What otherwise, not inherited. Unlike disorders that are autosomal

What are mitochondrial
inherited diseases?

Mitochondrial disorders are defines as a group of clinically
heterogeneous diseases which ultimately results in deficiency of energy in the
cell due to defects in oxidative phosphorylation (or formally known as OXPHS).
These diseases are either mutation in nuclear DNA or mtDNA with translational
effects on proteins that are responsible for events in mitochondria. First
mtDNA (mitochondrial DNA) was found in 1998 and currently, 250 mtDNA mutations
have been identified1 .

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As far as prevalence is concerned around 11 persons are
affected in every 0.1 million population.2 Following figure shows
the mutations in mtDNA with diseases that are induced due to them.


Fig #1 mutations in
mtDNA with diseases that are induced due to them



Some of the important factors:

There are around 1000 proteins that are located in
mitochondria with 13 of them are encoded by mtDNA3. The effects of
mtDNA mutation are usually more prominent in the organs which require more
energy such as brain, eyes, heart and muscles hence leading to muscle fatigue,
diabetes, poor vision and intellectual disabilities. mtDNA has a characteristic
behavior that that they are also prone to somatic mutations, which are
otherwise, not inherited. Unlike disorders that are autosomal recessive in
nature the age of onset of disorder takes place late in life including in
preschoolers, adolescents, toddlers and adults. But the symptoms can also
appear as same as that of autosomal recessive disorders including infant severe
disorders. 4

Peculiarities of mitochondrial genetics:

Mitochondrial DNA is different form the nuclear DNA due to
the following three reasons:

Inheritance is based on one parent only (maternal).

Genetics pattern is far more different from that of
Mendelian genetics.

Polypoid cells.

mtDNA differs from the universal genetic code5.

With respect to these peculiar characteristics one can say that
pathogenic mutations in the DNA of mitochondria have many drastic functional

Types of mitochondrial diseases:

There are two different types of mitochondrial mutations:

Primary Mitochondrial Disease

These are the mitochondrial disorders that can be identified
through clinical testing and in some cases (when applicable) can be confirmed
with the help of pointing out the mutation that has taken in mtDNA or nDNA of
the affected individual. The mutations that are responsible for these disorders
happens in the gene that codes for oxidative phosphorylation proteins.
Oxidative phosphorylation is the basic mechanism for the energy production in
the cell, so mutations in the proteins of this cycle will ultimately affect the
body. PMD may also effects the genes of such proteins that somehow affect the
pathway of oxidative phosphorylation6.

Secondary Mitochondrial Dysfunction

These are the mitochondrial mutations in the genes that are
not related to oxidative phosphorylation reaction. These disorders accounts for
many non-mitochondrial disorders which are hereditary in nature. They can also
be due to epigenetic effects. So SMD accounts for all of the mitochondrial
disorders which are other than PMD, in other words SMD affects either ETC
proteins or proteins who influence ETC in one way or another7.


What is the inheritance pattern?

Mitochondrial diseases are inherited from one parent i.e. mother only, which
is contrary to the nDNA in the fact that latter one passes mutations from both
father and mother. This fact shows that girls always pass mtDNA mutation in
progeny while boys don’t. In other words the mtDNA of the children is exactly
same with that of the mother, moreover the mtDNA of the child’s aunts and uncle
(mother’s brother and sisters and even grandmother) is exactly the same with
the children of the mother8. A general pattern is shown in the
figure below:


Character of heteroplasmy

A single cell contains many copies of mtDNA. But as far as normal cells are
concerned they are homoplasmic (all mtDNA are exactly same, the normal one).9
But mtDNA also involves the concept of ” heteroplasmy”. This means that mtDNA
of affected individual may contain both normal and affected mtDNA . More the
number of mutated mtDNA in a cell, more symptoms will be expressed in the
affected patient, this is the reason why different patients show different
symptoms severity (different clinical effects) 10. This is shown in
figure below:

Examples of
Mitochondrial Genetic Disorders in human:

inherited diabetes and deafness:

MIDD is a
mitochondrial induced genetic disorder that is followed by loss in hearing
capability and diabetes. MIDD is characterized by sensorineural deafness
and hyperglycemia in which sugar levels of the blood raised to the hazardous
level due to limited availability of insulin hormone.1


than deafness and diabetes, Symptoms of MIDD includes cardiomyopathy,
dysfunction of kidney and problems related to GI track.2


beginning of diabetes in MIDD takes place between the age of 15 to 70 years
(average is 32.8 to 38.8 yr), while the age of inception of deafness occurs at
the mean age of 33.2 years with a progressive nature.3


exact commonness of MIDD is
not known but around 0.2 to 3% of the patients of diabetes suffer from MIDD.4


MIDD is the consequence
of point mutation in MT-TL1, MT-TE and MT-TK
genes which codes for mt tRNA for Leucine, Glutamic Acid and
Lysine respectively.

