Mitochondrial Disease
RITE Review
Andrew Sas
Neurology Resident
12/28/2015
Objectives
• Discuss different types of mitochondrial disease
• Recognize common features
• Review options for treatment if they exist
• Focus on RITE diseases/topics
• RITE type questions
Mitochondrial Diseases
• Summary
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Encephalopathy
Myopathy
Neuropathy
Cardiomyopathy
Retinopathy
Exercise intolerance
Short stature
Hearing loss
Elevated lactate
Ragged red fibers
Inheritance
• Maternal, recessive, or
sporadic
• Treatment:
• Creatine, Co-Q10, ketogenic diet (other than beta oxidation defects with high carb diet), carnitine,
avoidance of fasting, supportive
Mitochondrial Disorders or “Cytopathies”
• Result from mutations in
mitochondrial or nuclear genes
resulting in failures of oxidative
phosphorylation characterized by:
• Genetic and clinical heterogeneity
• Painful ACRONYMS and Eponyms (or
both!)
• Lactic acidosis
• Some treatments exist, but no cures
• Could try creatine or CoQ10
Types of disease
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Alpers Disease
Barth syndrome
Beta-oxidation Defects
Carnitine-Acyl-Carnitine Deficiency
Carnitine Deficiency
Creatine Deficiency Syndromes
Co-Enzyme Q10 Deficiency
Complex I Deficiency
Complex II Deficiency
Complex III Deficiency
Complex IV Deficiency
Complex V Deficiency
COX Deficiency
CPEO
CPT I Deficiency
CPT II Deficiency
Glutaric Aciduria Type II
KSS
Lactic Acidosis
LCAD
LCHAD
Leigh Disease or Syndrome
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LHON
LIC (Lethal Infantile Cardiomyopathy)
Luft Disease
MAD
MCAD
MELAS
MERRF
MIRAS
Mitochondrial Cytopathy
Mitochondrial DNA Depletion
Mitochondrial Encephalopathy
Mitochondrial Myopathy
MNGIE
NARP
Pearson Syndrome
Pyruvate Carboxylase Deficiency
Pyruvate Dehydrogenase Deficiency
POLG Mutations
Respiratory Chain
SCAD
SCHAD
VLCAD
www.umdf.org – The United Mitochondrial Disease Foundation
*found in RITE database
Types of disease
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LHON
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MAD
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MELAS
MERRF
• Beta-oxidation Defects
• Creatine Deficiency Syndromes
• Co-Enzyme Q10 Deficiency
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• CPEO
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Mitochondrial DNA Depletion
Mitochondrial Encephalopathy
Mitochondrial Myopathy
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NARP
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Pyruvate Dehydrogenase Deficiency
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Respiratory Chain
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• Glutaric Aciduria Type II
• KSS
• Lactic Acidosis
• Leigh Disease or Syndrome
www.umdf.org – The United Mitochondrial Disease Foundation
Mitochondrial Disorders: Inheritance
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Mitochondrial Disorders: Inheritance
• About ½ of mitochondrial
diseases are inherited from
mitochondrial DNA in a
maternal fashion
• The other ½ are due to
nuclear mutations that affect
mitochondrial function
• Many are sporadic mutations
Mitochondrial Disorders: Inheritance
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Maternal Inheritance
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Autosomal recessive
* Barth syndrome is X-linked recessive
Respiratory Chain
• Complex
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I
II
III
IV
V
Mitochondrial Myopathy - Pathology
Normal SDH
Succinyl Dehydrogenase)
SDH +
Ragged Red Fibers
Paracrystalline inclusions (MELAS)
COX –
Cytochrome oxidase
Answer
This substance is found in high concentrations in serum and CSF of
patients with mitochondrial cytopathies.
Question
What is lactic acid?
Lactate and glucose levels in various disease:
Mitochondrial cytopathy – low glucose, high lactate
14 questions in 14 years
Answer
This anesthetic infusion used for sedation inhibits mitochondrial
fatty acid oxidation, oxidative phosphorylation, carnitine palmitoyl
transferase, and secondarily inhibits Complex II.
Question
What is propofol?
• Propofol infusion syndrome
• More common in children than adults
• metabolic acidosis, heart failure, renal failure, hyperkalemia and rhabdo
• Prevent by giving carbohydrate load/infusion (children have limited
carbohydrate reserves)
• Treat by hemofiltration
•3 times in 14 years
Case 1
• 16 year-old boy
• CC: Ataxia and droopy eyelids.
