2 Objectives Discuss different types of mitochondrial disease Recognize common featuresReview options for treatment if they existFocus on RITE diseases/topicsRITE type questions
3 Mitochondrial Diseases SummaryEncephalopathyMyopathyNeuropathyCardiomyopathyRetinopathyExercise intoleranceShort statureHearing lossElevated lactateRagged red fibersInheritanceMaternal, recessive, orsporadicTreatment: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 heterogeneityPainful ACRONYMS and Eponyms (or both!)Lactic acidosisSome treatments exist, but no curesCould try creatine or CoQ10
5 Types of diseaseAlpers DiseaseBarth syndromeBeta-oxidation DefectsCarnitine-Acyl-Carnitine DeficiencyCarnitine DeficiencyCreatine Deficiency SyndromesCo-Enzyme Q10 DeficiencyComplex I DeficiencyComplex II DeficiencyComplex III DeficiencyComplex IV DeficiencyComplex V DeficiencyCOX DeficiencyCPEOCPT I DeficiencyCPT II DeficiencyGlutaric Aciduria Type IIKSSLactic AcidosisLCADLCHADLeigh Disease or SyndromeLHONLIC (Lethal Infantile Cardiomyopathy)Luft DiseaseMADMCADMELASMERRFMIRASMitochondrial CytopathyMitochondrial DNA DepletionMitochondrial EncephalopathyMitochondrial MyopathyMNGIENARPPearson SyndromePyruvate Carboxylase DeficiencyPyruvate Dehydrogenase DeficiencyPOLG MutationsRespiratory ChainSCADSCHADVLCAD– The United Mitochondrial Disease Foundation
6 Types of disease *found in RITE database Beta-oxidation DefectsCreatine Deficiency SyndromesCo-Enzyme Q10 DeficiencyCPEOGlutaric Aciduria Type IIKSSLactic AcidosisLeigh Disease or SyndromeLHONMADMELASMERRFMitochondrial DNA DepletionMitochondrial EncephalopathyMitochondrial MyopathyNARPPyruvate Dehydrogenase DeficiencyRespiratory Chain– The United Mitochondrial Disease Foundation
8 Mitochondrial Disorders: Inheritance About ½ of mitochondrial diseases are inherited from mitochondrial DNA in a maternal fashionThe other ½ are due to nuclear mutations that affect mitochondrial functionMany are sporadic mutations
11 Mitochondrial Myopathy - Pathology Normal SDHSuccinyl Dehydrogenase)SDH +Ragged Red FibersCOX –Cytochrome oxidaseParacrystalline inclusions (MELAS)
12 AnswerThis 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 lactate14 questions in 14 years
14 AnswerThis 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 adultsmetabolic acidosis, heart failure, renal failure, hyperkalemia and rhabdoPrevent by giving carbohydrate load/infusion (children have limited carbohydrate reserves)Treat by hemofiltration3 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 staturediabetescomplete heart blockExam: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 boyCC: 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 staturediabetescomplete heart blockExam: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 sporadic5 question in 14 years
18 Kearns-Sayre Syndrome Insidiously progressive disease with CPEO before the age of 20.Symptoms/Clinical Features:Mitochondrial Myopathy (proximalweaknessCPEOretinal degeneration (pigmentary retinopathy)cardiac conduction defects (heart block)Ataxia/cerebellar syndromeOther symptoms include small stature, deafness, dementia, delayed puberty, and endocrine dysfunctionLaboratory: Increased CSF protein and lactateMRI- bilateral subcortical white matter T2 hyperintensitiesinvolving basal ganglia, thalamus, and brainstemPathology: ragged red fibersNote: Pearson’s syndrome- sideroblastic anemia,pancreatic insufficiency, and low birth weight precede KSS symptoms.
19 Chronic Progressive External Ophthalmoplegia PtosisSymmetric ophthalmoplegia with relative sparing of downgazeFacial weakness, frontalisDysarthriaSparing of ciliary and iris musclesCommon presentation of any mitochondrial myopathyLid surgery is usually not performed due to risk for exposure keratopathyCan 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 bodyPMH:Normal childhood and development, previously healthyExam: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, thalamusSpectroscopy shows increased lactate peakDiagnosis?
