Abstract
Article abstract Tyrosine hydroxylase deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose l-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.
Tyrosine hydroxylase (TH/EC 1.14.16.2) is the rate-limiting step in dopamine biosynthesis ( figure). Deficiency of the enzyme or its cofactor tetrahydrobiopterin (BH4) lead to a dopamine deficiency syndrome. Genetically confirmed TH deficiency (THD) was first described by Lüdecke et al.1,2⇓ in two families suffering from Segawa’s syndrome or l-dopa–responsive dystonia1 and from l-dopa–responsive parkinsonism in infancy.2 The disease has autosomal recessive inheritance. It is biochemically characterized by low CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenyl-ethyleneglycol (MHPG) and normal 5-hydroxyindoleaceticacid (5-HIAA).3
Figure. Catecholamine and serotonin biosynthetic and catabolic pathways and biosynthesis of the cofactor BH4. 1: GTP cyclohydrolase, 2: 6-pyruvoyltetrahydropterin synthetase, 3: dihydropteridine reductase, 4: phenylalanine hydroxylase, 5: tyrosine hydroxylase, 6: aromatic l-amino acid decarboxylase, 7: dopamine beta-hydroxylase, 8: monoamine oxidase.
We describe the clinical aspects of THD in four unrelated Dutch patients. Clinical findings are compared with cases from literature and with cases with a BH4 biosynthesis defect. The reactions of our four patients to low-dose l-dopa medication during a 4-year follow-up period also are described.
Case report.
Patient 1.
The patient was the first child of healthy unrelated Dutch parents. Pregnancy and labor were without complications. A severe disturbance in motor development became apparent at 4 months. At 12 months, the patient developed generalized rigidity. The child was irritable and had very little spontaneous movement, some sporadic dystonic movements of the hands, and progressive generalized rigidity. He was hypertonic in arms and legs while truncal hypotonia was present. He had bilateral ptosis and hypersalivation. There was no diurnal fluctuation in the symptoms. Routine clinical chemistry, metabolic investigations (including lactate), chromosome analysis, EEG, CT scan, and MRI of the head were normal. CSF indicated a very low level of HVA, low MHPG, and normal 5-HIAA.
The case reports of Patients 2 through 4 are not shown but were similar ( table 1).
Clinical symptoms of our patients with THD compared with the other genetically confirmed TH-deficient cases in the literature and those with GTPCH deficiency
Methods.
Results.
Clinical presentation.
The patients came to our outpatient clinic at the ages of 12, 27, 30, and 36 months because of serious delay in motor development, without any sign of perinatal asphyxia. They had an extrapyramidal syndrome, starting in the first 6 months of life. The key symptoms are severe motor retardation with rigidity, hypokinesia, and truncal hypotonia (table 1). Only sporadic dystonic movements were observed, probably because of the extreme hypokinesia. There was no diurnal fluctuation in the symptoms. The symptoms worsened in the four patients. Diagnosis of THD was made at the ages of 25, 29, 39, and 37 months.
Diagnostic laboratory data.
CSF HVA and MHPG and the HVA/5-HIAA ratio were low in all four patients with normal 5-HIAA.3 Normal urinary and CSF pterins and normal dihydropteridine reductase activity in blood excluded a tetrahydrobiopterin biosynthesis defect. The biochemical data suggested THD.
DNA analysis.
A homozygous mutation G698A was found in three patients.4 Case 1 was heterozygous for this mutation. The second mutation in this patient is a one-nucleotide deletion (DelC291) in Exon 3, leading to a frame shift, abnormal amino acids (amino acids 97–112: DPWRLWPLRRRRGRPC instead of the normal: DPLEAVAFEEKEGKAV), and premature truncation of the protein. The patients were all homozygous for the frequent sequence variant (nucleotide change: G334A causing V112M).
Therapy with l-dopa/carbidopa and follow-up.
