Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease)

Abstract

Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealed a decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiological studies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused by heterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

“…Genomic DNA was extracted from peripheral blood lymphocytes and all six exons, intron-exon boundaries and 5'UTR-region of the GCH1 gene were amplifi ed separately using the polymerase chain reaction (PCR), according to standard procedures 2,3 . The fragments were amplifi ed and analyzed by direct sequencing using Big Dye Terminator v1.1 (Applied Biosystems) on a 310 ABI PRISM genetic analyzer.…”

“…Hereditary progressive dystonia with marked diurnal fl uctuation or Segawa's disease (OMIM: #128230) is an inherited form of dopa-responsive dystonia (DRD), classifi ed as an autosomal dominant metabolic disorder that results in dopamine defi ciency in the basal ganglia [1][2][3][4] . The incidence is estimated to be between 0.5 and 1 per million people and the typical clinical picture includes onset in childhood, early foot dystonia with progression to multifocal or generalized dystonia, diurnal fl uctuation and dramatic response to levodopa (L-dopa) [1][2][3] .…”

“…The incidence is estimated to be between 0.5 and 1 per million people and the typical clinical picture includes onset in childhood, early foot dystonia with progression to multifocal or generalized dystonia, diurnal fl uctuation and dramatic response to levodopa (L-dopa) [1][2][3] . It is caused by mutation in the guanosine triphosphate (GTP) cyclohydrolase 1 (GCH1) [1][2][3]5 . There is also an autosomal recessive form caused by mutation in the tyrosine hydroxylase gene (OMIM: #650407) 3 .…”

“…This disease was fi rst described in 1971, by Segawa et al, as dystonia with diurnal fl uctuation affecting the gait with a benefi cial therapeutic response to L-dopa [1][2][3][4][5] . Diagnosis can be based on clinical fi ndings (including dramatic and sustained response to low doses of L-dopa), plasma levels of phenylalanine/tyrosine after an oral phenylalanine load and molecular analysis of GCH1 gene [1][2][3][4][5][6] .…”

“…Diagnosis can be based on clinical fi ndings (including dramatic and sustained response to low doses of L-dopa), plasma levels of phenylalanine/tyrosine after an oral phenylalanine load and molecular analysis of GCH1 gene [1][2][3][4][5][6] .…”