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 bodyPMH:Normal childhood and development, previously healthyExam: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, thalamusSpectroscopy shows increased lactate peakDiagnosis?
22 Case 2 – Leigh’s DiseaseSubacute Necrotizing Encephalomyelopathy (SNEM)Clinical FeaturesDevelopmental delay or psychomotor regressionBrainstem dysfunctionRespiratory disorders (episodic hyperventilation)OphthalmoplegiaAtaxiaDystoniaSeizures, lactic acidosis, vomiting, weaknessPeripheral neuropathy, reduced nerve conduction velocity, demyelinationGeneticsMutations in either mtDNA or nuclear DNAPyruvate dehydrogenase (PDHC) most commonImaging/PathologyBilateral, symmetric necrotizing lesions with spongy changes, microcysts in the basal ganglia, thalamus, brainstem, and spinal cordPrognosisPoor, survival of months from disease onset5 questions in 14 years
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 headacheNausea, vomitingRoommate noticed she was sleepy today and not her normal selfPMH:HeadachesSensorineural hearing lossDiabetesExam:Short statureRight homonymous hemianopsia, right hemiparesis, language problemsWorkup:Serum lactic acidosisMRI
27 Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) Clinical features-MyopathyEncephalopathy with headaches and vomitingStroke like symptoms: hemiparesis, hemianopsia most commonShort stature, hearing loss, lactic acidosis and diabetesMutation- mtDNA point mutationsLaboratory: Lactic acidosis with exerciseMRI: 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 fibersTreatment: Carnitine, Co-Enzyme Q10, Vitamin K, Vitamin C, L-Arginine8 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, painlessDiagnosed originally with optic neuritisPresents for second time 2 months later with similar subacute vision painless central vision loss in left eyePMH:None – healthy otherwiseExam:Central visual field loss bilaterally, color desaturation, relatively preserved peripheral visionWorkup:MRI brain - normalVisual field testingLP – negative for OCB, IgG index normal
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/lesionsFundoscopic exam: Telangiectatic microangiopathy, disc pseudoedema, microangiopathy, or vascular tortuosity.Pathology:mtDNA point mutationsNo 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 objectsShe says that she has a hard time feeling the ground, trips easily over cracks in the sidewalk or on carpetFeels a little weak in the legs, has some difficulty standing from a low-seated chairPMH:Poor vision, has glassesLearning disorder, has an IEPExam:MS WNL. CNs show decreased visual acuity, ptosis, fundus exam shows…Proximal LE weakness and decreased sensation distally in lower extremities.Brisk patellar reflexesFNF and HKS shows significant dysmetria.Gait ataxiaWorkup:MRI brain - normalEMG shows peripheral sensory polyneuropathy, worse LE than UE
33 Case 5 - Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Clinical featuresSensory neuropathyCerebellar ataxiaRetinitis pigmentosaProximal weakness myopathyPtosisMutationmtDNA point mutation that is the same as seen in KSS and Leigh’sEMGSensorimotor polyneuropathy, myopathic features on needle examPathologyRagged red fibersTreatment?Gene therapy and skin-derived pluripotent stem cell grafts are being studiedFor retinitis pigmentosaVitamin A, lutein, docosahexaenoic acid, acetazolamide, calcium channel blockers, and valproic acid1 question in 14 years – does not have opsoclonus
34 Case 622 year old manCC: Seizures and limb jerking, also has weakness and clumsinessHPI: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 consciousnessHas 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 feetNoted some problems with coursework, now getting failing grades in college – he previously graduated high school without difficultyPMH:Hearing lossShort statureIdiopathic cardiomyopathy diagnosed on echo, ordered for mild murmur on examExam:MS, CNs, reflexes are normalProximal LE weakness and decreased sensation distally in lower extremities.FNF and HKS shows mild dysmetria.Gait ataxia
35 Case 6Workup:Biopsy:EMG: Small amplitude, short duration motor unit action potentialsLP: Elevated lactate and pyruvateDiagnosis ?
