Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
Female ; Humans ; Infant ; Male ; Benserazide/therapeutic use* ; Dystonia/genetics* ; Hypokinesia/drug therapy* ; Levodopa/pharmacology* ; Muscle Hypotonia ; Retrospective Studies ; Tyrosine 3-Monooxygenase/genetics*

OBJECTIVE: To explore the clinical phenotype and genetic features of two children with MEGDEL syndrome due to variants of the SERAC1 gene. METHODS: Two children who had presented at the Fujian Medical University Union Hospital respectively on July 14, 2020 and July 28, 2018 were selected as the study subjects. Clinical features and results of genetic testing were retrospectively analyzed. RESULTS: Both children had featured developmental delay, dystonia and sensorineural deafness, along with increased urine 3-methylglutaric acid levels. Magnetic resonance imaging revealed changes similar to Leigh-like syndrome. Gene sequencing revealed that both children have harbored pathogenic compound heterozygous variants of the SERAC1 gene, including c.1159C>T and c.442C>T in child 1, and c.1168C>T and exons 4~9 deletion in child 2. CONCLUSION Children with MEGDEL syndrome due to SERAC1 gene variants have variable clinical genotypes. Delineation of its clinical characteristics and typical imaging changes can facilitate early diagnosis and treatment. Discovery of the novel variants has also enriched the spectrum of SERAC1 gene variants.
Humans ; Retrospective Studies ; Metabolism, Inborn Errors ; Hearing Loss, Sensorineural/genetics* ; Dystonia ; Carboxylic Ester Hydrolases

Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%-80.7%) in relatives and 74.5% (95% CI 70.2%-78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.
Dystonia ; Epilepsy, Benign Neonatal/genetics* ; Humans ; Membrane Proteins/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree ; Penetrance ; Seizures/genetics*

The clinical manifestations of five children with paroxysmal kinesigenic dyskinesia (PKD) were retrospectively analyzed and their gene mutations were analyzed by high-throughput sequencing and chromosome microarray. The 5 patients consisted of 4 males and 1 female and the age of onset was 6-9 years. Dyskinesia was induced by sudden turn movement, scare, mental stress, or other factors. These patients were conscious and had abnormal posture of unilateral or bilateral extremities, athetosis, facial muscle twitching, and abnormal body posture. The frequency of onset ranged from 3-5 times a month to 2-7 times a day, with a duration of <30 seconds every time. Electroencephalography showed no abnormality in these patients. Three patients had a family history of similar disease. The high-throughput sequencing results showed that a heterozygous mutation in the PRRT2 gene, c.649_650insC (p.R217PfsX8), was found in two patients; the mutation c.436C>T (p.P146S) was found in one patient; a splice site mutation, IVS2-1G>A, was found in one patient. The two mutations c.436C>T and IVS2-1G>A had not been reported previously. The chromosome microarray analysis was performed in one patient with negative results of gene detection, and the chromosome 16p11.2 deletion (0.55 Mb) was observed. Low-dose carbamazepine was effective for treatment of the 5 patients. PKD is a rare neurological disease. The detection of the PRRT2 gene by multiple genetic analysis can help the early diagnosis of PKD.
Carbamazepine ; therapeutic use ; Child ; Chromosome Deletion ; Chromosomes, Human, Pair 16 ; Dystonia ; complications ; diagnosis ; drug therapy ; genetics ; Electroencephalography ; Female ; Humans ; Male ; Membrane Proteins ; genetics ; Mutation ; Nerve Tissue Proteins ; genetics

OBJECTIVETo explore the feasibility of using PCR-based capillary electrophoresis method to analysis mutation of the TOR1A gene in a family affected with primary torsion dystonia (PTD).

METHODSPeripheral blood sample was collected from proband and amnionic fluid from her fetus for the extraction of DNA. The 5th exon of the TOR1A gene and its flanking sequences were amplified with PCR and analyzed with agarose electrophoresis, fluorescence labeled fragment analysis and Sanger sequencing.

RESULTSFluorescence labeled fragment analysis was performed through capillary electrophoresis, which showed that the proband carried a c.907_909delGAG (p.Glu303del) deletional mutation of the TOR1A gene. The result was verified by Sanger sequencing. The fetus DNA was also found with the same mutation by capillary electrophoresis, inferring that the fetus was probably affected with the disease.

CONCLUSIONThe mutation of c.907_909delGAG of the TOR1A gene was speculated as pathologic cause of proband in this family. Fragment analysis by capillary electrophoresis combined with DNA sequencing is an efficient test for small deletional mutations and feasible for its prenatal diagnosis.

Adult ; Dystonia ; diagnosis ; genetics ; Electrophoresis, Capillary ; Female ; Humans ; Molecular Chaperones ; genetics ; Mutation ; Prenatal Diagnosis ; Sequence Analysis, DNA

BACKGROUNDParoxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.

METHODSA cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.

RESULTSA total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.

CONCLUSIONSThe phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2- negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.

Adolescent ; Adult ; Child ; Chloride Channels ; genetics ; Chorea ; genetics ; Dystonia ; diagnosis ; genetics ; Female ; Glucose Transporter Type 1 ; genetics ; Humans ; Male ; Membrane Proteins ; genetics ; Muscle Proteins ; genetics ; Mutation ; Myotonia Congenita ; genetics ; Nerve Tissue Proteins ; genetics

OBJECTIVETo screen potential mutations of PRRT2 gene in a Chinese family affected with paroxysmal kinesigenic dyskinesia (PKD).

