Background: Homozygous or compound heterozygous loss-of-function variants in GNPTAB cause mucolipidosis type II/III, a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. ML III is milder, with an older age of onset and a less severe phenotype. We report two siblings with arrhythmogenic cardiomyopathy and ventricular arrhythmias with compound heterozygous variants in GNPTAB. Methods and Results: The family presented due to the sudden cardiac death of a male in his early 30’s with arrhythmogenic cardiomyopathy identified at autopsy. His sister was found to have cardiomyopathy and experienced a ventricular tachycardia storm. Both siblings had history of skeletal dysplasia first investigated during adolescence. Clinical genetic testing did not identify a cause for the cardiomyopathy, and they were enrolled in the Elusive Hearts study. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5( GNPTAB ): c.3503_3504del, and a heterozygous missense variant, NM_024312.5( GNPTAB ): c.1400A>G, p.(Asp467Gly), occurring in trans . Enzymatic testing showed elevated plasma lysosomal enzyme activity, confirming the clinical diagnosis. Cardiomyopathy has rarely been reported in patients with ML III. Conclusion: We expand the cardiac phenotypic features of ML III and suggest that GNPTAB could be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest.

BACKGROUND:Deaths due to poisoning involving novel benzodiazepines (NBZDs) are increasing. We aimed to determine: 1. The characteristics, toxicology and major autopsy findings of known cases of NBZD-related poisoning in Australia, 2000-2025; and 2. Changes in characteristics of known cases from 2020 onwards compared to earlier known cases. METHODS:Retrospective study of fatal NBDZ-related poisoning in Australia retrieved from the National Coronial Information System. RESULTS:258 cases were identified, the first in 2013 (2013-2019: 33, 2020-2025: 225). The mean age was 31.9 years and 217 were male, which did not change. 2020s cases were more likely to have histories of injecting drug use (52.0v 21.2 %, OR 4.0) and mental health issues (55.1v 30.3 %, OR 2.8). Fifteen NBZDs were detected, nine first detected in the 2020s. The most frequent were etizolam (48.9 %) and bromazolam (38.0 %). Cases in the later period were more likely to have multiple NBZDs detected (39.6v 12.1 %, OR 4.7). The most common other drug classes were opioids (74.8 %) and registered hypnosedatives (62.4 %). There were no differences between cases in the later and earlier periods in the presence of depressants (94.7v 93.9 %), or psychostimulants (52.0v 39.4 %). Acute bronchopneumonia was less common in the later period (18.2v 40.0 %, OR 1.5). CONCLUSIONS:The 2020s saw a large increase in poisoning deaths related to NBZDs. As testing varied across time and jurisdiction and new NBZDs are constantly appearing the true extent of NBZD-related poisoning deaths is likely to be higher than those identified.

ABSTRACT Selenoproteins are a specialised group of proteins that incorporate selenium, an essential micronutrient, in the form of selenocysteine. The SECIS binding protein 2 (SBP2), encoded by SECISBP2 , is a crucial component of the selenocysteine incorporation machinery. SECISBP2 deficiency compromises selenoprotein synthesis, and its knockout causes embryonic lethality in mice. Selenium is critical to cardiac function, and nutritional deficiency causes Keshan disease, a progressive cardiomyopathy. Biallelic variants in SECISBP2 cause pleiotropic phenotypes including abnormal thyroid hormone metabolism, neurodevelopmental disorders and aortic aneurysms. No reported phenotypes to date include cardiomyopathy. We report a consanguineous South Asian family with a history of perinatal deaths due to progressive cardiomyopathy and intractable arrhythmias with a rare homozygous loss-of-function splice site variant in SECISBP2 . The SECISBP2 c.1303-2A>G variant was homozygous in four affected offspring and heterozygous in the parents. One child without cardiac disease did not carry this variant. RNA sequencing confirmed that almost all transcripts would undergo nonsense-mediated decay. Further, we observed a pronounced decrease in GPX1 and SELENOH selenoprotein mRNA, as well as a large decrease in SELENOH, GPX1, GPX3 and GPX4 cardiac protein abundance in homozygotes, a molecular hallmark of SECISBP2 deficiency. Notably, we observed a >12-fold decrease in cardiac GPX4, a key selenoprotein that suppresses lipid peroxidation and ferroptosis, suggesting a possible ferroptosis-mediated mechanism for heart failure. Our analysis suggests that c.1303-2A>G is likely the most damaging homozygous variant discovered to date. For the first time, we show that SECISBP2 is essential for human life, with almost complete loss-of-function causing a lethal perinatal cardiomyopathy characterised by pronounced cardiac selenoprotein loss.

Background:New psychoactive stimulants and hallucinogens (NPSH) poisonings have generated considerable public health concern in recent years. We aimed to determine: 1. The characteristics, toxicology and major autopsy findings of known cases of NBZD-related poisoning in Australia, 2000-2025; and 2. Changes in characteristics of known cases from 2020 onwards compared to earlier known cases. Methods:Retrospective study of fatal NPSH-related poisonings in Australia retrieved from the National Coronial Information System. Results:70 cases were identified, the first occurring in 2007. In 22.9% the decedent appeared unaware they were consuming a NPHS, and in 32.9% the NPSH had been injected. The most commonly observed signs and symptoms of acute NPSH poisoning were intense agitation (22.9%), sudden collapse (22.9%) and hyperthermia (20.0%). There were 31 NPSH identified, of which 13 were first detected in the 2020 s. The most commonly detected NPSH were cathinones (48.6%), most frequently α-pyrrolidinovalerophenone and methylenedioxypyrovalerone. Phenethylamines were present in 38.6%, with paramethoxymethamphetamine and a range of the N-benzylphenethylamine series (NBOMe) the most common. Tryptamines were present in 18.6%, and three cases involved piperazines. In 18 cases (25.7%) multiple NPSH were detected in the blood. 2020 s cases were more likely to have tryptamines detected (36.7 v 5.0%), but less likely to have phenethylamines (23.3 v 50.0%). Psychoactive drugs in addition to NPSH were present in 92.9%, most commonly psychostimulants (68.6%) and hypnosedatives (40.0%). Conclusions:A wider range of NPHS have been detected in recent fatal poisonings, with tryptamines becoming more common in the 2020 s, and phenethylamines less common.

INTRODUCTION:Drowning is the third leading cause of unintentional injury death. We aimed to determine the toxicology and circumstances of all adult drowning deaths that occurred in bath/hot tubs in Australia over the period 2015-2024. METHODS:Retrospective study of all adult (≥ 15 years) drowning deaths in baths or hot tubs in Australia (1 January 2015-1 November 2024) retrieved from the National Coronial Information System (n = 195). In all cases the formal finding was based upon police, toxicology and forensic pathology reports. RESULTS:There were 195 adult drownings in baths or hot tubs. The mean age was 54.9 years (range 15-98) and 127 (65.1%) were female. Most fatal (171, 87.7%) incidents occurred in a bath. In 113 (57.9%) cases proximal substance use was noted in the coronial conclusions as contributory. The majority (108, 55.4%) were unintentional, with 73 (37.4%) deemed intentional. A psychotropic drug was detected in the blood of 152/179 (84.9%), most commonly hypnosedatives (77/179, 43.0%) and alcohol (75/179, 41.9%). Amongst alcohol positive cases the mean blood alcohol concentration was 0.176 g/100 mL (range 0.010-0.537). In 33 (16.9%) there appeared to have been a medical episode, such as a seizure or a cardiovascular event, that preceded drowning, and a slip or fall in 17 (8.7%). DISCUSSION AND CONCLUSIONS:Substances were present in the majority of cases. The risk of drowning in such settings in the presence of drugs needs to be widely appreciated. Public campaigns that focus on the potential dangers of substance use in these settings would appear prudent.

