1. Mitochondrial Disease
RITE Review
Andrew Sas
Neurology Resident
12/28/2015

2. 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

3. Mitochondrial Diseases
Summary
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

4. 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

5. Types of disease
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
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
– The United Mitochondrial Disease Foundation

6. Types of disease *found in RITE database
Beta-oxidation Defects
Creatine Deficiency Syndromes
Co-Enzyme Q10 Deficiency
CPEO
Glutaric Aciduria Type II
KSS
Lactic Acidosis
Leigh Disease or Syndrome
LHON
MAD
MELAS
MERRF
Mitochondrial DNA Depletion
Mitochondrial Encephalopathy
Mitochondrial Myopathy
NARP
Pyruvate Dehydrogenase Deficiency
Respiratory Chain
– The United Mitochondrial Disease Foundation

7. Mitochondrial Disorders: Inheritance?

8. 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

9. Mitochondrial Disorders: Inheritance
Maternal Inheritance
Autosomal recessive
* Barth syndrome is X-linked recessive

10. Respiratory Chain
Complex I II
III IV V

11. Mitochondrial Myopathy - Pathology
Normal SDH
Succinyl Dehydrogenase)
SDH +
Ragged Red Fibers
COX –
Cytochrome oxidase
Paracrystalline inclusions (MELAS)

12. Answer
This substance is found in high concentrations in serum and CSF of patients with mitochondrial cytopathies.

13. Question What is lactic acid?
Lactate and glucose levels in various disease:
Mitochondrial cytopathy – low glucose, high lactate
14 questions in 14 years

14. Answer
This anesthetic infusion used for sedation inhibits mitochondrial fatty acid oxidation, oxidative phosphorylation, carnitine palmitoyl transferase, and secondarily inhibits Complex II.

15. 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

16. Case 1 16 year-old boy CC: Ataxia and droopy eyelids. HPI: PMH: Exam:
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?

17. Case 1 – Kearns-Sayre Syndrome
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.
Genetics: mtDNA deletions, usually sporadic
5 question in 14 years

18. 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.

19. Chronic Progressive External Ophthalmoplegia
Ptosis
Symmetric ophthalmoplegia with relative sparing of downgaze
Facial weakness, frontalis
Dysarthria
Sparing of ciliary and iris muscles
Common presentation of any mitochondrial myopathy
Lid surgery is usually not performed due to risk for exposure keratopathy
Can be isolated or part of KSS

20. Case 2 14 year old girl CC: New onset seizures HPI:
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
PMH:
Normal childhood and development, previously healthy
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.
Workup:
MRI shows changes in the basal ganglia, thalamus
Spectroscopy shows increased lactate peak
Diagnosis?

21. Case 2 – Leigh’s Disease 14 year old girl CC: New onset seizures HPI:
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
PMH:
Normal childhood and development, previously healthy
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.
Workup:
MRI shows changes in the basal ganglia, thalamus
Spectroscopy shows increased lactate peak
Diagnosis?

22. Case 2 – Leigh’s Disease
Subacute Necrotizing Encephalomyelopathy (SNEM)
Clinical Features
Developmental delay or psychomotor regression
Brainstem dysfunction
Respiratory disorders (episodic hyperventilation)
Ophthalmoplegia
Ataxia
Dystonia
Seizures, lactic acidosis, vomiting, weakness
Peripheral neuropathy, reduced nerve conduction velocity, demyelination
Genetics
Mutations in either mtDNA or nuclear DNA
Pyruvate dehydrogenase (PDHC) most common
Imaging/Pathology
Bilateral, symmetric necrotizing lesions with spongy changes, microcysts in the basal ganglia, thalamus, brainstem, and spinal cord
Prognosis
Poor, survival of months from disease onset
5 questions in 14 years

23. Case 2 – Leigh’s Disease

24. Case 2 – Leigh’s Disease

25. Case 3 20 year old woman CC: Right-sided weakness HPI:
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
PMH:
Headaches
Sensorineural hearing loss
Diabetes
Exam:
Short stature
Right homonymous hemianopsia, right hemiparesis, language problems
Workup:
Serum lactic acidosis
MRI

26. Diagnosis?

27. Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Episodes (MELAS)
Clinical features-
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

28. Case 4 22 year old man CC: Vision loss HPI:
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
PMH:
None – healthy otherwise
Exam:
Central visual field loss bilaterally, color desaturation, relatively preserved peripheral vision
Workup:
MRI brain - normal
Visual field testing
LP – negative for OCB, IgG index normal

29. Case 4
Diagnosis?

30. Hint

31. 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

32. Case 5 17 year old girl CC: Numbness and clumsiness HPI:
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
PMH:
Poor vision, has glasses
Learning disorder, has an IEP
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
Workup:
MRI brain - normal
EMG shows peripheral sensory polyneuropathy, worse LE than UE

33. Case 5 - Neuropathy, Ataxia, Retinitis Pigmentosa (NARP)
Clinical features
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
Vitamin A, lutein, docosahexaenoic acid, acetazolamide, calcium channel blockers, and valproic acid
1 question in 14 years – does not have opsoclonus

34. Case 6
22 year old man
CC: Seizures and limb jerking, also has weakness and clumsiness
HPI:
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
PMH:
Hearing loss
Short stature
Idiopathic cardiomyopathy diagnosed on echo, ordered for mild murmur on exam
Exam:
MS, CNs, reflexes are normal
Proximal LE weakness and decreased sensation distally in lower extremities.
FNF and HKS shows mild dysmetria.
Gait ataxia

35. Case 6
Workup:
Biopsy:
EMG: Small amplitude, short duration motor unit action potentials
LP: Elevated lactate and pyruvate
Diagnosis ?

36. Case 6 - Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
Clinical Features:
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

37. Cases 7, 8, and 9 3 month old girl
Recurrent episodes of hypoglycemia, hypotonia, and profound acidosis
35 year old man
Elevated CK and recurrent rhabdomyolysis after vigorous exercise
60 year old woman
Asymptomatic
What type of mitochondrial disease could they all have?

38. Beta Oxidation Defects
Autosomal recessive
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
Treatment: High carbohydrate, low fat diet, administration of medium-chain triglyceride oil, and diet supplementation with carnitine and/or riboflavin. Avoidance of fasting.
5 questions in 14 years

39. Cases 7, 8, and 9 3 month old girl
Recurrent episodes of hypoglycemia, hypotonia, and profound acidosis
More likely shorter chain defect
35 year old man
Elevated CK and recurrent rhabdomyolysis after vigorous exercise
More likely longer chain defect
60 year old woman
Asymptomatic
Any beta oxidation defect

40. Case 10 14 year old girl CC: Dystonia and cognitive regression HPI:
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
PMH:
Cognitive impairment
Epilepsy
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

41. Case 10 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
Diagnosis?

42. 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 Aug 8;67(3):480-4.

43. Answer
Mitochondrial depletion, caused by this drug, can result in myalgias, weakness, and elevated CK in patients with HIV

44. 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

45. Answer
This anti-epileptic should not be used in patients with mitochondrial depletion syndromes because of the risk of hepatotoxicity

46. 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

47. Other conditions to consider

48. 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

49. 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
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.

50. Co-Enzyme Q10 Deficiency
Just like all other mitochondrial disease
Ataxia
Encephalopathy
Myopathy
Endocrine abnormalities
Causes in myopathy in patients started on a statin.
3 question in 14 years

51. Mitochondrial Diseases
Summary
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