Mitochondrial Disorders

Question 1

Barth syndrome

Answer 1

X-linked
cardiomyopathy, skeletal myopathy, cyclic neutropenia
gene: tafazzin

Question 2

Kearns-Sayre syndrome

Answer 2

caused by large mtDNA deletion especially 5kb “common” deletion; also A3243G and nuclear genes
symptoms: chronic progressive external ophthalmoplegia (weakness of eye muscles), proximal muscle weakness, onset 100mg/dL, dementia (some)

Question 3

Leigh disease

Answer 3

cranial nerve abnormalities, respiratory dysfunction and ataxia
progressive and lethal
Many etiologies including complex 1 deficiency, complex 4 deficiency, mtDNA T8993G/C, and PDHC deficiency

Question 4

Lebers Hereditary Optic Neuropathy

LHON

Answer 4

rapid central vision loss in adolesence/young adults; may also have dystonia
usually caused by homoplasmic mtDNA mutations most commonly G11778A, G3460A, T14484C
low penetrance; blindenss in males 3-4x more likely than females

Question 5

MELAS

Answer 5

Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes
Onset 5-15 years
Most commonly heteroplasmy for A324G however variety of other genetic etiologies possible
RRF and abnormal ETC activity frequently absent

Question 6

MERRF

Answer 6

Myocolonic epilepsy and ragged red fibers
Mulitple symmetrical lipomatosis around neck (some patients)
most commonly heteroplasmy of A8344G

Question 7

MNGIE

Answer 7

Mitochondrial myopathy, peripheral neuropathy, GI and encephalopathy
GL disease includes diarrhea and pseudoobstruction
adult onset; multiple mtDNA mutations or secondary to auto recessive mutations in thymidine phosphorylase gene

Question 8

mtDNA depletion syndrome

Answer 8

Infantile onset; AR mutations in nuclear encoded genes involved in mtDNA replication or maintenance
myopathy form caused by TK2 mutations; hepatic form caused by dGK mutations
Diagnosis caused by muscle biopsy comparison of mtDNA:nDNA ratio

Question 9

NARP

Answer 9

Neuropathy, ataxia, retinitis pigmentosa

caused by moderate heteroplasmy for T8993G/C (high heteroplasmy causes Leigh syn)

Question 10

Pearson syndrome

Answer 10

Infantile refractory sideroblastic anemia (with variable other blood cell anomalies) and other exocrine pancreatic dysfunction
caused by large mtDNA del/dups
KSS can occur in survivors

Question 11

A1555G

Answer 11

Aminoglycoside-associated deafness, non-syndromic deafness, maternally inherited cardiomyopathy

Question 12

A3243G

Answer 12

MELAS
Also variety of neuromuscular, endocrine, renal disease
Common phenotypes: migranes, diabetes, deafness

Question 13

What percentage of diabetes is likely caused by A3243G mutation?

Answer 13

1 percent

Question 14

A8344G

Answer 14

MERRF

Question 15

T8993G/C

Answer 15

Moderate levels of heteroplasmy cause NARP, higher levels cause Leigh disease

Question 16

12S rRNA gene mutations

Answer 16

amniglycoside and “sporadic” hearing loss

Question 17

tRNA leucine gene UUR

Answer 17

mutational hotspot; includes mutations for that cause MELAS or myopathy/cardiomyopathy

Question 18

tRNA isoleucine gene

Answer 18

mutations here cause cardiomyopathy

Question 19

Cytochrome B gene

Answer 19

sporadically mutated in some patients with isolated cardiomyopathy