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Author Affiliations: Section of Clinical and Molecular Neurogenetics, Department of Neurology (Drs Brüggemann, Schneider, and Klein), Department of Pediatrics (Drs Spiegler and Sperner), and Institute of Human Genetics (Drs Hellenbroich and Gillessen-Kaesbach), University of Lübeck, Lübeck, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Heidelberg (Dr Opladen), Department of Neuropediatrics, University of Kiel, Kiel (Dr Stephani), and Northern Epilepsy Center for Children and Adolescents, Schwentinental/Raisdorf (Dr Boor), Germany.
Objective To report the first prenatal dopaminergic replacement therapy in autosomal recessive (AR) guanosine triphosphate cyclohydrolase 1 (GTPCH) deficiency without hyperphenylalaninemia.
Design Case reports, literature review, and video presentation.
Setting University of Lübeck, Lübeck, Germany.
Patients Two boys from a consanguineous family.
Main Outcome Measures Physical and mental development as a function of replacement initiation.
Results The older sibling presented with typical features of AR GTPCH deficiency due to a homozygous mutation in the GCH1 gene with proven pathogenicity. Levodopa treatment was initiated at age 10 months and resulted in a distinct motor improvement. However, mental development was delayed. In the younger sibling, prenatal replacement therapy was initiated after a prenatal diagnosis of AR GTPCH deficiency was made. At age 17 months, both motor and mental development were normal for his age.
Conclusions This report highlights the importance of an early diagnosis, including prenatal diagnosis, of complex dopa-responsive extrapyramidal syndromes. Prenatally initiated dopaminergic replacement therapy is beneficial and thus justified in AR GTPCH deficiency, allowing prevention of significant impairment of mental abilities.
Dopa-responsive dystonia (DRD, DYT5) is a nondegenerative neurometabolic disorder that presents with dystonia, sometimes associated with parkinsonism, and has an excellent response to dopaminergic medication. It is usually caused by mutations in genes involved in tetrahydrobiopterin biosynthesis. Tetrahydrobiopterin is the essential cofactor required for the hydroxylation of aromatic amino acids and the synthesis of both dopamine and serotonin.1 The most common DRD form is caused by heterozygous guanosine triphosphate cyclohydrolase 1 (GTPCH) gene (GCH1 ; GenBank U19523) mutations following an autosomal dominant inheritance pattern with considerably reduced penetrance.2 The autosomal recessive (AR) DRD form is very rare, resulting most commonly from mutations in the tyrosine hydroxylase gene or the sepiapterin reductase gene and usually presenting without hyperphenylalaninemia (HPA).3 The recessive DRD forms typically present with a more complex phenotype and distinct clinical features, infantile onset in most cases, and a poor or only moderate response to levodopa or other drugs (DRD-plus syndromes). In contrast, HPA is considered a cardinal feature of GTPCH enzyme deficiency, which can rarely be caused by deleterious homozygous GCH1 mutations with an AR inheritance pattern.1 A handful of case series, however, reported the unusual finding of an AR-inherited GCH1 -associated form of a DRD-plus syndrome without HPA showing considerable clinical overlap with classic GTPCH deficiency with HPA.1,4-8
Herein, we describe the clinical and laboratory findings of 2 siblings with a recessive form of a DRD-plus syndrome harboring homozygous mutations in the GCH1 gene. For the first time to our knowledge, we report a prenatal diagnosis and levodopa replacement therapy and comment on the clinical implications.
Report of cases
Both children were male and products of a consanguineous marriage of first-degree cousins (III-1 and III-2) of Roma background (Figure). The 3-year-old index patient IV-1 had been delivered vaginally in week 37 after an uneventful pregnancy. Apgar scores were normal and neonatal screening test results were unremarkable. At age 3 months, the parents noticed intermittent jerky leg movements in combination with a hyperextended head and a persistent inability to control the head position. Two months later, the child was admitted to a hospital for suspected generalized epileptic tonic-clonic seizures based on the observation of involuntary jerks of all extremities, although vigilance was unchanged. At age 8 months, the neurological examination revealed truncal dystonia with hyperlordosis, lateral flexion of the trunk, and intermittent opisthotonus (video 1). His arms tended to remain in a flexed posture. The body position was reminiscent of a fencer's posture. At the extremities, a highly frequent postural tremor was superimposed by irregular myoclonic jerks. The extremities showed a leg-pronounced increase of muscle tone caused by a spasticity with brisk tendon reflexes and rigidity. The face was expressionless and the mouth was partly opened. Reaction capacity and alertness were reduced; grasping performance was poor. The patient displayed episodes of involuntary upward gaze deviations for a duration of 1 to 2 minutes in keeping with oculogyric crises. Personal communication with the community attending pediatrician revealed the presence of subtle motor abnormalities even in the first 3 months of life, such as mild generalized stiffness. Owing to diagnostic uncertainty, however, these findings were not yet communicated with the parents at this time and not documented in the patient's medical records.
