Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.
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ABSTRACT:
SUBMITTER: Sun ZF
PROVIDER: S-EPMC4152247 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:An exome sequencing result on a child with atypical gait was reported as negative; follow-up biochemical evaluation and reanalysis led to diagnosis of treatable DOPA-responsive dystonia.
| S-EPMC8840640 | biostudies-literature
Project description: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.
| S-EPMC6418328 | biostudies-literature
Project description:ObjectiveTo identify the cause of cervical dopa-responsive dystonia (DRD) in a Muslim Indian family inherited in an apparently autosomal recessive fashion, as previously described in this journal.MethodsPrevious testing for mutations in the genes known to cause DRD (GCH1, TH, and SPR) had been negative. Whole exome sequencing was performed on all 3 affected individuals for whom DNA was available to identify potentially pathogenic shared variants. Genotyping data obtained for all 3 affected individuals using the OmniExpress single nucleotide polymorphism chip (Illumina, San Diego, CA) were used to perform linkage analysis, autozygosity mapping, and copy number variation analysis. Sanger sequencing was used to confirm all variants.ResultsAfter filtering of the variants, exome sequencing revealed 2 genes harboring potentially pathogenic compound heterozygous variants (ATM and LRRC16A). Of these, the variants in ATM segregated perfectly with the cervical DRD. Both mutations detected in ATM have been shown to be pathogenic, and ?-fetoprotein, a marker of ataxia telangiectasia, was increased in all affected individuals.ConclusionBiallelic mutations in ATM can cause DRD, and mutations in this gene should be considered in the differential diagnosis of unexplained DRD, particularly if the dystonia is cervical and if there is a recessive family history. ATM has previously been reported to cause isolated cervical dystonia, but never, to our knowledge, DRD. Individuals with dystonia related to ataxia telangiectasia may benefit from a trial of levodopa.
| S-EPMC3795596 | biostudies-literature
Project description:The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low-dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by GCH1 mutation on chromosome 14q22.1-q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa. The patient's father who had the same mutation presented parkinsonism in old age. We also review the literature to address the broad clinical heterogeneity of Segawa disease and the influence of onset age on clinical presentation.
| S-EPMC5822572 | biostudies-literature
Project description:Background: The aim of this study was to investigate the genetic and clinical features of dopa-responsive dystonia (DRD) in China. Method: Characteristics of gene mutations and clinical manifestations of 31 patients diagnosed with DRD were analyzed retrospectively. Result: From January 2000 to January 2019, 31 patients were diagnosed with DRD. Twenty (64.5%) were male, and 11 (35.5%) were female. Ten patients (32.3%) had classic DRD, 19 (61.3%) had DRD-plus, and 2 (6.4%) patients had mutations in the dopamine synthetic pathway (PTS gene mutation) without a typical phenotype (not DRD or DRD-plus). Twenty-eight (90.3%) patients underwent genetic testing. Homozygous or compound heterozygous TH gene mutations were found in 22 patients. GCH1 and PTS gene mutations were found in 2 patients. Heterozygous TH mutation and genetic testing were negative in 1 patient. They took different doses of L-dopa, ranging from 0.4 to 8.7 mg/kg/d. Patients with classic DRD responded well. In patients with DRD-plus, 94.7% (18/19) responded well with residual symptoms. One patient (5.3%) did not show any improvement. Conclusion: DRD can be divided into classic DRD and DRD-plus. In this cohort, the most common pathogenic gene was TH. Fever was the important inducing factor of the disease. L-dopa has sustained and stable effects on patients with classic DRD. In patients with DRD-plus, treatment with L-dopa could ameliorate most of the symptoms.
| S-EPMC7058807 | biostudies-literature
Project description:Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study.
| S-EPMC4061475 | biostudies-literature
Project description:Ataxia-telangiectasia (AT) is a complex genetic neurodegenerative disease with autosomal recessive inheritance. The typical initial features of ataxia telangiectasia include ataxia, cutaneous telangiectasia, and immune deficiency with recurrent infections. Usually, movement disorder occurs late in the course of the disease. A diagnosis of variant or atypical ataxia-telangiectasia (variant AT) is considered in case of any deviation from the normal course of illness giving rise to variable presentations of the disease. Only a few cases of variant AT with predominant movement disorder have been reported worldwide. A knowledge of atypical presentations helps in early diagnosis and thus to initiate management and counselling of the family at the earliest. Here, we report a case of genetically confirmed ataxia-telangiectasia with an initial presentation of dopamine responsive dystonia.
| S-EPMC9996480 | biostudies-literature
Project description:GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family.We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed.We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype.We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.
| S-EPMC4379065 | biostudies-literature
Project description:IntroductionAlthough the diurnal fluctuation of motor dysfunction, reversible with small doses of dopamine, is a cornerstone for the phenotype of the autosomal dominant Segawa syndrome, the non-motor symptoms of this neurotransmitter deficiency have still received limited attention.ObjectiveThis study aims to evaluate non-motor symptoms of this dopa-responsive dystonia through an intrafamilial comparative cross-sectional study.MethodsSeventeen individuals with a c.IVS5 + 3insT (c.626 + 3insT) variation in the GTP cyclohydrolase-1 gene (GCH1, HGNC: 4193) and 34 intrafamilial controls were studied using the Beck Depression Inventory-II, the Wiener Matrizen Test 2, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the MINI/MINI PLUS Questionnaires, the World Health Organization Quality of Life - BREF Instrument and a drug use assessment questionnaire.ResultsNo significant difference was found between the groups in the prevalence of sleep disorders and in cognitive function. Nevertheless, generalized anxiety disorder (p = 0.050) and attention-deficit/hyperactivity disorder in childhood (p = 0.011) were observed only in individuals without the molecular variation. The group with the GCH1 variation presented a worse perception about how safe they feel in their daily lives (p = 0.034), less satisfaction with themselves (p = 0.049) and with their relationships (p = 0.029), and a higher prevalence of past major depressive episodes before use of L-Dopa (p = 0.046).ConclusionLow dopamine could have been protective against generalized anxiety disorder and attention-deficit/hyperactivity disorder in childhood in Segawa group individuals. The prevalence of depression was higher in individuals with the molecular variant prior to the L-Dopa treatment. Considering it, the penetrance estimates for the variant carriers increased from 58.8% to up to 88% in this large studied family. Additionally, neuropsychiatric tests of all individuals with a molecular diagnosis in an affected family are a valuable instrument for its clinical management.
| S-EPMC9248209 | biostudies-literature
Project description:Accurate diagnosis of the primary cause of an individual's kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathologic features despite being caused by defects in different genes. In this report, we describe 2 consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histologic features initially believed to be consistent with focal segmental glomerulosclerosis.Case series.We studied members of 2 apparently unrelated families from Saudi Arabia with kidney disease.Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis.The 2 apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from affected individuals lacked sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional polymerase chain reaction-based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known focal segmental glomerulosclerosis-associated gene.The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease.This analysis shows the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology.
| S-EPMC3291334 | biostudies-literature