Dyskinesias as a Limiting Factor in the Treatment of Segawa Disease

Abstract

Patients with autosomal dominant Segawa disease (dopa-responsive dystonia) show an excellent and sustained response to small doses of levodopa. In contrast, the development of levodopa limiting treatment dyskinesias is thought to support the diagnosis of other early onset dystonia/parkinsonism syndromes. We describe an atypical phenotype, that of persistent treatment limiting dyskinesias, in a family with prominent brachial dystonia and a novel GCH1 mutation. The pedigree comprised two affected members, the proband aged 13 years and her mildly affected mother aged 48 years. Phenylalanine loading test, cerebrospinal fluid for biogenic amines and pterins, guanosine triphosphate cyclohydrolase I enzyme activity, and direct exonic sequencing of GCH1were performed revealing a novel mutation (c.235_240delCTGAGC[p.L79_S80del]) in the GCH1 gene. Despite continuous l-dopa therapy from age 7 years, the proband developed a severe writer’s cramp at the age of 10 years, and persistent treatment limiting dyskinesias even with low doses of levodopa leading to treatment challenges. We conclude that dyskinesias as limiting side effects of levodopa should not preclude the diagnosis of dopa-responsive dystonia during diagnostic levodopa trials and that the diagnosis of Segawa disease should still be considered if there is partial improvement with levodopa, but dose limiting dyskinesias.

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

“…In AD-GTPCHD, most patients first received L-Dopa/DC inhibitor. Trihexyphenidyl was added due to incomplete control of symptoms on L-Dopa/DC inhibitor alone and/or due to dyskinesia at higher L-Dopa/DC inhibitor doses [141,142]. In the majority of AD-GTPCHD patients, a moderate to excellent effect on dystonia and tremor was noted; however, not all patients exhibited clinical benefit.…”

“…There are no patients described with botulinum toxin injections as monotherapy. In one case, botulinum toxin injections were used before the diagnosis of the underlying BH 4 D. 2 other cases were concurrently treated with L-Dopa/DC inhibitor [142,148], and with trihexyphenidyl in 1 case, which did not resolve dystonic symptoms completely (writer's cramp, blepharospasm, and retrocollis). All patients improved with botulinum toxin injections; however, the co-administration of other medications does not permit evaluation of the effect of botulinum toxin alone.…”

Dopa-responsive dystonia—clinical and genetic heterogeneity

“…107 When levodopa-induced dyskinesia does occur, it usually presents at the initiation of treatment and is the result of unusually high doses. 19,25,35,[111][112][113] As in patients with PD, amantadine can suppress levodopa-induced dyskinesia in GTP-CH-I deficiency. 114 The available evidence indicates that levodopa can be used safely during pregnancy to treat GTP-CH-I deficiency, as studies that included treatment of pregnant patients reported no fetal abnormalities.…”

Dopa-responsive dystonia or early-onset Parkinson disease – Genotype–phenotype correlation

“…later slow increment in dose [14,15]. However, it is known, that some GCH1 mutations like in frame deletion in exon 1 c.235_240delCTGAGC/p.Leu79_Ser80del cause persistent treatment limiting dyskinesias, which may develop after few years of continuous L-dopa therapy [16]. Some patients may also present with DRD showing atypical symptoms such as hand tremor, spastic paraplegia, rigidity [11,12,15].…”