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Objective: To explore the clinical characteristics and genetic variants in a child with tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay., Methods: Clinical feature of the patient was summarized. Genomic DNA was extracted from peripheral blood samples taken from the child and her family members. All exons of GCH1, TH and SPR genes were subjected to targeted capture and next-generation sequencing. Suspected variants were verified by Sanger sequencing., Results: The child could not sit alone at 7 month and 11 days. Physical examination suggested motor retardation and hypotonia, limb stiffness, head nodding, slight torticollis, and language and intellectual developmental delays. She developed involuntary shaking of limbs at 3 month old, which lasted approximately 10 seconds and aggregated with excitement and before sleeping. Cranial MRI revealed widening of subarachnoid space on the temporomandibular and particularly temporal sides. Genetic testing revealed that she has carried a nonsense c.457C>T (p.R153X) variant, which was known to be pathogenic, and a novel missense c.720C>G (p.I240M) variant of the TH gene. The two variants were derived from her father and mother, respectively., Conclusion: The child was diagnosed as tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay due to compound heterozygous variants of the TH gene. Above finding has enriched the spectrum of TH gene variants.

Objective: To explore the clinical characteristics and genotyping results of childhood-onset myoclonus dystonia syndrome caused by SGCE variants. Methods: The clinical data of 9 children with SGCE-related myoclonus dystonia syndrome admitted at either the Department of Neurology, Beijing Children's Hospital, Capital Medical University or the Department of Pediatrics, Peking University First Hospital from May 2018 to October 2019 were collected and the patients were followed up. The definite diagnosis was made on the basis of whole exome sequencing and multiple ligation-dependent probe amplification. The clinical features and gene test results were analyzed retrospectively. Results: Data of 9 patients (4 boys and 5 girls) diagnosed as myoclonus dystonia syndrome caused by SGCE variants were collected. The onset age ranged from 1 year to 3 years and 2 months. The first symptom was myoclonus in 4 cases, while dystonia in the remaining 5 cases. In the course of the disease, 9 cases had myoclonus and 8 had dystonia. Myoclonic jerks were characterized by involuntary jerks in both upper limbs in 8 patients. Six patients had involuntary jerks of lower limbs, resulting in gait instability or even falling. The myoclonus was exacerbated during the fine motor activities, emotional stress or fatigue. Dystonia was characterized by abnormal gait, including 5 cases with right leg dystonia, and 3 cases with the left leg dystonia. Three probands had a positive family history. Intellectual development was normal in all cases. There was no obvious abnormality in video-electroencephalogram (EEG) during both ictal and interictal periods. Electromyography (EMG) and brain magnetic resonance imaging (MRI) of 9 patients were normal. Nine patients carried SGCE gene variants, including 3 frame shift variants, 2 nonsense variants, 2 missense variants, 1 fragment deletion variant and 1 splice site variant. Seven variants were inherited paternally, and 2 variants were de novo. Madopar was used in 8 patients, and nitrazepam in 4 patients, leading to the decrease in the myoclonus jerks and improvement of gait in 6 and 2 patients, respectively. Conclusions: SGCE gene variants can cause myoclonus dystonia syndrome. The onset of the disease may occur at infancy or preschool age, with either myoclonic jerks or dystonia as the initial symptom. Non-epileptic myoclonus is the prominent symptom, with upper limb mainly involved. Most of the patients have the accompanying symptoms of dystonia, and some of them may have spontaneous symptom relief. SGCE gene is imprinted maternally, and the inherited variants of SGCE are paternal in origin.

Objective: To explore genetic mutations and clinical features of a pedigree affected with dopa-responsive dystonia., Methods: PCR and Sanger sequencing were applied to detect mutations of the GCH1 gene among 7 members from the pedigree., Results: The family was detected to have a known heterozygous mutation of the GCH1 gene (c.550C>T). For the 7 members from the pedigree, the age of onset has ranged from 13 to 60 years. The mother of the proband has carried the same mutation but was still healthy at 80. The symptoms of the other three patients were in slow progression, with diurnal fluctuation which can be improved with sleeping, dystonias of lower limbs, and tremor of both hands. Treatment with small dose of levodopa has resulted in significant improvement of clinical symptoms. By database analysis, the c.550C>T mutation was predicted as probably pathological., Conclusion: The c.550C>T mutation probably underlies the disease in this pedigree. The clinical phenotypes of family members may be variable for their ages of onset. Some may even be symptom free.

