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Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency.

Tyrosine hydroxylase (TH,[4] EC 1.14.16.2) catalyzes the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-dopa), the rate-limiting step in the biosynthesis of the catecholamines Catecholamines
Family of neurotransmitters containing dopamine, norepinephrine and epinephrine, produced and secreted by cells of the adrenal medulla in the brain.
 dopamine, norepinephrine, and epinephrine (Fig. 1). The iron-containing mixed function oxidase requires molecular oxygen and the cofactor cofactor

An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may
 tetrahydrobiopterin (BH4) for activity. TH is expressed mainly in specific brain areas and in the adrenal medulla (1).

A central role of TH for prenatal development and postnatal survival was indicated by the nonviability of TH-knockout mice (2). In humans, secondary impairment of TH enzymatic activity occurs in defects of BH4 synthesis and recycling, mostly referred to as variant phenylketonurias. The first indication of primary genetic TH deficiency (THD) in humans was provided in 1994 by Clayton et al. (3). To date, four different mutations have been described in six index cases from unrelated families. In two siblings, a point mutation in exon 11c.1141C [right arrow] A (Q381K) (4, 5) and in another girl a point mutation in exon 5c.614T [right arrow] C (L205P) (3, 6) have been identified. Recently, a missense mutation in exon 6c.698G [right arrow] A (R233H) a "common" mutation in The Netherlands and a deletion delC291 in exon 3 could be identified in patients with autosomal recessive L-dopa-responsive infantile parkinsonism (7, 8). Patients were described as having autosomal recessive L-dopa-responsive dystonia dystonia /dys·to·nia/ (-to´ne-ah) dyskinetic movements due to disordered tonicity of muscle.dyston´ic

dystonia musculo´rum defor´mans
, or Segawa syndrome, or as L-dopa-responsive parkinsonism in infancy (4-7). Clinical symptoms of dystonia, hypokinesia, rigidity, and truncal truncal /trun·cal/ (trung´k'l) pertaining to the trunk.

trun·cal
adj.
1. Of or relating to the trunk of the body.

2. Of or relating to an arterial or nerve trunk.
 hypotonia hypotonia /hy·po·to·nia/ (-ton´e-ah) diminished tone of the skeletal muscles.

hy·po·to·ni·a
n.
1. Reduced tension or pressure, as of the intraocular fluid in the eyeball.

2.
 were reported to develop in early childhood. All patients showed marked clinical improvement on low doses of L-dopa together with the decarboxylase decarboxylase /de·car·box·y·lase/ (de?kahr-bok´si-las) any enzyme of the lyase class that catalyzes the removal of a carbon dioxide molecule from carboxylic acids.

de·car·box·yl·ase
n.
 inhibitor carbidopa.

We identified a new mutation in a new case of THD with a very severe clinical and biochemical picture. The case extends both the biochemical and the clinical phenotype of the disease.

[FIGURE 1 OMITTED]

Patient and Methods

CASE REPORT

The boy was born prematurely (33rd week of gestation) to healthy consanguineous con·san·guin·e·ous
adj.
Exhibiting consanguinity.


consanguineous adjective Referring to a blood relationship–ie, descendent from a common ancestor
 Italian parents. Severe respiratory distress complicated the perinatal period. Moderate hypotonia and swallowing difficulties were present since birth. Marked axial hypotonia, severe hypokinesia, and reduced facial mimicry increased over the first months of life. Prolonged diurnal periods of lethargy with increased sweating alternated with irritability and rare sporadic dystonic movements and prompted further investigation. The routine clinical chemistry investigations for neurometabolic disorders and the electroencephalogram electroencephalogram /elec·tro·en·ceph·a·lo·gram/ (EEG) (-en-sef´ah-lo-gram?) a recording of the potentials on the skull generated by currents emanating spontaneously from nerve cells in the brain, with fluctuations in potential seen as  were normal. Magnetic resonance imaging magnetic resonance imaging (MRI), noninvasive diagnostic technique that uses nuclear magnetic resonance to produce cross-sectional images of organs and other internal body structures.  at 5 months of age revealed an unexpected degree of cerebral atrophy. A diagnosis of THD was suggested on the basis of cerebrospinal fluid (CSF Cerebrospinal Fluid (CSF) Analysis Definition

Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord.
) investigations of neurotransmitter metabolites, and therapy with a low dose of L-dopa (6 mg/kg body weight per day) together with the decarboxylase inhibitor carbidopa was initiated. After 10 months of treatment, there was only partial clinical improvement of axial tone, appearance of spontaneous movements, and reduced sweating. The child tolerated only a very gradual increase of medication, complicated by dose-dependent side effects, mainly hyperkinesia hyperkinesia /hy·per·ki·ne·sia/ (-ki-ne´zhah) hyperactivity.

hy·per·ki·ne·sia or hy·per·ki·ne·sis
n.
1. Pathologically increased muscular movement.

2.
 and irritability.

BIOCHEMICAL INVESTIGATIONS

The neurotransmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy4-hydroxyphenylglycol (MHPG) in CSF and 5-HIAA, HVA, and vanillylmandelic acid (VMA VMA vanillylmandelic acid. ) in urine were measured with HPLC HPLC high-performance liquid chromatography.

HPLC

high performance liquid chromatography.

HPLC High-performance liquid chromatography Lab instrumentation A highly sensitive analytic method in which analytes are placed
 and electrochemical detection, and the metabolites 3-o-methyldopa and L-dopa in CSF and dopamine, epinephrine, and norepinephrine in urine were measured with HPLC and fluorometric detection. The CSF samples were collected according to a standardized protocol for lumbar puncture (9). The catecholamines were measured in an acidified acidified /acid·i·fied/ (ah-sid´i-fid) having been made acid.  24-h urine. The analytical techniques used for the biochemical investigations recently have been described in detail (9).

MUTATION DETECTION STUDIES

Genomic DNA was extracted from leukocytes by standard methods. All exons of the TH gene were amplified by PCR PCR polymerase chain reaction.

PCR
abbr.
polymerase chain reaction


Polymerase chain reaction (PCR) 
. The amplimers obtained were subjected to single-strand confirmation polymorphism analysis by the Pharmacia Phast System. Running conditions for exon 10 were as follows: 12.5% polyacrylamide gel, 20[degrees]C, 400 V, 5 mA, and 1 W (prerun at 100 V-h and separation at 135 V-h). The primers used for PCR amplification and sequence analysis of exon 10 were as follows: forward primer, 5'-GCACTCCCCTGAGCCGTGAG-3'; and reverse primer, 5'-GAGCAGGCAGCACACTTCACC-3'. Cycle sequencing of the coding and the noncoding strands of exon 10 was carried out by the Taq Dye Deoxy Terminator method in an ABI DNA sequencer (Applied Biosystems type 377). To confirm the mutation in genomic DNA, the 265-bp amplimers of exon 10 of the index patient and the parents were digested with the restriction enzyme ItaI, which spliced the wild-type allele seven times (fragments of 79, 59, 41, 33, 31, 10, 9, and 3 bp) and the mutant allele six times (fragments of 79, 59, 51, 33, 31, 9, and 3 bp).

MUTATION NOMENCLATURE

The reports by of Ludecke and co-workers (4, 6,10) and Knapskogg et al. (5) have used a nomenclature strategy based on human mRNA type 1. We have used a nomenclature strategy for indicating TH mutations based on human mRNA type 4 as published by Nagatsu et al. (11). In the human mRNA type 1, a part of exon 1 and the full-length exon 2 are missing (11). This has consequences for the numbering of the exons, nucleotides, and amino acids. A table with the known mutations in the TH gene comparing both nomenclature strategies has been published (8).

