Sudden death in children aged 12 months to 4 years is rare. Awareness of causes from inborn errors of metabolism (IEM) can aid in rapidly identifying life-threatening biochemical derangements for immediate treatment. LPIN1 deficiency (OMIM 268200) and inorganic pyrophosphatase 2 (PPA2) deficiency (OMIM 617222) (OMIM617223) are recently described IEM 1, 2 that can result in unexpected death from sudden cardiac arrest. LPIN1 deficiency, from biallelic pathogenic variants in the LPIN1 gene (OMIM 605518), causes severe rhabdomyolysis with refractory hyperkalaemia. PPA2 deficiency, from biallelic pathogenic variants in the PPA2 gene (OMIM 609988), causes sudden cardiac arrhythmia. Both are largely nonresponsive to resuscitation by emergency services. Decompensation is triggered by seemingly innocuous illness and children tend to have no significant medical history prior to catastrophic presentation. Recognition of patterns of acute presentation can raise clinical suspicion of these disorders, helping to ensure that appropriate investigations and subspecialist consultation occur to optimise intervention, provide diagnostic certainty and facilitate genetic counselling for families. We reviewed the records of the Queensland Lifespan Metabolic Medicine Service (QLMMS) to identify children who experienced sudden cardiac arrest with subsequent death without prior known diagnosis of IEM, aged between 12 months and 4 years of age during 2010–2025. We aimed to describe patterns of presentation including clinical signs and laboratory findings to improve diagnosis recognition. This included three cases with LPIN1 deficiency (Table 1) and two cases (who were siblings) with PPA2 deficiency (Table 2). LPIN1 c. 2513 + 1G > A p. Asp804ValfsX6—pathogenic LPIN1 c. 2295863₂410-27del p. Glu766Ser838del—pathogenic LPIN1 deletion (exon 18) —pathogenic LPIN1 c. 921del (p. Gln308Argfs*36) —pathogenic PPA2 c. 191A > G p. (His64Arg) —variant of uncertain significance (pat) PPA2 c. 683C > T p. (Pro228Leu) —pathogenic (mat) PPA2 c. 191A > G p. (His64Arg) —variant of uncertain significance (pat) PPA2 c. 683C > T p. (Pro228Leu) —pathogenic (mat) This male child died at age 4 years. He experienced 24 h of reduced oral intake prior to presentation, waking with a painful knee followed by elbow and tongue pain. He rapidly deteriorated on arrival to the emergency department and cardiac arrest ensued (arrest dysrhythmia not recorded) secondary to severe hyperkalaemia of 9. 1 mmol/L (3. 2–4. 5 mmol/L). Resuscitation efforts (details unavailable) were unsuccessful. Elevated creatinine kinase (CK) level was identified at 10 100 U/L (31–152 U/L). His medical history included three prior episodes of mild joint pain and dark urine. During one of these episodes, abnormal liver function tests demonstrated a raised aspartate transferase to alanine transaminase ratio, indicating muscle origin. This normalised on repeat testing and was not further investigated. Postmortem single gene testing identified biallelic pathogenic variants in LPIN1, confirming LPIN1 deficiency. After diagnosis, the significance of earlier events was appreciated. This female child died at age 2 years. She had overnight vomiting and woke with significant lethargy. She was described as appearing ‘flat’ on arrival to the emergency department. Resuscitation was immediately commenced. Hyperkalaemia was identified at 6 mmol/L (3. 6–5. 2 mmol/L) and management with inhaled salbutamol and intravenous calcium gluconate was attempted. She rapidly deteriorated into asystolic cardiac arrest and was unable to be revived. Her CK level was 56 800 U/L (31–152 U/L). Her background history included a precalcaneal fibrolipomatous hamartoma. A postmortem rhabdomyolysis gene panel was uninformative. Postmortem copy number variant analysis was not performed for technical reasons. Exome sequencing (ES) subsequently identified homozygous pathogenic deletions in the LPIN1 gene. This female child with no prior medical history died at age 3 years. She presented with 72 h of vomiting and diarrhoea with a provisional diagnosis of viral gastroenteritis. She deteriorated rapidly in the emergency department with severe hyperkalaemia at 8. 5 mmol/L (3. 6–5. 2 mmol/L) and sudden cardiac arrest (arrest dysrhythmia not recorded). Intravenous insulin and calcium gluconate were administered. She was unable to be revived. After dark urine was observed during resuscitation efforts, postmortem analysis revealed a urine myoglobin of 167 000 U/L (< 10 U/L). Rhabdomyolysis gene panel identified compound heterozygous pathogenic variants in the LPIN1 gene. This female child died at age 23 months. She had symptoms of viral gastroenteritis with vomiting and diarrhoea for 72 h. Nasogastric rehydration was commenced before deteriorating rapidly in the emergency department with cardiac arrest (arrest dysrhythmia not recorded). She was resuscitated onto venoarterial extracorporeal membrane oxygenation (VA-ECMO). She sustained a cerebral infarct and demonstrated poor cardiac left ventricular function. Life-sustaining support was withdrawn after discussion with family. Previous medical history was significant, having sustained a hypoxic brain injury and cerebral infarct at age 13 months in the context of a cardiac arrest secondary to presumed (unproven) viral myocarditis. In retrospect, this event was probably caused by her IEM. Case four's sister presented at age 21 months with 6 days of vomiting and diarrhoea. She collapsed suddenly at home with rapid loss of consciousness. Cardiopulmonary resuscitation was initiated by family but she died before arrival to hospital. Trio ES was performed. Compound heterozygous variants