Liver cirrhosis is a progressive disease with high morbidity and mortality requiring effective management strategies to improve patient outcomes. Various therapies including albumin infusion, volume expanders (VEs), and vasoactive agents are used to manage patients with cirrhosis. Despite numerous clinical trials, a comprehensive meta-analysis comparing the effectiveness of albumin infusion against alternative treatments is limited. This study provides the current and comprehensive synthesis of evidence, offering key insights for optimizing therapeutic strategies in patients with liver cirrhosis. To systematically update available data on therapies of liver cirrhosis, we performed a meta-analysis to evaluate and compare the clinical efficacy of albumin infusion vs other VEs and vasoactive agents in patients with liver cirrhosis. A literature search from the PubMed and Embase databases (inception till June 2024) focused on hyponatremia (primary outcome) and various outcomes such as gastrointestinal bleeding, hepatic encephalopathy, severe infection, post-paracentesis-induced circulatory dysfunction (PICD), ascites reappearance, spontaneous bacterial peritonitis, hepatorenal syndrome, renal impairment, hospital stay, mortality, and safety was performed. The primary analysis pooled studies that compared albumin infusion with control. In the subgroup analysis, comparisons were made within the stratified treatment categories included in the control group. Of the 2957 studies retrieved, 31 studies (27 randomized controlled trials and 4 observational studies) comprising 6255 patients were included. Albumin use was significant in reducing odds of hyponatremia [odds ratio (OR) = 0.67; 95% confidence interval (95%CI) = 0.53-0.85] and PICD (OR = 0.38; 95%CI = 0.20-0.71), whereas the reduction in severe infection (OR = 0.55; 95%CI = 0.28-1.07) did not reach statistical significance. In the subgroup analysis, albumin demonstrated a favorable improvement in lowering the incidence of hyponatremia vs inactive/standard medical therapy (OR = 0.54; 95%CI = 0.27-1.09). For PICD, albumin use was significant compared with other VEs (OR = 0.31; 95%CI = 0.11-0.85) but not with vasoconstrictors (OR = 0.63; 95%CI = 0.21-1.91). In the overall subgroup analysis, a significant reduction was observed in hyponatremia (OR = 0.67; 95%CI = 0.53-0.85) and PICD (OR = 0.38; 95%CI = 0.20-0.71). Human albumin has been shown to significantly reduce the incidence of hyponatremia and PICD in patients with liver cirrhosis, whereas its effect on severe infection remains suggestive but not statistically significant.

The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. The proband is an 11-year-old Iranian-Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10-20th days of life, when refractory epileptic gaze and unilateral tonic-clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian-Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.

Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation. We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation. Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.