• HPI:
• His ptosis started at age 5 and his parents note that he turns his head more then usual when trying to look
around. He also has noted that his balance is off and he occasionally drops objects.
• PMH:
• short stature
• diabetes
• complete heart block
• Exam:
• Bilateral ptosis and restricted bilateral horizontal eye movements. His fundoscopic exam reveals pigmentary
retinopathy. His has 4/5 strength in his proximal arms and legs and is unable to tandem walk.
• Workup:
• Serum lactate is slightly elevated. CSF shows elevated protein and lactate. Muscle biopsy shows ragged red
fibers.
• Diagnosis?
Case 1 – Kearns-Sayre Syndrome
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16 year-old boy
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CC: Ataxia and droopy eyelids.
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HPI:
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PMH:
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short stature
diabetes
complete heart block
Exam:
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His ptosis started at age 5 and his parents note that he turns his head more then usual when trying to look around. He also has
noted that his balance is off and he occasionally drops objects.
Bilateral ptosis and restricted bilateral horizontal eye movements. His fundoscopic exam reveals pigmentary
retinopathy. His has 4/5 strength in his proximal arms and legs and is unable to tandem walk.
Workup:
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Serum lactate is slightly elevated. CSF shows elevated protein and lactate. Muscle biopsy shows ragged red
fibers.
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Genetics: mtDNA deletions, usually sporadic
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5 question in 14 years
Kearns-Sayre Syndrome
• Insidiously progressive disease with CPEO before the age of 20.
• Symptoms/Clinical Features:
• Mitochondrial Myopathy (proximal
weakness
• CPEO
• retinal degeneration (pigmentary retinopathy)
• cardiac conduction defects (heart block)
• Ataxia/cerebellar syndrome
• Other symptoms include small stature, deafness, dementia, delayed puberty, and
endocrine dysfunction
• Laboratory: Increased CSF protein and lactate
• MRI- bilateral subcortical white matter T2 hyperintensities
involving basal ganglia, thalamus, and brainstem
• Pathology: ragged red fibers
• Note: Pearson’s syndrome- sideroblastic anemia,
pancreatic insufficiency, and low birth weight precede KSS symptoms.
Chronic Progressive External Ophthalmoplegia
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Ptosis
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Symmetric ophthalmoplegia with
relative sparing of downgaze
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Facial weakness, frontalis
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Dysarthria
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Sparing of ciliary and iris muscles
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Common presentation of any
mitochondrial myopathy
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Lid surgery is usually not performed
due to risk for exposure keratopathy
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Can be isolated or part of KSS
Case 2
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14 year old girl
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CC: New onset seizures
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HPI:
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Normal up until 2 months prior to presentation when she started having falls. She then had several
seizures, when her parents brought her to the hospital. She became comatose and was intubated.
After extubation and waking, she had difficulty using the right side of her body
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PMH:
 Normal childhood and development, previously healthy
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Exam:
 Cogwheel rigidity in the right arm and wrist, cervical dystonia, bradykinesia and apraxia on the right.
Diffuse hyperreflexia, worse right than left, and right Babinksi sign.
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Workup:
 MRI shows changes in the basal ganglia, thalamus
 Spectroscopy shows increased lactate peak
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Diagnosis?
Case 2 – Leigh’s Disease
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14 year old girl
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CC: New onset seizures
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HPI:
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Normal up until 2 months prior to presentation when she started having falls. She then had several
seizures, when her parents brought her to the hospital. She became comatose and was intubated.
After extubation and waking, she had difficulty using the right side of her body
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PMH:
 Normal childhood and development, previously healthy
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Exam:
 Cogwheel rigidity in the right arm and wrist, cervical dystonia, bradykinesia and apraxia on the right.
Diffuse hyperreflexia, worse right than left, and right Babinksi sign.
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Workup:
 MRI shows changes in the basal ganglia, thalamus
 Spectroscopy shows increased lactate peak
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Diagnosis?
