Mitochondrial Diseases

 

Mitochondrial Diseases

PKGhatak,MD

Mitochondrial diseases arise from the mutation of gene/genes in the DNA of mitochondria. Mitochondrial diseases are rare but fascinating to study, like solving a murder mystery.

What is the common link between all known mitochondrial diseases.

The abnormal gene is inherited solely from the mother. At the time of fertilization father's contribution is only one copy of chromosomes, and the mother gives the entire egg containing mitochondria along with the other copy of the chromosomes.

One mitochondrion has 3,000 genes, and about 100 of these genes are involved in cellular respiration and energy production. The rest of the genes are responsible for all other cellular functions based on the tissues they are located in, for example, hormone production in endocrine organs, neurotransmitter production in nerve tissue, muscle contraction in the heart and other muscles including the GI tract.

Any mitochondrial gene abnormality related to cellular respiration so inherited, results in a deficiency in one out of 8 group cellular respiratory enzymes that are essential for releasing the potential energy of food in the form of heat and ATP (adenosine triphosphate). ATPs are used by the cells for carrying out all other cellular functions that are energy dependent.

In some instances, mitochondrial DNA gene mutations take place later in life. In most cases, the nuclear DNA gene mutations are responsible for Mitochondrial diseases.

The first mitochondria disease was described by Dr. Robert Lust in 1951. In 1957 Dr. Archibald Denis Leigh demonstrated pathological lesions in the nervous system and located the abnormality in the mitochondria. At that time, to detect the cause of an inherited disease required painstaking tracing of illness among the family members, like contact tracing in the covid pandemic. Nowadays, detection of gene mutation tests and blood and urine biochemical tests are easily available and cases are diagnosed early. In the coming years, more and more Mitochondrial diseases will be identified.

Understanding the symptoms of Mitochondrial diseases.

1. Energy generation and ATP synthesis.

We consume food that can be grouped into 3 categories.  Starch and sugars are called Carbohydrates. Oil and fat as Fat. Animal flesh and plant proteins as Proteins. After digestion, the carbohydrates end up as sugars, fat as fatty acids and proteins as amino acids. Each one of these energy producing molecules becomes a Two-Carbon compound called Acetyl CoA by the action of enzymes. The acetyl CoA is then combined with a four carbon molecule - oxaloacetate to form a six carbon compound Citrate. That is the beginning of the tricarboxylic acid cycle or Krebs cycle.

Citrate in turn becomes alpha glutamate in stages. Enzyme NADH (Nicotinamide Adenine Dinucleotide) dehydrogenase strips 2 electrons (Hydrogen atom) from alpha glutamate and transfers the electrons to NAD, a cofactor and H ion receptor, which now becomes NADH. The NADH in turn transfers the electrons to FAD (flavin adenine nucleotide) to become FADH by the enzyme succinyl dehydrogenase. In the next two stages, the electrons pass to Cytochrome C by the enzyme cytochrome C reductase and the final stage by cytochrome C oxidase to one radical of oxygen to form one molecule of water and energy. The excess energy immediately mopped up ADP (adenosine diphosphate) and the energy is stored in ATP, a high energy molecule.

Going back to the citric acid cycle, the alpha glutamate has turned into succinate then to fumarate and then back to oxaloacetate which is again ready to take another molecule of acetyl CoA. These 8 steps citric acid cycle continues. All the stages in the citric acid cycle are reversible enzymatic actions. But the final stage of the electron transfer pathway is not reversible.

 

Biochemical basis of symptoms in mitochondrial diseases.

1. In mitochondrial disease, if a gene mutation takes place in the tricarboxylic acid cycle or electron transfer cycle, then the newborns appear weak, lethargic and fail to thrive. In absence of oxidative reduction Lactic acid accumulates, patients will be acidotic and life will be hanging on a thread.

   2.  Distribution of Mitochondria. The metabolically highly active cells have more mitochondria than those tissues that are less active. However, Red Blood Cells (RBC) have no nucleus or mitochondria, even RBCs are highly active in transporting Oxygen. The eyelid muscle, eye movement muscles, heart, muscles of the throat, respiratory muscle, and nerve cells have more mitochondria and as a result, exhibit early signs of the illness.

