Mitochondrial Disorders

Monogenic, nuclear (Mendelian): the majority of currently recognised mitochondrial-disease genes are nuclear-encoded; nuclear-gene defects account for a substantial share of paediatric-onset mitochondrial disease in particular. There is no single reliable population-wide percentage split between nuclear and mtDNA causes, estimates vary by cohort and age at presentation.^[1]

Acquired: rare (e.g. some drug-induced mtDNA depletion)^[1]

Monogenic, mtDNA (non-Mendelian): mtDNA point variants (maternally transmitted, with heteroplasmy) and single large mtDNA deletions (typically sporadic/de novo, not usually maternally inherited) are the two main mtDNA mechanisms and behave differently for genetic counselling purposes (a distinct mechanism, not polygenic)^[1]

Inheritance patterns: mitochondrial disease is genetically heterogeneous, with contributions from mtDNA point variants (maternal inheritance, all children of an affected mother are at risk; fathers do not transmit mtDNA point variants to offspring), single large mtDNA deletions (usually sporadic/de novo, low recurrence risk to siblings), and nuclear-gene variants (autosomal recessive most common, but autosomal dominant and X-linked patterns also occur). There is no single reliable population-wide percentage that applies across all mitochondrial disease.^[1]

Familial proportion: maternal transmission applies specifically to mtDNA point variants, virtually all of these are maternally inherited and de novo mtDNA point variants are rare; but not every mtDNA disorder is maternally inherited, single large mtDNA deletions are typically sporadic. For nuclear gene variants, standard Mendelian inheritance applies (AR: 25% sibling risk; AD: 50% offspring risk; XL: sex-dependent). Genetic counselling is complex and depends on which of these mechanisms is confirmed.^[1]

Heteroplasmy: Variable proportion of mutant vs wild-type mtDNA in different tissues → unpredictable severity and tissue distribution

Genetic testing complex: May require muscle biopsy, whole mtDNA sequencing, nuclear gene panels (WES/WGS)

Mitochondrial disease affects approximately 1 in 5,000 individuals, one of the most common groups of inherited metabolic disorders.^[1]

Cardiac involvement (cardiomyopathy, conduction disease, or arrhythmia) develops in approximately 40–60% of patients with mitochondrial disease, varying substantially by syndrome and mutation type.^[1]

An HCM phenotype is the most common cardiac manifestation, occurring in over 50% of those with mitochondrial cardiomyopathy.

Cardiac manifestations:

• Hypertrophic cardiomyopathy phenotype (most common)
• Dilated cardiomyopathy
• Conduction defects (especially CPEO syndromes)
• Pre-excitation (WPW)

Multi-system involvement typical:

• Neurological: Seizures, stroke-like episodes, myopathy, neuropathy
• Ophthalmological: Ophthalmoplegia, retinopathy
• Endocrine: Diabetes, growth hormone deficiency
• Renal, GI, hearing loss

Syndromes with prominent cardiac involvement: MELAS, Kearns-Sayre, CPEO

Confirming the diagnosis: molecular confirmation should be sought wherever possible, so clinical suspicion (cardiomyopathy plus multisystem disease, elevated lactate, ragged-red/COX-negative fibres) is ideally confirmed by genetic testing before the label is applied. A proportion of cases remain genetically unresolved despite thorough testing, and in those patients a diagnosis may still rest on clinical, biochemical and histological evidence reviewed in a specialist mitochondrial service. The m.3243A>G variant in MT-TL1 (the MELAS mutation) is the single commonest point mutation underlying cardiac disease.^[2] Because heteroplasmy varies between tissues, a blood test can be falsely negative, when suspicion is high, test urinary epithelial cells or skeletal muscle rather than relying on blood alone, and proceed to nuclear gene panels (WES/WGS) if mtDNA testing is negative.^[1]

Lactate: Elevated at rest or post-exercise, screening test for mitochondrial disease^[1]

Echo/CMR: Cardiomyopathy (HCM or DCM pattern); annual cardiac screening once mitochondrial disease confirmed^[1]

ECG: Conduction abnormalities, pre-excitation (WPW), AV block (especially Kearns-Sayre syndrome)

Muscle biopsy: Ragged red fibres, COX-negative fibres, histological gold standard^[1]

Genetic testing: Whole mtDNA sequencing; nuclear gene panels (WES/WGS if mtDNA-negative)

No curative treatment exists: management is supportive, syndrome-tailored, and directed at the highest-risk complication (conduction disease and heart failure).

1. General measures:

• Coenzyme Q10 and L-carnitine are commonly used but evidence is limited
• Manage diabetes, seizures, and other multisystem complications
• Genetic counselling and family cascade testing, see the Genetic Testing page
• Avoid: valproate and aminoglycosides (can worsen mitochondrial function); use metformin with caution (lactic-acidosis risk)

2. Medical therapy:

• Heart failure / cardiomyopathy: standard guideline-directed medical therapy for the HCM or DCM phenotype present.
• Arrhythmia: treat AF/ventricular arrhythmia per standard pathways; ventricular ectopy and conduction block are independent markers of major adverse cardiac events and warrant closer surveillance.^[2]

3. Device therapy, low threshold for prophylactic pacing:

• In neuromuscular disease with conduction disorders (including Kearns-Sayre syndrome), permanent pacing is recommended for second-degree AV block, third-degree AV block, or an HV interval ≥70 ms regardless of symptoms, because progression to complete heart block is unpredictable and a recognised cause of sudden death
• Consider added defibrillator capability where survival >1 year is expected^[3]

4. Advanced heart failure and/or transplant referral:

• Standard advanced-heart-failure pathways apply if cardiomyopathy progresses to refractory heart failure, individualised alongside the broader multisystem prognosis

• Cardiomyopathy (hypertrophic or dilated): leading to heart failure^[1]
• Conduction block: especially in Kearns-Sayre, which can progress rapidly to complete heart block and sudden death, so there is a low threshold for prophylactic pacing
• Arrhythmia: including pre-excitation in some syndromes
• Multisystem disease: stroke-like episodes (MELAS), diabetes, sensorineural deafness, skeletal myopathy and lactic acidosis

Prognosis highly variable depending on specific mutation and organ involvement; cardiac disease is a major determinant of outcome in some syndromes (e.g. Kearns-Sayre).

Independent predictors of major adverse cardiac events (260-adult cohort, mean follow-up ~7 years): intraventricular conduction block, diabetes, frequent ventricular ectopy, and left-ventricular hypertrophy. The presence of any of these should prompt closer cardiac surveillance and a lower threshold for device therapy.^[2]

Based on mitochondrial cardiomyopathy expert reviews^[1].

Advanced / complicated = conduction disease (e.g. Kearns-Sayre), LVEF decline, significant arrhythmia, or symptomatic heart failure.

	Uncomplicated / Stable	Advanced / Complicated
Frequency	Annual	Every 6 months
Clinical review	Symptoms, multisystem assessment	As above + device check
ECG	Annual 12-lead (conduction disease, pre-excitation)	Each visit
Echocardiography	Annual	6-monthly
Holter / ambulatory	Annual (heart block, esp. Kearns-Sayre)	6-monthly
Pacing	Low threshold for pacemaker in conduction disease	As indicated

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Genetic counselling complex - maternal vs Mendelian inheritance^[1]
• Suspect if cardiomyopathy + multi-system disease (neuromuscular, diabetes, etc.)^[1]
• Conduction disease can progress rapidly (Kearns-Sayre) - monitor closely^[1]
• Annual cardiac screening if diagnosed with mitochondrial disorder