Quetiapine is an atypical antipsychotic that has been associated with both intentional and unintentional deaths. We aimed to determine, stratified by intentionality: (1) The characteristics and circumstances of adult deaths attributed solely to quetiapine toxicity in Australia, 2000-2024; (2) The blood toxicology of cases for quetiapine and other drugs; and (3) The major autopsy findings for cardiovascular, lung, kidney, and liver disease. All cases of death aged ≥15 years attributed solely to quetiapine toxicity in Australia, 2000-2024, were retrieved from the National Coronial Information System. We identified 136 adult cases attributed solely to quetiapine toxicity. In 64.7% (n = 88), the fatal poisoning was deemed intentional, unintentional in 19.9% (n = 27), and of undetermined intent in 15.4% (n = 21). The mean age was 42.4 years (range 15-69) and 58.1% (n = 79) were male. A history of mental health problems was documented in 92.6% (n = 126). The median quetiapine concentration was 12.0 mg/L (range 1.2-600.0), with that of intentional cases being twice that of unintentional cases (13.0 vs. 6.3 mg/L). Other psychotropic drugs not considered contributory to death were present in 73.0% (n = 92) of cases, most commonly hypnosedatives (34.1%, n = 43) and antidepressants (33.3%, n = 42). Hearts were examined in 87 cases, of which 31.0% (n = 27) were diagnosed with cardiovascular disease. Given these findings, screening patients prescribed quetiapine for suicide histories and ideation is prudent, as is monitoring cardiovascular disease. For forensic pathologists, the extent and nature of cardiovascular disease appear important for the formulation of death, and suicide should be borne in mind.

Intravascular injection of dissolved medicinal preparations such as crushed tablets is associated with a risk of injecting particulate material into the vasculature. This particulate material will naturally pass to the lungs where it will be largely filtered out in the pulmonary vascular bed, and in turn, it can result in a range of pathological processes in the lungs including pulmonary arterial hypertension, granulomatous lung disease, and pulmonary fibrosis. On rare occasions, a rapid increase in pulmonary vascular resistance can result in sudden death of the injecting drug user.

INTRODUCTION:Recent years have seen marked increases in the non-medical use of ketamine. We aimed to determine: (i) the population mortality rates of self-administered fatal ketamine-related poisoning cases in Australia, 2000-2022; (ii) the characteristics, toxicology and major autopsy findings of cases in Australia, 2000-2025; and (iii) changes in case characteristics across the period 2000-2025. METHODS:Retrospective study of fatal ketamine-related poisoning in Australia retrieved from the National Coronial Information System. RESULTS:118 cases were identified, 100 (84.7%) of which occurred after 2014. There was a significant upward trend in event rates between 2000 and 2022 (IRR = 1.16). The mean age was 36.2 years and 77.1% were male. The majority (72.9%) of poisonings were unintentional, in 19.5% the final route of ketamine administration was by injection, and a history of substance use problems was documented in 50.8%. There were no significant differences in these case characteristics across the study period. In 14 cases, the decedent was documented as being prescribed take-home ketamine at the time of death and had consumed this medication. The median blood ketamine concentration was 0.20 mg/L (range 0.01-25.0), which did not significantly differ across time. Psychoactive drugs other than ketamine were present in all cases, most frequently hypnosedatives (68.6%) and opioids (62.7%), with a significant difference across time observed in the presence of hypnosedatives (OR 1.45). Cardiomegaly was diagnosed in 13.9% and cardiac fibrosis in 11.1%. DISCUSSION AND CONCLUSIONS:There has been a significant increase in self-administered ketamine-related poisoning deaths. Caution should be exercised in prescribing ketamine for self-administration.

OBJECTIVES:To determine: (1) the characteristics, clinical presentation and circumstances of death for deaths related to lithium toxicity in Australia, 2000-2024; (2) the toxicology of cases; and (3) the major autopsy findings. METHODS:A retrospective study of all cases of death aged ⩾15 years associated with lithium toxicity in Australia, 2000-2024, retrieved from the National Coronial Information System. RESULTS:We identified 93 cases, with a mean age of 48.7 years (range, 18-89), 12% being aged under 30 years and 51% being male. A diagnosis of bipolar disorder was documented in 52%, with 28% having a documented psychotic disorder. The circumstances of death were unintentional toxicity (58%), intentional toxicity (23%) and undetermined intent (19%). The median blood lithium concentration was 0.68 mmol/L (range, 0.01-17.3). Concentrations were higher for ante-mortem versus post-mortem samples (2.3 vs 0.5 mmol/L), intentional overdose versus unintentional (2.2 vs 0.5 mmol/L) and cases in which lithium was the sole drug detected versus multiple drugs (2.1 vs 0.6 mmol/L). Other drugs were present in the majority (87%), most commonly antipsychotics (67%) and antidepressants (57%). Cardiomegaly was diagnosed in 22% and nephro/arteriosclerosis in 26%. DISCUSSION:Toxicity remains a rare event compared to exposure to lithium, with intentional cases comprising a fifth of the series. Deaths were not the sole preserve of the middle-aged or elderly.

