Mitochondrial Diseases

Introduction

Mitochondria are the “power plants” found in every cell of the human body except in red blood cells. The number of individual mitochondria can vary from several hundreds to thousands depending on the type of cell. Mitochondria are vital to cell integrity and function including energy production¹. The functional integrity of mitochondria relies on both the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). A nucleus is a part (organelle) within a cell containing DNA (nDNA) which can determine our physical characteristics (e.g. hair colour) and the majority of proteins that make our body work including energy production. However, another set of DNA is present in the mitochondria (mtDNA) that contains crucial information to make proteins and generate energy too.

Mitochondrial diseases (MD) refer to a heterogeneous group of inherited metabolic disorders (IMD) caused by primary dysfunction of the oxidative phosphorylation (OXPHOS), the process by which energy is generated from cells.

Causes and Prevalence

The prevalence of MD is 5-20 cases per 100,000 individuals⁸. This varies across different ethnicities. MD is due to changes (so called variants / mutations) in genes affecting the related functions of mitochondria. The genes can be found in both nuclear DNA (nDNA) and inside the mitochondrial DNA (mtDNA).

Inheritance

• Due to the influence of nDNA and mtDNA, MD can have any pattern of inheritance including autosomal recessive, autosomal dominant, X-linked for nDNA mutations and mitochondrial for mtDNA mutations.
• Rare sporadic cases due to mutations not inherited from a parent (de novo) may occur².
• Mutations in the mtDNA are usually not present in all mtDNA copies, a condition known as heteroplasmy. For common, inheritable mutations, the presence of at least 80-90% of the mutated copies is required for disease manifestation (threshold effect)³.
• Both the heteroplasmy and threshold levels can differ significantly between cells and tissues, often resulting in a plethora of multi-organ syndromes.
• Up till now, more than 400 genes are implicated in MD⁸.

Signs and Symptoms

As mitochondria are present in all cells of the body except the red blood cells, MD can therefore present at any age with involvement of one or more organ systems, both neurological and non-neurological.

Neurological presentations may include:

• Central nervous system: stroke-like episodes, epilepsy, movement disorders, migraine, dementia, developmental delay, psychiatric or mood disorder, developmental regression
• Neuromuscular: ptosis (drooping of eyelids), progressive external ophthalmoplegia (difficulty to move eyeballs), exercise intolerance, weakness due to muscles and / or nerves involvement
• Eye: cataract, optic atrophy etc.
• Ear: sensorineural hearing impairment

Non-neurological presentations may include:

• Cardiopulmonary: respiratory failure, cardiomyopathy, arrhythmia
• Kidney: kidney dysfunction including failure
• Endocrine: cortisol insufficiency, diabetes mellitus, thyroid dysfunction, parathyroid dysfunction, premature ovarian failure, male infertility, short statue
• Gastrointestinal: failure to thrive, gastrointestinal dysmotility, liver failure
• Others: kyphoscoliosis, bone marrow failure

Patients might present with a combination of clinical features which are compatible with a discrete clinical syndrome such as Leigh syndrome, Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) or Pearson syndrome etc.

However, the majority of them do not have a definite mitochondrial syndromal diagnosis.^2,6

Some patients with MD may develop a metabolic crisis i.e. a period of time when the patient may become seriously ill. That might occur during an episode of infection, fever, prolonged fasting with lack of adequate energy intake and operation.

Diagnosis

General

MD cannot be detected by newborn screening programmes for inherited metabolic disorders. The aims for investigating a patient with suspected MD include:

• Looking for potential biomarkers for MD through blood, urine and / or cerebrospinal fluid analyses
• Detecting the extent of involvement of different organ systems
• Establishing a definitive molecular diagnosis through targeted gene sequencing or next generation sequencing involving both nuclear and mitochondrial genomes
• Documenting mitochondrial dysfunction directly through biopsies e.g. skin and muscle if molecular analysis is unrevealing

Special tests / investigations available in HKCH

• The HKCH metabolic team provides assessment, counselling, diagnostic workup, and treatment for children suspected with MD.
• Special diagnostic and biochemical tests including targeted gene sequencing, next generation sequencing of both nDNA and mtDNA, and OXPHOS analyses of muscle samples are available in HKCH.

Management and Follow-up

General

• Once a diagnosis of MD is made, continuous surveillance and management of complications from various organs should be done with respective care, aiming to reduce morbidity and mortality.
• Certain drugs are to be avoided e.g. Propofol. Valproate is contraindicated in patients with POLG mutations.
• Although the vast majority of MD do not have licensed therapies, specific treatment modalities may be possible in a small subset of genetic defects in MD.
• For certain patients, a special diet may be prescribed and it is necessary to follow it regularly without going on long periods of fasting.
• It is important to attend the nearby accident and emergency department (A&E) immediately for timely in-hospital support and monitoring, in case of any medical emergency including a metabolic crisis. A letter or information sheet on the emergency management of MD is a helpful quick reference for presenting to the A&E or other healthcare professionals in case they have not encountered MD before.
• Patients with MD need to see the metabolic medicine team regularly for clinical assessment, blood / urine test monitoring, and update of treatment plans in order to match the body’s needs.

Special management and follow up-available in HKCH

HKCH provides expert paediatric metabolic service to manage patients with MD and its associated medical problems in a holistic manner.

The multi-disciplinary metabolic medicine team comprises of paediatricians, geneticists, biochemical pathologists, nurses, dietitians, pharmacists, physiotherapists, occupational therapists, speech therapists, clinical psychologists, and medical social workers. The management of this potentially multi-systemic disease is further enhanced through collaboration with various paediatric (sub)specialties.

We offer in-patient, day-patient, and out-patient assessment and follow-up for patients, as well as tele-support for regional hospitals, clinics, and families. Carers and patients are educated and empowered for home management, whilst staying in contact with the team for advice and support.

References and Useful Resources

¹Mitochondrial disorders in children: toward development of small-molecule treatment strategies. Koopman WJ, Beyrath J, Fung CW, Koene S, Rodenburg RJ, Willems PH, Smeitink JA. EMBO Mol Med. 2016 Apr 1;8(4):311-27.

²Mitochondrial diseases. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M, Turnbull DM. Nat Rev Dis Primers. 2016 Oct 20;2:16080.

³Mitochondrial genetics. Chinnery PF, Hudson G. Br Med Bull. 2013;106:135-59.

⁴Recognition, investigation and management of mitochondrial disease. Davison JE, Rahman S. Arch Dis Child. 2017 Jun 24. (Epub ahead of print)

⁵The mitochondrial proteome and human disease. Calvo SE, Mootha VK. Annu Rev Genomics Hum Genet. 2010;11:25-44.

⁶Mitochondrial medicine: a clinical guideline. Koene S, Smeitink J. Nijmegen: Khondrion BV, 2011.

⁷Biochemical diagnosis of mitochondrial disorders. Rodenburg RJ. J Inherit Metab Dis. 2011 Apr;34(2):283-92.

⁸Genetic basis of mitochondrial diseases. Gusic and Prokisch. FEBS Letters. 2021:1132-1158.

Acknowledgement

Principal author: Dr Fung Cheuk-wing on behalf of Metabolic Medicine Team, HKCH
Initial posting: Mar 2024

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