Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review.

Nitrogen permease regulator-like 3 (NPRL3) has been reported to play a role in seizure onset. The principal manifestation of NPRL3-related epilepsy is a range of epilepsy-associated syndromes, such as familial focal epilepsy with variable foci (FFEVF), sleep-related hypermotor epilepsy (SHE), and temporal lobe epilepsy (TLE). The association between phenotype and genotype of NPRL3 mutations remains inadequately described. This study aimed to explore the phenotypic and genotypic spectra of NPRL3-related epilepsy. We reported two novel NPRL3 variants in two unrelated epilepsy cases, including a nonsense (c.1174C > T, p.Gln392*) and a missense variant (c.1322C > T, p.Thr441Met). Following a review of the literature, a total of 116 cases of NPRL3-related epilepsy were assessed, mostly with nonsense and frameshift mutations. Our findings suggest that patients harboring various NPRL3 variants exhibit variable clinical manifestations. In addition, it may be worthwhile to consider the existence of NPRL3 mutations in epilepsy patients with a family history. This study provides useful information for the treatment and prognosis by expanding the phenotypic and genotypic spectrum of NPRL3-related epilepsy. PLAIN LANGUAGE SUMMARY: This study expands the phenotypic and genotypic spectra of NPRL3-related epilepsy by reporting two cases with different novel variants. Following a review of the literature, it was observed that patients harboring various NPRL3 variants exhibited a variability of clinical manifestations. Also, patients carrying nonsense mutations are frequently prone to drug resistance and other severe comorbidities such as developmental delay, but more cases need to be collected to confirm these findings.

Safety and efficacy of gene therapy with onasemnogene abeparvovec in the treatment of spinal muscular atrophy: A systematic review and meta-analysis.

Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease which leads to progressive muscle weakness and atrophy. Our systematic review and meta-analysis aims to explore the efficacy and safety of onasemnogene abeparvovec in SMA patients. We searched PubMed, EMBASE, Web of Science and Cochrane through April 2022. Ten reports enrolling 250 SMA patients were included. CHOP INTEND and motor-milestone significant improvements were detected at both short- and long-term follow-up. Common adverse events included pyrexia, vomiting, thrombocytopenia and elevated aminotransferases. Thrombocytopenia (79.3%, 95%CI: 65.8~90.5) and elevated aminotransferases (71.7%, 95%CI: 62.5~80.1) were more common in SMA patients aged older than 8 months. Despite the paucity of randomized control trial data and low quality of evidence to establish the safety and efficacy of onasemnogene abeparvovec in the treatment of SMA, the data suggest that it is a valuable option for patients with this condition.

HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration.

Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.

Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis.

Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na+/H+ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 in a 14-month-old boy with early-onset seizures. According to The American College of Medical Genetics and Genomics (ACMG)/the Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. The proband presented with several core symptoms of typical epilepsy, including microcephaly, motor delay, distal muscle weakness, micrognathia, occasional unprovoked laughter, swallowing and speech difficulties. Electroencephalography (EEG) showed spikes-slow waves in frontal pole, frontal, anterior temporal and frontal midline point areas. Gesell development schedules (GDS) indicated generalized developmental delay. We also summarized all the reported variants and analyzed the correlation of genotype and phenotype of CS. Our study extends the mutation spectrum of the SLC9A6 gene, and it might imply that the phenotypes of CS are not correlated with SLC9A6 genotypes.

A graphene oxide-aided triple helical aggregation-induced emission biosensor for highly specific detection of charged collagen peptides.

Aggregation-induced emission (AIE) probes have emerged as promising "turn-on" sensing tools for DNA and proteins, and the AIE biosensors conjugated with graphene oxide (GO) have shown improved selectivity. Collagen is an essential structural protein in the human body, and its degraded products are involved in a plethora of severe diseases. Collagen has a high content of charged amino acids, while EOG represents one of the most abundant charged triplets in Type I collagen. We, herein, for the first time report the construction of a GO-aided AIE biosensor for the detection of charged collagen peptides. We have shown that an AIE fluorophore TPE conjugated with a triple helical peptide TPE-PRG possesses strong fluorescence due to the restriction of intramolecular rotation of TPE in the trimer state. The adsorption of the probe TPE-PRG by GO leads to efficient fluorescence quenching, while the addition of target collagen peptide EOG releases the probe peptide from the GO surface and recovers its fluorescence. We have demonstrated that the TPE-PRG/GO complex provides a highly specific "turn-on" sensing platform for the target collagen peptide with a typical charged amino acid-rich sequence. The assay has shown little interference from other biomolecules, and it can also effectively distinguish the target charged collagen peptide from its single amino acid mutant type. The development of robust analytical assays for charged collagen peptides could pronouncedly extend our capability to investigate the pathology of collagen diseases, showing great potential for their molecular diagnosis.

Streptococcal infection and immune response in children with Tourette's syndrome.

BACKGROUND: Streptococcal infection and basal ganglia inflammation are hypothesized to be involved in Tourette's syndrome (TS). There is a need for effective therapies for managing TS. We studied streptococcal infection and immunity in TS following immunomodulator (pidotimod) therapy. METHODS: Blood samples from 58 patients with TS and 128 age-matched healthy controls enabled measurement of antistreptolysin O (ASO), T cells, natural killer (NK) cells, interleukin-6 (IL-6) and interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Forty-four patients with abnormal T cell numbers were divided into two groups and treated with pidotimod granules (pidotimod group, n = 20) or pidotimod plus dopaminergic receptor antagonists (combination group, n = 24). Yale Global Tic Severity Scale (YGTSS) scores and immunologic indices were assessed after treatment. RESULTS: An ASO >1:200 was found in 22.4% of children with TS, 7.5% of controls, and 38.9% of children with both TS and attention deficit hyperactivity disorder (ADHD) compared to 15.0% of children with TS alone (P < 0.05). Children with TS showed decreased CD3(+) and CD4(+) T cells, CD4(+)/CD8(+) ratio, IL-6 and IL-8, increased NKC and TNF-α (P < 0.05) as compared to controls. ASO-positive children with TS had lower CD4(+) T cells as compared to ASO-negative children with TS, and lower IL-6 and IL-8 levels as compared to controls (P < 0.05). After 8 weeks of pidotimod treatment, IL-8 was increased compared to either tiapride hydrochloride or haloperidol and pidotimod (P < 0.05). CONCLUSIONS: Streptococcal infection in TS patients is associated with immune and cytokine dysfunction, which can be potentially managed with immunomodulator therapy.

[Diagnostic value of serum Cystatin C in renal function impairments in children with viral encephalitis].

OBJECTIVE: To study the value of serum Cystatin C (Cyst C) in the evaluation of glomerular filtration function in children with viral encephalitis. METHODS: Serum levels of Cyst C, urea nitrogen (BUN) and creatinine (Cr) were measured in 92 children with viral encephalitis and in 50 healthy children as a control group. According to glomerular filtration rate (GFR), the encephalitis group was subdivided into normal renal function, renal insufficiency in the compensatory or decompensatory stage, and renal failure /end-stage groups. RESULTS: Serum levels of Cyst C, BUN and Cr in the encephalitis group increased and GFR decreased significantly compared with those in the control group (P<0.01). With the decline of renal function, GFR decreased and serum levels of Cyst C, BUN and Cr increased gradually. Serum levels of Cyst C and GFR were significantly different among the encephaitis subgroups (P<0.01). For serum levels of BUN and Cr, there were significant differences among the subgroups except between the normal renal function and the compensatory renal insufficiency groups. Serum Cyst C level was positively correlated with serum BUN and Cr levels, and negatively correlated with GFR. CONCLUSIONS: The children with viral encephalitis have different degrees of renal impairments. Cyst C appears to be superior to BUN and Cr as a marker for the evaluation of glomerular filtration function. Measurement of serum Cyst C levels is very valuable in renal function monitoring in children with viral encephalitis.