Mitochondrial Disorders Pt. 2

Question 1

1 in ___ children in the US will develop mito disease by the age of 10y

Answer 1

4000

Note: the more severe, the earlier it presents, there is no precise data for adult incidence

Question 2

What should raise suspicions for mito disease?

Answer 2

Involvement of 3 or more organ systems

Question 3

Mito diseases are ___ and ___

Answer 3

Progressive, multisystemic

Question 4

Mito disease w/ prominent muscular problems

Answer 4

Mitochondrial Myopathy

Question 5

Mito disease w/ both muscular and neuro problems

Answer 5

Mitochondrial encephalomyopathy

Question 6

When should you suspect mito disease?

Answer 6

Wide spectrum of symptoms and signs in an individual patient

Note: any symptom in any organ at any age

Question 7

Why is mito disease a difficult dx?

Answer 7

Absence of reliable screening or diagnostic biomarker that is both sensitive and specific in all cases of mito disease

Question 8

Name 9 neuro red-flags in mito disease

Answer 8

• Cerebral stroke-like lesions in a nonvascular pattern
• Basal ganglia disease
• Encephalopathy
• Neurodegeneration
• Epilepsia partialis continua (intractable epilepsy)
• Myoclonus
• Ataxia
• MRI findings consistent w/ Leigh disease
• Characteristic MRS peaks

Question 9

What is cerebral stroke-like lesions in a nonvascular pattern associated with?

Answer 9

Mitochondrial encephalopathy lactic acidosis (MELAS)

Question 10

What is basal ganglia disease associated with?

Answer 10

LEIGH syndrome

Question 11

What is myoclonus associated with?

Answer 11

Mitochondrial Encephalopathy Ragged Red Fibers (MERRF)

Question 12

What is ataxia associated with?

Answer 12

Neurogenic ataxia-retinitis pigmentosa (NARP)

Question 13

Name 5 cardio red-flags in mito disease

Answer 13

• HCM w/ rhythm disturbance
• unexplained heart block in a child
• CM w/ lactic acidosis (>5 mM)
• DCM w/ muscle weakness
• Wolff-Parkinson-White arrhythmia

Question 14

Name 5 ophthalmologic red-flags in mito disease

Answer 14

• retinal degeneration w/ signs of night blindness, color-vision deficits, decreased visual acuity, or pigmentary retinopathy
• ophthalmoplegia/paresis: unable to move eyes
• fluctuating, dysconjugate eye movements: roving eyes
• ptosis: droopy eyelids
• sudden- or insidious-onset optic neuropathy/atrophy: sudden blindness

Question 15

Name 3 GI red-flags in mito disease

Answer 15

• unexplained or valproate-induced liver failure
• severe dysmotility: severe constipation
• pseudo-obstructive episodes: intestinal obstruction/non-surgical

Note: valproate is a common seizure/depression drug

Question 16

Name 4 other red-flags in mito disease (not neuro, cardio, opthalmological, or GI)

Answer 16

• unexplained hypotonia, weakness, FTT and metabolic acidosis (e.g. lactic acidosis) in a newborn, infant, or young child
• exercise intolerance that is not in proportion to weakness
• hypersensitivity to general anesthesia
• episodes of acute rhabdomyolysis: high CK, muscle breakdown

Question 17

Describe myopathy

Answer 17

• Muscle weakness and wasting
• Exercise intolerance
• Weakness/wasting in face and neck lead to slurred speech and dysphagia

Question 18

Describe exercise intolerance

Answer 18

• Unusual feeling of exhaustion brought on by physical exertion
• Spectrum of severity
• Sometimes associated w/ muscle cramps and/or injury-induced pain

Question 19

What can occur if someone who has exercise intolerance “overdoes it”?

Answer 19

Cramps, Rhabdomyolysis

Note: this can occur during or after the overexertion

Question 20

What symptoms are associated w/ encephalomyopathy and how can they be managed?

