Mitochondrial Disorders

Question 1

What is the mnemonic of mitochondrial disorders?

Answer 1

LUMP

Question 2

What are the mitochondrial diseases?

Answer 2

L = Leber’s optic atrophy (= LHON: Leber’s hereditary optic neuropathy)

Leigh syndrome

U = Usher’s syndrome

M = MELAS syndrome

MERRF syndrome

Mitochondrially inherited: Diabetes mellitus, and Deafness

P = Pearson syndrome

Progressive external ophthalmoplegia: Kearns-Sayre syndrome

Progressive neurodegenrative disease: NARP syndrome

Question 3

Apart from nucleus, where else is the DNA located?

Answer 3

Mitochondria

Question 4

Are Mitochondrial DNAs single stranded or double-stranded?

Answer 4

Double stranded

Question 5

How does mitochondrial genes differ from nuclear genes?

Answer 5

• Mitochondrial genes have NO introns
• They encode some different amino acid codon

Question 6

What are the functions of mitochondrial DNA?

Answer 6

To encode >>

• Respiratory chain enzyme subunits (protein components)
• Transfer RNAs (tRNAs)

Question 7

Who can transmit the disease? father/mother?

Answer 7

Mother

(inheritence is only via maternal line)

Question 8

Why is the inheritence of mitochondrial diseases only via maternal line?

Answer 8

because, mitochondria is present in cytoplasm

& sperm do NOT contribute any cytoplasm to the zygote

Question 9

Type & Amount of genome in the cytoplasm of ovum (that is contributed to zygote)

Answer 9

Circular genome

16.5kilobase (kb)

Question 10

What is heteroplasmy?

Answer 10

Within cells/tissues >>> mixed population of normal and abnormal mitochondria

Question 11

Which type of genetic disorders does show heteroplasmy?

Answer 11

Mitochondrial disorders

Question 12

What is threshold effect?

Answer 12

Different proportion of abnormal mitochondria may be required to cause disease in different tissues

Question 13

If a male or female is affected with a mitochondrial disease, what is his/her family history?

Answer 13

Mother surely has the disease.

Father is not affected/not predictable.

Question 14

If father is affected, what are the chances among children?

Answer 14

NONE of the children will be affected.

(presumed: mother is normal)

Question 15

Can an affected father transmit the disease to his his children?

Answer 15

NO.

No transmission from father.

Question 16

Which genetic inheritences have no male-to-male transmission?

Answer 16

X-linked dominant

X-linked recessive

Mitochondrial disorders

Question 17

Which genetic inheritences have no male-to-female transmission?

Answer 17

Mitochondrial disorders

Question 18

If mother is affected, what are the chances among children to inherit the disease?

Answer 18

All children will inherit the disease (sons/daughters all)

(father is normal/affected does not matter)

Question 19

Which systems are involved commonly?

Answer 19

Muscles (Myopathy), brain (neurological diseases), eye (retinitis pigmentosa), heart, GIT

Question 20

How is the correlation between genotype and phenotype in mitochondrial disorders?

Answer 20

Poor

Question 21

Result of muscle biopsy in mitochondrial diseases

Answer 21

Histology: classical ‘red-ragged fibres’

(more in MERRF syndrome)

Question 22

What do ‘red-ragged fibers’ indicate?

Answer 22

Increased number of mitochondria

Question 23

Which nature of an organ is affected by mitochondrial diseases?

Answer 23

Organs that are highly dependant upon oxidative metabolism (e.g. muscles)

Question 24

What is LHON?

Answer 24

Leber’s hereditary optic neuropathy

(AKA Leber’s optic atrophy)

Question 25

**What is the underlying pathology of LHON/Leber's optic atrophy?**

Answer 25

**Degeneration of retinal ganglion cells (RGCs)**

Question 26

**What is the first presentation of LHON/Leber's optic atrophy?**

Answer 26

**Sudden blurring/cloudiness of central vision** (one/both eyes)

Question 27

**What is Leigh disease?**

Answer 27

**1. Subacute necrotising encephalopathy** **2. Retinitis pigmentosa** **2. Psychomotor regression:** - Cognitive impairment - Ataxia - Weakness **Commonly death within 2-3years due to respiratory failure**

Question 28

**What is Usher's syndrome?**

Answer 28

**Sensorineural deafness (non-progressive partial/total)** **+** **vision loss (due to retinitis pigmentosa) (worsen over time)**

Question 29

**What is MELAS syndrome?**

Answer 29

**ME = Mitochondrial encephalomyopathy** **LA = Lactic acidosis** **S = Stroke like episodes** (also myopathy)

Question 30

**What is MERRF?**

Answer 30

**M**yoclonus **E**pilepsy with **R**ed **R**agged **F**ibres

Question 31

**Can diabetes mellitus be mitochondrial disorder?**

Answer 31

**Yes, there are some mitochondrially inherited diabetes mellitus**

Question 32

**What are the features of Pearson syndrome?**

Answer 32

**Sideroblastic anaemia +** **Exocrine pancreatic dysfunction**

Question 33

**What is the prognosis of Pearson syndrome?**

Answer 33

**Most are fatal in infancy**

Question 34

**If Pearson syndrome survive to adulthood \>\>\> what happens?**

Answer 34

**they develop Kearns-Sayre syndrome**

Question 35

**What is the age of onset for Kearns-Sayre syndrome?**

Answer 35

**\<20years**

Question 36

**What is the triad of Kearns-sayre syndrome?**

Answer 36

**External ophththalmoplegia** **Retinitis pigmentosa** **Heart block**

Question 37

**What is external ophththalmoplegia?**

Answer 37

**weakness of eye muscles (ocular myopathy)**

Question 38

**What are the features of external ophthalmoplegia in Kearns-Sayre?**

Answer 38

**Ptosis** **Symmetrical loss of eye movements (side to side mainly)** (so, usually no diplopia)

Question 39

**What are the features of retina in Kearns-Sayre?**

Answer 39

**Retinitis pigmentosa** **Night blindless**

Question 40

**What are the features of heart in Kearns-Sayre?**

Answer 40

**Cardiomyopathy** **Heart block** **Syncope** **Heart failure**

Question 41

**What are the features of ear in Kearns-Sayre syndrome?**

Answer 41

**deafness** **vestibular function loss/loss of balance**

Question 42

**What are the CNS features of Kearns-Sayre syndrome?**

Answer 42

**dementia** **raised protein in CSF** sometimes: seizures, tremor, stroke before 40years

Question 43

**What are the overall common features of Kearns-Sayre syndrome?**

Answer 43

**Triad:** ## Footnote 1. External ophththalmoplegia 2. Retinitis pigmentosa 3. Heart block **Eye features:** 1. external ophthalmoplegia (ptosis, side-to side loss of eye movement) 2. Retinitis pigmentosa 3. Night blindness **Heart features:** 1. Cardiomyopathy 2. Heart block 3. syncope 4. Heart failure **Ear features:** 1. deafness 2. vestibular function loss (loss of balance) **CNS features:** 1. dementia 2. raised protein in CSF 3. seizure, tremor 4. maybe, stroke \<40years **Others:** symptoms releated smooth/skeletal muscle myopathies in different organs

Question 44

**What is NARP?**

Answer 44

**N**europathy **A**taxia **R**etinitis **P**igmentosa Progressive neurodegenrative disorder