Affected individuals in all families were shown to have GTP cyclohydrolase deficiency by enzymatic and molecular analyses. A defect in the gene encoding GTP cyclohydrolase (GCH1
) was demonstrated in two families, a heterozygous gene deletion and a missense mutation, respectively, and can be assumed in the third family because all affected individuals share the same haplotype in the GCH1
chromosomal region. In our laboratory, the phenylalanine loading test readily identified affected patients, with the time point at 4 h having the best diagnostic value (fig 2), but did not predict the extent of clinical symptoms. However, CSF neurotransmitter metabolite values, obtained in clearly affected patients, were more variable. Despite the consistent finding of reduced dopamine on histochemical staining in autopsied patients,30
similar variation of CSF metabolites has been observed and may reflect the difficulties of assessing a partial deficiency against a broad normal range in CSF. Decreased CSF biopterin levels have been described in GTP cyclohydrolase deficient patients, but this analysis was not available in this study.
Most patients with typical Segawa syndrome and all probands presented with typical symptoms of dystonia, frequently with noticeable diurnal variation as had been originally described.1
However, family investigations revealed many affected patients with less typical symptoms. In particular, the presentation with recurrent tendonitis and mild rigidity has not been described previously. The consistent response to l‐
dopa/carbidopa therapy suggests that these symptoms are indeed causally related. Both symptomatic presentations, childhood onset typical Segawa syndrome and late onset atypical presentations, occur in the same family in patients affected with the same mutation. This variability indicates that other factors, be they environmental or other modifying genes, influence the expression of symptoms.31
In this study, the frequency of major depressive disorder, particularly recurrent major depressive disorder, and of obsessive‐compulsive disorders was clearly increased above the population frequency. However, this study may underestimate the frequency of psychiatric morbidity since several asymptomatic patients were less than 20 years of age, and psychiatric symptoms tended to have onset after 20 years of age (fig 3). Although the occurrence of major depressive disorder is significantly increased in the study group, a increased risk due to genetic factors independent of GTP cyclohydrolase deficiency cannot completely be excluded. However, this explanation is unlikely as no depressive disorders were reported in the non‐carriers in the studied families, although these were not assessed as control subjects. Moreover, it is unlikely that an independent increased risk would be found in three unrelated families. Increased frequency of major depressive disorder and anxiety was previously recognised in a single large family with GTP cyclohydrolase deficiency,5
and depression was reported in three other patients.32,33
In that family,5
obsessive‐compulsive disorder was also present in a single patient. In our study, anxiety was also observed in a number of patients but did not exceed the high population frequency. It is important to note that most patients with psychiatric morbidity were not yet aware that they had Segawa syndrome when their psychiatric morbidity developed. Therefore, psychiatric morbidity cannot be attributed to the stress of their knowing about their chronic neurological disorder. In the previously reported family5
and in our three families, patients with psychiatric morbidity responded well to serotonin reuptake inhibitors or to other serotonin neurotransmission enhancing medication including supplementation with 5‐hydroxytryptophan. In contrast to a previous report,33
we did not observe a reduction in the efficacy of l‐
dopa treatment on dystonia symptoms with these medications; nonetheless, caution is advisable as severe parkinsonism was seen with neuroleptic medications and with metoclopramide.
The role of disturbed dopamine metabolism in the pathogenesis of the motor dysfunction in Segawa syndrome has been well studied.34
Decreased striatal biopterin results in a reduction in the quantity and activity of tyrosine hydroxylase, enhancing the dopamine deficiency.35
In this condition, the functional consequences of impairment in the synthesis of the other neurotransmitters, serotonin and noradrenaline, have received less attention. Preclinical research and, in particular, clinical studies with serotonin reuptake inhibitors, strongly suggest that a deficit in serotonergic neurotransmission plays a key role in the pathogenesis of major depressive disorder.36,37,38
Whether a sole serotonergic dysfunction is sufficient to cause depression or is a necessary risk factor remains unclear. Although the role of serotonin depletion in humans has not been studied, the impact of depletion of its precursor l‐
tryptophan has been investigated. l‐
tryptophan depletion only leads to depressed mood in patients who have a history of major depressive disorder, especially in patients with recently remitted major depressive disorder.39
We propose that similar biochemical consequences on serotonin levels result from either the depletion of tryptophan or from a genetic impairment of the synthetic enzyme in the serotonin biosynthetic pathway from tryptophan. This would imply that a specific vulnerability factor contributes to the expression of psychiatric symptoms in combination with the serotonin depletion. Modifier genes, or historic or environmental contributions, such as a previous depression, may affect this vulnerability. Consequently, patients lacking specific risk factors may only have the neurological symptoms of Segawa syndrome but not the psychiatric symptoms.
The deficit in the synthesis of l‐
dopa in Segawa syndrome theoretically also results in decreased noradrenaline, as is evidenced by somewhat decreased MHPG levels in CSF, and would be expected to be increased with l‐
dopa therapy. Noradrenergic deficiency, particularly in the locus coeruleus, has been hypothesised to contribute to depressive symptoms,40,41,42
and selective noradrenaline reuptake inhibitors are effective in its treatment.42
Several of our patients reported some improvement in mood following initiation of l‐
dopa therapy. The presence of a major depressive disorder in a single patient with tyrosine hydroxylase deficiency and very low MHPG levels (20 nmol/l, controls 29–64) (unpublished observation) also suggests a contribution of the noradrenergic neurotransmission. However, chronic l‐
dopa therapy did not prevent the occurrence of depressive symptoms in some patients who subsequently responded promptly to a serotonergic/noradrenergic reuptake blocker.
In conclusion, we would hypothesise that impairment of the synthesis of both serotonergic and noradrenergic neurotransmission may be related to the particularly high frequency of depression in this genetic condition. The patients have a well documented genetic impairment in the synthetic capacity of these neurotransmitters. The direct measurement of the metabolites of serotonin (5‐HIAA) and of noradrenalin (MHPG) in CSF did not provide proof of a deficiency. However, analysis of CSF metabolites provides an indirect measurement at a distance of the presence of these neurotransmitters in brain with a wide normal range, and thus the measured low normal values do not disprove the possibility of a partial deficiency in the brain.
Sleep disturbances were very frequently reported in our adult Segawa patients and were sometimes the predominant symptoms. Previous studies documented reduced gross and twitch movements during sleep in Segawa patients, which improved under l‐
and sleep disorders are frequent in patients with extrapyramidal disease.43
Both dopaminergic and serotonergic neurotransmission have been implicated in sleep mechanisms. Serotonergic raphe neurons have a crucial role in the initiation and maintenance of the sleep state.44
Further, serotonin is a precursor of melatonin, which is implicated in the initiation and persistence of sleep. Occasional patients reported improved sleep with melatonin intake.
Physicians caring for patients with Segawa syndrome should be aware of the development of late symptoms in adults affected with this disorder. Patients who are asymptomatic in childhood may develop dopa responsive atypical symptoms as adults. Further, patients are at increased risk for depression and obsessive‐compulsive disorders. These disorders respond well to serotonergic neurotransmission enhancing medications, although monitoring for worsening of dystonia is advisable.35
Finally, sleep disturbances are very frequent in affected individuals. Finding such treatable conditions underscores the value of extensive biochemical and molecular testing in families with Segawa syndrome.