Clinical Aspects of Mitochondrial Disorders Part One

Question 1

What is heteroplasmy?

Answer 1

• Heteroplasy is variation in the load of mitochondrial DNA in different tissues.- Heteroplasmy is uniques to mitochondrial disorders.- Can get mixtures of normal and mutant mitochondrial DNA in one cell.

Question 2

Describe the 2 main subtypes of primary mtDNA disorders.

Answer 2

There are 2 main subtypes:1). Point mutations- Mainly occur in the tRNA genes (m.3243A>G) or protein coding genes (LHON - m.11778G>A, MILS m.8993T>G/C).- Often heteroplasmic (unless LHON).- Maternally inherited.2). mtDNA rearrangements- Typically large (approximately 2-8 kb) deletions.- Heteroplasmic.- Usually sporadic.

Question 3

Describe the commonest mutation that we see in clinical practice.

Answer 3

m.3243A>G: paradigm for maternally inherited mtDNA disease.- Commonest cause of MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes).- One of the most common pathogenic mtDNA mutations (along with common LHON mutations): 1 in 400 carry the mutation.- Prevalence of MELAS itself is more like 1 in 5000.- Commonest presentation is MIDD (Maternally Inherited Diabetes and Deafness).- Heteroplasmy levels variable between tissues.

Question 4

What is the carrier frequency of the mt.3243A>G mutation?

Answer 4

1 in 400 individuals carry this mutation.

Question 5

How does the mutant load of A2343G change with ages?

Answer 5

• The levels of m.3243A>G mutant in a females blood decrease with age.

Question 6

What are the reproduction options for those at risk of passing on mitochondrial disorders?

Answer 6

1). Oocyte donation.2). Pre-implantation genetic diagnosis - select low level mutant offspring.3). Nuclear transfer - take out nuclear DNA and put it in an equivalent stage embryo with a different mitochondria.4). Prenatal testing - very likely to get an intermittent level of mutant mitochondria - hard to call - CVS has a limited place in mitochondrial disorders.

Question 7

Give an example of a mitochondrial disease that doesn’t fit the threshold value theory.

Answer 7

• LHON - most patients will have homoplasmy.

Question 8

How do we get evidence of mtDNA disease thresholds for prenatal diagnosis?

Answer 8

• Clinical studies.- Single fibre PCR - muscle biopsy, find obviously abnormal cells and the look at what level of mutant the abnormal cell has. Look at what level of mutant is present in the normal cells.- Cybrid studies.