Multi-dimensional Insight into the Coexistence of Pathogenic Genes for ADAR1 and TSC2: Careful Consideration is Essential for Interpretation of ADAR1 Variants.

Aicardi-Goutières syndrome 6 (AGS6) is a serious auto-immunization-associated acute neurologic decompensation. AGS6 manifests as acute onset of severe generalized dystonia of limbs and developmental regression secondary to febrile illness mostly. Dyschromatosis symmetrica hereditaria (DSH), as pigmentary genodermatosis, is a characterized mixture of hyperpigmented and hypopigmented macules. Both AGS6 and DSH are associated with ADAR1 pathogenic variants. To explore the etiology of a proband with developmental regression with mixture of hyperpigmentation and hypopigmentation macules, we used the trio-WES. Later, to clarify the association between variants and diseases, we used guidelines of ACMG for variants interpretation and quantitative Real-time PCR for verifying elevated expression levels of interferon-stimulated genes, separately. By WES, we detected 2 variants in ADAR1 and a variant in TSC2, respectively, were NM_001111.5:c.1096_1097del, NM_001111.5:c.518A>G, and NM_000548.5:c.1864C>T. Variants interpretation suggested that these 3 variants were both pathogenic. Expression levels of interferon-stimulated genes also elevated as expected. We verified the co-occurrence of pathogenic variants of ADAR1 and TSC2 in AGS6 patients with DSH. Our works contributed to the elucidation of ADAR1 pathogenic mechanism, given the specific pathogenic mechanism of ADAR1, and it is necessary to consider with caution when variants were found in ADAR1.

[Analysis of DPYS gene variants in a child with dihydropyrimidase deficiency].

OBJECTIVE: To explore the genetic basis for a child with dihydropyrimidase (DHP) deficiency. METHODS: High-throughput sequencing was carried out for the child. Suspected variants were verified by using Sanger sequencing. RESULTS: The proband was found to carry compound heterozygous variants of the DPYS gene, namely c.1468C>T (a missense variant) and c.1339-1363del (a frameshifting variant). CONCLUSION: The compound heterozygous variants of the DPYS gene probably underlie the DHP in this child. Above result has enabled genetic counseling and prenatal diagnosis for his parents.

Clinical and Magnetic Resonance Imaging Characteristics of Pediatric Acute Disseminating Encephalomyelitis With and Without Antibodies to Myelin Oligodendrocyte Glycoprotein.

Background: Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated disorders (MOGADs) have been considered as a new inflammatory disease entity of the central nervous system (CNS) and have heterogeneous clinical and imaging presentations. Acute disseminated encephalomyelitis (ADEM) is one of the most important phenotypes. Our research is aimed to compare the clinical and magnetic resonance imaging (MRI) characteristics of ADEM with or without MOG-IgG in pediatric-acquired demyelinating syndromes (ADSs). Methods and Results: We retrospectively reviewed the clinical characteristics, MRI features, and outcomes of pediatric patients with ADSs from March 2017 to February 2021 in our center. MOG-IgG was analyzed by transfected cell-based assay (CBA). Among 46 children with ADEM, 21 children (11 girls and 10 boys) were positive for MOG-IgG. Headache, fever, vomiting, vertigo, ataxia, and decreased muscle strength were common in all enrolled children. No significant difference existed in demographic characteristics, symptoms at an initial episode, or laboratory cerebrospinal fluid (CSF) findings between children with MOG-IgG and children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed widespread, poorly demarcated bilateral lesions, especially in cortical and subcortical white matter, and spinal MRI often showed lesions spanning more than three segments. The significant difference in MRI features between the two groups was the presence of lesions in the thalamus and cortical area (p < 0.05). Most children in both groups showed clinical improvement 1 week after immunotherapy and achieved recovery during their hospital stay. Three children with MOG-IgG and four children without MOG-IgG had one or more relapsing courses with median interattack intervals of 4 (range: 1-7) months and 10 (range: 1-24) months, respectively. New clinical symptoms and lesions on cerebral and spinal MRI were found during relapsing courses in two groups. No recurrences were recorded 6-51 months after each patient's last episode. Conclusions: There was no significant difference in clinical characteristics between ADEM children with MOG-IgG and ADEM children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed large, bilateral lesions and spinal MRI often showed lesions spanning more than three segments. Children achieved a favorable outcome regardless of MOG-IgG serostatus.

