Mitochondrial Diseases

Question 1

Common features of mito diseases

Answer 1

●Poor growth
●Exercise intolerance
●Muscle weakness
●Vision/hearing loss
●Learning disabilities
●Seizures and strokes

Question 2

Nuclear-encoded Mito Disorders

Answer 2

●Majority are autosomal recessive (majority of ALL mito disorders are AR)
●MITOCHONDRIAL COMPLEX II IS THE ONLY ALL-NUCLEAR ENCODED MITO COMPLEX!!!
●Mutations in nuclear mito genes can lead to mitochondrial DNA depletion/mito complex deficiencies

Question 3

Barth syndrome: Genetics

Answer 3

Inheritance: X-linked recessive
Gene: TAZ

Question 4

Barth syndrome: Major features

Answer 4

●Cardiomyopathy
oLeft ventricular non-compaction
●Neutropenia
●Underdeveloped muscles and muscle weakness
●Growth delay
●Exercise intolerance
●Normal intelligence or Mild-to-moderate learning disabilities
●Growth problems resolve after puberty
●Major causes of death are CM and neutropenia

Question 5

Leigh Syndrome: Genetics

Answer 5

Inheritance: X-linked or autosomal recessive, can also be mitochondrial
Genes: Over 50 nuclear genes, MT-ATP6, MT-CO3, MT-ND1 through MT-ND6, MT-TK, MT-TL1, MT-TV, MT-TW

Question 6

Leigh Syndrome: Major features

Answer 6

●Rapid developmental regression
●Onset in first months/years of life
●Onset after an energetically taxing event
●Failure to thrive
●Diarrhea
●Vomiting
●Dysphagia
●Seizures
●Lactic acidosis
●Muscular deterioration
●Hyptoonia
●Dystonia
●Ataxia
●Ophthalmoparesis
●Nystagmus
●Cardiac and respiratory failure
●Pyruvate dehydrogenase deficiency
●VSDs
●Peripheral neuropathy
●Lifespan is 6-7 years
   oUsually death is caused by respiratory failure

Question 7

POLG-related disorders: Genetics

Answer 7

Inheritance: Autosomal recessive, autosomal dominant
Gene: POLG

Question 8

POLG-related disorders: Major Features

Answer 8

Disorders caused by POLG exist on a spectrum with some overlap, features seen include:
●Psychiatric illness
     oDepression, psychosis, dementia
●Seizure disorders/epilepsy
●Extrapyramidal movement disorders
      oParkinsonianism, chorea
●Cerebrovascular involvement
●Sensorineural deafness
●Retinopathy
●Myopathy
●Exercise intolerance
●Peripheral neuropathy
●Endocrine/gonadal failure
●GI problems
●Liver failure
●Cardiomyopathy
●Cataracts
●Early death may occur

Question 9

Pyruvate Dehydrogenase Deficiency: Genetics

Answer 9

Inheritance: X-linked

Question 10

Pyruvate Dehydrogenase Deficiency: Features

Answer 10

Metabolic form:
   ●Lactic acidosis/elevated blood lactate
   ●Hyperventilation secondary to metabolic acidosis
Neurologic form:
   ●Onset in the first year of life
   ●Hypotonia
   ●Poor feeding
   ●Lethargy
   ●Brain MRI abnormalities
   ●Developmental delay
   ●Intellectual
   ●Seizures
   ●Microcephaly
   ●Blindness
   ●Spasticity
   ●Progressive disorder
Severe infantile-onset cases have a lifespan of ~6 months

Treatment:
● Sodium bicarbonate for acute metabolic episodes
● Ketogenic diet

Question 11

Senger’s Syndrome

Answer 11

Inheritance: Autosomal recessive

Major features:
●NORMAL COGNITION
●Developmental delay
●Muscle weakness
●Congenital cataracts
●HCM
●Lactic acidosis
●High risk of death in infancy due to cardiac failure

Question 12

Mitochondrial-encoded mito disorders

Answer 12

●Subject to heteroplasmy

●Only inherited from mom

Question 13

Leber’s Hereditary Optic Neuropathy (LHON)

Answer 13

Inheritance: Mitochondrial

Major features:
●Rapid central vision loss
●Dystonia
●Blindness is 3-4x more common in males than females
●Low penetrance

Question 14

MELAS

Answer 14

Inheritance: Mitochondrial

Major features:
●Mypopathy
●Encephalopathy
●Lactic Acidosis
●Stroke
●Onset between 5-15 years

Question 15

MERRF

Answer 15

Inheritance: Mitochondrial

Major features:
   ●Myoclonic Epilepsy
   ●Ragged Red Fibers – clumps of diseased mitochondria that accumulate in the muscle fibers
   ●Symmetrical lipomatosis around neck
  ●Hearing loss

Question 16

NARP

Answer 16

Inheritance: Mitochondrial
●Moderate heteroplasmy at T8993G (high heteroplasmy causes Leigh syndrome)

Major features:
●Neuropathy
●Ataxia
●Retinitis Pigmentosa

Question 17

mtDNA Deletion Syndromes

Answer 17

Inheritance: Mitochondrial
Genes: Caused by large deletions of mtDNA

Kearns-Sayre syndrome:
●Chronic progressive external ophthalmoplegia (CPEO) Some individuals with mtDNA deletions may present with CPEO without other symptoms of KSS

Pearson syndrome
Leigh syndrome

Question 18

Kearns-Sayre syndrome:

Answer 18

●Chronic progressive external ophthalmoplegia (CPEO)
●Pigmentary retinopathy
   oMild visual acuity loss
●Cardiac conduction abnormalities
  oAV block
●Onset before 20 years of age
●Cerebellar ataxia may be seen
●Some individuals with mtDNA deletions may present with CPEO without other symptoms of Kearns-Sayre

Question 19

Pearson syndrome

Answer 19

●Fatal in infancy
●Failure to thrive
●Sideroblastic anemia
●Exocrine pancreas dysfunction

Question 20

Leigh syndrome

Answer 20

●Rarely due to mtDNA deletions