Aim: To review genetic biomarkers of agranulocytosis and efficacy with clozapine as a screening tool for the safe and effective use of clozapine.

Methods: A PubMed search was performed using PRISMA guidelines for English articles. Separate searches were conducted using “clozapine” AND “agranulocytosis,” and “clozapine” AND (“response” OR efficacy “outcome”) AND “schizophrenia”. Eligible studies reported positive findings with genetic polymorphism(s) associated with clozapine-induced agranulocytosis (CIA) and clozapine’s efficacy. Case reports/series, abstracts, systematic reviews, and meta-analyses were excluded. Negative and genome-wide studies were not formally reviewed but included in the discussion.

Results: Twelve out of 572 CIA studies and 32 out of 126 efficacy studies met the eligibility criteria for this review. Most reviewed studies were conducted in small samples of Jewish, Caucasian, and Asian populations using a candidate gene approach.

Conclusion: Future research needs to address the limitations of the findings from the reviewed studies to enable a combined genetic screening for CIA and clozapine response to optimize the safe and effective use of clozapine without unnecessarily exposing potential clozapine nonresponders to CIA or neutropenia.

Kabuki syndrome (KS) is a genetic disorder characterized by typical facial dimorphisms, various degrees of cognitive disability, and congenital anomalies involving the heart, kidneys, gastrointestinal system, and bones. It is accompanied by hypotonia, failure to thrive, obesity, and immunodeficiency. Association with neoplastic lesions has been recently described. We report a 13-year-old girl with KS, an insulinoma, and a benign phyllodes breast tumor with two hepatic lesions: a neuroendocrine tumor metastasis and a ciliated foregut cyst associated with hepatic fibrosis. She had a pilomatrixoma and a junctional melanocytic nevus with cytological atypia. Genetic analysis revealed a heterozygous frameshift variant in the KMT2D gene. Somatic KMT2D variants are in various types of tumors. The role of KMT2D variants in malignancies in KS appears to be related to defective transcription regulation and altered gene expression; however, the mechanism remains unclear. This aims to clarify the relationship between KMT2D gene variants, KS, and susceptibility to neoplastic lesions. For this purpose, a more extensive case series will be needed to accurately describe the patients' neoplastic phenotypes and precise genetic characterization.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive mitochondrial disease characterised by recurrent life-threatening metabolic crises generally presenting in neonates or infancy during catabolic stress triggered by prolonged fasting or intercurrent illness. Acute decompensations with lethargy, vomiting, hypoketotic hypoglycemia and metabolic acidosis may evolve into Reye-like syndrome if untreated, with acute liver failure, hyperammonemic encephalopathy, dilated cardiomyopathy, and death in 20% of cases. Long-term health complications include psychomotor retardation, white matter abnormalities, epilepsy, hepatic steatosis, pancreatitis, cardiomyopathy, and arrythmia. The mitochondrial enzyme catalyses the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, the common final step of ketogenesis and leucine degradation, resulting in diagnostic urinary organic acid pattern (elevated 3-hydroxy-3-methylglutaric, 3-methylgutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids) with the absence of ketonuria, when deficient. Therapeutic interventions include dietary protein or leucine and fat restriction, carnitine supplementation, avoidance of fasting, and use of carbohydrate-based high caloric intake when unwell. We describe the clinical course and diagnostic work-up in two affected siblings, with the proband presenting with severe neonatal onset disease with metabolic acidosis, non-ketotic hypoglycaemia, hyperammonemia and white matter changes on brain MRI. High-risk screening for a younger sibling led to pre-emptive management with good outcomes. Sodium D, L-3-hydroxybutyrate (S-DL-3OHB) was used in both siblings as an adjunct therapy to prevent cerebral dysfunction and cardiomyopathy, with the rationale that decreased ketogenesis in this disorder may impact the major energy source for the brain and heart during starvation. S-DL-3OHB therapy is a well-tolerated and effective therapeutic option for this disorder.