Novel CAD gene mutations in a boy with developmental and epileptic encephalopathy 50 with dramatic response to uridine therapy: a case report and a review of the literature.

BACKGROUND: Developmental and epileptic encephalopathy-50 (DEE-50) is a rare clinical condition believed to be caused by a mutation in the CAD gene and is associated with a bleak prognosis. CAD-related diseases have a wide range of clinical manifestations and other symptoms that may be easily overlooked. Like other rare diseases, the clinical manifestations and the treatment of DEE-50 necessitate further investigation. CASE PRESENTATION: A 1-year-old male patient presented with developmental delay, seizures, and anaemia at 3 months of age. He further developed refractory status epilepticus (SE), rapid deterioration of cognitive and motor function, and even became comatose at 5 months of age. Whole-exome sequencing of trios (WES-trios) revealed a compound heterozygous variant in the CAD gene, with one locus inherited from his father (c.1252C>T: p.Q418* nonsense mutation) and one from his mother (c.6628G>A: p.G2210S, missense mutation). This compound heterozygous CAD variant was unreported in the Human Gene Mutation Database. After uridine treatment, his cognitive faculties dramatically improved and he remained seizure-free. Forty two cases with CAD gene mutation reported in the literatures were reviewed. Among them, 90% had onset before 3 years of age, with average of 1.6±1.8 years old. The average age of diagnosis was 7.7 ± 10 years. The mortality rate was approximately 9.5%, with all reported deaths occurring in patients without uridine treatment. The clinical entity could be improved dramatically when the patient treated with uridine. CONCLUSIONS: We present a boy with DEE 50 caused by novel CAD gene mutations and reviewed the clinical features of 42 patients reported previously. DEE 50 has early onset, refractory seizures, even status epilepticus leading to death, with favorable response to treatment with oral uridine. Early uridine treatment is recommended if CAD defect is suspected or genetically diagnosed. This study enhances the knowledge of DEE 50 and expands the spectrum of CAD gene mutations.

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia.

BACKGROUND: More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. OBJECTIVE: The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. METHODS: We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells. RESULTS: We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5-6 in controls), whereas the number of 3' pure CAG repeats was up to 32 to 87 (4-16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats. CONCLUSIONS: This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males.

BACKGROUND: Germline mosaicisms could be inherited to offspring, which considered as "de novo" in most cases. Paternal germline MECP2 mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on MECP2 germline mosaicism in males, not only RTT fathers. METHODS: Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms. RESULTS: Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms. CONCLUSIONS: Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as "de novo", more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.

Ultrasound-guided interlaminar approach for nusinersen administration in patients with spinal muscular atrophy with spinal fusion or severe scoliosis.

BACKGROUND: Intrathecal injection of medications can be challenging in spinal muscular atrophy (SMA) patients with severe scoliosis or after spine surgery. Here we report our experience with real-time ultrasound (US)-guided intrathecal administration of nusinersen in patients with SMA. METHODS: Seven patients (six children and one adult) with either spinal fusion or severe scoliosis were enrolled. We performed intrathecal injections of nusinersen under US guidance. The efficacy and safety of US-guided injection were explored. RESULTS: Five patients had undergone spinal fusion, while the other two presented severe scoliosis. Success was achieved in 19/20 lumbar punctures (95%), 15 of which were performed through the near-spinous process approach. The intervertebral space with a designated channel was selected for the five postoperative patients, while the interspaces with the smallest rotation angle were chosen for the other two patients with severe scoliosis. In 89.5% (17/19) of the punctures, the number of insertions was no more than two. No major adverse events were observed. CONCLUSION: Given its safety and efficacy, real-time US guidance is recommended for SMA patients with spine surgery or severe scoliosis, and the near-spinous process view can be used as a interlaminar puncture approach for US guidance.

Clinical and genetic spectrum of hereditary spastic paraplegia in Chinese children.

AIM: To explore the clinical and genetic spectrum of hereditary spastic paraplegia (HSP) in Chinese children. METHOD: This retrospective study was conducted between January 2014 and October 2021 in children clinically diagnosed with either pure HSP (pHSP) or complex HSP (cHSP). RESULTS: We investigated 45 children (32 males, 13 females; mean age [SD] at symptom onset 4 years [7 months]). clinically diagnosed with HSP and identified genetic causes in 35 patients. Most patients with autosomal dominant HSP had pHSP (16/18), whereas most patients with autosomal recessive HSP tended to have cHSP (14/16). SPG11 was the most common autosomal recessive subtype, followed by FA2H/SPG35, whereas SPAST/SPG4 was the most frequent cause of autosomal dominant HSP. Two patients with CPT1C mutations presented with a complex phenotype. Meanwhile, 10 patients were found to have likely pathogenic variants/variants of uncertain clinical significance in six genes related to HSP. INTERPRETATION: SPG11 and SPG4 were the most frequent subtypes in Chinese children with autosomal recessive HSP and autosomal dominant HSP. However, the prevalence of SPG4 was much lower than that in adults, which might be explained by the late onset of the disease. On the other hand, FA2H/SPG35 was common in our cohort, while it contributed to only a small proportion of adult cases, which might be explained by its rapid progression and early death in some patients. We also expanded the genetic and clinical spectra of SPG73.