Results

BIOCHEMICAL INVESTIGATIONS

Routine clinical investigations and investigations for neurometabolic disorders in our patient, including organic acids in urine and amino acids in urine, blood, and CSF, were all normal. Pterin concentrations in the urine were within the reference interval. Biopterin in the CSF was borderline increased together with a low normal dihydropteridine reductase reductase /re·duc·tase/ (-tas) a term used in the names of some of the oxidoreductases, usually specifically those catalyzing reactions important solely for reduction of a metabolite.  activity in blood (Dr. N. Blau, Zurich, Switzerland), excluding a defect in B[H.sub.4] biosynthesis.

Analysis of the CSF revealed a severe impairment of dopamine biosynthesis with undetectable HVA (lower limit of detection, 5 nmol/L) and a very low MHPG concentration (6% of the lower reference range; Table 1). The concentrations of 5-HIAA, the end product of the serotonin pathway, and 3-o-methyldopa in CSF as well as the urinary excretion of vanillyllactic acid, a metabolite of L-dopa, were within the appropriate reference intervals, which excluded aromatic L-amino acid decarboxylase Aromatic L-amino acid decarboxylase (EC 4.1.1.28, synonyms: DOPA decarboxylase, tryptophan decarboxylase, 5-hydroxytryptophan decarboxylase, AAAD) is a lyase enzyme. Reactions
It catalyzes several different decarboxylation reactions:
 deficiency and pointed to THD as the primary defect (12).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Urine analysis (Table 1) revealed a decreased concentration of HVA (6% of the lower reference range). The concentration of 5-HIAA deriving from serotonin and of VMA as the main metabolite of norepinephrine in the periphery were within the reference ranges. The concentrations of dopamine and epinephrine were in the lower reference range, and only the concentration of norepinephrine was decreased (15% of the lower reference range). The ratio of epinephrine to norepinephrine was increased (4.8; reference, <1). The excretion of the free metanephrines was very low; however, total normetanephrine and metanephrine were within the reference range.

After treatment with increasing doses of L-dopa (up to 6 mg/kg body weight per day) with decarboxylase inhibitor, the HVA concentration in the CSF increased but remained far below the reference range (32% of the lower reference range). In urine, the treatment led to an increase of HVA (48% of the lower reference range). The catecholamines norepinephrine and epinephrine and the ratio epinephrine/norepinephrine normalized, and dopamine increased (371% above the upper reference range) after treatment with L-dopa. Higher doses of L-dopa led to severe adverse clinical symptoms of irritability and violent, abrupt alternating flinging of the arms (ballism).

MOLECULAR ANALYSIS

Single-strand confirmation polymorphism analysis was carried out on all exons of the TH gene under at least two different conditions (temperature and gel type). Only exon 10 displayed an aberrant migration pattern in the patient (Fig. 2A) and in both parents (not shown). Direct sequencing revealed that the patient has a novel, homozygous ho·mo·zy·gous
adj.
Having the same alleles at one or more gene loci on homologous chromosome segments.


Homozygous
Identical genes controlling a specified inherited trait.
 missense mutation, 1076G [right arrow] T (Fig. 2B). Both parents were heterozygous het·er·o·zy·gous
adj.
1. Having different alleles at one or more corresponding chromosomal loci.

2. Of or relating to a heterozygote.
 for this mutation. The finding of a homozygous mutation is in line with parental consanguinity consanguinity (kŏn'săng-gwĭn`ĭtē), state of being related by blood or descended from a common ancestor. This article focuses on legal usage of the term as it relates to the laws of marriage, descent, and inheritance; for its . This transversion trans·ver·sion
n.
Eruption of a tooth in a position normally occupied by another.


transversion,
n eruption of a tooth in the wrong position
 produces an amino acid exchange from cysteine cysteine (sĭs`tēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of mammalian protein.  to phenylalanine phenylalanine (fĕn'əlăl`ənēn'), organic compound, one of the 22 α-amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein.  at codon 359 (C359F). The mutation abolishes an ItaI restriction site, producing a 51-bp fragment in the patient DNA DNA: see nucleic acid.
DNA
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
 instead of the 41- and 10-bp fragments in wild-type DNA (Fig. 3). The mutation was not found in 100 control alleles. In addition, the patient is homozygous for the common polymorphism V112M (10).