Objective: To explore clinical characteristics, treatment, and prognosis of a family with childhood-onset rapid-onset dystonia parkinsonism (RDP) caused by ATP1A3 gene mutation and review literatures. Method: The clinical data of a RDP child, his brother and mother had been analyzed retrospectively. This family was admitted to Xiangya Hospital in January 2016. DNA samples were analyzed by the next-generation sequencing and confirmed by Sanger sequencing. Related literature from PubMed, Online Mendelian Inheritance in Man (OMIM), CNKI and Wanfang databases to date (up to October 2016) with"Rapid-onset dystonia-parkinsonism""RDP""DYT12" as key words was reviewed. Result: The proband boy was three years and four months old (April 2015) when he had the first attack of the disease. After a febricity, he suddenly acquired acute aphasia and limb movement disorder. Rehabilitation therapy and supportive treatment made his speech gradually recovered but still slurred. However, his abnormal walking posture still existed. Nine months later (January 2016, 4 years and one months old), symptoms including aphasia, dysphagia, and weakness with rostrocaudal gradient reoccured after fever. The disease progressed to the critical condition within 24 hours. He"seizured" four times with tonic spasms of limbs but without loss of consciousness. Family history showed his grandparents were consanguineous marriage. His mother and brother also developed abnormal gait and dysarthria after an infection before primary school age. Their symptoms improved gradually without relapsing. However, they did not recover entirely with mild intellectual disability. His mother had a healthy brother and sister. This proband had no other siblings but the brother. Heterozygous missense mutation p. R756H in ATP1A3 gene was detected in this proband, his mother and his brother. This mutation had been reported pathogenically related to RDP, and it located in highly conserved gene region. Benzodiazepine was used for the proband and his brother, with the proband being improved better although not completely. Meanwhile, benzodiazepine had no significant effect on his mother because of poor compliance. This is the first case report of RDP in China. The mutations of ATP1A3 have been previously reported in 51 patients including 6 large families and 16 other unrelated patients. A total of 14 different mutations in ATP1A3 gene with RDP have been reported to date, including 12 missense mutations, a 3-bp in-frame deletion, and a 3-bp in-frame insertion. The sporadic cases all had the typical clinical phenotypes of RDP, such as the abrupt onset of dysarthria, dysphagia, limb dystonia with bradykinesia, and postural instability. The symptoms of bulbar and arms were much more obvious. It was hard to diagnose RDP in a family because some patients had typical symptoms of RDP, while the others might experience from mild symptoms to no symptoms, which might be related to incomplete penetrance of RDP. Two cases carrying the same mutation as our patients also presented some overlapping phenotypes. Conclusion: The p. R756H heterozygous mutation in ATP1A3 gene is the pathogenic mutation of RDP, analysis of genotype-phenotype correlations of RDP will be very important and meaningful.

Objective: To identify potential mutation of the GCH1 gene in a Chinese family affected with dopa-responsive dystonia., Methods: Genomic DNA of patients was extracted from peripheral blood samples. The 6 exons of the GCH1 gene and at least 100 bp of flanking intronic sequences were amplified with PCR. Potential mutations were screened by direct sequencing. Identified mutation was verified with denaturing high performance liquid chromatography (DHPLC) in 100 healthy controls., Results: All patients were found to be heterozygous for a novel c.597delT (p.Ala200LeufsX5) deletion in the exon 5 of the GCH1 gene. The deletion of T has resulted in formation of a shorter (203 amino acids) truncated non-functional guanosine triphosphate cyclohydrolase I. The same mutation was not found in the 100 controls., Conclusion: A novel GCH1 gene frameshifing mutation probably underlies the dopa-responsive dystonia in this Chinese family.

Objective: To analyze the clinical characteristics of the patient with tyrosine hydroxylase deficiency, and investigate it's molecular mechanism., Method: The clinical characteristics of a patient with tyrosine hydroxylase deficiency were summarized and analyzed, his and his family's peripheral blood specimens were collected after informed consent was signed. All exons and the intron-exon boundaries of guanosine triphosphate hydroxylase I gene, tyrosine hydroxylase gene and sepiapterin reductase gene were examined by DNA-PCR, bi-directional sequencing., Result: The patient was a 3-year-old boy, presented with unexplained dystonia for 3 years, without significant impairment of intelligence. Physical examination showed limb muscle strength grade V, rigidity of extremities, hypertonicity, brisk deep tendon reflexes in limbs, without obvious abnormalities in auxiliary examination, such as brain MRI, hepatic biochemical panel, creatine kinase, and ceruloplasmin. He dramatically responded to small doses of levodopa in the follow-up for half a year. A homozygous missense change in exon 5 of TH gene, c.605G > A (p.R202H), which was a known pathogenic mutation, was found in the patient. His parents were heterozygous for the R202H mutation., Conclusion: The age of onset in tyrosine hydroxylase deficiency patients is usually within the first year of life. Unexplained dystonia and hypokinesia were the main clinical features of tyrosine hydroxylase deficiency. The dopa-responsive effects for some patients are so obvious that we should strengthen awareness of the disease. TH gene c.605G > A (p.R202H) may be a common type of causative mutations for the mild form at home and abroad.

Objective: To evaluate the value of denaturing high-performance liquid chromatography (DHPLC) in detection of mutations in the DYT1 gene in the patients with primary torsion dystonia (PTD) and to explore the distribution of mutation in China., Methods: Peripheral blood samples were collected from 13 early PTD patients, 8 males and 5 females, aged 20 +/- 6. PCR was used to amplify the exon 5 of the DYT1 gene. The mutations were identified by DHPLC and DNA sequencing., Results: A 3 bp (GAG) deletion mutation in the exon 5 of the DYT1 gene resulting in Glu302del was found in 5 patients. The result of DHPLC was consistent with that of PCR-RFLP. There was not any mutation in other sites of the DYT1 gene., Conclusion: DHPLC technique is an effective tool for detecting 3 bp deletion mutation in the DYT1 gene. The GAG (3 bp) deletion in the DYT1 gene may play an important role in causing early-onset and generalized dystonia in China.

Objective: To clone a new deafness associated gene., Methods: Molecular database search, RACE and cDNA library screen were applied., Results: A new gene, named dystonia/deafness peptide like (DDPL) (GeneBank Accession Number: DDPL2 AF165967) and mapped to 11q22.1-22.2, was cloned. DDPL had two different mRNA splicing types and accordingly encoded 83 and 51 amino acids. DDPL transcripts were detected in a range of adult and fetal tissues. A pseudogene of DDPL, named DDPLphi which was shown lying within Xq25-q26, showed 96.9% sequence identity with DDPL1 cDNA sequence across 382 bp., Conclusion: DDPL lies within the 5.2 Mb interval of 11q22.1-q22.2 between D11S939 and D11S1347, and has a high identity with the DFN-1/MTS associated gene-DDP.