization of mouse and human GTP cyclohydrolase I genes: mutations
in patients with GTP cyclohydrolase I deficiency. J Biol Chem. 1995;270:10062-10071.
FREE FULL TEXT
15. Mucklow ES, Metz HT. Remarkable response to benzhexol hydrochloride (Artane) in children
with an unusual progressive striatal syndrome. Dev Med Child Neurol. 1964;6:598-605.
16. Kishore A, Nygaard TG, de la Fuente-Fernandez R, et al. Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive
dystonia measured with [11C]-raclopride and positron-emission tomography. Neurology. 1998;50:1028-1032.
FREE FULL TEXT
17. Bräutigam C, Wevers RA, Jansen RJT, et al. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin Chem. 1998;44:1897-1904.
FREE FULL TEXT
18. Duvoisin RC, Yahr MD, Lieberman J, Antunes J, Rhee S. The striatal foot. Trans Am Neurol Assoc. 1972;97:267.
19. Nygaard TG, Trugman JM, deYebenes JG, Fahn S. Dopa-responsive dystonia: the spectrum of clinical manifestations in
a large North American family. Neurology. 1990;40:66-69.
FREE FULL TEXT
20. Bandmann O, Marsden CD, Wood NW. Atypical presentations of dopa-responsive dystonia. In: Fahn S, Marsden CD, DeLong M, eds. Dystonia
3. Philadelphia, Pa: Lippincott-Raven Publishers; 1998:283-290. Advances in Neurology; vol 78.
21. Chutorian AM, Nygaard TG, Waran S. Dopa-responsive dystonia. Int Pediatr. 1994;9(suppl 1):49-54.
22. Fink JK, Barton N, Cohen W, Lovenberg W, Burns RS, Hallett M. Dystonia with marked diurnal variation associated with biopterin deficiency. Neurology. 1988;38:707-711.
FREE FULL TEXT
23. LeWitt PA, Miller LP, Levine RA, et al. Tetrahydrobiopterin in dystonia: identification of abnormal metabolism
and therapeutic trials. Neurology. 1986;36:760-764.
FREE FULL TEXT
24. Briley M. Current and future therapeutic approaches to the treatment of depression. Neurosci News. 1998;1:8-13.
25. Costeff H, Gadoth N, Mendelson L, Harel S, Lavie P. Fluctuating dystonia responsive to levodopa. Arch Dis Child. 1987;62:801-804.
ABSTRACT
26. Mayeux R, Stern Y, Cote L, Williams JBW. Altered serotonin metabolism in depressed patients with Parkinson's
disease. Neurology. 1984;34:642-646.
FREE FULL TEXT
27. Siemers ER, Shekhar A, Quaid K, Dickson H. Anxiety and motor performance in Parkinson's disease. Mov Disord. 1993;8:501-506.
FULL TEXT
|
ISI
| PUBMED
28. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y. Reduction of cortical dopamine, noradrenaline, serotonin and their
metabolites in Parkinson's disease. Brain Res. 1983;275:321-328.
FULL TEXT
|
ISI
| PUBMED
29. Volkow ND, Wang GJ, Fowler JS, et al. Parallel loss of presynaptic and postsynaptic dopamine markers in normal
aging. Ann Neurol. 1998;44:143-147.
FULL TEXT
|
ISI
| PUBMED
30. Hayes MW, Ouvrier RA, Evans W, Somerville E, Morris JGL. X-linked dystonia-deafness syndrome. Mov Disord. 1998;13:303-308.
FULL TEXT
|
ISI
| PUBMED
31. Jin H, May M, Tranebjaerg L, et al. A novel X-linked gene, DDP, shows mutations in families with deafness
(DFN-1), dystonia, mental deficiency and blindness. Nat Genet. 1996;14:177-180.
FULL TEXT
|
ISI
| PUBMED
32. Sadovnick D, Kurlan R. The increasingly complex genetics of Tourette's syndrome. Neurology. 1997;48:801-802.
ISI
| PUBMED
33. Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia: long-term treatment response and prognosis. Neurology. 1991;41:174-181.
ISI
34. Dewey RB, Muenter MD, Kishore A, Snow BJ. Long-term follow-up of levodopa responsiveness in generalized dystonia. Arch Neurol. 1998;55:1320-1323.
FREE FULL TEXT
35. Mena MA, Davila V, Sulzer D. Neurotrophic effects of L-dopa in postnatal midbrain dopamine neurons/cortical
astrocyte cocultures. J Neurochem. 1997;69:1398-1408.
ISI
| PUBMED
36. Murer MG, Dziewczapolski G, Menalled LB, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead
promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol. 1998;43:561-575.
FULL TEXT
|
ISI
| PUBMED
37. Fahn S. Welcome news about levodopa, but uncertainty remains. Ann Neurol. 1998;43:551-554.
FULL TEXT
|
ISI
| PUBMED
38. Oldendorf WH. Saturation of blood brain barrier transport of amino acids in phenylketonuria. Arch Neurol. 1973;28:45-48.
ISI
| PUBMED
39. Ishida A, Takada G, Kobayashi Y, Toyoshima I, Takai K. Effect of tetrahydrobiopterin and 5-hydroxytryptophan on hereditary
progressive dystonia with marked diurnal fluctuation: a suggestion of the
serotonergic system involvement. Tohoku J Exp Med. 1988;154:233-239.
ISI
| PUBMED
40. Hyland K, Fryburg JS, Wilson WG, et al. Oral phenylalanine loading in dopa-responsive dystonia: a possible
diagnostic test. Neurology. 1997;48:1290-1297.
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