GTP Cyclohydrolase Deficiency
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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.1.86 on 1 January 1999. Downloaded from 86 J Neurol Neurosurg Psychiatry 1999;66:86–89 SHORT REPORT GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness Richard Robinson, Gillian T McCarthy, Oliver Bandmann, Michael Dobbie, Robert Surtees, Nicholas W Wood Abstract Materials and methods A family with a dominant form of partial This family first came to our attention through GTP cyclohydrolase deficiency is de- presentation of the 6 year old boy II-5 (fig 1). scribed. Clinical severity varied from mild Subsequently members I-1–3 and II-1−5 have involvement with complete responsive- all been examined in detail. ness to levodopa to severe dystonia pre- cluding any voluntary activity including CLINICAL DETAILS talking, progressive contractures, and The proband II-5 was initially hypotonic, fed only partial responsiveness to levodopa. well initially, but then experienced increasing Although there are several possible feeding problems from about 3 months. His reasons for intrafamilial variability, any tone then variably increased and, with the age patient with dystonia, the cause of which is appropriate onset of voluntarily initiated activ- not clearly identified, should receive a ity, extra pyramidal features mainly of dystonia trial of levodopa. appeared. A diagnosis of cerebral palsy was (J Neurol Neurosurg Psychiatry 1999;66:86–89) made by the local paediatrician. Intelligible words appeared during his second year. His Keywords: GTP cyclohydrolase; dystonia; levodopa; vocabulary developed with eVortful articula- phenotype gene expression tion, albeit with gradual improvement in speed and clarity. However, this became increasingly diYcult for him and he spoke less and less from Cerebral palsy is incurable—although its ef- the age of 5. Seen when aged 6 he was an alert fects may be alleviated. Great care must be receptive child, apparently intellectually unim- taken when assigning such a diagnosis which http://jnnp.bmj.com/ paired with normal social behaviour. He had a implies lifelong disabilities. Nowhere is this pure dystonic syndrome with variable rigidity. more true than when making a diagnosis of His fundi were normal. He was unable to roll dystonic cerebral palsy. Wrongly applied, the purposefully as his arm became trapped chance may be missed of eVecting a lifelong beneath him. A form of assisted walking Department of cure for a patient with Segawa type levodopa Paediatrics, Guy’s required a lot of pelvic and trunk support. His responsive dystonia (DRD). attempted coordination was best in the morn- Hospital, London, UK Responsiveness to levodopa, however, may R Robinson ing and least eVective after mid-day, until there vary considerably between dystonic syn- was again some improvement in the evening. on September 25, 2021 by guest. Protected copyright. Chailey Heritage, East dromes. Segawa type dystonia commonly Comprehensive investigations for causes of Sussex, London, UK presents in infancy with dystonic equinus pos- G T McCarthy secondary dystonia were unrevealing. How- turing in the feet, sometimes mistakenly ever, CSF neopterin and hydroxyindoleacetic diagnosed as a spastic diplegia. Responsiveness acid (HIAA) were marginally reduced (table), Institute of Neurology, to levodopa seems complete and enduring. London, UK consistent with partial GTPCH 1 deficiency. O Bandmann Less well known is that some cases of second- 12 There was an immediate response to 50 mg NWWood ary dystonia also respond to levodopa. Hith- levodopa daily with decreased rigidity, resump- erto it has been assumed that the degree of tion of speech, and improved head and trunk Institute of Child responsivity is related to the underlying cause. control. Increasing the dose to 220 mg daily Health, London, UK Identification of the GTP cyclohydrolase I M Dobbie R Surtees (GTPCH 1) gene as the causative gene in most cases of levodopa responsive dystonia has per- Correspondence to: mitted a broadening of the phenotype from Professor R O Robinson, Segawa type DRD at one extreme to partially Newcomen Centre, Guy’s Hospital, St Thomas Street, responsive but severe four limbed dystonia at 3 London SE1 9RT, UK. the other. Reported here is a family with the dominant form of partial GTPCH I deficiency Received 17 November 1997 within which the phenotype, including respon- and in revised form 27 July 1998 siveness to levodopa, varied widely to embrace Accepted 18 August 1998 both extremes. Figure 1 Family tree. The proband is II-5. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.1.86 on 1 January 1999. Downloaded from GTP cyclohydrolase deficiency 87 CSF metabolites in II-1, II-4, and II-5 the onset of progressive ataxia when aged 13. Her CSF neopterin, biopterin, and HIAA lie 11-5 11-4 11-1 Normal range within the normal range although her HVA is Homovanillic acid (nmol/l) 152 91 61 72–656 somewhat lower (table). She lacks the GTPCH 5-Hydroxy-indole acetic acid (nmol/l) 49 65 62 58–222 I gene mutation of her aVected family members Tetrahydrabiopterin (nmol/l) 16 6.6 18 9–40 Dihydrobiopterin (nmol/l) 1.3 2.2 3.8 0–14 and is homozygous for the GAA expansion in Neopterin (nmol/l) 4.3 5.9 8.6 7–65 intron 1 of the Friedreich’s ataxia gene. I-1, I-2, and I-3 are all clinically unaVected. CSF monoamine metabolites and individual was accompanied by acquisition of independ- pterin species were measured in II-1, II-4, and ent sitting, control of individual finger move- II-5 using established high performance liquid ments, and increase in clarity of speech. How- chromatography (HPLC) methods.4 The ever, with disappearance of the dystonia, small GTPCH I gene has also been sequenced in amplitude chorea emerged. Further escalation these members. This family is the family Hu, of the dose was prevented by nausea. Six included as one of the five previously reported months after starting levodopa, his speech was with point mutations of the GTPCH I gene.4 clear and fluent, he was walking independently Members II-4 and II-5 have a point mutation and was, for example, able to do up his on codon 224 of the gene changing lysine to shoelaces. Further motor progress now seems arginine (AAA –> AAG). to rely more on practice than in reduction of motor disorder. Discussion Member II-4 (the older sister of II-5) was GTPCH I is the initial and rate limiting likewise hypotonic initially but without feeding enzyme de novo in BH4 synthesis from GTP. diYculties. Although smiling with normal Tetrahydrobiopterin is an essential cofactor for visual behaviour by 6 weeks, her severe motor phenylalanine, tyrosine, and tryptophan hy- delay thereafter became more evident. She droxylases. Tyrosine hydroxylase in turn is the never acquired independent sitting or standing initial and rate limiting enzyme in dopamine or useful hand function. Occasional single synthesis. A deficiency in GTPCH I activity words first appeared at the age of 18 months, therefore readily explains both the movement but she did not progress to phrases. The disorder and the changes in CSF HIAA, neop- diagnosis of cerebral palsy was made at this terin, and BH4 concentrations (fig 2). time. She developed dysphagia when aged 5. The autosomal recessive form of GTPCH I Throughout her childhood and adolescence she deficiency causes no detectable enzyme was severely handicapped by rigidity. There activity56 Patients are normally detected on was, however, clear evidence of diurnal variabil- newborn screening for phenylketonuria but ity with easily intelligible words in the morning most already have symptoms of dopamine which became impossible for her in the deficiency (personal observations).6 CSF con- afternoon. Her intelligence, as judged by eye centrations of homovanillic acid (HVA), pointing and comprehension of language, 5HIAA, neopterin, and BH4 are all markedly seemed unimpaired. She developed dislocated reduced (personal observations).5 Heterozy- hips and a long thorocolumbar kyphoscoliosis. gotes do not manifest clinical symptoms and 5 Examined when aged 17, she had a generalised have 30% to 50% residual enzyme activity. By http://jnnp.bmj.com/ dystonic syndrome with underlying tone, ap- contrast, it has been suggested that in the parently normal between spasms. There were dominant form of GTPCH I deficiency no pyramidal signs. Extraocular movements described here residual enzyme activities are were preserved. Sensation was normal. Al- 2% to 20% of normal (instead of the 50% though her CSF neopterin and tetrahydrobi- expected) implying that the mutation causes opterin (BH4) concentrations were reduced, dysfunction of the normal gene. In recessively her CSF HIAA concentration lay within the inherited GTPCH I deficiency, heterozygotes 7 normal range (table). Starting initially on 100 have 30% to 46% activity and are normal. on September 25, 2021 by guest. Protected copyright. mg levodopa a day, she developed troublesome Biochemical abnormalities in CSF are also dyskinesias. Restarted at a lower dose, she like- more subtle in the dominant form. The only wise has begun to improve, being able to toler- consistent abnormality in the aVected patients ate gradually escalating doses of levodopa. She here is a modest reduction in CSF neopterin to is now able to support her own head, talk more 22% to 30% of mean reference values, similar clearly, and feed herself when taking 800 mg to that previously found.89A reduction of CSF levodopa daily. She retains, however, a degree of BH4 was found in II-4 but not II-5 and a dystonia with some fixed flexion contractures as reduction in HIAA was found in II-5 but not well as developing some unwanted movements. II-4. Surprisingly, CSF HVA was normal in Member II-3, the half sister of II-4 and II-5, II-4 and II-5 at a time when both had developed symptoms of stiVness and toe walking symptoms of dopamine deficiency, but was aged 7 years.