Mitochondria

What does this appear to be

LHON: Leber Hereditary Optic Neuropathy

What is LHON: Leber Hereditary Optic Neuropathy

Bilateral, painless, subacute visual failure that develops during young adult life

Are males/females more likely to get LHON

Males are approximately four times more likely to be affected than females

How does LHOn present

Entirely asymptomatic until onset in one eye

Similar symptoms appear in the other eye an average of eight weeks later

In about 25% of cases, visual loss is bilateral at onset

In a small percentage of cases, central vision gradually improves – but recovery is incomplete

For most central vision loss is profound and permanent

women with LHON may also have what as well when described as LHON plus

Some individuals with LHON, usually women, may also have a multiple sclerosis (MS)-like illness – termed ‘LHON-plus

What is the founder effect

A community within a community that share common genetics due to intermarriage

Approximately 95% of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA). Name these point mutations

Heteroplasmy

Coexistence of both normal (wild-type) and mutated mtDNA within the same cell/tissue.

The proportion of mutant mtDNA determines whether disease manifests (threshold effect).

Heteroplasmy in Polymorphonuclear Leukocytes occurs in what % of those with a pathogenic LHON causing mtDNA mutation

Heteroplasmy in Polymorphonuclear Leukocytes occurs in 10 - 15 % of those with a pathogenic LHON causing mtDNA mutation

Individuals with which pathogenic variant load of less than ___% in their leukocytes may be unaffected

Individuals with a m.11778G>A pathogenic variant load of less than 75% in their leukocytes may be unaffected

However in general heteroplasmy of <75% pathogenic variant load is rare – majority of LHON carriers are homoplasmic

How is LHON managed

Treatment is mainly supportive:

• Avoid smoking! Smokers more likely to be symptomatic

• Limit alcohol use

• Avoid other environmental toxins

• Diet

Proband

The affected individual through whom a family with a genetic disorder is first brought to medical attention.

Does LHON have gender- and age-dependent penetrance

Yes - 95th centile for age of onset = 50 years

Will the father of a LHON proband show any link to the condition

No. A male (affected or unaffected) with a primary LHON-causing mtDNA mutation cannot transmit the mutation to any of his offspring.

Will the mother of a LHON proband show any link to the condition

Mother of a proband usually has the mtDNA mutation and may or may not have symptoms.

A female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring but to varying degrees (heteroplasmy)

Up to 40% of LHON cases are simplex. What does this mean

It occurs in a single individual in a family

Can you get a prenatal diagnosis for LHON 

Not really.

The mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues

The presence of the mtDNA mutation does not reliably predict the occurrence, age of onset, severity, or rate of disease progression

Approximately __% of males & approximately _% of females who harbor a primary LHON-causing mtDNA mutation become affected

Approximately 50% of males & approximately 10% of females who harbor a primary LHON-causing mtDNA mutation become affected

What factors play into carriers being affected or not

A compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number may explain why some carriers are unaffected

This is promoted by estrogens in females, which may partially explain the gender bias

Haplogroup

Describes individual branches – or closely related groups of branches – on the genetic family tree of all humans.

All members of a haplogroup can trace their ancestry back to a single individual.

Haplogroups arose through mutation and migration

How do we trace haplogroups

mtDNA sequence polymorphism variations that have occurred over more than 150 000 years and correlate with the geographic origins of populations traced through the maternal lineages.

There is no meiosis - no crossing over → linear inheritance (matrilineal).

By aligning mtDNA sequences we can identify groups of individuals that appear to have a more/less recent common ancestor

MRCA

More recent common ancestor

MRCAs are marked with a what and subclades within haplogroups are marked with a what

MRCAs market with a letter

Subclades marked with a number

Most mtDNA codes for what 

Significance?

Proteins

As most mtDNA codes for proteins, mitochondrial polymorphisms can influence energy metabolism and contribute to the expression of the overall clinical phenotype

A meta-analysis of 159 European LHON pedigrees indicated a:

• Greater risk when what mutations arose on haplogroup J background

• Greater risk when what mutation arose on haplogroup K background

• Lower risk when what mutation arose on haplogroup H

• Greater risk when the m.11778G>A and m.14484T>C mutations arose on haplogroup J background

• Greater risk when the m.3460G>A mutation arose on haplogroup K background

• Lower risk when the m.11778G>A mutation arose on haplogroup H

What race LHON pedigrees show no association between mtDNA haplogroups and the risk of visual loss

Southeast Asian

Parkinson Disease has been found to be higher among mtDNA haplogroup _, but lower for haplogroups _ and _

Parkinson Disease has been found to be higher among mtDNA haplogroup H, but lower for haplogroups J and K

Haplogroup _ associated with protection from sepsis

H

Haplogroups _, _ & _ are associated with increased longevity

I, J and T also associated with increased longevity

We can follow the maternal line through haplogroups. Is there a way of following the paternal line

Yes – the Y Chromosome (except for the pseudoautosomal region)

Y – Chromosomal Adam

Is paternal mtDNA ever passed to offspring

Only in very exceptional cases

What is Leigh Syndrome

A progressive neurometabolic disorder first described in 1951

Leigh Syndrome mortality %

Mortality 50% per year from diagnosis

Leigh Syndrome is caused by what

Mitochondrial dysfunction caused by a hereditary genetic defect

How is Leigh syndrome characterised

Characterized by MRI necrotizing lesions in the midbrain and brainstem

Bilateral symmetrical degeneration of the brain stem, cerebellum and basal ganglia

Typical onset in infancy or childhood, often after a viral infection (metabolic challenge), but may begin later

Estimated incidence of Leigh syndrome

at least 1 in 40,000 births

What is Leigh-like syndrome

Criteria for LS only partially met despite overall clinical picture indicative of LS

What is different with Leigh-like Syndrome compared to Leigh Syndrome

Often peripheral nervous system involvement, including polyneuropathy or myopathy

Often non neurologic abnormalities – dysmorphic features, cardiac, endocrine and GI

Respiratory impairment due to brainstem involvement usually absent

Mutations in how many genes have been identified with Leigh Syndrome

at least 75 genes

It is the mitochondrial disorder with broadest genetic (and clinical) heterogeneity

What mutations cause the Respiratory chain enzyme defects of complexes I, II, IV, and V associated with Leigh syndrome

The NARP mutation (mtDNA)

The MERRF mutation (mt DNA)

What in the citric acid cycle is affected by Leigh syndrome

Pyruvate dehydrogenase (PDHC) deficiency (citric acid cycle)

There are 4 different ways of inheriting Leigh syndrome - name them

• Matrilineal (mitochondrial) ~20%

• De novo mutation

• X-linked recessive

• Autosomal recessive

True/False Most inherited disorders of mitochondria are related to changes in nuclear DNA rather than mtDNA

True - most mitochondrial proteins are encoded on nuclear genome, synthesised in cytoplasm & transported to mitochondria.

These mutations are inherited according to the classic Mendelian rules, not mitochondrial (matrilineal) inheritance

• Autosomal recessive

• X linked recessive

• Matrilineal (mitochondrial)

• De novo mutation in Kevin

• X linked dominant

X linked recessive

Is there a way to prevent passing on your hereditary mitochondrial disease

Mitochondrial transplantation/donation

Can be done before or after fertilisation

3-parent embryo

Why is predicting phenotype from mtDNA genotype particularly difficult

heteroplasmy

If the mutation is on the nuclear genome, for e.g. 80% of Leigh Syndrome, then the inheritance pattern of the mitochondrial disease will usually be ________

Mendelian