Mitochondria plays an important role in the
pancreatic beta cells by maintaining the sugar level of the body, as the sugar
increases mitochondria up regulate the synthesis of insulin that will utilize
glucose and decrease blood sugar level. But mutation in any one of the MT-TL1,
MT-TE and MT-TK gene results in diminished capability of the
transfer RNA to attach new amino acids to the developing polypeptide chain,
which ultimately results in the decline of the function of mitochondria to
produce insulin. Hence these point mutations reults in diabetes.5

MT-TL1 gene codes for tRNA that is known as tRNALeu(UUR).
UUR is the triplet codon of Leucine, where R can either be A or G.  it is coded by the sequence of nucleotides
ranging from 3230 to 3304. The point mutation that prevails in this gene is
replacement of Adenine with Guanine at the nucleotide position of 3243 hence
known as A3243G6

gene codes for tRNA of
lysine amino acid. It is coded by the sequence of nucleotides ranging
from 8295 to 8364. The point mutation that prevails in this gene is replacement
of Adenine with Guanine at the nucleotide position of 8296 hence known as

gene codes for mt
tRNA of Glutamic acid. It is coded by the sequence of nucleotides ranging
from 14674 to 14742. And this nucleotide range falls in L-strand of the DNA. The
point mutation that prevails in this gene is replacement of Thymine with
Cytosine at the nucleotide position of 14709 hence known as T14709C. 8


is inherited in a mitochondrial pattern, which is also known as maternal
inheritance. This pattern of inheritance applies to genes contained in
mitochondrial DNA. Because egg cells, but not sperm cells, contribute
mitochondria to the developing embryo, only females pass mitochondrial
conditions to their children. 9


Leigh Syndrome is the syndrome that involves in the
loss of various movement and mental capabilities (also known as psychomotor
regression) with failure in respiratory system that within 3 years, ultimately
results in the death of the patient. It is a genetic disorder that can either
be caused by mutation in nuclear DNA or mitochondrial DNA, with more chances in
nuclear DNA. 10


of the syndrome includes; Loss in appetite, seizures, vomiting, crying
(continuos one) and irritability. While with the progression of the disorder
body undergo different problems including weakness and continuos contraction of
muscles. It also results in lactic acidosis that eventually leads to kidney and
respiratory functions impairment. 11

Onset Age

This neurological syndrome most commonly occurs at
the 1st year of child’s life. 12


As far as prevalence of Leigh syndrome is concerned
it affects 1 person in every 30,000 to 40,000 individuals at the time of
birth.  Mt DNA induced disorder are less
prevalent it affects 1 out of 100,000 to 140,000 individuals at the time of
birth. 13


In total 75 genes are responsible efor Liegh
Syndrome. Out of which only 20% mutations are present in mtDNA. As it is known
fact that most of the mitochondrial genes are involved in the the production of
energy productions mechanism. Mitochondria is involved in the oxidative
phosphorylation which requires oxygen for the convertion of food into useable
energy i.e. ATP. In total there are 5 protein complexs that are involved in
this process of oxidative phosphorylation. Most of the mutations, responsible
for leigh syndrome, influence the structure of these complexes that ultimately
leads to leigh’s syndrome.14

Fig 1# different complexes are
involved in oxidative phosphorylation

Mutations is complex 1

1 is also known as NADH:ubiquinone
oxidoreductase, which is the most prevalent cause of Leigh syndrome out of 75
genese responsible for the disorder, 25 (both in nuclear and mitochondria) are
responsible for mutation in complex 1. Following are the mutations in
mitochondrial DNA.


Mutations in Complex 4

like complex 1, mutation in complex 4 can also be coded by mitochondrial DNA
.i.e. MTCO3.

Mutations in Complex V

gene mutation is the most frequent mutation caused by mitochondrial DNA, and
this mutation affects the assembly of complex 5.  The normal product of the gene codes for ATP
synthase enzyme that produce in oxidative phosphorylation step of energy
generation. Around 10% of the patients of Leigh syndrome are affected with this

Fig 2# genes that are involved in
complexes of oxidative phosphorylation


tRNA Mutations:

above mentioned mutations other mutations also exists that codes for Trna of
mitochondria which are; MTTK, MTTV, MTTL1and MTTW 16.

Pearson syndrome

is a other mt disorder that consists of exocrine pancreas dysfunction and sideroblastic anemia (combination of
sideoblasts  and anemia). 17


Syndrome usually affects 1 person in every million births of the population.18

 Age of onset

disease occurs at the time of birth with death of the patient usually takes
place within three years. This disease is due to lactic acidosis and septic
risks. While if some lucky soul survives he gets suffered from ataxia,
Kearns-Sayre syndrome, pigmentary retinitis and even myopathy.19

Genetic Basis:

syndrome is due to a large, single deletion mutation ranging from 1K to 10k
Nucleotides. Around 20% of the patients undergo deletion of 4997 nucleotides.20


Fig 3# mtDNA with pointing out which
set of genes are involved in which syndromes.

Effects of Mutation:

mutations in mtDNA causes the deformation of proteins that are involved in the
process of oxidative phosphorylation, hence cells deplete out of the energy.
Till now it is absolutely not clear that how does these deletion mutations
results in symptoms of  Pearson’s

major effect of this disorder is dysfunctioning of Bone marrow which involves
hematopoitic cells that leads to the formation of RBCs, WBCs and Platelets.

Fig 4# Bone marrow dysfunctioning
involves blood cells problems


are the symptom of Pearson Syndrome:


Anemia is the major symptom of
Pearson syndrome which involves in reduction of RBCs which results in general
weakness, pale coloration of body and early tiredness.

Fig 5# Anemia a
consequence of Pearson syndrom


This is the condition of reduced
WBCs which leads to reduction in immunity of the body.

Fig 6# Reduction of WBCs
in the patients of Pearson’s syndrome.



This is the condition of less platelets in the body. Whose consequence
is reduction in cloting capacity of the blood. That may results in excessive
loss of blood as a result of injury or cuct.

Fig7# thrombocytopenia
condition in the patients of Pearson syndrome


Other symptoms of person syndrome includes; Diarrhea, hard
to overfeed, pain in stomach and even diabetes (in extreme and limited cases).
Other patients may have effects on kidney, eyes, heart, ears and liver.22