Mitochondrial Disorders Pt. 2 Flashcards
1 in ___ children in the US will develop mito disease by the age of 10y
4000
Note: the more severe, the earlier it presents, there is no precise data for adult incidence
What should raise suspicions for mito disease?
Involvement of 3 or more organ systems
Mito diseases are ___ and ___
Progressive, multisystemic
Mito disease w/ prominent muscular problems
Mitochondrial Myopathy
Mito disease w/ both muscular and neuro problems
Mitochondrial encephalomyopathy
When should you suspect mito disease?
Wide spectrum of symptoms and signs in an individual patient
Note: any symptom in any organ at any age
Why is mito disease a difficult dx?
Absence of reliable screening or diagnostic biomarker that is both sensitive and specific in all cases of mito disease
Name 9 neuro red-flags in mito disease
- 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
What is cerebral stroke-like lesions in a nonvascular pattern associated with?
Mitochondrial encephalopathy lactic acidosis (MELAS)
What is basal ganglia disease associated with?
LEIGH syndrome
What is myoclonus associated with?
Mitochondrial Encephalopathy Ragged Red Fibers (MERRF)
What is ataxia associated with?
Neurogenic ataxia-retinitis pigmentosa (NARP)
Name 5 cardio red-flags in mito disease
- HCM w/ rhythm disturbance
- unexplained heart block in a child
- CM w/ lactic acidosis (>5 mM)
- DCM w/ muscle weakness
- Wolff-Parkinson-White arrhythmia
Name 5 ophthalmologic red-flags in mito disease
- 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
Name 3 GI red-flags in mito disease
- 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
Name 4 other red-flags in mito disease (not neuro, cardio, opthalmological, or GI)
- 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
Describe myopathy
- Muscle weakness and wasting
- Exercise intolerance
- Weakness/wasting in face and neck lead to slurred speech and dysphagia
Describe exercise intolerance
- Unusual feeling of exhaustion brought on by physical exertion
- Spectrum of severity
- Sometimes associated w/ muscle cramps and/or injury-induced pain
What can occur if someone who has exercise intolerance “overdoes it”?
Cramps, Rhabdomyolysis
Note: this can occur during or after the overexertion
What symptoms are associated w/ encephalomyopathy and how can they be managed?
- 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
What are the characteristics of mito disease in older children and young adults?
- 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)
What are the characteristics of mito disease in older folks?
Regression manifested as:
- nonvascular stroke
- ophthalmoplegia
- visual decline
- mental status changes
- array of new neurologic complaints
- worsening exercise intolerance and fatigue
True or false: the first episode of metabolic stroke in MELAS or metabolic encephalopathy in Leigh disease may be fatal at any age
True
True or false: there is a definitive biomarker to diagnose mito disease
False
Note: lactic acidosis is neither sensitive nor specific
Diagnosis of mito disease can be done by these 3 methods
- 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
Who should you refer a patient to if symptoms and signs strongly suggest mito disease?
Metabolic specialist
What baseline screening tests should be ordered for suspected mito disease?
- 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)
What other evals are beneficial to order in suspected mito disease?
- ophthalmology
- audiology
- EKG and Echo
- child neuro consult
- genetics consult
True or false: a normal lactate rules out mito disease
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
Which mito diseases frequently occur w/ minimal to no rise in lactate?
- Leigh disease
- Kearns-Sayre syndrome
- Leber hereditary optic neuropathy
- Mitochondrial polymerase-associated diseases
What is a risk of a patient who experiences repeated “bad days”?
Often leads to decompensation and difficulty returning to baseline
What can lead to a missed mito disease dx?
- 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
What is the prognosis for people with mito disease?
Variable and unpredictable –> some people live a normal life and are minimally affected while other are severely compromised
True or False: Prenatal testing is available for all types of mito disease
False
Name 5 outcomes of mito disease
- life threatening/life limiting
- more severe in children
- can cause little disability if person has enough functional mitochondria
- no cure
- supportive care
- illness management
What are the origins of mtDNA mutations?
- damage to DNA: environmental factors, endogenous oxidative stress
- spontaneous errors: DNA replication, translation synthesis, DNA repair re-synthesis