Figure. Pedigree of the family. Solid symbols represent affected individuals; open symbols, unaffected family members; and dots, confirmed asymptomatic carriers of a single GCH1 mutation.
Findings on a cranial magnetic resonance imaging scan and subsequent electroencephalogram were unremarkable. The genetic workup excluded mutations in the ARX and POLG genes; the chromosomal analysis disclosed a regular male karyotype (46,XY). Cerebrospinal fluid analysis revealed a normal cell count and unremarkable values for glucose, lactate, and proteins, including immunological markers. Biochemical cerebrospinal fluid workup showed a moderate decrease of both homovanillic acid and 5-hydroxyindoleacetic acid and a massive reduction of neopterin and tetrahydrobiopterin (Table 1). The phenylalanine concentration was normal in both cerebrospinal fluid and serum. Subsequent mutational analysis of the tyrosine hydroxylase gene was negative, whereas comprehensive genetic testing of the GCH1 gene revealed homozygosity for a previously undescribed missense mutation in exon 1 (c.309G>C, p.Q103H). In fibroblasts of this patient, the GTPCH activity was considerably reduced with values between 17% and 31%.
Levodopa with 25% carbidopa treatment was initiated at age 10 months with a stepwise and symptom-oriented dosage increase, starting with 1 mg/kg body weight/d and a final dosage of 10 mg/kg body weight/d, resulting in a dramatic improvement of his motor impairment. Dystonia and muscle tone abnormalities almost completely resolved during the year following treatment initiation. The initially suspected epileptic source of the condition could be ruled out retrospectively.
Reoccurrence of oculogyric crises, axial hypotonia, and abnormal head position were good clinical predictors for the necessity to increase the levodopa dosage. At age 20 months, the patient was able to stand, walk, and run but showed a moderate clumsiness when performing movements in general (video 2). Six months later, developmental milestones of mental function were clearly delayed, affecting global cognitive impairment in both verbal and nonverbal tasks according to the developmental state of a 15-month-old child (Bayley Scales of Infant Development II: mental development index score <50 [reference range, 85-114], psychomotor development index score of 77 [reference range, 85-114]).
Both parents were asymptomatic and heterozygous for the described sequence variation. Their neurological examination findings were unremarkable.
The mother became pregnant again 1 year after the first delivery. Prenatal diagnosis was performed in the 12th week of pregnancy. In the fetus, the missense mutation c.309G>C (p.Q103H) was also confirmed in the homozygous state. The mother agreed to a prenatal replacement therapy with levodopa carbidopa, 25%, and started with 50/12.5 mg 3 times a day in week 18.
Patient IV-2 was born by cesarean delivery in week 38 after an uneventful pregnancy. Apgar scores and body dimensions were unremarkable. Inversion of his right foot without response to low dosages of levodopa was observed and thus diagnosed as a postnatal pes adductus rather than a dopa-responsive dystonic foot posture. On day 7, he showed an intermittent mild, irregular action and postural tremor of all extremities (video 3) but also a generally increased muscle tone during rest and activity and an increased startle reflex. Levodopa with 25% carbidopa treatment was initiated on day 5 immediately after a first period of enteral adaption starting with 1 mg/kg body weight/d and slowly increasing to 10 mg/kg body weight/d without any reported adverse effects. However, during the time of dosage titration, the mother described intermittent abnormal eye movements suspicious of oculogyric crises (ie, due to suboptimal dosages). The subtle abnormal findings resolved completely once the desired dosage was reached. At age 5 months, the clinical examination findings were normal for his age. He was agile and showed good head control and normal muscle tone (video 4). At age 17 months, he started walking. He began to speak single words and to imitate syllables. There was no suspicion of delayed mental development.
This report of 2 new cases of AR GTPCH deficiency without HPA demonstrates a phenotype that is well comparable to cases described previously (Table 1 and Table 2). However, the oculogyric crises as in our cases have been less frequently reported before. The diagnosis of this rare disorder is challenging and based on the striking improvement by treatment with levodopa, a characteristic cerebrospinal fluid neurotransmitter profile, reduced GTPCH enzyme activity in fibroblasts, and detection of 2 mutated GCH1 alleles in affected individuals (Table 1 and Table 2).