Low-dose l-dopa/carbidopa therapy was started (3 mg/kg and 0.75 mg/kg bodyweight, given 3 times daily). Within 36 hours, the patients showed a spectacular improvement with a marked and sustained improvement in rigidity, hypokinesia, and other parkinsonian symptoms. They moved better with their arms and legs. Facial expression became normal, and ptosis disappeared. In the following months, the developmental score improved ( table 2). Later, the l-dopa dose was increased in Patients 1 and 3 (5–6 mg/kg body weight), resulting in further improvement in motor performance. During therapy, CSF HVA ranged between 35% and 58% and MHPG between 42% and 94% of the lower reference range limit in the four cases.
Developmental score in % according to the standard scale of Griffith
The follow-up period on the patients after the start of treatment amounts to 65, 52, 52, and 51 months. All children now can walk without support but have a slight subnormal range of action. They have a somewhat clumsy gait and are mildly mentally retarded. After the start of treatment, the frequency and severity of the oculogyric crises (Case 4) decreased significantly. Negative side effects of the l-dopa medication have not been observed in any of the four cases.
Discussion.
Clinical signs and symptoms have been described in two families with genetically confirmed THD. Two affected siblings had a relatively mild phenotype starting at approximately age 4 years with dystonia in the lower extremities with diurnal variation.1,5⇓ This family illustrates that THD actually can present as l-dopa–responsive dystonia (DRD). The Greek patient in the second family2 had a more severe form of the disease with a similar clinical presentation to our four cases. The onset of signs and symptoms was in the first months of life in all cases. They developed progressive parkinsonism with various extrapyramidal signs and symptoms. Dystonia was not very obvious and could easily be overlooked. There was no diurnal fluctuation in symptoms. This demonstrates that THD can cause an l-dopa–responsive dopamine deficiency syndrome that may present either as a recessive l-dopa responsive dystonia or as a recessive infantile hypokinetic rigid parkinsonian syndrome. It is conceivable that cases with THD have been missed and diagnosed as infantile encephalopathy or spasticity. The progressive course of THD together with the normal MRI and the normal perinatal anamnesis should discriminate THD from perinatal damage and birth defects. Two other dopamine deficiency syndromes are known as inborn errors of metabolism: aromatic l-amino acid decarboxylase (AADC) deficiency and GTP-cyclohydrolase I (GTPCH) deficiency (DRD or Segawa’s disease6-8⇓⇓). AADC deficiency may present clinically as THD.9 Table 1 compares the clinical features of THD with the autosomal dominant form of GTPCH deficiency. GTPCH mainly presents as dystonia. Differences in clinical presentation between GTPCH and TH deficiency may relate to the presumably higher residual TH activity in GTPCH deficiency (only one affected allele). Equally, the residual TH activity seems to determine the variable picture among THD cases. THD with relatively high residual activity presents as a dystonia, whereas patients with lower residual activity have a hypokinetic rigid parkinsonian syndrome.5 It may be anticipated that cases will be found with still other mutations in the TH gene, allowing higher or lower residual enzymatic activity.10 This may further extend the clinical phenotype of THD.
Treatment in our patients gave an obvious and lasting improvement of all clinical signs and symptoms. The remaining mild motor performance abnormalities may relate to the concentrations of CSF HVA and MHPG that did not normalize on treatment. It may be meaningful that Cases 3 and 4 had the lowest CSF HVA and MHPG values before treatment and that the residual signs and symptoms in these patients are more severe than in the other two. Perhaps a further increase of the l-dopa dose in these cases would be beneficial. We hesitated in this respect because of possible adverse effects. The therapy in each patient must find a balance between the short-term beneficial aspects and the longer-term side effects.
We advise that defects of catecholamine biosynthesis must be considered in any child presenting in the first decade with a hypokinetic-rigid parkinsonian syndrome, in children with a dystonia-parkinsonian complex, and also in children with dystonia as a presenting symptom.
Acknowledgments
Acknowledgment
The authors thank Prof. N. Blau (Zurich) for pterin analysis in body fluids of our patients.
- Received December 21, 1998.
- Accepted August 24, 2000.
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