Discussion
Our study examined the clinical drivers of hospitalisation in adult patients with mitochondrial diseases in Australia. We investigated the association between the type of presenting symptoms or complications of mitochondrial diseases with rate and length of hospitalisation, which contribute to an understanding of healthcare resource utilisation for mitochondrial diseases in an inpatient setting.
The total number of hospital bed days and the number of admissions per patient with mitochondrial disease between 2013 and 2022 showed a broad range (figure 1). This reflects the clinical heterogeneity and spectrum of disease severity in mitochondrial disorders.2 3 Our study showed an increase in hospital bed days by an average of 6.11 for every additional admission, consistent with previous findings that people with CCs have a higher rate of admission than those without CCs.10
Of the study participants in our cohort, 52% required one or more admissions over the 10 years. As shown in figure 2, the highest proportion of admissions was observed within the group with nDNA variants (mtDNA SNVs=46%; nDNA variants=67%; nil pathogenic variant identified=52%). In our study, the participants with nDNA variants constituted the smallest group but the rate of hospital admissions was comparatively higher. Shepherd et al showed in their study that a decrease in ATP synthesis in fibroblasts from patients with nDNA-related mitochondrial disease was more marked than in fibroblasts from patients with mtDNA-related mitochondrial disease.16 This underlies the notion that nDNA disorders can cause a more severe biochemical defect and may explain why patients within this subgroup of mitochondrial diseases typically present earlier and/or have a more rapid and severe disease course.
Neurological symptoms were the most common presenting feature in the 144 admissions recorded over the 10-year analysis period. The neurological presentations in our study population included exacerbation or progression of myopathy, stroke-like episodes, intractable migraines, seizures and encephalopathy (table 2). Consistently, in a study by Grier et al, the most frequent patient-reported symptoms were neurological, including weakness, fatigue, walking difficulty, ptosis and incoordination.17 They also reported that in 55% of cases, a diagnosis of mitochondrial disease was made by neurologists. Our results, consistent with prior research, underscore the prominent role of neurological manifestations in the clinical profile of patients with mitochondrial diseases, including those undergoing hospital admission.
Here, the length of hospitalisation was strongly associated with neurological and gastroenterological presentations and symptoms categorised as ‘other’. Using multivariate linear regression modelling, the highest average increase in the number of hospital bed days was demonstrated by neurological presentations, followed by gastroenterological and ‘other’ presentations (9.90, 7.94 and 5.11 days, respectively). Patients with certain neurological presentations, such as stroke-like episodes and status epilepticus, and gastroenterological presentations, like intestinal pseudo-obstruction (table 2), can be quite unwell with greater risk of acute deterioration leading to longer and more complex hospitalisation.
Stroke-like episodes are most commonly reported in association with the m.3243A>G variant, followed by recessive POLG variants.18 Recovery from stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is typically complete early in the disease course, but following the first episode, the neurological status continues to deteriorate, resulting in disability and premature death.19 L-arginine infusion, along with aggressive seizure management and treatment of concomitant complications, is recommended, often requiring close monitoring in the ICU.20 However, the semiology of epileptic seizures in mitochondrial diseases is variable, with drug-resistant epilepsy and a higher occurrence of status epilepticus apparent in MELAS.21 22 In our cohort, two patients with the pathogenic m.3243A>G variant presented with recurrent seizures and status epilepticus requiring repeated ICU-based care.
Comparatively, cardiac and gastroenterological complaints led to approximately similar numbers of admissions, as shown in figure 3. 28 (15%) admissions were due to cardiac presentations, including 10 for cardiomyopathy and 7 for conduction abnormalities. Wahbi et al reported major adverse cardiac events in 10% of their study cohort with both mtDNA and nDNA variants.23 These included sudden death, heart failure, third-degree atrioventricular block and sinus node dysfunction. The main cardiac complications reported in adult patients with mitochondrial diseases are hypertrophic cardiomyopathy complicated by congestive cardiac failure and cardiac conduction abnormalities, with the highest prevalence described in patients with m.3243A>G variants and large-scale mtDNA deletions, respectively.23–25 Our study findings are consistent with the literature, with cardiac presentations contributing to hospitalisation being most frequent in patients with mtDNA SNVs and deletions (20%), compared with the other two groups (nDNA variants=15%, nil pathogenic variant identified=9%).
Refractory constipation and intestinal pseudo-obstruction were the most frequent gastroenterological causes for hospitalisation in our study population. Gastrointestinal dysmotility in mitochondrial diseases leads to symptoms such as abdominal pain and distension, dysphagia, constipation and intestinal pseudo-obstruction.26 27 Ng et al demonstrated that stroke-like episodes, cardiomyopathy, low body mass index or high mtDNA heteroplasmy in patients with the m.3243A>G variant are strong predictors for the development of severe intestinal pseudo-obstruction.28
Of the participants in this study with mtDNA variants, 18% had endocrinological presentations related to management or complications of mitochondrial diabetes. Mitochondrial diabetes is most commonly observed in patients with pathogenic m.3243A>G variants. The onset of diabetes in mitochondrial disease can be insidious and is usually diagnosed by the late 30s or early 40s.29 30 Up to 8% of mitochondrial diabetes may present acutely with diabetic ketoacidosis, but the majority of patients do not require insulin at onset.31 32 In our cohort, 2 of the 11 endocrinological presentations were due to diabetic ketoacidosis. Mitochondrial diabetes has been reported in patients with mtDNA deletions and pathogenic nDNA variants in genes such as POLG.29 33 In our study population, two participants with nDNA variants and seven participants with no identified pathogenic variant on WGS had diabetes, but none of these participants were hospitalised with primary endocrinological presentations over the 10-year period, as shown in figure 3.
Symptoms categorised as ‘other’ led to 38% and 32% of admissions, respectively, in participants with nDNA variants and those with no genetic diagnosis. Among the participants with nDNA variants, one patient with YARS2 variants had a total of 16 admissions, 12 of which were due to haematological issues, explaining the higher admission frequency attributed to ‘other’ symptoms in this group. Pathological YARS2 variants are associated with the MLASA syndrome. Patients develop early transfusion dependency, with progressive shortening of intervals between transfusions. Multisystem involvement is common and death in the adult cohort has been reported in late teens and 20s.34 35 Our patient died during the study period at the age of 37 years.
In the ‘other’ category of symptoms, 13 hospital admissions were also due to renal presentations. 12 of these admissions were in a single participant with no pathogenic variant identified on WGS. As per the medical records, other non-mitochondrial causes of kidney dysfunction had been excluded in this patient. Nephropathies associated with mitochondrial diseases reported in the literature include tubulointerstitial nephropathies and glomerular diseases with focal segmental glomerulosclerosis.36 37
Of note, six presentations in the ‘other’ symptoms were due to recurrent falls. Skeletal myopathy, exercise intolerance, generalised polyneuropathy, cerebellar dysfunction, vestibulopathy and visual impairment, alone or in combination, can contribute to falls in adults with mitochondrial diseases.38–40 The participants who presented with falls in our cohort were 70 years or older at the time of recruitment. The falls were attributed to progressively worsening mitochondrial disease in the medical records. However, age-related decline in mobility and function due to sarcopenia and other geriatric comorbidities may have contributed, even if not explicitly mentioned in the medical records. Nevertheless, falls risk is potentially greater in patients with mitochondrial disease, with associated risk of hospitalisation, reduced mobility, decline in QoL and increased need for carer support.
Our study shows that all types of presenting complaints were associated with an increase in the number of admissions on presentation to ED, irrespective of the age at diagnosis or gender. For participants with more than one admission, the reasons for hospitalisation were variable, as shown in figure 4, consistent with protean clinical manifestations and wide variation in disease spectrum.