Mitochondrial DiseaseRITE ReviewAndrew Sas

Neurology Resident12/28/2015

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

• 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• 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

www.umdf.org – The United Mitochondrial Disease Foundation

Types of disease

• 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

www.umdf.org – The United Mitochondrial Disease Foundation

*found in RITE database

Mitochondrial Disorders: Inheritance

?

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

Maternal Inheritance Autosomal recessive

* Barth syndrome is X-linked recessive

Respiratory Chain

• Complex• I• II• III• IV• V

SDH +

COX –Cytochrome oxidase

Ragged Red Fibers

Paracrystalline inclusions (MELAS)

Normal SDHSuccinyl Dehydrogenase)

Mitochondrial Myopathy - Pathology

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 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

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 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

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?

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?

Case 2 – Leigh’s Disease

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

Case 2 – Leigh’s Disease

Case 2 – Leigh’s Disease

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

Diagnosis?

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

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

Case 4

Diagnosis?

Hint

• 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 4 – Leber’s Hereditary Optic Neuropathy

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

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

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

Case 6 Workup:

Biopsy:

EMG: Small amplitude, short duration motor unit action potentials

LP: Elevated lactate and pyruvate

Diagnosis ?

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

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?

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

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

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

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?

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• 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• Ataxia• Encephalopathy• Myopathy• Endocrine abnormalities

Causes in myopathy in patients started on a statin.

3 question in 14 years

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