Juvenile Generalized Myasthenia Gravis With AChR and MuSK Antibody Double Positivity: A Case Report With a Review of the Literature.

Myasthenia gravis is an autoimmune disease mediated by B cells and is associated with acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK) antibodies in the postsynaptic membrane at the neuromuscular junction. The presence of both antibodies in the serum of patients with myasthenia gravis has been rarely reported. Case description: A 9-year-old girl was admitted to our hospital with the chief complaints of reduced facial expression for 3 months and unclear speech and choking from drinking water for 2 months. The diagnosis of generalized myasthenia gravis was made based on clinical manifestations, repetitive electrical nerve stimulation, neostigmine tests, specific antibody tests and other auxiliary examinations. We found the rare coexistence of two key antibodies (anti-AChR and anti-MuSK antibodies) in the patient's serum. The patient experienced myasthenic crisis and received respiratory support even though she was taking prednisone therapy. Due to the poor response to treatment with pyridostigmine bromide, glucocorticoids and IVIG, we administered rituximab therapy, and she responded well and achieved clinical remission. This suggests that clinicians should pay more attention to atypical cases and antibody detection. Rituximab should be considered when conventional treatment fails.

A novel homozygous SLC39A14 variant in an infant with hypermanganesemia and a review of the literature.

Background: Manganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification. Methods: A male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism-dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature. Results: The motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement. Conclusion: We identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.

Genetic analysis and prenatal diagnosis of 76 Chinese families with X-linked adrenoleukodystrophy.

BACKGROUND: Variants in the ATP binding cassette protein subfamily D member 1 (ABCD1) gene are known to cause X-linked adrenoleukodystrophy (X-ALD). This study focused on the characteristics of ABCD1 variants in Chinese X-ALD families and elucidated the value of genetic approaches for X-ALD. METHODS: 68 male probands diagnosed as X-ALD were screened for ABCD1 variants by the Sanger sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) combined with long-range PCR. Prenatal diagnosis was performed in 20 foetuses of 17 probands' mothers. Descriptive statistics were used to summarise the gene variants and prenatal diagnosis characteristics and outcomes. RESULTS: This study allowed the identification of 61 variants occurring in 68 families, including 58 single nucleotide variants or small deletion/insertion variants and 3 large deletions. Three probands with no variants detected by next-generation sequencing were found to have variants by PCR-sequencing. Prenatal diagnosis found that 10 of the 20 foetuses had no variants in ABCD1. CONCLUSION: PCR primers that do not amplify the pseudogenes must be used for PCR-sequencing. MLPA combined with long-range PCR can detect large deletions and insertions, which are usually undetectable by PCR-sequencing. Prenatal diagnosis could help to prevent the birth of infants with X-ALD.

Mitochondrial DNA Copy Number in Rett Syndrome Caused by Methyl-CpG-Binding Protein-2 Variants.

OBJECTIVE: To determine changes in mitochondrial DNA (mtDNA) copy number in peripheral blood in Rett syndrome caused by methyl-CpG-binding protein-2 (MECP2) variants and explore the mechanism of mitochondrial dysfunction in Rett syndrome. STUDY DESIGN: Female patients who were diagnosed with Rett syndrome and had an MECP2 variant (n = 142) were recruited in this study, along with the same number of age- and sex-matched healthy controls. MtDNA copy number was quantified by real-time quantitative polymerase chain reaction with TaqMan probes. The differences in mtDNA copy number between the Rett syndrome group and the control group were analyzed using the independent-samples t test. Linear regression, biserial correlation analysis, and one-way ANOVA were applied for the correlations between mtDNA copy number and age, clinical severity, variant types, functional domains, and hot-spot variants. RESULTS: MtDNA copy number was found to be significantly increased in the patients with Rett syndrome with MECP2 gene variants compared with the control subjects. Age, clinical severity, variant types, functional domains, and hot-spot variants were not related to mtDNA copy number in patients with Rett syndrome. CONCLUSIONS: MtDNA copy number is increased significantly in patients with Rett syndrome, suggesting that changes in mitochondrial function in Rett syndrome trigger a compensatory increase in mtDNA copy number and providing new possibilities for treating Rett syndrome, such as mitochondria-targeted therapies.

Report of the Largest Chinese Cohort With SLC19A3 Gene Defect and Literature Review.

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.

Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.

The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare neurotransmitter metabolic disorder caused by DDC gene mutations, which leads to the metabolic disturbance of dopamine and serotonin. Most of the reported cases came from Taiwan China, but patients from mainland China were seldomly reported. The current study was the largest AADCD patient cohort from mainland China. Twenty-three patients with clinical features of AADCD and DDC gene variants were recruited. A total of 16 DDC variants were identified in this study, of which four variants (c.2T>C, c.277A>G, c.1021+1G>A, c.565G>T) were never reported previously. The intronic variant c.714+4A>T was the most common one, with an allele frequency of 45.7%. And patients carried this intronic variant presented with severe clinical manifestations, all of whom were bedridden. In this study, the average onset age was 3.61 ± 1.28 months and the average age of diagnosis was 12.91 ± 5.62 months. Early onset hypotonia, oculogyric crises, and autonomic symptoms such as excessive sweating, nasal congestion and profuse nasal, and oropharyngeal secretions, were common in our patients. Eighteen patients (78.3%) got various degree of improvement after using pyridoxine monotherapy or different combination of pyridoxine, dopamine agonists, and monoamine oxidase (MAO) inhibitors.

MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort.

The dysfunction of methyl-CpG-binding protein 2 (MeCP2) is associated with several neurological disorders, of which Rett syndrome (RTT) is the most prominent. This study focused on a Chinese patient cohort with MECP2 mutations, and analyzed the characteristics of these mutations and their clinical manifestations. In total, 666 patients were identified with 126 different MECP2 mutations, including 22 novel mutations. Over 80% of patients carried an MECP2 mutation on exon 4. Nonsense and missense mutations were the most commonly reported types. Missense mutations were mainly located on methyl-CpG-binding domain (MBD), and nonsense mutations predominantly occurred on transcription repression domain (TRD) and inter domain. The predilection site of large deletion was exon 3 and/or exon 4. Patients with p.R133C, p.R294*, p.R306C, and C-terminal domain (CTD) deletions were less severely affected. Significant differences were found in ambulation ability, hand function, and language among different mutation groups. Three female patients with MECP2 mutations (1 with p.R306P and 2 with p.R309W) only presented with intellectual disability/developmental delay (ID/DD), and no obvious RTT symptoms were reported. Eight male individuals with MECP2 mutations were also identified in this study, including 2 diagnosed with typical RTT, 3 with atypical RTT and 3 with ID/DD.

Analyzing clinical and genetic characteristics of a cohort with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS).

OBJECTIVE: To summarize and extend the phenotypic characterization of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome, and to discuss genotype-phenotype correlations. METHODS: Collecting clinical information of 17 patients with pathogenic variants in PIGN, PIGA, and PIGT. Genetic studies were performed on all patients. RESULTS: There were 7 patients with 15 PIGN mutations (one patient carrying 3 mutations), 8 patients with 8 PIGA mutations, and 2 patients with 5 PIGT mutations (one patient carrying 3 mutations). All patients had epilepsy and developmental delay, with 71% of them showed hypotonia. And among these patients' various seizure types, the focal seizure was the most common one. Eighty-two percent patients showed a significant relationship between seizures and fever. Serum ALP was elevated in one patient with PIGN mutations and in two patients with PIGA mutations. Brain MRI showed enlarged subarachnoid space in 56% of patients. Some other different characteristics had also been found in our patients: First, atypical absence seizures presented in three patients with PIGN mutations; Second, diffuse slow waves mixed with focal or multifocal discharges of interictal EEG in 88% cases with PIGA-deficient; Third, phenotypes of seven out of eight patients with PIGA mutations were difficult to be classified as severe or less severe group; Last, mild neurological symptoms and developmental status rather than severe conditions occurred in one patient with PIGT mutations. CONCLUSION: With epilepsy, developmental delay, and/or hypotonia as common features, the knowledge of MCAHS in terms of phenotype and genotype has been expanded. In cases with PIGN-deficient, we expanded the types of atypical absence seizures, and described one patient with elevated serum ALP. Focal seizures with diffuse slow waves mixed with focal or multifocal discharges on EEG rather than infantile spasms with hypsarrhythmia, which as previously reported were often seen in our patients with PIGA mutations. The classifications of phenotypes caused by PIGA mutations should be more continuous than discrete. The mild phenotype of one patient with PIGT mutations expanded the clinical presentation of MCAHS3.

Clinical and Genetic Heterogeneity in a Cohort of Chinese Children With Dopa-Responsive Dystonia.

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.

Rett syndrome-causing mutations compromise MeCP2-mediated liquid-liquid phase separation of chromatin.

Rett syndrome (RTT), a severe postnatal neurodevelopmental disorder, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a chromatin organizer regulating gene expression. RTT-causing mutations have been shown to affect this function. However, the mechanism by which MeCP2 organizes chromatin is unclear. In this study, we found that MeCP2 can induce compaction and liquid-liquid phase separation of nucleosomal arrays in vitro, and DNA methylation further enhances formation of chromatin condensates by MeCP2. Interestingly, RTT-causing mutations compromise MeCP2-mediated chromatin phase separation, while benign variants have little effect on this process. Moreover, MeCP2 competes with linker histone H1 to form mutually exclusive chromatin condensates in vitro and distinct heterochromatin foci in vivo. RTT-causing mutations reduce or even abolish the ability of MeCP2 to compete with histone H1 and to form chromatin condensates. Together, our results identify a novel mechanism by which phase separation underlies MeCP2-mediated heterochromatin formation and reveal the potential link between this process and the pathology of RTT.

A splice site mutation c.1251G>A of ISPD gene is a common cause of congenital muscular dystrophy in Chinese patients.

The predicted synonymous mutation c.1251G>A of ISPD (NM_001101426.3) is a hot spot causing exon 9 skipping in five patients.