Case 2 – Leigh’s Disease
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Subacute Necrotizing Encephalomyelopathy (SNEM)
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Clinical Features
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Developmental delay or psychomotor regression
Brainstem dysfunction
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Respiratory disorders (episodic hyperventilation)
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Ophthalmoplegia
Ataxia
Dystonia
Seizures, lactic acidosis, vomiting, weakness
Peripheral neuropathy, reduced nerve conduction velocity, demyelination
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Genetics
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Mutations in either mtDNA or nuclear DNA
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Pyruvate dehydrogenase (PDHC) most common
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Imaging/Pathology
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Bilateral, symmetric necrotizing lesions with spongy changes, microcysts in the basal
ganglia, thalamus, brainstem, and spinal cord
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Prognosis
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Poor, survival of months from disease onset
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5 questions in 14 years
Case 2 – Leigh’s Disease
Case 2 – Leigh’s Disease
Case 3
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20 year old woman
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CC: Right-sided weakness
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HPI:
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New symptom of right-sided face, arm, and leg weakness, started yesterday along with a headache
Nausea, vomiting
Roommate noticed she was sleepy today and not her normal self
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PMH:
 Headaches
 Sensorineural hearing loss
 Diabetes
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Exam:
 Short stature
 Right homonymous hemianopsia, right hemiparesis, language problems
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Workup:
 Serum lactic acidosis
 MRI
Diagnosis?
Mitochondrial Encephalopathy Lactic Acidosis and
Stroke-Like Episodes (MELAS)
• Clinical features•
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Myopathy
Encephalopathy with headaches and vomiting
Stroke like symptoms: hemiparesis, hemianopsia most common
Short stature, hearing loss, lactic acidosis and diabetes
• Mutation- mtDNA point mutations
• Laboratory: Lactic acidosis with exercise
• MRI: T1-weighted hyperintense cortical signal that are compatible with cortical laminar necrosis &
cytotoxic edema. Lesions do not conform to single vascular territories. Also see bilateral basal ganglia
calcifications, cerebellar and cerebral atrophy.
• Pathology: ragged red fibers
• Treatment: Carnitine, Co-Enzyme Q10, Vitamin K, Vitamin C, L-Arginine
• 8 questions in 14 years
Case 4
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22 year old man
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CC: Vision loss
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HPI:
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Blind spot in central visual field in right eye, onset over 5-6 days, painless
Diagnosed originally with optic neuritis
Presents for second time 2 months later with similar subacute vision painless central vision loss in
left eye
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PMH:
 None – healthy otherwise
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Exam:
 Central visual field loss bilaterally, color desaturation, relatively preserved peripheral vision
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Workup:
 MRI brain - normal
 Visual field testing
 LP – negative for OCB, IgG index normal
Case 4
Diagnosis?
Hint
Case 4 – Leber’s Hereditary Optic Neuropathy
• Bilateral subacute optic neuropathy caused by mtDNA mutations.
• Clinical Features:
• Painless, severe and permanent subacute central visual loss.
• Can be initially unilateral- with second eye often affected in following 1-2 months.
• Usually starts in Late teens/early adulthood.
• Can occasionally be associated with MS like symptoms/lesions
• Fundoscopic exam: Telangiectatic microangiopathy, disc pseudoedema,
microangiopathy, or vascular tortuosity.
• Pathology:
• mtDNA point mutations
• No ragged red fibers seen on pathology- only mitochondrial disease with this.
• 2 questions in 14 years
Case 5
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17 year old girl
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CC: Numbness and clumsiness
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HPI:
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Has always been clumsy, but recently she started falling and tripping over objects
She says that she has a hard time feeling the ground, trips easily over cracks in the sidewalk or on
carpet
Feels a little weak in the legs, has some difficulty standing from a low-seated chair
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PMH:
 Poor vision, has glasses
 Learning disorder, has an IEP
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Exam:
 MS WNL. CNs show decreased visual acuity, ptosis, fundus exam shows…
 Proximal LE weakness and decreased sensation distally in lower extremities.
 Brisk patellar reflexes
 FNF and HKS shows significant dysmetria.
 Gait ataxia
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Workup:
 MRI brain - normal
 EMG shows peripheral sensory polyneuropathy, worse LE than UE
Case 5 - Neuropathy, Ataxia, Retinitis Pigmentosa
(NARP)
Clinical features
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Sensory neuropathy
Cerebellar ataxia
Retinitis pigmentosa
Proximal weakness myopathy
Ptosis
• Mutation
• mtDNA point mutation that is the same as seen in KSS and Leigh’s
• EMG
• Sensorimotor polyneuropathy, myopathic features on needle exam
• Pathology
• Ragged red fibers
• Treatment?
