Monitoring Clinical Progression with Mitochondrial Disease Biomarkers

Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies.P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). GlaxoSmithKline provides support for H.E.S. as part of their Early Talent Review Board (ETRB) Clinical Fellow program

Mitochondrial DNA mutations in individuals occupationally exposed to ionizing radiation

Mutations in a 443-bp amplicon of the hypervariable region HVR1 of the D-loop of mitochondrial DNA (mtDNA) were quantified in DNA extracted from peripheral blood samples of 10 retired radiation workers who had accumulated external radiation doses of .0.9 Sv over the course of their working life and were compared to the levels of mutations in 10 control individuals matched for age and smoking status. The mutation rate in the 10 exposed individuals was 9.92 3 1025 mutations/ nucleotide, and for the controls it was 8.65 3 1025 mutations/ nucleotide, with a procedural error rate of 2.65 3 1025 mutations/ nucleotide. No increase in mtDNA mutations due to radiation exposure was detectable (P 5 0.640). In contrast, chromosomal translocation frequencies, a validated radiobiological technique for retrospective dosimetric purposes, were significantly elevated in the exposed individuals. This suggests that mutations identified through sequencing of mtDNA in peripheral blood lymphocytes do not represent a promising genetic marker of DNA damage after low-dose or low-doserate exposures to ionizing radiation. There was an increase in singleton mutations above that attributable to procedural error in both exposed and control groups that is likely to reflect age-related somatic mutation

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.This study was funded by Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), Medical Research Council (UK) (G0601943), and Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). Funding bodies had no influence on study design or data interpretation.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/NXG.000000000000011

Chronic pain is common in mitochondrial disease

In the absence of cure, the main objectives in the management of patients with mitochondrial disease are symptom control and prevention of complications. While pain is a complicating symptom in many chronic diseases and is known to have a clear impact on quality of life, its prevalence and severity in people with genetically confirmed mitochondrial disease is unknown. We conducted a survey of pain symptoms in patients with genetically confirmed mitochondrial disease from two UK mitochondrial disease specialist centres. The majority (66.7%) of patients had chronic pain which was primarily of neuropathic nature. Presence of pain did not significantly impact overall quality of life. The m.3243A>G MTTL1 mutation was associated with higher overall pain severity and increased the likelihood of neuropathic pain compared to other causative nuclear and mitochondrial gene mutations. Although previously not considered a core symptom in people with mitochondrial disease, pain is a common clinical manifestation, frequently of neuropathic nature, and influenced by genotype. Given the impact on quality of life and treatment options available, pain-related symptoms should be carefully characterised and actively managed in this patient population

Childhood-onset Leber hereditary optic neuropathy

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor

Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia.

Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation