Neurological Perspective

1. MELAS
Neurological Perspective
Ade Wijaya, MD – April 2018

2. Outline:
– Introduction
– Epidemiology
– Diagnostic Criteria
– Clinical Manifestation
– Pathology
– Pathogenesis
– Management
– Summary

3. Introduction
Mitochondria are double membrane
organelles found in all nucleated
human cells and perform a variety of
essential functions, including the
generation of ATP
A.W. El-Hattab, F. Scaglia, Mitochondrial disorders, in: B. Lee, F. Scaglia (Eds.), Inborn Errors of Metabolism: From Neonatal Screening to Metabolic Pathways, Oxford University Press, New
York, NY, USA 2015, pp. 180–202

4. Introduction
Mitochondrial
encephalomyopathy
Stroke-like
episodes
Lactic acidosis
One of the most frequent maternally inherited mitochondrial disorders which was first
delineated in 1984.
S.G. Pavlakis, P.C. Phillips, S. DiMauro, D.C. De Vivo, L.P. Rowland, Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome, Ann. Neurol. 16 (1984) 481–488.

5. Epidemiology
– The prevalence of MELAS syndrome has been estimated to be 0.2:100,000 in
Japan.
– MELAS syndrome at the severe end to asymptomatic carrier status, was found
to be relatively common with a prevalence of 16–18:100,000 in Finland.
S. Yatsuga, N. Povalko, J. Nishioka, K. Katayama, N. Kakimoto, T. Matsuishi, T. Kakuma, Y. Koga, TaroMatsuoka for MELAS Study Group in Japan, MELAS: a nationwide prospective cohort study of
96 patients in Japan, Biochim. Biophys. Acta 1820 (2012) 619–624.
K. Majamaa, J.S. Moilanen, S. Uimonen, A.M. Remes, P.I. Salmela, M. Kärppä, K.A. Majamaa-Voltti, H. Rusanen, M. Sorri, K.J. Peuhkurinen, I.E. Hassinen, Epidemiology of A3243G, themutation for
mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population, Am. J. Hum. Genet. 63 (1998) 447–454.
J. Uusimaa, J.S. Moilanen, L. Vainionpää, P. Tapanainen, P. Lindholm, M. Nuutinen, T. Löppönen, E. Mäki-Torkko, H. Rantala, K. Majamaa, Prevalence, segregation, and phenotype of the
mitochondrial DNA 3243ANG mutation in children, Ann. Neurol. 62 (2007) 278–287.

6. Diagnostic Criteria
2 Criteria A & 2 Criteria B
Criteria A
– Headaches with vomiting,
– seizures,
– hemiplegia,
– cortical blindness,
– and acute focal lesions in
neuroimaging.
Criteria B
– High plasma or cerebrospinal fluid
(CSF) lactate,
– mitochondrial abnormalities in
muscle biopsy,
– and a MELAS related gene
mutation.
S. Yatsuga, N. Povalko, J. Nishioka, K. Katayama, N. Kakimoto, T. Matsuishi, T. Kakuma, Y. Koga, TaroMatsuoka for MELAS Study Group in Japan, MELAS: a nationwide prospective cohort
study of 96 patients in Japan, Biochim. Biophys. Acta 1820 (2012) 619–624.

7. Neurological Manifestation
(common)
– Stroke-like episodes are one of the cardinal features of MELAS syndrome that
occur in 84–99% of affected individuals.
– Dementia occurs in 40–90% of affected individuals.
– Epilepsy is another common neurological manifestation occurring in 71–96% of
individuals with MELAS syndrome.
– Recurrent headaches occur in 54–91% of individuals with MELAS syndrome.
– Hearing impairment occurs in 71–77% of individuals with MELAS syndrome.
– Peripheral neuropathy is another common manifestation of MELAS syndrome
occurring in 22–77% of affected individuals.
M. Hirano, S.G. Pavlakis, Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts, J. Child Neurol. 9 (1994) 4–13.
S. DiMauro, M. Hirano,MELAS, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, et al., (Eds.), GeneReviews®, University of Washington, Seattle, 2013 [Internet].
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome, Ann.
N. Y. Acad. Sci. 1142 (2008) 133–158.
S. Yatsuga, N. Povalko, J. Nishioka, K. Katayama, N. Kakimoto, T. Matsuishi, T. Kakuma, Y. Koga, TaroMatsuoka for MELAS Study Group in Japan, MELAS: a nationwide prospective cohort
study of 96 patients in Japan, Biochim. Biophys. Acta 1820 (2012) 619–624.