Secondary structure prediction according to Chou and Fasman (13) and Gamier et al. (14) predicted an extra turn in the secondary structure of the mutant protein (not shown). The mutation is present in all different splice variants known to be present for human TH (15). Human TH has seven cysteine residues. Six of the seven cysteine residues are conserved in other species (rat, bovine, and quail) (11), including the cysteine residue in our point mutation. The cysteine residues are located in the carboxy-terminal half of the enzyme where the catalytic domain is situated (11). The 20 amino acids around cysteine 359 are highly (90-100%) conserved among species (rat, bovine, and quail; Fig. 4). The mutant cysteine residue is one of five cysteine residues also conserved in the other human aromatic amino acid hydroxylases, tryptophan hydroxylase and phenylalanine hydroxylase (Fig. 4). The percentage of homology of the 20 amino acids surrounding this cysteine residue is 71% for human phenylalanine hydroxylase and 67% for human tryptophan hydroxylase. This part of the protein and the cysteine residue therefore seem pivotal for enzymatic function of aromatic amino acid hydroxylases.

[FIGURE 4 OMITTED]

Discussion

THD has hitherto been described as a rare cause of autosomal recessive dopa-responsive dystonia or L-doparesponsive infantile parkinsonism (4, 5, 7). The diagnosis was suspected in our patient because the concentration of HVA in the CSF was undetectable (<5 nmol/L) at the time of diagnosis. In previously described patients, HVA in the CSF was between 8% and 30% of the lower reference range (9) or 5% of the lower reference range (6). The biochemical results in the CSF together with the clinical picture indicated a severe deficiency of TH. The point mutation 1076G [right arrow] T in the TH gene probably has a profound effect on the catalytic activity of the enzyme, and when present in the homozygous form, it does not seem to allow substantial residual enzymatic activity. The 1076G [right arrow] T transversion produced an amino acid change from cysteine to phenylalanine at codon 359 mRNA type 4 (codon 329 in mRNA type 1). TH is composed of two functional domains, i.e., a catalytic domain, which is located proximal to the C-terminal region, and a regulatory domain, which is located at the N[H.sub.2] terminus. The catalytic domain of the enzyme contains residues 188456, and any truncation within these residues produces a protein that expresses extremely poorly and has no detectable activity (16). The six cysteine residues that are conserved in their positions in other species are located in the C-terminal half and form a catalytic domain. In addition, the amino acids around them are highly conserved among species. This suggests that these cysteine residues may play an important role in enzymatic function by keeping the conformation of the protein by means of intra- or intermolecular 5-5 bonds and/or by interacting with ferrous ion, which is an essential component for the catalytic action of TH (11). The C359F mutation seems to be the most severe disease-causing mutation described to date in THD.

Our findings extend the biochemical phenotype of THD. Because HVA was undetectable in the CSF of our patient and MHPG was very low, both dopamine and norepinephrine biosynthesis are severely impaired in our patient. There seems to be hardly any flux through the catecholamine biosynthesis pathway in the brain. In all earlier studies on patients in whom a defect in TH was genetically confirmed, there seemed to be some degree of residual TH activity. As evidenced by the CSF HVA concentrations in these patients, they all had the capability of synthesizing catecholamines to some extent. This also may explain the limited beneficial reaction to L-dopa in our patient. The side effects of very low L-dopa doses may be explained by receptor up-regulation. Iolopride-Spect scanning, however, did not show evidence for dopamine DZ receptor up-regulation.