In early childhood, the required levodopa dosages in AR GTPCH deficiency are usually higher than in classical DRD (approximately 6-10 mg/kg body weight/d)4-6 but may decrease with increasing age (eg, 2 mg/kg/d).8 A higher frequency of intolerable levodopa-induced dyskinesias may restrain the therapeutic effort to optimally alleviate extrapyramidal signs.9 Additional administration of tetrahydrobiopterin is a matter of debate and recommended by a few investigators.9 Our observation highlights the importance of an early dopaminergic replacement in these patients because reduced dopaminergic neurotransmission in the developing brain of a child may result in impairment of motor and mental maturation. With regard to the described family, the situation was favorable for 2 reasons: (1) the pathogenicity of the homozygous GCH1 mutation had already been confirmed in the index patient, and (2) a prenatal genetic test was available in the younger brother. However, we cannot rule out that a milder phenotype was responsible for the favorable outcome of patient IV-2.
Knowledge about the safety of levodopa and decarboxylase inhibitors during pregnancy is limited and based on single case reports or small case series.10,11 Treatment of 20 pregnancies in patients with DRD, however, was safe without any reported adverse effects on the fetus.12 Recently published case studies did not report a significantly increased rate of embryopathies or prenatal and perinatal problems due to levodopa treatment.13 At this moment, no final conclusions can be drawn with respect to the levodopa dosage given at pregnancy under those circumstances.
Although well documented, the impairment of serotonin biosynthesis with its clinical consequences has hardly been systemically investigated yet. Serotonin deficiency may considerably contribute to psychomotor dysfunction. However, we decided against serotonin replacement therapy in both children because the psychomotor development was favorable in the younger brother prenatally treated with levodopa and had improved in the older brother at the latest follow-up examination (aged 3.5 years) even though it was still not entirely appropriate for his age. In a recent article, Nardocci et al8reported normal cognitive development in twins with AR GTPCH deficiency following levodopa treatment. However, at age 15 years the twins had comparatively low IQs, 75 and 76, suggesting that additional serotonin replacement therapy may indeed be beneficial.
Given the current difficult family situation, it is impossible to monitor the children's mental development appropriately. Once the psychosocial problems are resolved, allowing for repeated mental test batteries and a more systemic follow-up of the brothers, we will initiate a trial serotonin replacement therapy.
Taken together, prenatal levodopa and carbidopa treatment is beneficial and should be considered in this rare cause of recessive GCH1 -associated DRD without HPA to avoid impairment of mental (and physical) development.
Correspondence: Christine Klein, MD, Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany (firstname.lastname@example.org).
Accepted for Publication: January 20, 2012.
Published Online: April 2, 2012. doi:10.1001/archneurol.2012.104
Author Contributions: Dr Klein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Brüggemann and Spiegler contributed equally. Study concept and design: Brüggemann, Hellenbroich, Boor, Gillessen-Kaesbach, and Klein. Acquisition of data: Brüggemann, Spiegler, Hellenbroich, Schneider, Stephani, Boor, Gillessen-Kaesbach, Sperner, and Klein. Analysis and interpretation of data: Brüggemann, Spiegler, Hellenbroich, Opladen, Schneider, Boor, Gillessen-Kaesbach, and Sperner. Drafting of the manuscript: Brüggemann, Hellenbroich, and Gillessen-Kaesbach. Critical revision of the manuscript for important intellectual content: Spiegler, Hellenbroich, Opladen, Schneider, Stephani, Boor, Gillessen-Kaesbach, Sperner, and Klein. Obtained funding: Klein. Administrative, technical, and material support: Brüggemann, Hellenbroich, Opladen, Schneider, Stephani, Gillessen-Kaesbach, Sperner, and Klein. Study supervision: Boor, Sperner, and Klein.
Financial Disclosure: None reported.
Online-Only Material: The videos are available here.
Additional Contributions: We gratefully thank all participants for their invaluable collaboration.
This article was corrected for errors on July 10, 2013.
Brüggemann N, Spiegler J, Hellenbroich Y, et al. Beneficial Prenatal Levodopa Therapy in Autosomal Recessive Guanosine Triphosphate Cyclohydrolase 1 Deficiency. Arch Neurol. 2012;69(8):1071–1075. doi:10.1001/archneurol.2012.104
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