8. Neurological Manifestation
(others)
– learning disability, memory impairment, myoclonus, ataxia, episodes of altered
consciousness.
– Basal ganglia calcifications in neuroimaging, and elevated protein in CSF
analysis.
– Ophthalmological complications include optic atrophy, pigmentary retinopathy,
and ophthalmoplegia.
– Psychiatric illnesses can occur in MELAS syndrome and include depression,
bipolar disorder, anxiety, psychosis, and personality changes.
R.E. Anglin, S.L. Garside, M.A. Tarnopolsky, M.F. Mazurek, P.I. Rosebush, The psychiatric manifestations of mitochondrial
disorders: a case and review of the literature, J. Clin. Psychiatry 73 (2012) 506–512.
M. Hirano, S.G. Pavlakis, Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts, J. Child Neurol. 9 (1994) 4–13.
S. DiMauro, M. Hirano,MELAS, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, et al., (Eds.), GeneReviews®, University of Washington, Seattle, 2013

9. Stroke-like Episodes
– Partially reversible aphasia,
– cortical vision loss,
– motor weakness,
– headaches,
– altered mental status, and
– seizures with the eventual progressive accumulation of neurological deficits.
M. Hirano, E. Ricci, M.R. Koenigsberger, R. Defendini, S.G. Pavlakis, D.C. DeVivo, S. DiMauro, L.P. Rowland, MELAS: an original case and clinical criteria for diagnosis, Neuromuscul. Disord. 2 (1992)
125–135.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome, Ann. N. Y.
Acad. Sci. 1142 (2008) 133–158.

10. Neuroimaging
– The affected areas in neuroimaging do not correspond to classic vascular
distribution (hence called “stroke-like”), are asymmetric, involve predominantly
the temporal, parietal, and occipital lobes, and can be restricted to cortical
areas or involve subcortical white matter.
– Normal MRA.
– MR spectroscopy shows decreased N-acetylaspartate signals and accumulation
of lactate.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome, Ann. N. Y.
Acad. Sci. 1142 (2008) 133–158.
M. Hirano, E. Ricci, M.R. Koenigsberger, R. Defendini, S.G. Pavlakis, D.C. DeVivo, S. DiMauro, L.P. Rowland, MELAS: an original case and clinical criteria for diagnosis, Neuromuscul. Disord. 2 (1992)
125–135.

11. Neuroimaging
M. Hirano, E. Ricci, M.R. Koenigsberger, R. Defendini, S.G. Pavlakis, D.C. DeVivo, S. DiMauro, L.P. Rowland, MELAS: an original case and clinical criteria for diagnosis, Neuromuscul. Disord. 2 (1992)
125–135.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome, Ann. N. Y.
Acad. Sci. 1142 (2008) 133–158.

12. Dementia
– Intelligence,
– language,
– perception,
– attention,
– memory function,
– executive function.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome, Ann. N. Y.
Acad. Sci. 1142 (2008) 133–158.

13. Seizures
– Focal or generalized
– Manifestation of stroke-like episodes or independent
– Imaging: white matter lesions, cortical atrophy, and corpus callosum agenesis or
hypogenesis
J. Finsterer, S. Zarrouk-Mahjoub, Focal and generalized seizures may occur in mitochondrial encephalomyopathy, lactic acidosis,
and strokelike episodes (MELAS) patients, J. Child. Neurol. (2015)

14. Headaches & Hearing Impairment
Headaches
– Migrainous headaches in the form
of recurrent attacks of severe
pulsatile headacheswith frequent
vomiting
Hearing impairment
– Sensorineural hearing loss
inMELAS syndrome is typically
mild, insidiously progressive, and
often an early clinical
manifestation
K. Ohno, E. Isotani, K. Hirakawa, MELAS presenting as migraine complicated by stroke: case report, Neuroradiology 39 (1997) 781–784.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical
phenotype, and therapeutic management of MELAS syndrome, Ann. N. Y. Acad. Sci. 1142 (2008) 133–158.