• Gene therapy and skin-derived pluripotent stem cell grafts are being studied
• For retinitis pigmentosa
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Vitamin A, lutein, docosahexaenoic acid, acetazolamide, calcium channel blockers, and valproic acid
• 1 question in 14 years – does not have opsoclonus
Case 6
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22 year old man
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CC: Seizures and limb jerking, also has weakness and clumsiness
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HPI:
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In the last year, has developed seizures of staring, followed by rhythmic jerking of the upper
extremities. Occasionally, he has jerking muscle twitches in his arms without loss of consciousness
Has fallen twice in the last 6 months at home walking down the stairs and feels a little unsteady
while walking, feeling both weak in his legs and having difficulty feeling the ground with his feet
Noted some problems with coursework, now getting failing grades in college – he previously
graduated high school without difficulty
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PMH:
 Hearing loss
 Short stature
 Idiopathic cardiomyopathy diagnosed on echo, ordered for mild murmur on exam
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Exam:
 MS, CNs, reflexes are normal
 Proximal LE weakness and decreased sensation distally in lower extremities.
 FNF and HKS shows mild dysmetria.
 Gait ataxia
Case 6
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Workup:
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Biopsy:
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EMG: Small amplitude, short duration motor unit action potentials
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LP: Elevated lactate and pyruvate
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Diagnosis ?
Case 6 - Myoclonic Epilepsy with Ragged
Red Fibers (MERRF)
• Clinical Features:
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Starts in 20’s to 30’s
Proximal muscle weakness
Epilepsy with Myoclonus
Dementia
Ataxia
Cardiomyopathy
Also get pyramidal tract signs, neuropathy, optic nerve atrophy, and neurosensory hearing loss.
• Mutation: mtDNA point mutations or deletions or POLG-1 mutation
• Laboratory: Increased CSF lactate and pyruvate.
• EMG: Myopathic features
• Pathology: Neuronal loss in dentate, inferior olive, substantia nigra, gliosis in the cerebellar
cortex, and degeneration of the posterior column.
• Treatment: Treat Seizures with Keppra rather than VPA, as VPA can cause hepatic failure in
these pts with increased frequency.
• 3 question in 14 years
Cases 7, 8, and 9
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3 month old girl
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Recurrent episodes of hypoglycemia, hypotonia, and profound acidosis
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35 year old man
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Elevated CK and recurrent rhabdomyolysis after vigorous exercise
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60 year old woman
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Asymptomatic
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What type of mitochondrial disease could they all have?
Beta Oxidation Defects
• Autosomal recessive
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Very Long-Chain Acyl-CoA Dehydrongenase Deficiency
Long-Chain Acyl-CoA Dehydrongenase Deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Multiple Acyl-CoA Dehydrogenase Deficiency/Glutaritic Aciduria Type II
Medium-Chain Acyl-CoA Dehydrongenase Deficiency
Short-Chain Acyl-CoA Dehydrogenase Deficiency.
Short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency
• Common features include liver disease, heart disease, encephalopathy
• May include pigmentary retinopathy, neuropathy, myoglobinuria
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Treatment: High carbohydrate, low fat diet, administration of medium-chain
triglyceride oil, and diet supplementation with carnitine and/or riboflavin.
Avoidance of fasting.
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5 questions in 14 years
Cases 7, 8, and 9
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3 month old girl
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Recurrent episodes of hypoglycemia, hypotonia, and profound acidosis
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More likely shorter chain defect
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35 year old man
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Elevated CK and recurrent rhabdomyolysis after vigorous exercise
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More likely longer chain defect
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60 year old woman
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Asymptomatic
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Any beta oxidation defect
Case 10
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14 year old girl
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CC: Dystonia and cognitive regression
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HPI:
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Met normal milestones until about 18 months and began toe walking
Initially spoke in sentences, but regressed to single words only
Significant cognitive impairment, but able to physically keep up with peers until last year when she
began to have dystonic posturing of extremities
Now is having agitation, outbursts, crying and screaming episodes
Dystonia also now involves face, jaw, neck, trunk, and tongue
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PMH:
 Cognitive impairment
 Epilepsy
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Exam:
 MS – impaired language, follows only simple 1-word commands
 CNs – abnormal dystonic posturing of head with neck rotation
 Strength full but tone increased, reflexes brisk but equal, no obvious sensory changes, cannot do
complicated coordination test, gait is stiff-appearing
Case 10
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Workup:
 MRI – no significant abnormalities
 Muscle biopsy – no ragged red fibers
 CK – not elevated, if anything ~ low
 Nerve conduction/EMG – no neuropathic or myopathic changes
 Skin biopsy - normal
 Copper level, ceruloplasmin – normal range
 Urine organic acids, plasma amino acids normal
 VLCFA (Beta oxidation diseases) normal
 Niemann-Pick A and B, Fragile X, Rett – negative
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Diagnosis?