METHODSPolymerase chain reaction, DNA sequencing and restriction endonuclaese analysis were used to analyze all members of the family.

RESULTSA heterozygous mutation c.649dupC was identified in the PRRT2 gene in all patients, while no similar mutation was found in healthy members from the family.

CONCLUSIONThe c.649dupC mutation of the PRRT2 gene probably underlies the PKD in this family. Prenatal diagnosis can reduce the risk for further birth of affected children for this family.

Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Dystonia ; genetics ; Female ; Frameshift Mutation ; Humans ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Molecular Sequence Data ; Nerve Tissue Proteins ; genetics ; Young Adult

OBJECTIVETo investigate the clinical features and proline-rich transmembrane protein 2 (PRRT2) gene mutation in patients with paroxysmal kinesigenic dyskinesia (PKD).

METHODClinical information was collected at Peking University First Hospital from January 2004 to July 2014. In total, 10 patients with PKD were recruited, and all were males. Among them, four patients were the probands from four PKD families and the other six patients were sporadic cases. Clinical information was analyzed. Peripheral blood samples for DNA study were collected from PKD patients and their family members. Genomic DNA was extracted using standard procedures. Mutation analysis of PRRT2 was performed by Sanger sequencing after PCR.

RESULTOf the 10 patients, the median age of dyskinesias onset was 10 years, ranging from 4 to 13 years. The description of their attacks were abnormal involuntary movements provoked by sudden movements, without loss of consciousness. Five patients exhibited dystonia, two patients exhibited choreoathetosis, and three patients had mixed (dystonia and choreoathetosis) dyskinesias. The duration of the attacks lasted for 3 to 30 seconds. The frequency ranged from once per month to twenty times per day. PRRT2 mutations, c. 649_650insC (p. R217PfsX8), were found in all the four PKD families. Mutation c. 649_650insC was also detected in two of the six sporadic PKD cases, inheriting from their asymptomatic mother.

CONCLUSIONThe onset age of PKD could be in the early childhood. The clinical features of the familial cases and sporadic cases showed no difference. The attacks manifested as dystonia, choreathetosis, or mixed. PRR2 mutations could be identified in familial or sporadic cases with PKD. Mutation c. 649_650insC is the hotspot mutation of PRRT2 gene.

Adolescent ; Child ; Child, Preschool ; DNA Mutational Analysis ; Dystonia ; genetics ; Humans ; Male ; Membrane Proteins ; genetics ; Mutation ; Nerve Tissue Proteins ; genetics

OBJECTIVETo analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient, and review the latest clinical research reports.

METHODClinical, laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology, Beijing Children's Hospital in November, 2013 were reported, and through taking "SUCLA2" as key words to search at CNKI, Wanfang, PubMed and the Human Gene Mutation Database (HGMD) professional to date, the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed.

RESULT(1) The patient was 5 years and 9 months old, born as a term small for gestational age infant whose birth weight was 2 400 g, and presented since birth with severe muscular hypotonia, feeding difficulties, failure to thrive, psychomotor retardation and hearing impairment. Until now, he still showed severe developmental retardation, together with muscular atrophy, thoracocyllosis and scoliosis, and facial features. The patient is the first born from consanguineous healthy parents, whose relationship is cousins. Laboratory tests showed urinary excretion of mild methylmalonic acid (MMA), elevated plasma lactate concentration, and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling. MRI showed brain atrophy-like and bilateral T2 hyperintensities in bilateral caudate nuclei and putamen. By Next-Generation Sequencing (NGS), we identified a novel homozygous missense mutation (c.970G > A) in the SUCLA2 in a highly conserved amino acid residue. (2) The total number was only 25 with a male to female ratio of 14: 11, and age of onset of 23 was 0-4 months. The most common clinical features in patients with SUCLA2 mutation were permanent hypotonia, muscle atrophy, psychomotor retardation and scoliosis or kyphosis. Frequent signs included hearing impairment, hyperkinesia, dystonia or athetoid movements, feeding difficulties, growth retardation and ptosis or ophthalmoplegia. Epilepsy was occasionally observed. The combination of lactic acidemia, mild MMA-uria and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling were characteristic markers. MRI showed brain atrophy-like and bilateral basal ganglia involvement (mainly the putamen and caudate nuclei). Nineteen patients originated from Europe, with 13 of whom originated from Faroe Islands that carry a homozygous mutation (c.534+1G>A) in SUCLA2.

CONCLUSIONSUCLA2-related encephalomyopathic MDS is characterized by onset of severe hypotonia in early infancy, feeding difficulties, growth retardation, psychomotor retardation and hearing impairment. Metabolic findings usually include lactic acidemia, mild MMA-uria and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling. MRI showed brain atrophy-like and bilateral basal ganglia involvement (mainly the putamen and caudate nuclei). SUCLA2 pathogenic mutations would confirm the diagnosis.

Carnitine ; Child ; DNA, Mitochondrial ; genetics ; Dystonia ; Europe ; Female ; Homozygote ; Humans ; Magnetic Resonance Imaging ; Male ; Methylmalonic Acid ; Mitochondrial Encephalomyopathies ; diagnosis ; genetics ; Mutation ; Succinate-CoA Ligases ; genetics ; Syndrome

Child ; Dystonia Musculorum Deformans ; diagnosis ; etiology ; genetics ; Humans ; Magnetic Resonance Imaging ; Male