Answer 20

• hearing impairment –> managed using hearing aids and alternate forms of communication
• migraine-like headaches –> alleviated w/ medications
• Seizures –> preventative medications/anti-epileptics
• Strokes –> arginine can be used for stroke-like episodes
  Note: variability in type and severity

Question 21

What are the characteristics of mito disease in older children and young adults?

Answer 21

• later-onset –> chronic course
• isolated myopathic and/or CM presentations, frequently w/ exercise intolerance, are common
• fibromyalgia or chronic fatigue syndrome
• sometimes rapidly progressive disease course w/ sudden regression –> often associated w/ physiologic stressor (viral/bacterial infection, severe illness, pregnancy and delivery, surgery)

Question 22

What are the characteristics of mito disease in older folks?

Answer 22

Regression manifested as:

• nonvascular stroke
• ophthalmoplegia
• visual decline
• mental status changes
• array of new neurologic complaints
• worsening exercise intolerance and fatigue

Question 23

True or false: the first episode of metabolic stroke in MELAS or metabolic encephalopathy in Leigh disease may be fatal at any age

Answer 23

True

Question 24

True or false: there is a definitive biomarker to diagnose mito disease

Answer 24

False

Note: lactic acidosis is neither sensitive nor specific

Question 25

Diagnosis of mito disease can be done by these 3 methods

Answer 25

- identification of a pathogenic mtDNA or nDNA mutation via sequencing - tissue-biopsy evidence of abnormal electron-transport chain enzyme activity or impaired respiratory capacity - invasive procedures such as muscle or liver biopsy to obtain tissue for testing in specialized labs

Question 26

Who should you refer a patient to if symptoms and signs strongly suggest mito disease?

Answer 26

Metabolic specialist

Question 27

What baseline screening tests should be ordered for suspected mito disease?

Answer 27

- basic chemistry --> is there acidosis - liver enzymes and ammonia --> how is the liver - CK --> measure of muscle breakdown - blood lactate, pyruvate, and lactate/pyruvate ratio - CBC - quant plasma AAs - quant urine organic acids - plasma acylcarnitine analysis - routine CSF studies (cell count, glucose, protein measurement, CSF lactate, amino acids)

Question 28

What other evals are beneficial to order in suspected mito disease?

Answer 28

- ophthalmology - audiology - EKG and Echo - child neuro consult - genetics consult

Question 29

True or false: a normal lactate rules out mito disease

Answer 29

False Note: even when plasma levels of lactate and pyruvate are normal, CSF lactate levels might be elevated; lactate might only rise during episodes of metabolic decompensation

Question 30

Which mito diseases frequently occur w/ minimal to no rise in lactate?

Answer 30

- Leigh disease - Kearns-Sayre syndrome - Leber hereditary optic neuropathy - Mitochondrial polymerase-associated diseases

Question 31

What is a risk of a patient who experiences repeated "bad days"?

Answer 31

Often leads to decompensation and difficulty returning to baseline

Question 32

What can lead to a missed mito disease dx?

Answer 32

- lack of understanding of disease - misinterpretation of symtoms - teenagers can be thought to be exaggerating or malingering - older pts can be thought to be malingering or mentally unstable Note: misdiagnosis can lead to further progression of symptoms w/ missed opportunities for treatment and support

Question 33

What is the prognosis for people with mito disease?

Answer 33

Variable and unpredictable --> some people live a normal life and are minimally affected while other are severely compromised

Question 34

True or False: Prenatal testing is available for all types of mito disease

Answer 34

False

Question 35

Name 5 outcomes of mito disease

Answer 35

- life threatening/life limiting - more severe in children - can cause little disability if person has enough functional mitochondria - no cure - supportive care - illness management

Question 36

What are the origins of mtDNA mutations?

Answer 36

- damage to DNA: environmental factors, endogenous oxidative stress - spontaneous errors: DNA replication, translation synthesis, DNA repair re-synthesis