15. Peripheral Neuropathy
– Chronic and progressive, sensorimotor, and distal polyneuropathy.
– Nerve conduction studies typically show an axonal or mixed axonal and
demyelinating neuropathy.
M. Kärppä, P. Syrjälä, U. Tolonen, K. Majamaa, Peripheral neuropathy in patients with the 3243ANG mutation in mitochondrial DNA, J. Neurol. 250 (2003) 216–221.
P. Kaufmann, J.M. Pascual, Y. Anziska, C.L. Gooch, K. Engelstad, S. Jhung, S. DiMauro, D.C. De Vivo, Nerve conduction abnormalities in patients with MELAS and the A3243G mutation,
Arch. Neurol. 63 (2006) 746–748.
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome,
Ann. N. Y. Acad. Sci. 1142 (2008) 133–158.

16. S. Yatsuga, N. Povalko, J. Nishioka, K. Katayama, N. Kakimoto, T. Matsuishi, T. Kakuma, Y. Koga, TaroMatsuoka for MELAS Study
Group in Japan, MELAS: a nationwide prospective cohort study of 96 patients in Japan, Biochim. Biophys. Acta 1820 (2012) 619–624.
M. Hirano, S.G. Pavlakis, Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts, J.
Child Neurol. 9 (1994) 4–13.
S. DiMauro, M. Hirano,MELAS, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, et al., (Eds.), GeneReviews®, University of Washington, Seattle,
2013 [Internet].
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and
therapeutic management of MELAS syndrome, Ann. N. Y. Acad. Sci. 1142 (2008) 133–158.

17. Pathology
S. DiMauro, M. Hirano,MELAS, in: R.A. Pagon, M.P. Adam, H.H.
Ardinger, et al., (Eds.), GeneReviews®, University of Washington,
Seattle, 2013 [Internet].
D.M. Sproule, P. Kaufmann, Mitochondrial encephalopathy, lactic
acidosis, and strokelike episodes: basic concepts, clinical
phenotype, and therapeutic management of MELAS syndrome,
Ann. N. Y. Acad. Sci. 1142 (2008) 133–158.

18. Pathogenesis
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism. 2015 Sep 1;116(1):4-12.

19. Management
– Symptomatic
– Multidisciplinary: neurologist, cardiologist, endocrinologist, audiologist,
ophthalmologist, physical and occupational therapists, psychologist, and social
worker.
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism. 2015 Sep 1;116(1):4-12.

20. Management
– Evaluation of multi-organ involvement
– Management of complications
– Medications to avoid
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism. 2015 Sep 1;116(1):4-12.

21. Evaluation of multi-organ involvement
– Comprehensive neurological examination with cognitive assessments, brain
MRI,
– audiologic and ophthalmologic examinations,
– growth assessment,
– echocardiogram and electrocardiogram,
– screening for hypothyroidism,
– screening for diabetes by fasting blood glucose and glucose tolerance test.
S. DiMauro, M. Hirano,MELAS, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, et al., (Eds.), GeneReviews®, University of Washington, Seattle, 2013

22. Management of complications
– Symptomatic
– Regular exercise can improve exercise capacity
– Supplementation: L-arginine, citrulline, Coenzyme Q10 (CoQ10), Creatine, L-
carnitine.
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism. 2015 Sep 1;116(1):4-12.

23. Medications to avoid
– Valproic acid  deleterious on mitochondrial function
– Phenobarbital, carbamazepine, phenytoin, oxcarbazepine, ethosuximide,
zonisamide, topiramate, gabapentin and vigabatrin
– Metfomin  lactic acidosis
– Dichloroacetate  peripheral nerve toxicity
– Aminoglycosides, linezolid, and alcohol  mitochondrial toxicity
– Smoking
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism. 2015 Sep 1;116(1):4-12.

24. Summary
– MELAS syndrome is a frequent maternally inherited mitochondrial disorder.
– Multi-organ disease with broad manifestations.
– Classic triad: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes.
– The m.3243ANG mutation in the MT-TL1 gene occurs in 80% of individuals with
MELAS syndrome.
– Several mechanisms including impaired mitochondrial energy production,
microvasculature angiopathy, and NO deficiency.
– Management of MELAS syndrome is largely symptomatic and should involve a
multidisciplinary team.