Creatine Deficiency Syndromes
• Autosomal recessive
• Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency)
• L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency)
• X-linked
• SLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency)
• All have mental retardation, seizures, speech delay.
• GAMT - behavioral disorder - including autistic behaviors; movement disorders
• SLC6A8
• Growth retardation
• Males: mild to severe mental retardation
• Females: learning and behavior problems
• In a review of 27 patients with GAMT deficiency, oral creatine supplementation improved behavior
abnormalities in all patients, epilepsy in most patients and movement disorder in half of patients. Intellectual
ability and speech did not respond. Treatment response appeared more favorable in younger patients.*
• 1 question in 14 years
* Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, et al. GAMT deficiency: features, treatment, and outcome
in an inborn error of creatine synthesis. Neurology. 2006 Aug 8;67(3):480-4.
Answer
Mitochondrial depletion, caused by
this drug, can result in myalgias,
weakness, and elevated CK in patients
with HIV
Question
• What is AZT?
• AZT – a thymidine analog that inhibits reverse
transcriptase and mtDNA polymerase (POLG)
causing mitochondrial depletion, weakness,
myalgias, elevated CK, ragged red fibers\
4 questions in 14 years
Answer
This anti-epileptic should not be used in patients with
mitochondrial depletion syndromes because of the risk of
hepatotoxicity
Question
• What is valproic acid?
• Because of the risk of liver damage, valproic acid is
contraindicated in patients with mitochondrial
disease, as they are particularly susceptible
Other conditions to consider
CPT Deficiency
• Transport of LCFA from cytosol into the mitochondrial matrix via β-oxidation
• Autosomal recessive
• CPT I
• Hepatomegaly, mostly occurring in infants
• Reye’s syndrome “attacks” with fasting or illness
• Treatment can include maintaining high glucose intake and medium-chain triglyceride
supplementation
• CPT II
• “Benign” adult form (more than 200 families reported) is characterized by episodes of
rhabdomyolysis triggered by prolonged exercise.
• Infantile-type CPT2 presents as severe attacks of hypoketotic hypoglycemia, occasionally
associated with cardiac damage commonly responsible for sudden death before 1 year of age.
In addition to these symptoms, features of brain and kidney dysorganogenesis are frequently
seen in the neonatal-onset CPT2 deficiency, almost always lethal during the first month of life.
• Treatment involves avoidance of fasting and/or exercise, a low fat diet enriched with medium
chain triglycerides and carnitine.
• 3 questions in 14 years contained carnitine deficiency, but none were the correct answer
Carnitine/Acylcarnitine Translocase Deficiency
• Deficiency of this transport protein results in impaired long-chain fatty
acid oxidation and causes the accumulation of long-chain acylcarnitines
outside the mitochondria and in plasma.
• Begins soon after birth
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Seizures
Arrhythmias
Hypoketotic hypoglycemia
Hyperammoniemia
Hepatomegaly
Cardiomyopathy
• Many infants with CACT deficiency do not survive the newborn period.
Some affected individuals have a less severe form of the condition and
do not develop signs and symptoms until early childhood. These
individuals are at risk for liver failure, nervous system damage, coma,
and sudden death.
Co-Enzyme Q10 Deficiency
• Just like all other mitochondrial disease
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Ataxia
Encephalopathy
Myopathy
Endocrine abnormalities
Causes in myopathy in patients started on a statin.
3 question in 14 years
Mitochondrial Diseases
• Summary
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Encephalopathy
Myopathy
Neuropathy
Cardiomyopathy
Retinopathy
Exercise intolerance
Short stature
Hearing loss
Elevated lactate
Ragged red fibers
Inheritance
• Maternal, recessive, or
sporadic
• Treatment:
• Creatine, Co-Q10, ketogenic diet (other than beta oxidation defects with high carb diet), carnitine,
avoidance of fasting, supportive