Dopa-responsive Dystonia Research Articles

Clinical characteristics and genetic analysis of patients with autosomal recessive dopa-responsive dystonia

Objective To analyze the clinical characteristics and gene mutation of autosomal recessive dopa-responsive dystonia(AR-DRD), and to explore its therapeutic effect, follow-up findings and molecular genetic me-chanism. Methods The whole exome sequencing, which based on next-generation sequencing, was performed in 6 movement-disordered patients who denied family history at the outpatient clinic of Children′s Hospital Affiliated to Capital Institute of Pediatrics from April 2016 to September 2017.The mutations identified in probands were then confirmed in probands and their parents by Sanger sequencing in order to analyze the cause of mutations. Results (1)Clinical features: the onset of 6 patients was around infancy, complicated with muscle weakness and abnormal muscle tone.(2)Gene mutation analysis: All 6 patients carried TH gene mutations.Five patients were of complex heterozygosis mutations, 1 patient was of homozygosis mutation.Five mutations were detected: c.605 G>A, c.601 C>T, c.364C>T, c.1412_1413insCCCCCAGGCCGTGC and c. 646G>A.(3)Therapeutic effect: all 6 patients achieved improvement of motor function after dopamine treatment, and they presented the different degrees of improvement in muscle tone and muscle strength. Conclusions The AR-DRD patients who carried c. 605 G>A mutation have a good therapeutic effect treated with L-Dopamine.This mutation may be a common mutation site of mild to moderate defective AR-DRD at home and abroad.The frameshift mutation c. 1412_1413insCCCCCAGGCCGTGC is a new TH gene pathogenicity mutation site discovered by this study. Key words: Dopa-responsive dystonia; Gene of tyrosine hydroxylase; L-dopamine; Next generation sequencing

Leaky splicing variant in sepiapterin reductase deficiency: Are milder cases escaping diagnosis?

Sepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH4) synthesis.1 Unlike other forms of BH4-deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening. Owing to its variable presenting features and need for a sensitive method of CSF analysis, diagnosis of SRD may be compromised in mild phenotypes.2

Dystonic crises in dopa-responsive dystonia induced by energy drinks

We present an interesting case of recurrent dystonic crises in dopa-responsive dystonia (DRD) likely induced by excessive consumption of aspartame-containing products, in particular sugar-free energy drinks. This has a strong...

Progress on study of guanosine triphosphate cyclohydrolase 1

Guanosine triphosphate cyclohydrolase 1 (GTPCH1) is a protein encoded by the GCH1 gene, which catalyze GTP to tetrahydrofolinine (BH4) under physiological condition. BH4 is a coenzyme of aromatic amino acid hydroxylase and a cofactor of nitric oxide synthases. BH4 involves in the synthesis of various hormones and neurotransmitters and plays an important role in a series of pathophysiological processes in vivo. Recent studies showed that GTPCH1 is involved in the pathogenesis of neuropathic pain, dopa-responsive dystonia, cancer and cardiovascular diseases. In this review, we will discuss the role of GTPCH1 in those diseases mentioned above. Key words: GTP cyclohydrolase; Dystonia, dopa-responsive; Cardiovascular diseases; Neoplasms; Neuralgia; Review

'Atypical' Parkinson's disease - genetic.

Genetic atypical Parkinson's disease (PD) describes monogenic forms of PD that resemble idiopathic PD but feature prominent atypical clinical signs and symptoms and can be sub-grouped into i) atypical monogenic forms caused by mutations in the ATP13A2, DNAJC6, FBXO7, SYNJ1, VPS13C, and DCTN genes; ii) monogenic PD more closely resembling idiopathic PD, but associated with atypical features in at least a subset of cases (SNCA-, LRRK2-, VPS35-, Parkin-, PINK1-, and DJ-1-linked PD; iii) carriers of mutations in genes that are usually associated with other movement disorders but may present with parkinsonism, such as dopa-responsive dystonia. Some atypical features are shared by almost all forms, such as an overall early age at onset. Other clinical signs are present in carriers of mutations across several different genes, such as for example, early cognitive decline. Finally, several clinical features can serve as red flags for specific forms of atypical PD including a supranuclear gaze palsy in ATP13A2 mutation carriers or hypoventilation linked to mutations in the DCTN1 gene.

Genetic study in a family with dopa-responsive dystonia revealed a novel mutation in sepiapterin reductase gene.

Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.