The biochemical findings in our patient are in line with the obviously very severe clinical signs and symptoms that include structural abnormalities in the brain as observed in the magnetic resonance imaging. Therefore, our patient also extends the clinical phenotype of THD. THD in most cases reacts favorably to low-dose L-dopa therapy and is considered a treatable disease. Therefore, it is important to know the various possible clinical presentations of the disease. The present case illustrates that THD should be considered in all children with severe encephalopathy, especially when dominated by extrapyramidal extrapyramidal /ex·tra·py·ram·i·dal/ (-pi-ram´i-d'l) outside the pyramidal tracts; see under system.

ex·tra·py·ram·i·dal
adj.
 signs and hypokinesia even when there are magnetic resonance imaging abnormalities in the central nervous system.

We thank Dr. 5. Mentzel (University Nijmegen, Department of Pathology, Nijmegen, The Netherlands) for the Chou-Fasman calculation, Dr. N. Blau (University Children s Hospital Zurich, Clinical Chemistry and Biochemistry, Zurich, Switzerland) for pterin measurements in CSF and measurement of the dihydropteridine reductase activity, Dr. R. Duran (University Children s Hospital, Utrecht, The Netherlands) for measurements of the urinary pterins, and Dr. N. Abeling (Academic Medical Centre Amsterdam, Clinical Chemistry and Paediatrics, Amsterdam, The Netherlands) for metanephrine measurements in urine.

References

(1.) Cooper JR, Bloom FE, Roth RH. The biochemical basis of neuropharmacology neuropharmacology /neu·ro·phar·ma·col·o·gy/ (-fahr?mah-kol´ah-je) the scientific study of the effects of drugs on the nervous system.

neu·ro·phar·ma·col·o·gy
n.
. New York: Oxford University Press, 1996:230pp.

(2.) Zhou Q-Y, Qualfe CJ, Palmiter RD. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 1995;374:640-3.

(3.) Clayton PT, Heales SJR, Brand M, Clelland J, Surtees RJ. An infant with clinical features, a metabolic profile to treatment suggestive of tyrosine hydroxylase deficiency [Poster]. 32nd Annual Symposium of SSIEM SSIEM Society for the Study of Inborn Errors of Metabolism , September 6-9, 1994, Edinburgh, Scotland.

(4.) Ludecke B, Dworniczak B, Bartholome K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum Genet 1995;95:123-5.

(5.) Knappskog PM, Flatmark T, Mallet J, Ludecke B, Bartholome K. Recessively inherited L-dopa-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet 1995;4:1209-12.

(6.) Ludecke B, Knappskog PM, Clayton PT, Surtees RAH, Clelland JD, Heales SJR, et al. Recessively inherited L-dopa-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum Mol Genet 1996;5:1023-8.

(7.) van den Heuvel LPWJ, Luiten B, Smeitink JAM, de Rijk-van Andel JF, Steenbergen-Spanjers GCH, Jansen RJT, et al. A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-dopa responsive dystonia (DRD) in the Dutch population. Hum Genet 1998;102:644-6.

(8.) Wevers RA, de Rijk-van Andel JF, Brautigam C, Geurtz B, van den Heuvel LPWJ, Steenbergen GCH, et al. A review on biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (Del291). J Inherit Metab Dis 1999; 22:364-73.

(9.) Brautigam C, Wevers RA, Jansen RJT, Smeitink JAM, de Rijk-van Andel JF, Gabreels FJM, Hoffmann GF. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin Chem 1998;44:1897-904.

(10.) Ludecke B, Bartholome K. Frequent sequence variant in the human tyrosine hydroxylase gene. Hum Genet 1995;95:716.

(11.) Nagatsu T, Ichinose H. Comparative studies on the structure of human tyrosine hydroxylase with those of the enzymes of various mammals. Comp Biochem Physiol 1991;980:203-10.

(12.) Blau N, Hoffmann GF. Differential diagnosis of disorders of biogenic biogenic /bi·o·gen·ic/ (-jen´ik) having origins in biological processes.

biogenic

having the property of originating in a biological process.
 amines metabolism. Eur J Pediatr Neurol 1998;2:219-20.