AIMS:To determine: (1) the circumstances of death and case characteristics of heroin-related toxicity deaths aged ≥ 65 years in Australia, 2000-2025 and (2) the toxicological profile and major autopsy findings. DESIGN:Retrospective study of fatal heroin overdose cases aged ≥65 years, 2000-2025. SETTING:Australia-wide. CASES:59 cases were identified (65-69 years: 37, ≥70 years: 22), 51 (86.4%) male. MEASUREMENTS:Circumstances of death, toxicology, major autopsy findings. FINDINGS:No case occurred in the period 2000-2010, two between 2011 and 2015 and 57 between 2016 and 2025. All had documented histories of both substance use problems and injecting drug use. Cause of death was drug toxicity (n = 36, 61.0%) or combined drug toxicity and disease (n = 23, 39.0%), the majority being unintentional (n = 49, 83.1%). The final route of administration was by injection in 58 cases. Amongst cases in which toxicology was available for inspection (n = 52), the median free morphine concentration was 0.2 mg/l (0.0-3.7 mg/l), and 6-acetylmorphine was present in 34 (65.4%). Psychoactive drugs other than heroin were present in 45 (86.5%) cases. Of autopsied cases, 18 (56.3%) had severe coronary artery disease, 14 (43.8%) cardiomegaly and 11 (34.4%) replacement fibrosis, indicating a past infarct. Five cases (15.6%) were diagnosed with acute bronchopneumonia, and chronic obstructive pulmonary disease was detected in 12 (37.5%). CONCLUSIONS:A new senior demographic of people who use heroin has emerged in Australia and is being reflected in overdose deaths. Systemic disease contributed to a large proportion of deaths between 2000 and 2025, and the toxicology is consistent with shorter survival times compared with younger cases.

In Australia, the therapeutic indication of baclofen (oral tablets) is for the treatment of muscle spasm. Deaths related to baclofen have been reported, as well as misuse, dependence and self-poisoning. This national retrospective study aimed to investigate the number, characteristics, circumstances, and toxicology of baclofenrelated deaths in Australia, 2000-2022. We identified 102 baclofen-related deaths, with a mean age of 45.6 years and 51 % being male. Circumstances of death were: intentional toxicity (54.9 %), unintentional toxicity (30.4 %), unintentional toxicity/disease (9.8 %), and accidental injury (4.9 %). Multiple sclerosis or spinal injury was documented in 15.7 % of cases, substance use problems in 43.1 % and specifically alcohol use problems in 38.2 %. Mental health problems were documented in 73.5 %, a previous self-harm or suicide attempt in 30.4 %, and chronic pain in 37.3 %. The median baclofen blood concentration for all cases was 3.10 mg/L (25th 0.70, 75th 8.10, range 0.04-110.00), unintentional toxicity 1.95 mg/L (25th 0.70, 75th 4.35, range 0.04-24.0), intentional toxicity 6.00 mg/L (25th 1.10, 75th 13.0, range 0.05-110.0). Concomitant substance use was seen in 93.8 %, with antidepressants (69.8 %) and benzodiazepines (64.6 %) most frequently detected. In conclusion, the 'typical' case was middle-aged, most dying due to intentional toxicity, and likely to have a history of mental health and substance use problems. We suggest caution is needed in prescribing baclofen given its potential to be used in intentional and non-intentional overdose.

