Non-mendlian inheritance

Mitochondrial disorders
Dr.Baraa Maraqa MD
General pediatrician
Medical genetics
3rd year / 1st sem.
2020

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 Mitochondrial disorders
• Diseases that are caused by mutations in
mitochondrial DNA.
• characteristic modes of inheritance and a
large degree of phenotypic variability.
• Each human cell contains several hundred
mitochondria in its cytoplasm. .
• Mitochondria produce adenosine
triphosphate (ATP), the energy source
essential for cellular metabolism.
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mtDNA • The circular mitochondrial DNA
genome. Locations of protein-
encoding genes (for reduced
nicotinamide adenine
dinucleotide [NADH]
dehydrogenase, cytochrome c
oxidase, cytochrome c
oxidoreductase, and adenosine
triphosphate [ATP] synthase)
are shown, as are the locations
of the two ribosomal RNA
genes and 22 transfer RNA
genes (designated by single
letters).
• The replication origins of the
heavy (OH) and light (OL)
chains and the noncoding D
loop (also known as the control
region) are shown.

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 Mitochondrial genome
• The mitochondria have their own DNA molecules,
which occur in several copies per mitochondrial
body and consist of 16,569 base pairs arranged
on a double-stranded circular molecule.
• The mitochondrial genome encodes: two
ribosomal RNAs (rRNAs), 22 transfer RNAs
(tRNAs), and 13 polypeptides involved in
oxidative phosphorylation.
• P.s. : Approximately 1000 nuclear DNA genes also
encode polypeptides that are transported into
the mitochondria.

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• Transcription of mitochondrial DNA (mtDNA) takes
place in the mitochondrion, independently of the
nucleus.
• Unlike nuclear genes, mtDNA genes contain no introns.
• The mutation rate of mtDNA is about 10 times higher
than that of nuclear DNA. This is caused by a relative
lack of DNA repair mechanisms in the mtDNA and also
by damage from free oxygen radicals released during
the oxidative phosphorylation process.

• Because it is located in the cytoplasm, mtDNA is

inherited exclusively through the maternal line.

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A pedigree showing the inheritance of a disease caused by a
mitochondrial DNA mutation.
• Only females can transmit the disease mutation to their offspring.
P.s. Complete penetrance of the disease causing mutation is shown in
this pedigree, but heteroplasmy often results in incomplete
penetrance for mitochondrial diseases
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• Because each cell contains a population of
mtDNA molecules, a single cell can harbor
some molecules that have an mtDNA
mutation and other molecules that do not.
This heterogeneity in DNA composition,
termed heteroplasmy, is an important cause
of variable expression in mitochondrial
diseases. The larger the percentage of mutant
mtDNA molecules, the more severe the
expression of the disease.
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• Organ systems with large ATP requirements
tend to be the one most seriously affected by
mitochondrial diseases. For example, the
central nervous system consumes about 20%
of the body’s ATP production and therefore is
often affected by mtDNA mutations.

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 Leber hereditary
optic neuropathy (LHON)
• One of the best-known mtDNA diseases,.
• Affects about one in 10,000 persons.
• Missense mutations in protein-coding mtDNA genes.
• Rapid loss of vision in the central visual field as a result
of optic nerve death.
• Vision loss typically begins in the third decade of life
and is usually irreversible.
• Heteroplasmy is minimal in LHON, so expression tends
to be relatively uniform and pedigrees for this disorder
usually display a clear pattern of mitochondrial
inheritance.

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LHON is usually due to one of three pathogenic
mitochondrial DNA (mtDNA) point mutations. These mutations are
at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C,
respectively in the ND4, ND1 and ND6 subunit genes of complex I of
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the oxidative phosphorylation chain in mitochondria.
Myoclonic epilepsy with ragged-red fiber(MERRF)
and MELAS
• MERRF: a disorder characterized by epilepsy, dementia,
ataxia (uncoordinated muscle movement), and
myopathy (muscle disease).
• Single-base mutations in a tRNA gene.
• MERRF is characterized by heteroplasmic mtDNA and is
thus highly variable in its expression.

• Mitochondrial encephalomyopathy and stroke-like

episodes (MELAS) : Another example of a
mitochondrial disease caused by a single-base tRNA
mutation is. Like MERRF, MELAS is heteroplasmic and
highly variable in expression.
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RRF

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 Mitochndrial diseases caused by
Duplications and deletions
• Kearns–Sayre disease :muscle weakness,
cerebellar damage, and heart failure.
• Pearson syndrome : infantile pancreatic
insufficiency, pancytopenia, and lactic
acidosis.
• Chronic progressive external ophthalmoplegia
(CPEO).

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dr.baraa maraqa 2020