(13.) Chou PY, Fasman GD. Prediction of protein conformation. Biochemistry 1974;13:222-45.

(14.) Garnier J, Osguthorpe DJ, Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol 1978;120:97-120.

(15.) Dumas S, Le Hir H, Bodeau-Pean S, Hirsch E, Thermes E, Mallet J. New species of human tyrosine hydroxylase mRNA are produced in variable amounts in adrenal medulla and are overexpressed in progressive supranuclear palsy Progressive Supranuclear Palsy Definition

Progressive supranuclear palsy (PSP; also known as Steele-Richardson-Olszewski syndrome) is a rare disease that gradually destroys nerve cells in the parts of the brain that control eye movements, breathing, and
. J Neurochem 1996;67:19-25.

(16.) Goodwill KE, Sabatier C, Marks C, Raag R, Fitzpack PF, Stevens RC. Crystal structure of tyrosine hydroxylase at 2.3P, and its implications for inherited neurodegenerative diseases. Nat Struct Biol 1997;4:578-85.

CHRISTA BRAUTIGAM, [1] GERRY C.H. STEENBERGEN-SPANJERS, [3] GEORG F. HOFFMANN, [1] CARLO DIONISI-VICI, [2] LAMBERT P.W.J. VAN DEN HEUVEL, [3] JAN A.M. SMEITINK, [3] and RON A. WEVERS [3]

[1] University Hospital, Department of Neuropediatrics and Metabolic Diseases, D-35037 Marburg, Germany. [2] Bambino Gesu Hospital, Department of Metabolism, I-00165 Rome, Italy. [3] University Hospital Nijmegen, Laboratory of Paediatrics and Neurology, NL-6500 HB Nijmegen, The Netherlands.

[4] Nonstandard abbreviations: TH, tyrosine hydroxylase; L-dopa, L-dihydroxyphenylalanine; B[H.sub.4], tetrahydrobiopterin; THD, tyrosine hydroxylase deficiency; CSF, cerebrospinal fluid; 5-HIAA, 5-hydroxyindoleacetic acid; HVA, homovanillic acid; MHPG, 3-methoxy-4-hydroxy-phenylglycol; and VMA, vanillylmandelic acid.

* Address correspondence to this author at: University Hospital Nijmegen, Laboratory of Pediatrics and Neurology, Institute of Neurology, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands. Fax 31-24-3540297; e-mail r.wevers@ckslkn.azn.nl.

Received June 23, 1999; accepted September 7, 1999.
Table 1. Biochemical investigations in CSF and urine in our severe
THD patient at the age of 1.9 years.

                   CSF concentration,    Urine concentration (a)
                   nmol/L

                   Index    Reference    Index   Reference
                   case     range (b)    case    range (b)

HVA                <5       429-789      0.3     5-15
MHPG               2        33-71
5-HIAA             176      156-275      6.3     3-12
HVA/5-HIAA ratio   <0.1     1.6-3.3
3-o-methyldopa     <5       <50
L-Dopa             <5       <25
VMA                                      3.9     2-15
Dopamine                                 77      70-975
Epinephrine                              7.2     1.5-30
Norepinephrine                           1.5     10-100

(a) Concentrations in [micro] mol/mmol creatinine for HVA, 5-HIAA, and
VMA; concentrations in nmol/mmol creatinine for dopamine, epinephrine,
and norepinephrine.

(b) Reference ranges represent age-matched controls (9).
COPYRIGHT 1999 American Association for Clinical Chemistry, Inc.
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Title Annotation:Molecular Diagnostics and Genetics
Author:Brautigam, Christa; Steenbergen-Spanjers, Gerry C.H.; Hoffmann, Georg F.; Dionisi-Vici, Carlo; van d
Publication:Clinical Chemistry
Date:Dec 1, 1999
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