The phenotypic spectrum of polymerase gamma (POLG) disease from birth to late adulthood

Variants in POLG, the gene encoding the catalytic subunit of DNA-polymerase gamma (polγ), the enzyme that replicates and repairs the mitochondrial genome, are among the most common causes of inherited mitochondrial disease. The clinical phenotypes of POLG disease are overlapping and extremely heterogeneous, making early clinical recognition challenging. The aim of my PhD project was to study the clinical spectrum and natural course of POLG disease in a large cohort of patients in order to provide a reliable clinical classification that was useful in both paediatric and adult populations, and to identify robust diagnostic and prognostic biomarkers which could facilitate early diagnosis and/or predict the prognosis. Multinational, retrospective studies of individuals recruited from 13 centres in seven European countries (Norway, Sweden, Denmark, Finland, Netherlands, Spain and the United Kingdom) were performed. Clinical, laboratory, neurophysiological, neuro-imaging, and genetic data were systematically collected using a standardized electronic, web-based clinical record form. The results of this project provide clear evidence that the clinical features of POLG disease are a continuum, i.e. the same spectrum of symptoms/features is found in all age groups. This allowed us to classify POLG disease more simply than the earlier attempts which only generated a plethora of syndromes with overlapping features. The project provides also an extensive phenotypic characterisation of patients with early onset disease and demonstrated the breadth of clinical manifestations and natural history of the disease in this age group. Highlighting the existence of POLG disease without seizures will improve diagnosis of those with early onset disease. The study cohort included individuals with disease onset from birth to late adulthood; this enabled us to study the clinical spectrum of the disease through all the ages. We could identify clear phenotypic and prognostic differences by grouping the patients simply using age of onset to: early onset, juvenile and adult, and late onset disease. We believe that our simplified classification will facilitate early clinical recognition, guide the investigation and predict the prognosis of the disease. Further, the results of this project showed that POLG disease is associated with blood brain barrier dysfunction and that the presence of raised cerebrospinal fluid protein/albumin can be used as a biomarker both for early diagnosis and to predict those who will be at risk to develop epilepsy. Moreover, the project revealed, for the first time, that anaemia is a feature of POLG disease, and the presence of anaemia is associated with significantly worse survival and can be used as a predictor for poor prognosis

Mitokondriesykdom forårsaket av m.3243A>G-mutasjonen

Mitokondriesykdom er blant de vanligste metabolske sykdommene og er relevant for mange medisinske spesialiteter. Denne kliniske oversiktsartikkelen omtaler en av de vanligste mutasjonene bak mitokondriesykdom: m.3243A>G. Mutasjonen kan føre til diabetes mellitus, hørselsreduksjon, hjerte- og muskelaffeksjon, encefalopati og epilepsi, mage- og tarmproblemer og synsforstyrrelser, ofte i kombinasjoner. Økt kunnskap om mitokondriesykdommen forårsaket av m.3243A>G-mutasjonen vil kunne forbedre både diagnostisering og behandling av pasienter som kan lide av alvorlig og livstruende sykdom.publishedVersio

Mental health and health related quality of life in mitochondrial POLG disease

We aimed to assess the impact of POLG disease on mental health and quality of life in 15 patients using the Symptom Checklist-90-R (SCL-90-R)and Short-Form 36 HealthSurvey (RAND-36). Wefound increased scores in all nine subscales of SCL-90-R, particularly phobic anxiety, depression and somatization. Further, patients reported considerably lower scores in all RAND-36 domains. This study revealed a global decline in mental health and poor quality of life in patients with POLG disease and highlights the need for increased awareness andsystematic assessment in order to improve their quality of life and mental health

Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy takenPeer reviewe

Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population : a multicentre study

Background Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset. Methods A retrospective multicentre study was performed in patients with clinical onsetPeer reviewe

Renal Phenotype in Mitochondrial Diseases : A Multicenter Study

Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease. Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona. Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis. Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.Peer reviewe

The impact of gender, puberty, and pregnancy in patients with POLG disease

Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.Peer reviewe

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases

Background Variants inPOLGare one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods A multinational, retrospective study using data from 155 patients withPOLGvariants recruited from seven European countries. Results We describe the spectrum of clinical features associated withPOLGvariants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset-onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.Peer reviewe

Elevated cerebrospinal fluid protein in POLG-related epilepsy : Diagnostic and prognostic implications

Objective: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. Methods: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries-Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF bather. Results: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). Significance: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.Peer reviewe

The phenotypic spectrum of polymerase gamma (POLG) disease from birth to late adulthood

Variants in POLG, the gene encoding the catalytic subunit of DNA-polymerase gamma (polγ), the enzyme that replicates and repairs the mitochondrial genome, are among the most common causes of inherited mitochondrial disease. The clinical phenotypes of POLG disease are overlapping and extremely heterogeneous, making early clinical recognition challenging. The aim of my PhD project was to study the clinical spectrum and natural course of POLG disease in a large cohort of patients in order to provide a reliable clinical classification that was useful in both paediatric and adult populations, and to identify robust diagnostic and prognostic biomarkers which could facilitate early diagnosis and/or predict the prognosis. Multinational, retrospective studies of individuals recruited from 13 centres in seven European countries (Norway, Sweden, Denmark, Finland, Netherlands, Spain and the United Kingdom) were performed. Clinical, laboratory, neurophysiological, neuro-imaging, and genetic data were systematically collected using a standardized electronic, web-based clinical record form. The results of this project provide clear evidence that the clinical features of POLG disease are a continuum, i.e. the same spectrum of symptoms/features is found in all age groups. This allowed us to classify POLG disease more simply than the earlier attempts which only generated a plethora of syndromes with overlapping features. The project provides also an extensive phenotypic characterisation of patients with early onset disease and demonstrated the breadth of clinical manifestations and natural history of the disease in this age group. Highlighting the existence of POLG disease without seizures will improve diagnosis of those with early onset disease. The study cohort included individuals with disease onset from birth to late adulthood; this enabled us to study the clinical spectrum of the disease through all the ages. We could identify clear phenotypic and prognostic differences by grouping the patients simply using age of onset to: early onset, juvenile and adult, and late onset disease. We believe that our simplified classification will facilitate early clinical recognition, guide the investigation and predict the prognosis of the disease. Further, the results of this project showed that POLG disease is associated with blood brain barrier dysfunction and that the presence of raised cerebrospinal fluid protein/albumin can be used as a biomarker both for early diagnosis and to predict those who will be at risk to develop epilepsy. Moreover, the project revealed, for the first time, that anaemia is a feature of POLG disease, and the presence of anaemia is associated with significantly worse survival and can be used as a predictor for poor prognosis