INTRODUCTION:In recent years gamma hydroxybutyrate (GHB) use appears to have increased. This study aimed to determine: (i) population rates of GHB-related death in Australia, 2001-2021; and (ii) whether there have been changes in the characteristics of GHB-related death in Australia over the period 2001-2023. METHODS:Retrospective study of all Australian cases in which GHB was a mechanism contributory to death retrieved from the National Coronial Information System (n = 217). Joinpoint regression models were used to analyse trends in overall rates. RESULTS:Death rates were stable between 2001 and 2015 ('stable period') (annual percent change [APC] = 3.7) but showed marked acceleration between 2016 and 2021 ('accelerated period') (APC = 44.4). Circumstances of death were: unintentional toxicity (81.6%), intentional toxicity (5.1%), self-harm (6.0%), traumatic injury (7.4%). Compared to the stable period, later cases were slightly older (34.2 vs. 30.7 years, p < 0.05), less likely to be employed (odds ratio [OR] 0.4), but more likely to have substance use problems (OR 3.9), a history of injecting drug use (OR 3.5), mental health problems (OR 3.6), and to have present in their blood at toxicological screening opioids (OR 3.2) and hypnosedatives (OR 3.7). The median blood GHB concentration was 170 mg/L, (range 0-3210), which did not change significantly. There were no differences in major organ pathology, but the proportion with aspiration pneumonia declined (OR 0.4). DISCUSSION AND CONCLUSIONS:GHB-related death rates increased from 2016, accompanied by changes in case characteristics. In recent years GHB use appears to have extended to a population more likely to have substance use problems and use other respiratory depressants.

BACKGROUND AND AIMS:Lysergic acid diethylamide (LSD) and psilocybin are used as recreational drugs, and there is renewed interest in their clinical use. The current study aimed to (1) determine the circumstances of death and case characteristics of LSD- and psilocybin-related death in Australia, 2000-23; and (2) determine the toxicological profile and major autopsy findings of these cases. METHODS:This was a retrospective exploratory study of all cases of LSD- and psilocybin-related death in Australia, 2000-23, retrieved from the National Coronial Information System. RESULTS:A total of 43 cases were identified: 33 LSD and 10 psilocybin. The median ages were 24 years [interquartile range (IQR) = 13, range = 16-53] (LSD) and 26 years (IQR = 18.5, range = 20-58) (psilocybin), and fewer than five cases were female. The most common circumstance of death among both groups was traumatic accident (LSD 36.4%, psilocybin 40.0%). There were 12 cases of self-harm, all of which involved LSD, all by physical means. In a fifth, death was attributed to multiple drug toxicity (LSD 18.2%, psilocybin 20.0%). In one case, death was attributed solely to LSD toxicity, while in a further two cases death was attributed to a cardiovascular event following LSD consumption (one LSD only, one multiple drug toxicity). In four psilocybin cases, the cause of death was undetermined. The most common clinical presentation was severe agitation (LSD 27.3%, psilocybin 20.0%). Median blood concentrations were LSD 0.8 μg/l (IQR = 1.7, range = 0.1-3), psilocin 20 μg/l (IQR = 53.5, range = 6-83). LSD was the only drug present in 25.0% of LSD cases and psilocybin in 20.0% of psilocybin cases. Pre-existing organ pathology was uncommon. CONCLUSIONS:Lysergic acid diethylamide (LSD)- and psilocybin-related death in Australia from 2000 to 2023 was primarily due to traumatic injury, whether through accident or self-harm. Cases of acute toxic reactions that were attributed solely to LSD were rare.

Background: The age of people who use illicit opioids has increased, with a clinical picture of accelerated ageing. The study aimed to determine, stratified by age: 1. The circumstances and characteristics of heroin-related toxicity deaths in Australia, 2020-2022; 2. The toxicological profile and autopsy findings; 3. The proportion of cases in which blood 6-acetyl morphine (6AM) was detected, as a measure of survival time. Methods: Retrospective study of 610 cases of fatal heroin-related drug toxicity in Australia, 2020-2022. Cases were stratified as: <30 years, 30-39 years, 40-49 years, >= 50 years. Results: Compared to the youngest group, those aged >= 50 years were more likely to have a history of chronic pain (12.4 v 3.3 %), to have their death attributed to combined drug toxicity/disease (20.1 v 3.3 %), and to have evidence of a sudden collapse (21.3 v 11.1 %). There were no differences in free morphine concentrations or glucuronide concentrations. Compared to the youngest group, however, the two older groups were significantly more likely to have 6AM present in blood, a proxy measure of a shorter survival time (52.0, 55.2 v 34.5 %). Compared to the youngest group, cases aged >= 50 years were more likely to be diagnosed with cardiomegaly (44.0 v 16.7 %), coronary artery disease (46.0 v 15.0 %), emphysema (35.0 v 5.1 %), hepatic steatosis (15.4 v 3.4 %), hepatic fibrosis (17.6 v 3.4 %), and cirrhosis (19.8 v 0.0 %). Conclusions: Older cases of heroin overdose had more extensive heart, lung, and liver disease, and appeared more likely to have shorter survival times.

