Mitochondrial Disorders - Inheritance, Implications, and Investigations

Introduction

Mitochondria are organelles (subunits in a cell) with vital functions in humans. They are described as cellular ‘powerhouses’ due to their essential role in energy (ATP; adenosine triphosphate) production. Mitochondria produce 90 percent of the energy the body requires for functioning. They communicate with the nucleus and other organelles to maintain cellular homeostasis (normal cell functions). They have a pivotal role in normal tissue homeostasis and metabolism, neurodegeneration, immunity, and infectious diseases.

Mitochondrial diseases are caused by defects in mitochondrial deoxyribonucleic acid (mtDNA) or nuclear genes encoding mitochondrial proteins. Hence, mitochondrial diseases have a broad impact on different organ systems. Further, mitochondrial diseases comprise a genetic and clinical group of diseases due to defects in mitochondrial oxidative phosphorylation (the cellular process for energy production).

What Is the Epidemiology of Mitochondrial Disease?

Studies suggest that one in 5,000 people has a genetic mitochondrial disease. The overall prevalence (a measure of a disease being common) of mitochondrial disease is similar to that of other neurogenetic diseases (genetic causes linked to brain disease). Primary mutations in the mtDNA are more prevalent in adult patients compared to mutations in the nuclear genes. Similarly, the pediatric (children's) population is affected. Although many mutations are reported in mtDNA, only a few are more frequent than others. However, individuals with these mutations may remain without symptoms throughout their lives.

What Is the Mode of Inheritance of Mitochondrial Diseases?

Primary mitochondrial disease is a genetic condition inherited in several ways. The modes of inheritance are:

1. Autosomal Recessive: There is a 25 percent possibility that each child will inherit a mitochondrial disease in the family. In an autosomal recessive pattern, a child inherits one mutated gene copy from each parent.

2. Autosomal Dominant: There is a 50 percent possibility that each child will inherit a mitochondrial disease. In an autosomal dominant pattern, the child receives one mutated gene copy from either parent.

3. Mitochondrial Inheritance: It is a unique type of inheritance. It is because the mitochondrial disorders caused by mitochondrial DNA mutations are exclusively inherited from mothers. If this happens, there is a 100 percent possibility that each child will inherit a mitochondrial disease in the family (as mitochondria contain DNA).

4. Random Mutations: Sometimes, genes develop a random mutation not inherited from a parent.

What Are the Types and Clinical Features of Mitochondrial Disease?

Mitochondria are present everywhere in the body. Hence, mitochondrial disease can affect any organ with high energy demands, such as the brain, muscles, and heart. Multiorgan involvement is detected with detailed clinical examination and investigations. Pediatric onset mitochondrial disease has more severe organ involvement and progression and a poorer prognosis.

Many mitochondrial syndromes have been described recently. Examples associated with adults include mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS), mitochondrial neuro-gastrointestinal involvement and encephalopathy (MNGIE), neuropathy, and chronic progressive external ophthalmoplegia (CPEO). On the other hand, syndromes with childhood-onset include Alpers disease (a neurodevelopmental disease), Pearson syndrome (a rare disorder affecting the bone marrow and the pancreas), Leigh disease (a central nervous system disorder), Sengers syndrome (a disorder involving the eyes, heart, and muscles), and Kearns-Sayre syndrome (a rare neuromuscular disorder). For convenience, the clinically relevant syndromes are described below.

1. Mitochondrial Encephalomyopathy, Lactic Acidosis With Stroke-Like Episodes (MELAS): MELAS syndrome is a severe multiorgan disease with recurrent strokes and an onset of less than 40 years. Headache and vision problems precede the stroke-like episodes and can occur days or weeks before seizures. The severity of a neurological deficit is related to the extent of brain involvement. Diagnosing mitochondrial disease early can prevent invasive diagnostic procedures such as brain biopsy (removing cells for examination) or immunosuppressant administration.

2. Leber Hereditary Optic Neuropathy (LHON): LHON presents with painless visual loss in young adults with a male predisposition. A majority of cases involve the opposite eye within a year and cause irreversible visual loss. Other features such as dystonia (abnormal muscle tone leading to spasms and abnormal posture), myoclonus (sudden twitching or jerking of a muscle), and deafness may occur.

3. Chronic Progressive External Ophthalmoplegia (CPEO): Many patients have external ophthalmoplegia (weakness of the eye muscles) and ptosis (drooping of eyelids). CPEO is one of the main features of adult mitochondrial disease.

4. Myopathy: Myopathy in adult patients presents with fatigue, exercise intolerance, and muscle weakness. Early loss of movement due to muscle weakness is an atypical feature of adult mitochondrial disease. There is an increased risk of aspiration (breathing a foreign object) with facial, oral, and respiratory muscle weakness.

5. Neuropathy: Diminished or absent reflexes are the most common finding in nerve conduction studies in adult mitochondrial disease.

6. Cardiac Involvement: Cardiac involvement is a part of adult mitochondrial disease. However, there is limited data regarding the prevalence of cardiac involvement in various nuclear genes in adults.

What Is the Diagnostic Approach and Investigations for Mitochondrial Disease?

Diagnosing mitochondrial disease can be challenging due to its varied symptoms and multiorgan involvement.

1. Genetic Testing: It is the most accurate way to diagnose mitochondrial disease. Genetic testing is recommended for the child (and sometimes for the parents). Genetic testing begins with mtDNA analysis, followed by nuclear DNA for genes involved in mitochondrial disease. The type of genetic testing depends on the symptoms of the mitochondrial disease.

2. Non-genetic Tests: Non-genetic tests include:

• Biochemical Tests: Measurement of blood lactate (a product of normal metabolism and exercise) is indicated in individuals with myopathy.

• Muscle Biopsy: A biopsy of the relevant tissue (for example, skeletal muscle, liver, or skin cells) can be used to examine the mitochondria.

• Neuroimaging: It includes brain and spine magnetic resonance imaging (MRI) and electroencephalography (EEG) in those with suspected seizures.

Other investigations include an echocardiogram (ECG, which records the heart's rhythm), an electrocardiogram (EKG, which records the heart's electrical activity), an eye examination, and hearing tests. Baseline cardiac assessment with ECG and EKG should be done in all patients.

How Is Mitochondrial Disease Managed?

1. Specific Treatment: There is no effective and specific treatment for patients with mitochondrial disease. However, nutritional supplements, such as vitamins, have been tried based on individual studies.

2. Supportive Treatment and Genetic Counseling: These include medications, electrolytes, hydration, and antibiotic therapy. Exercises are advocated to increase muscle size, resistance, and strength. Genetic counseling and screening are essential for mitochondrial disease. Other treatments include speech therapy, physical therapy, respiratory therapy, and occupational therapy.

The prognosis for mitochondrial disease patients depends on organ and tissue involvement and disease severity.

Conclusion

Over the past few decades, there have been important advances in mitochondrial disease. The involvement of mitochondrial and nuclear genes makes mitochondrial disease challenging to manage. Hence, the clinician’s role is crucial for prompt diagnosis and management. Currently, the management of mitochondrial disease is supportive. However, a detailed understanding of the disease mechanism and newer treatment options can give hope to patients with mitochondrial disease.