in the PPA2 gene were identified including a maternally inherited pathogenic variant and paternally inherited variant of uncertain significance (VUS). These were also identified in her deceased sister's DNA and VUS classification was upgraded with segregation of affected individuals. In our state-based case series, we identified five children aged between 12 months and 4 years who experienced sudden cardiac arrest leading to death without previously diagnosed IEM over the period 2010–2024. This included three cases with LPIN1 deficiency, average age of death being 3 years and two cases with PPA2 deficiency, with the average age at death being 22 months. Most did not have medical co-morbidities and presented with a rapidly progressive deterioration in the setting of viral-like illness triggering the metabolic decompensation. In retrospect, where medical history was present, there were features suspicious of these conditions (myoglobinuria, cardiac arrhythmia). LPIN1 deficiency causes severe rhabdomyolysis and refractory hyperkalaemia with an extreme mortality of up to 30% 3. The LPIN1 gene encodes lipin-1, a protein present in skeletal muscle and adipose tissue, responsible for phosphatidic acid phosphatase activity 4. It also appears to play a regulatory role in gene expression. Phosphatidic acid phosphatase is involved in glycerolipid biosynthesis with the enzyme dephosphorylating phosphatidic acid in diacylglycerol formation. While the mechanism behind decompensation in LPIN1 deficiency is not fully understood, environmental and genetic components appear to contribute with lipid metabolism, inflammatory dysregulation and energy depletion involved 5. Death from LPIN1 deficiency in the setting of acute rhabdomyolysis is most common under the age of 6 years 3 with older children appearing less likely to suddenly deteriorate. Complications include renal failure and ventricular arrhythmias 6. The cases in our series, apart from a lack of detail of the cardiac arrest dysrhythmia, were typical of this description with death resulting from cardiac arrhythmia with refractory hyperkalaemia. Patients are largely reported to be asymptomatic between episodes 6, as evident in our case series, although one case had a notable history for previous episodes of likely rhabdomyolysis. Rhabdomyolysis is usually triggered by infection 4, as in all patients in our series, but has also been reported without infection 7. Previous reports, and anecdotal experience, observe that peak CK rise is commonly reached within the first 3 days of illness 5 and that the lifetime peak does not always correlate with terminal presentation. It is also recognised that interpreting biochemistry in the setting of acute resuscitation is challenging with poor peripheral perfusion elevating levels of lactate, potassium and CK. Diagnosis is confirmed through genetic testing. Recommended management options include a high calorie diet to prevent catabolism 3, hyperhydration with illness 8 and restriction of dietary fat 5. Administration of corticosteroids 8 has been reported, including oral and intravenous, with suspected decompensation 5. During illness, frequent blood gas monitoring (e. g. , 30 min) is recommended for managing rising hyperkalaemia early. Haemofiltration is likely to be necessary, and cardiac monitoring is recommended for early arrhythmia detection 7. In our cases, as diagnosis had not been prior made, there was no opportunity to instigate acute intervention before terminal hyperkalaemic arrest occurred. The PPA2 gene encodes the PPA2 protein which converts pyrophosphate into inorganic phosphate through hydrolysation. Inorganic phosphate is necessary for adenosine triphosphate (ATP) oxidative phosphorylation. Deficiency leads to mitochondrial dysfunction in critical cardiac tissues causing energy failure with cardiac arrhythmia and arrest 9. Sudden cardiac death in PPA2 deficiency has been reported with mild illnesses and after consumption of alcohol and other triggers 9. Our case series depicted the death of two siblings aged under 2 years with gastroenteritis presentations. In noting the first sibling's previous diagnosis of viral myocarditis, PPA2 deficiency is a critical consideration for presentation with sudden cardiac arrythmia. Management has included implantable cardiac defibrillators in some living cases and avoidance of triggers such as alcohol and vinegar 9. Other management considerations include supplementation with B vitamins and coenzyme Q10 to support mitochondrial function 9. LPIN1 deficiency and PPA2 deficiency are IEM that can cause sudden death in the 12 month to 4 year age group from rapid metabolic decompensation leading to cardiac arrest. Metabolic medicine consultation should be considered for children in this age group presenting with severe rhabdomyolysis, refractory hyperkalaemia or sudden cardiac arrhythmia and/or arrest. This will allow appropriate biospecimen collection including potassium, CK, urine myoglobin and DNA for molecular testing. Diagnosis of an IEM can lead to potentially life-saving intervention for children and siblings, facilitate diagnostic certainty and provide options for future family planning with appropriate genetic counselling in this unfortunate scenario. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. The authors have nothing to report. Local human research ethics committee protocols were followed. The Children's Health Queensland Hospital and Health Service Human Research Ethics Committee endorsed this case series. Written informed consent was obtained from caregivers. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Manoy et al. (Wed,) studied this question.