36 Case 6 - Myoclonic Epilepsy with Ragged Red Fibers (MERRF) Clinical Features:Starts in 20’s to 30’sProximal muscle weaknessEpilepsy with MyoclonusDementiaAtaxiaCardiomyopathyAlso get pyramidal tract signs, neuropathy, optic nerve atrophy, and neurosensory hearing loss.Mutation: mtDNA point mutations or deletions or POLG-1 mutationLaboratory: Increased CSF lactate and pyruvate.EMG: Myopathic featuresPathology: 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 acidosis35 year old manElevated CK and recurrent rhabdomyolysis after vigorous exercise60 year old womanAsymptomaticWhat type of mitochondrial disease could they all have?
38 Beta Oxidation Defects Autosomal recessiveVery Long-Chain Acyl-CoA Dehydrongenase DeficiencyLong-Chain Acyl-CoA Dehydrongenase DeficiencyLong-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencyMultiple Acyl-CoA Dehydrogenase Deficiency/Glutaritic Aciduria Type IIMedium-Chain Acyl-CoA Dehydrongenase DeficiencyShort-Chain Acyl-CoA Dehydrogenase Deficiency.Short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiencyCommon features include liver disease, heart disease, encephalopathyMay include pigmentary retinopathy, neuropathy, myoglobinuriaTreatment: 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 acidosisMore likely shorter chain defect35 year old manElevated CK and recurrent rhabdomyolysis after vigorous exerciseMore likely longer chain defect60 year old womanAsymptomaticAny 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 walkingInitially spoke in sentences, but regressed to single words onlySignificant cognitive impairment, but able to physically keep up with peers until last year when she began to have dystonic posturing of extremitiesNow is having agitation, outbursts, crying and screaming episodesDystonia also now involves face, jaw, neck, trunk, and tonguePMH:Cognitive impairmentEpilepsyExam:MS – impaired language, follows only simple 1-word commandsCNs – abnormal dystonic posturing of head with neck rotationStrength 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 fibersCK – not elevated, if anything ~ lowNerve conduction/EMG – no neuropathic or myopathic changesSkin biopsy - normalCopper level, ceruloplasmin – normal rangeUrine organic acids, plasma amino acids normalVLCFA (Beta oxidation diseases) normalNiemann-Pick A and B, Fragile X, Rett – negativeDiagnosis?
42 Creatine Deficiency Syndromes Autosomal recessiveGuanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency)L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency)X-linkedSLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency)All have mental retardation, seizures, speech delay.GAMT - behavioral disorder - including autistic behaviors; movement disordersSLC6A8Growth retardationMales: mild to severe mental retardationFemales: learning and behavior problemsIn 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 AnswerMitochondrial depletion, caused by this drug, can result in myalgias, weakness, and elevated CK in patients with HIV
44 QuestionWhat 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 AnswerThis 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
48 CPT DeficiencyTransport of LCFA from cytosol into the mitochondrial matrix via β-oxidation Autosomal recessiveCPT IHepatomegaly, mostly occurring in infantsReye’s syndrome “attacks” with fasting or illnessTreatment can include maintaining high glucose intake and medium-chain triglyceride supplementationCPT 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 birthSeizuresArrhythmiasHypoketotic hypoglycemiaHyperammoniemiaHepatomegalyCardiomyopathyMany 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 diseaseAtaxiaEncephalopathyMyopathyEndocrine abnormalitiesCauses in myopathy in patients started on a statin.3 question in 14 years
51 Mitochondrial Diseases SummaryEncephalopathyMyopathyNeuropathyCardiomyopathyRetinopathyExercise intoleranceShort statureHearing lossElevated lactateRagged red fibersInheritanceMaternal, recessive, orsporadicTreatment:Creatine, Co-Q10, ketogenic diet (other than beta oxidation defects with high carb diet), carnitine, avoidance of fasting, supportive