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Título

DOPA-RESPONSIVE DYSTONIA (DYT-GCH1) MISDIAGNOSED AS SPASTIC PARAPLEGIA (SPG): A CASE REPORT

Apresentação do Caso

Introduction: An 11 year old female was diagnosed with gait disturbance and dystonia in the right lower limb when she was 7. Nevertheless, her developmental milestone was normal.
She was first evaluated at the age of 8, when a clinical diagnosis of her hereditary spastic paraplegia (HSP) was performed. She was submitted to brain and spinal cord Magnetic Resonance Imaging (MRI), cerebrospinal fluid (CSF) and HTLV serology and all of them were normal.
The patient also developed a progressive dystonia in the upper limb with diurnal fluctuations (symptoms were aggravated in the evening and ameliorated in the morning). Postural tremor and pyramidal signs (brisk deep-tendon reflexes, spasticity and intermittent extensor plantar response) were also presented. Between the ages of 9 and 10, she was diagnosed with task-specific focal dystonia for writing, rigidity, slowness of movements (bradykinesia) in her affected limbs and depression.
At this stage, the patient was submitted to a levodopa trial at 100 mg per day that yielded a dramatic improvement of her symptoms. A molecular genetic testing (next-generation sequencing) confirmed her diagnosis and identified a heterozygous pathogenic variant in GCH1 gene (c.275T>C; p.Leu92Pro).

Discussão

Discussion: Dopa-responsive dystonia (DRD) includes different genotypes such as TH, SR and GTPCH1-deficient (DYT-GCH1, DYT5a), the major form of DRD1. GTPCH1 is an enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, which is essential for dopamine-synthesis2. GTPCH1-deficient DRD is an autosomal dominant condition more prevalent among women (87% to 100%) than men (38% to 55%)3,4,5 , with onset of the symptoms in childhood (the average age is 6 years old). DYT-GCH1 is caused by a mutation in the gene GCH1 (14q22.1-q22.2) that encodes the enzyme GTPCH1. Overall, clinical manifestations are heterogeneous and can be represented by the following symptoms: task-specific focal dystonia, parkinsonism and DRD-simulating spastic paraplegia6. Other uncommon symptoms mentioned in the literature are cervical dystonia, adult-onset parkinsonism and non-motor symptoms7 (depression, anxiety, and sleep disturbance). Brain with DRD appear normal under a MRI scan.

Comentários Finais

Conclusion: DRD may have been misdiagnosed with SPG due to lower limb and gait disturbance. Therefore, a detailed clinical evaluation of SPG should be performed in order to assess the signs that may mimic this condition.

Referências (se houver)

References:
1. Furukawa Y. GTP cyclohydrolase 1-deficient dopa-responsive dystonia. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2021.
2. Krim E, Aupy J, Clot F, Bonnan M,Burbaud P, Guehl D. Mutation in the GCH1 gene with dopa-responsive dystonia and phenotypic variability. Neurol Genet 2018; 4:e231.
3. Furukawa Y, Lang AE, Trugman JM, Bird TD, Hunter A, Sadeh M, Tagawa T, St George-Hyslop PH, Guttman M, Morris LW, Hornykiewicz O, Shimadzu M, Kish SJ. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology. 1998b;50:1015–20.
4. Steinberger D, Weber Y, Korinthenberg R, Deuschl G, Benecke R, Martinius J, Muller U. High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol. 1998;43:634–9.
5. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol. 2003;54 Suppl 6:S32–45.
6. Furukawa Y, Guttman M, Nakamura S, Kish SJ. Dopa-responsive dystonia. In: Frucht SJ, ed. Movement Disorder Emergencies: Diagnosis and Treatment. 2 ed. New York, NY: Springer (Humana Press); 2013:319-40.
7. Trender-Gerhard I, Sweeney MG, Schwingenschuh P, Mir P, Edwards MJ, Gerhard A, Polke JM, Hanna MG, Davis MB, Wood NW, Bhatia KP. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry. 2009;80:839–45.

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