What are the common symptoms of the majority of mitochondrial diseases.

Poor growth in infants and children, failure to thrive in the newborn. Muscle weakens, drooping of upper eyelids, double vision from the weakness of moments of eye muscles. Deafness, heart failure, respiratory insufficiency, pneumonia, frequent infections. Autism, various neuropsychiatric symptoms. Hypothyroidism, adrenal insufficiency, Diabetes mellitus. Diarrhea, malabsorption. Lactic acidosis. 

 

Known Mitochondrial diseases.

Leigh syndrome, MELAS, Kean-Sayre syndrome, Mitochondrial deletion syndrome, Mitochondrial encephalopathy, Lactic acidosis, LHON syndrome, NARP syndrome, MANGIE syndrome.

Just by looking at the names, it becomes obvious when a rare case was first studied, they named the illness by the constellation of symptoms. Later they added the name/names of the investigators to the syndromes. Much later, chemical tests and genetic mutations were established and now that is the system of nomenclature.

Keans-Sayer Syndrome (KSS).

KSS is a neuromuscular disorder due to the mutation of mitochondrial genes. In some instances, deletion and duplication of genes are present. The enzyme-protein complex of the oxidative phosphorylation system results in the failure of choroid plexus cells to transfer Folic acid to nerve cells of the CNS.

The onset of symptoms begins before the age of 20. The earliest symptom is ptosis, then ophthalmoplegia develops. One side of the body may be involved initially, later, both sides are affected. Pigmentary retinopathy, cerebral ataxia, and deafness follows. Cardia impulse conduction abnormality of the heart, growth hormone and thyroid hormone deficiencies subsequently develop.

When biopsied tissue is stained with Gomera trichrome stain, the abnormal genes appear red; indicating a high ratio of abnormal genes compared with normal genes. The red colored genes are called Ragged Red Fibers (RRF). Finding RRF is considered diagnostic. Blood levels of lactate and pyruvate are elevated.

Treatment. Folinic acid, an active form of folic acid, is usually prescribed and improvement of symptoms occurs at least initially. Acidosis is treated in the usual manner.

MELAS syndrome. MELAS stands for encephalopathy, lactic acidosis, and stroke like episodes. MELAS was first reported in 1984. The illness results from mutations in genes involved in NADH dehydrogenase-protein complex.

Features of MELAS syndrome.

After normal early childhood development, the patients are present with drooping eyelids. By the time patients reach 40 years of age, most patients have experienced transient but repeated episodes of profound weakness of one side of the body or the other side. Altered consciousness and seizures are often present. Migraine like headache is an important feature. Late symptoms are lactic acidosis, loss of bowel control, labored breathing, ataxia, deafness, and muscle spasms.

In the early stage of the illness Enzyme CoQ10, nicotinamide, riboflavin, and L- arginine are prescribed and the results are variable.

Leigh syndrome.

The disease manifests in infancy.  The child fails to thrive. Diarrhea, vomiting, difficulty in swallowing, and seizures are usual presentations. Examination reveals hypotonia, dystonia, wasting of muscles, paralysis of the muscle of the eyes, nystagmus, saccades, hypertrophic cardiomyopathy, and Ventricular septal defect. A high forehead and large ears are distinct features. Peripheral neuropathy and Lactic acidosis follow. A more severe form of Leigh syndrome was reported from Quebec, Canada. The symptoms start in the newborn. The entire brain and liver are affected. Voluntary muscle weakness and atrophy dominate. Death usually happens at about 5 months of age. This subclass of Leigh syndrome is known as French Canadian Leigh syndrome.

In Leigh syndrome, in 80% of cases, genetic abnormalities are present in nuclear DNA genes, and 20 % in mitochondrial DNA. The defective genes are inherited by autosomal recessive mode and also rarely by autosomal dominant mode. The mutation of genes causes a deficiency of the cytochrome C dehydrogenase protein complex.

Other mitochondrial diseases mentioned above are still rare and are not highlighted here.

Mitochondrial diseases are not seen by practicing physicians unless they are specialists in Pediatric Neurology and Metabolism-Endocrinology. But this field is expanding due to the easier availability of gene analysis and understanding the complex biochemistry. Many more obscure diseases will be rebranded as mitochondrial diseases in the future.

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