Prader-Willi syndrome patient with atypical phenotypes caused by mosaic deletion in the paternal 15q11-q13 region: a case report.

BACKGROUND: Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by the loss of paternally expressed genes in the human chromosome region 15q11.2-q13. It is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity. Motor milestones and language development are delayed and most patients have intellectual disability. CASE PRESENTATION: Here we describe a rare PWS case caused by mosaic imprinting defect in the region 15q11.2-q13 of paternal origin. The proband was a male child with a clinical presentation of global developmental delay and hypotonia with specific facial features. Karyotype of the child was noted as mosaic: 45XY,der(15)?t(15;21),-21[26]/46,XY[24]. Whole-exome sequencing (WES) identified a deletion of 22.7 Mb in size at chr15q11.2q21.1 region and a deletion of 2.1 Mb in size at chr21q22.3 region. The Methylation-specific multiplex ligation-dependent probe amplification(MS-MLPA) of the 15q11.2-q13 region showed that the loading ratio of methylated alleles was 70% and that of unmethylated alleles was 30%(50% normal), which confirmed that the loss of mosaic imprinted defects in the paternal allele led to the diagnosis of PWS. CONCLUSIONS: We propose that complete clinical criteria for PWS should not be considered sensitive in diagnosing partial atypical PWS due to mosaic imprinting defects. In contrast, clinical suspicion based on less restrictive criteria followed by multiple techniques is a more powerful approach.

Case Report: Recurrent Hemiplegic Migraine Attacks Accompanied by Intractable Hypomagnesemia Due to a de novo TRPM7 Gene Variant.

Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed chanzyme comprised of a divalent cation channel permeable to calcium and magnesium and a cytosolic serine-threonine α-kinase domain. TRPM7 has a crucial role in magnesium ion homeostasis and anoxic neuronal death, which was identified as a potential non-glutamate target for hypoxic-ischemic neuronal injury. TRPM7 is implicated in ischemic stroke and hypomagnesemia in many studies, but it has not been associated with disease in the OMIM database. No clinical cases between TRPM7 gene variants and hypomagnesemia have been reported, so far. One patient with recurrent hemiplegic migraine attacks accompanied by intractable hypomagnesemia was followed up at Tianjin Children's Hospital from 2018 to 2021. We systematically summarized and analyzed the clinical manifestations, imaging features, and serum magnesium changes of the patient. Genetic analysis was performed by whole-exome sequencing and Sanger sequencing to infer the etiology of hemiplegic migraine attacks and hypomagnesemia in this patient. Gene sequencing revealed a novel heterozygous variant of the TRPM7 gene (c.2998A>G, p. Met1000Val), which has not been reported previously; this is also a de novo variant that is not inherited from his parents. We described a novel variant p. Met1000Val (c.2998A>G) located in the transmembrane region of TRPM7 protein, which is possibly crucial for the normal function of the ion channel. Our study expands the variation spectrum of the TRPM7 gene, highlights the importance of molecular genetic evaluation in patients with TRPM7 gene deficiency, and demonstrates the causal relationship between TRPM7 gene variants and disease manifestations.

Case Report: A Case of ß-Ureidopropionase Deficiency Complicated With MELAS Syndrome Caused by UPB1 Variant and Mitochondrial Gene Variant.

Background: ß-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare inherited disorder caused by genetic defects in mitochondrial DNA. Case Presentation: One 8-year-old boy presented with dizziness, vomiting, and convulsions. The gas chromatography-mass spectrometry results suggested ß-ureidopropionase deficiency. The whole-exome sequencing results revealed homozygous missense variant c.977G>A (p.R326Q) in UPB1. However, the patient presented with persistent hyperlactacidemia and metabolic acidosis, which did not correspond to the classic features of ß-ureidopropionase deficiency. Combined with the manifestations of developmental delay, poor academic performance, and poor sports stamina, whole-mitochondrial-genome sequencing was performed. The results exhibited the variant m.3243A>G of MT-TL1 gene. The level of heterogeneity was 65% in the patient and 17.8% in his mother. Eventually, the final diagnosis of ß-ureidopropionase deficiency combined with MELAS syndrome was made. Conclusion: The report about ß-ureidopropionase deficiency caused by a nuclear gene variant and MELAS syndrome caused by a mitochondrial gene variant coexisting in the same patient enriches the clinical study of these two rare diseases.