INTRODUCTION:Acute alcohol toxicity is a significant component of alcohol-related mortality. The study aimed to: (i) determine the circumstances of death and characteristics of fatal alcohol toxicity cases, 2011-2022; (ii) determine their toxicological profile and major autopsy findings; and (iii) determine trends in population mortality rates. METHODS:Retrospective study of acute alcohol toxicity deaths in Australia, 2011-2022, retrieved from the National Coronial Information System. RESULTS:A total of 891 cases were identified, with a mean age of 49.2 years, 71.0% being male. Alcohol use problems were noted in 71.3%. In 57.5% death was attributed solely to acute alcohol toxicity, and combined acute alcohol toxicity/disease in 42.5%. There was evidence of sudden collapse in 24.9% of cases. The mean BAC was 0.331 g/100 mL (range 0.107-0.936), and spirits were the most commonly reported beverages (35.8%). Cases of combined toxicity/disease had significantly lower BACs than those attributed solely to alcohol toxicity (0.296 vs. 0.358 g/100 mL). Cardiomegaly was diagnosed in 32.5%, and severe coronary artery disease in 22.1%. Aspiration of vomitus was noted in 18.0%, and chronic obstructive pulmonary disease in 19.6%. Severe liver steatosis was present in 33.4% and 13.6% had cirrhosis. There was an average annual percentage increase in deaths of 7.90. DISCUSSION AND CONCLUSIONS:The 'typical' case was a long-standing, heavy spirits drinker. BACs showed enormous variation and no arbitrary concentration may be deemed lethal. Clinically significant disease was associated with death at a lower BAC and people with such disease may be at increased risk of alcohol poisoning.

BACKGROUND:A major alcohol-related harm is structural pathology affecting the brain. The study aimed to: 1. Determine the frequency and nature of neuropathology amongst cases of death due to acute alcohol toxicity; 2. Compare diagnoses of brain atrophy with pathology in other organs; 3. Determine the demographic, clinical and organ pathology correlates of brain atrophy. METHODS:Retrospective study of 500 cases of death attributed to acute alcohol toxicity in Australia, 2011-2022. Data on clinical characteristics, toxicology, neuropathology and other organ pathology were retrieved from police reports, autopsies, toxicology and coronial findings. RESULTS:Mean age was 49.5 years, 69.4 % were male, with alcohol use problems documented in 70.2 %. Brain atrophy was diagnosed in 60 cases (12.0 %), most commonly in the cerebellum (32 cases, 6.4 %). Atrophy at other sites was present in 37 (7.4 %). The presence of brain atrophy was lower than other major pathologies: cardiomegaly (32.6 %, p<.001), nephro/arteriosclerosis (30.2 %, p<.001), and chronic obstructive pulmonary disease (21.8 %, p<.001) but not hepatic cirrhosis (11.9 % p=1.0). Those diagnosed with atrophy were older (53.4v 49.0 years, p<.001), more likely to have documented alcohol problems (85.0v 68.2 %, Odds ratio: OR 2.53) and seizure history (10.0v 3.0 %, OR 2.92), to have cardiomegaly (43.3v 31.0 %, OR 1.90, COPD (48.3v 18.2 %, 3.57) and nephro/arteriosclerosis (50.0 v 27.4 %, OR 2.27). CONCLUSIONS:Despite the majority of cases having a history of alcohol problems, the level of neuropathology amongst cases of death due to acute alcohol toxicity was comparatively low.