16 Pills by Carley Moore

Reviewed by: 16 Pills by Carley Moore Brandel France de Bravo (bio) Carley Moore. 16 Pills. Tinderbox Editions, 2018. "I've always been a sharer, a teller, a blurter and a huge talker," writes New York-based poet, novelist, and professor Carley Moore in her debut essay collection, 16 Pills. She's also, we discover in the course of the book, a voracious reader, movie-watcher, dancer, and crier. Her reactions to and engagement with an assortment of articles, books, and films figure large, and you may find yourself jotting down titles. Her emotional honesty doesn't drain or pain but awakens, recalling Frost's dictum: "No tears in the writer, no tears in the reader." The "I" that takes us by the hand and leads us through these sixteen essays is bold, never prissily italicized or punctiliously underlined. Moore is like the best friend you had as a child who whispers a secret in your ear before racing to the jungle gym to hang by her knees, shouting for you to join her. The writer uses her many selves—disabled child, mother, teacher, internet dater, pill-taker—as lenses through which to view and interrogate issues [End Page 228] we wrestle with as individuals and as a society. With vulnerability and disarming humor, she takes on divorce and co-parenting; reproductive technology; the role of prescription drugs in constructing a self; America's obsession with happiness; racism; sexism; gender; the wound of being unseen; the violence of narcissism, and our own complicity. After repeatedly watching the video of Eric Garner's chokehold death, she writes: "I saw how violence becomes spectacle and felt the nausea of implication that my viewing brings with it. Each viewing is, after all, called a hit." Ouch. At her most powerful, Moore leaves your cheek with a stinging, red handprint. For this author, process—an essay's construction—is itself a topic. Rather than hide the ropes and pulleys, she invites us backstage, sealing the intimacy she establishes with her readers. In "The Jealousy Exams," Moore reveals, "This essay is inspired in part by Leslie Jamison's The Empathy Exams. Like many readers, I loved the book, which made me think about writing as an act of empathy…" Moore uses her essay and jealousy of Jamison's success as a vehicle for exploring the green-eyed monster, which she admits to having welcomed on occasion: "I made a little nest for it in my heart and for that small stretch of time, I lived in that nest. I gathered my wrongs like scraps of paper and string." Her nurturing of a reviled emotion made me think of Tony Hoagland's poem "Hate Hotel:" "I take my room at the Hate Hotel, and sit and flip/ through the heavy pages of the photographs, / the rogue's gallery of the faces I loathe." About Jamison, Moore continues: A young successful writer, not totally unlike me, but different, too. I imagined her flat stomach and all the donuts she could consume without any effect. I decided she had sold her book effortlessly and that she was winning. I got mad about my own publishing struggles and at the publishing in dustry in general. I calmed down. I joked with a friend that I wanted to write a book called The Jealousy Exams. I grew bored with my own jealousy. Eventually, I started to work on this essay. Moore spins a creation myth, and we fall under its spell. Not only does she pay tribute to other essayists—past and present—she contributes to the corpus on the form with her own unique definition of the essay: an anti-palliative. While five of the sixteen essays bear the title "On______" (Unhappiness; Nitpicking and Co-Parenting; Spectacle and Silence; Eating; Portals), it's safe to say that Montaigne never conceived of the essay as anti-antidepressant! A connoisseur of pills (her first and longest-taken being a synthetic form of dopamine to treat a debilitating hereditary condition diagnosed in childhood, dopa-responsive dystonia: "I was in a perpetual state of discomfort. I could not rest or relax."), Moore recounts how the antidepressant Lexapro, which she took for anxiety, gave...

The quaternary structure of human tyrosine hydroxylase: effects of dystonia-associated missense variants on oligomeric state and enzyme activity.

Tyrosine hydroxylase (TH) is a multi‐domain, homo‐oligomeric enzyme that catalyses the rate‐limiting step of catecholamine neurotransmitter biosynthesis. Missense variants of human TH are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA‐responsive dystonia (DRD). We expressed isoform 1 of human TH (hTH1) and its dystonia‐associated missense variants in E. coli, analysed their quaternary structure and thermal stability using size‐exclusion chromatography, circular dichroism, multi‐angle light scattering, transmission electron microscopy, small‐angle X‐ray scattering and assayed hydroxylase activity. Wild‐type (WT) hTH1 was a mixture of enzymatically stable tetramers (85.6%) and octamers (14.4%), with little interconversion between these species. We also observed small amounts of higher order assemblies of long chains of enzyme by transmission electron microscopy. To investigate the role of molecular assemblies in the pathogenesis of DRD, we compared the structure of WT hTH1 with the DRD‐associated variants R410P and D467G that are found in vicinity of the predicted subunit interfaces. In contrast to WT hTH1, R410P and D467G were mixtures of tetrameric and dimeric species. Inspection of the available structures revealed that Arg‐410 and Asp‐467 are important for maintaining the stability and oligomeric structure of TH. Disruption of the normal quaternary enzyme structure by missense variants is a new molecular mechanism that may explain the loss of TH enzymatic activity in DRD. Unstable missense variants could be targets for pharmacological intervention in DRD, aimed to re‐establish the normal oligomeric state of TH.