Analysis of the genotype-phenotype correlation in isovaleric acidaemia: A case report of long-term follow-up of a chinese patient and literature review.

Background: Isovaleric acidaemia (IVA), characterized by an acute metabolic crisis and psychomotor delay, is a rare inherited metabolic disease caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD). Methods: We report the case of a Chinese patient with IVA who was admitted to Tianjin Children's Hospital and followed up for 8 years. Genetic analysis of the patient and his parents was conducted using the whole-exome sequencing and Sanger sequencing. We searched for similar reported cases in the PubMed and Wanfang databases using the term "isovaleric acidaemia," reviewed the related literature to obtain a summary of the clinical and genetic characteristics, and analyzed the genotype-phenotype correlations. Results: The patient presented with encephalopathic symptoms, such as vomiting, lethargy, and somnolence. We identified compound heterozygous variants of the IVD gene, including the unreported variant c.224A>G (p.Asn75Ser) and the reported variant c.1195G>C (p.Asp399His). The child was prescribed a low-protein diet supplemented with L-carnitine. During the 8-year follow-up, no metabolic disorder or encephalopathic symptoms recurred. At present, the child is 11 years of age and has normal mental and motor performance. Another 154 cases identified in 25 relevant references were combined with this case, resulting in a sample of 155 patients, including 52 asymptomatic patients, 64 with neonatal onset, and 39 with the chronic intermittent disease with onset from ages of 1 month to 10 years (median age, 2 years). Among articles that reported sex, the male-to-female ratio was 1:1.06. The cardinal symptoms included vomiting, lethargy, "sweaty foot" odor, poor feeding, developmental delay, and epilepsy. The proportion of variants in regions 123-159 and 356-403 of the IVD protein was greater in symptomatic patients than in asymptomatic patients. Conversely, in asymptomatic patients, the proportion of variants in the 282-318 region was greater than in symptomatic patients. Conclusion: This case report describes an unreported variant c.224A>G (p.Asn75Ser) of the IVD gene, and summarizes previously reported cases. Furthermore, the correlation between the genotype and clinical phenotype of IVA is analyzed to improve the understanding of this disease.

DNM1L-Related Mitochondrial Fission Defects Presenting as Encephalopathy: A Case Report and Literature Review.

Background: Mitochondrial dynamics, including mitochondrial fission and fusion, transport and distribution, biogenesis and degradation, are critical to neuronal function. The dynamin-1 like (DNM1L) gene encodes dynamin-related protein 1 (DRP1/DLP1), which is an evolutionarily conserved member of the dynamin family and is responsible for mitochondrial division. DNM1L variants can lead to mitochondrial fission dysfunction and neurological disorders. Methods: We report a case of DNM1L-related mitochondrial disease admitted to Tianjin Children's Hospital. We searched for similar reported cases in the PubMed database using the terms "DNM1L" and "mitochondrial," reviewed recent literature to summarize the clinical and genetic characteristics, and analyzed genotype-phenotype correlations. Results: The patient presented with psychomotor retardation, motor disturbance (muscle weakness with paroxysmal hypermyotonia), and a de novo variant (c.116G>A, g.22229G>A, p.S39N) in the GTPase domain of DNM1L (reference sequence NM_012062), which has not previously been reported in the literature. This case was combined with an additional 35 cases identified in 20 relevant references in order to analyze a total of 36 patients. The male-to-female ratio was 1:1.06, and the median age of onset was 6 months (range, neonatal period to 9 years). The cardinal symptoms included psychomotor retardation in 77.8% (28/36), limb paralysis in 66.7% (18/27), dystonia in 82.8% (24/29), and epilepsy in 59.4% (19/32). The clinical manifestations of variants in the GTPase domain of DRP1 were milder than those identified in the middle domain. Conclusion: This case report describes a new variant of the DNM1L gene, and summarizes previously reported cases. Furthermore, the clinical phenotype and the genotype of DNM1L gene-associated mitochondrial disease was analyzed to improve the understanding of this disease.