Common and rare GCH1 variants are associated with Parkinson'sdisease.

GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed. Three rare GCH1 variants, which were previously reported to be pathogenic in DRD, were found in five patients with PD and not in controls (sequence Kernel association test, p= 0.024). A common haplotype, tagged by rs841, was associated with a reduced risk for PD (OR= 0.71, 95% CI= 0.61-0.83, p= 1.24× 10-4), and with increased GCH1 expression in brain regions relevant for PD (www.gtexportal.org). Our results support a role for rare, DRD-related variants, and common GCH1 variants in the pathogenesis ofPD.

Dopa-responsive dystonia and its diagnostic challenges: A case report

Dopa-responsive dystonia and its diagnostic challenges: A case report

What a neurologist should know about PET and SPECT functional imaging for parkinsonism: A practical perspective

The diagnosis of a parkinsonian syndrome based on clinical criteria remains sometimes difficult, especially at disease onset. Brain or heart molecular imaging techniques (SPECT or PET) can provide a major help to improve and speed up diagnosis, influencing treatment strategies. Presynaptic dopaminergic imaging using either [18F]-Dopa PET or 123I -2β-Carbomethoxy-3β-(4-Iodophenyl)- N-(3-Fluoropropyl) Nortropane ([123I]-Ioflupane)SPECT demonstrates or rules out the presence of a dopaminergic degenerative process. This allows to distinguish Parkinson's disease, Parkinson “plus” syndromes and dementia with Lewy bodies (reduced radiotracers binding) from essential tremor, psychogenic, post-neuroleptic or vascular parkinsonisms, dopa-responsive dystonia and Alzheimer's disease (normal radiotracers binding). For differential diagnosis between Parkinson's disease and Parkinson “plus” syndromes, brain molecular imaging with [18F]-Fluorodeoxyglucose ([18F]-FDG) PET or 99mTc-HMPAO SPECT can provide useful information, whereas [18F]-Dopa PET or [123I]-Ioflupane does not separate these entities. Finally, sympathetic cardiac [123I]-Metaiodobenzylguanidine ([123I]-MIBG) scintigraphy or SPECT can help distinguishing Parkinson's disease and dementia with Lew bodies (decreased binding) from multiple system atrophy and progressive supranuclear palsy (normal binding). New radiotracers notably those targeting the pathological process itself such as Tau aggregates are under development and may provide interesting informations to delineate the different Parkinson “plus” syndromes.

Human tyrosine hydroxylase in Parkinson's disease and in related disorders.

Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline). PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD. However, this decrease in TH is thought to be secondary due to neurodegeneration of DA neurons caused by some as yet unidentified genetic and environmental factors, and thus, TH deficiency may not play a direct role in PD. This manuscript provides an overview of the role of human TH in the pathophysiology of PD, covering the following aspects: (1) structures of the gene and protein of human TH in relation to PD; (2) similarity and dissimilarity between the phenotypes of aging-related sPD and those of young-onset fPD or DOPA-responsive dystonia due to DA deficiency in the striatum with decreased TH activity caused by mutations in either the TH gene or GTP cyclohydrolase I (GCH1) gene; and (3) genetic variants of the TH gene (polymorphisms, rare variants, and mutations) in PD, as discovered recently by advanced genome analysis.

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia.

Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia. Unbiased stereological neuronal counts and Sholl analysis were used to address these issues. To determine the potential effect of aging on the number of ChIs, both young (3 months old) and aged (15 months old) mice were used. For purpose of comparisons with ChIs, the number of GABAergic parvalbumin (PV)-immunoreactive striatal interneurons was also quantified in young mice. Overall, no significant change in the prevalence of ChIs and PV-immunoreactive cells was found throughout various functional regions of the striatum in young DRD mice. Similar results were found for ChIs in aged animals. Subtle changes in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice. Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. Thus, together with our previous data from a knock-in mouse model of DYT-1 dystonia (Song et al., 2013), our data further suggest that the dysregulation of striatal cholinergic transmission in dystonia is not associated with major neuroplastic changes in the morphology or prevalence of striatal ChIs.Highlights -There is no significant change in the number of striatal ChIs in young and aged mice model of DRD-There is no significant change in the prevalence of striatal GABAergic PV-containing interneurons in the striatum of young mice models of DRD-Subtle morphological changes in the dendritic arborization of striatal ChIs are found in the middle and caudal tiers of the striatum in young mice models of DRD-The levels of both M1 and M4 muscarinic receptors immunoreactivity are not significantly changed in the striatum of DRD mice-Major changes in the prevalence and morphology of striatal ChIs are unlikely to underlie striatal cholinergic dysfunction in DRD

GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Mutation in the GCH1 gene with dopa-responsive dystonia and phenotypic variability.

Dopa-responsive dystonia (DRD) is an autosomal dominant neurologic disorder characterized by incomplete penetrance and high variability of its phenotypic expression.1 The usual phenotype is defined by early-onset isolated dystonia, predominant in the lower limb, with marked diurnal fluctuations and a dramatic and sustained response to low doses of l-DOPA.2 We report 2 members of the same family (mother and daughter) with a nonsense heterozygous mutation ( c.706G>T; p.Glu236* ) in the GCH1 gene and having DRD with phenotypic variability.

A Case of Dopa-responsive Dystonia with a Mutation in the GCH1 Gene Misdiagnosed as Cerebral Palsy for 2 Years

도파 반응성 근긴장이상증은 근긴장이상 증상이 하지부터 시작되고, 일간 변동성을 보이며, 레보도파 치료에 극적이고 지속적인 반응을 나타내는 특징을 갖는다. Segawa 병이라고도 불리는 상염색체 우성 GTP cyclohydrolase 1 결핍은 도파 반응성 근긴장이상증 중에 가장 흔하고 잘 알려진 질환이다. 하지만, 도파민의 생합성에 관련되는 다른 효소의...

Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity.

Human studies have demonstrated a correlation between noncoding polymorphisms of "the pain protective" haplotype in the GCH1 gene that encodes for GTP cyclohydrolase I (GTPCH1)-which leads to reduced tetrahydrobiopterin (BH4) production in cell systems-and a diminished perception of experimental and clinical pain. Here, we investigate whether heterozygous mutations in the GCH1 gene which lead to a profound BH4 reduction in patients with dopa-responsive dystonia (DRD) have any effect on pain sensitivity. The study includes an investigation of GCH1-associated biomarkers and pain sensitivity in a cohort of 22 patients with DRD and 36 controls. The patients with DRD had, when compared with controls, significantly reduced levels of BH4, neopterin, biopterin, and GTPCH1 in their urine, blood, or cytokine-stimulated fibroblasts, but their pain response with respect to non-painful stimulation, (acute) stimulus-evoked pain, or pain response after capsaicin-induced sensitization was not significantly different. A family-specific cohort of 11 patients with DRD and 11 controls were included in this study. The patients with DRD were heterozygous for the pain protective haplotype in cis with the GCH1 disease-causing mutation, c.899T>C. No effect on pain perception was observed for this combined haplotype. In conclusion, a reduced concentration of BH4 is not sufficient to alter ongoing pain sensitivity or evoked pain responses.

Dopa-Responsive Dystonia in Han Chinese Patients: One Novel Heterozygous Mutation in GTP Cyclohydrolase 1 (GCH1) and Three Known Mutations in TH.

BackgroundThis study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD).Material/MethodsRelevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted.ResultsOne novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site.ConclusionsPatients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD.

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike.

Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.

Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

We present a family in which the first child was diagnosed with dopa-responsive dystonia based on biochemical findings only. Dopa-responsive dystonia is a severe heterogeneous genetic disease. The possibly involved genes are GCH1 and TH.In their second pregnancy, the parents came for genetic counseling and prenatal diagnosis late, at 12 weeks of gestation. Genetic testing in the affected child was performed, but the results were difficult to interpret. The identified mutations were classified as VOUS – variants of unknown clinical significance. Although possibly causative, a homozygous variant in the TH gene was not reported before in children with dopa-responsive dystonia. Due to limited time, establishing the fetal prognosis was challenging.Our report emphasizes the importance of a multidisciplinary approach in the context of new diagnostic techniques, such as Next Generation Sequencing. We illustrate the fact that behind any laboratory result remains sophisticated clinical judgment. We also describe a previously not reported variant of the TH gene in a child with severe, early-onset dystonia.