Mitochondrial diseases in adultsnatural history

S.Servidei, G.Primiano, D.Sauchelli,

C.Cuccagna, D.Bernardo, C. Sancricca

Institute of Neurology Catholic University

Roma

• significant clinical and genetic heterogeneity• syndromic and non-syndromic • often multi-system diseases• onset between birth and senescence• a common cause of chronic morbidity and more prevalent

than previously thought

Common phenotypes in adultsPEO Progressive External OphthalmoplegiaKSS Kearns Sayre SyndromeMERRF Myoclonic Epilepsy with Ragged Red FibersMELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis

and Stroke-like episodes)

Mitochondrial diseases

PEO PEO plus KSS

mildmyopa thy

slowly progres sive

myopathy > = <CNS

variably multisy stem

variable severity and progression

CNS>>>>myo pathy

severe

single mtDNA deletionsporadic

S-Del, PointMut, M-Delsporadic, maternal, dominant recessive

single mtDNA deletionsporadic

mutation A3243G - phenotypesmost common mutation of mtDNA

PEO MELASMELAS

diabetes/neurosensorial deafness

cardiomyopaty

myopathy >>>>CNS

mild

CNS>>>>myo pathy

myopathy >>>>CNS

MERRFo PEO/myopathy (exercise intolerance

and/or muscle weakness) lactic acidosis o myoclonuso epilepsy (focal or generalized)o ataxiarespiratory dysfunction, cardiac

abnormalities, neuropathy, cognitive impairment, multiple lipomatosis.……

• A8344G tRNA Lys (most common mutation)

about half of our patients did not develop symptoms of CNS involvement even in later stagesof the disease -> miopathy, lactic acidosis and abnormal EEG is the most common phenotype associated to the A8344G “MERRF” mutation

+

PEO

MELAS

MERRF

14,8 18

,75

33,3

14,3

44,4

18,8

16,7

28,629,6

37,5

44,4

28,6

11,1

25,0

5,6

28,6

0

5

10

15

20

25

30

35

40

45

50

sDel mDel non Mut MutPunt

% d

i paz

ient

i

absentmildmoderatesevere

respiratory dysfunction in myopathic patients 

Respiratory monitoring -> spirometry, polysonnography, emogas•Patients with moderate or severe respiratory insufficiency may require nocturnal or continuous invasive or non-invasive positive pressure ventilation •Patients with mild phenotypes may have respiratory problems and or sleep-apnoea

S-Del M-Del no-mut point-mut

Mitochondrial disorders and CNS involvement

• neurons are particularly sensitive to oxidative metabolism dysfunction. Mitochondria are, in fact, the major source of ATP and participate in cellular Ca2+ homeostasis playing a central part in modulation of neuronal excitability and synaptic transmission

• paroxysmal symptoms such as stroke like episodes, migraine and epilepsy/myoclonus are characteristic of MELAS and MERRF respectively, and POLG-phenotypes

• ataxia and cerebellar involvement in Kearns Sayre syndrome, MERRF, NARP, and POLG-phenotypes

• leukoencephalopaty is present in some patients with mtDNA rearrangements and in MNGIE

• bilateral striatal necrosis is typical of NARP/MILS and Leigh syndromes and may be present in other mitochondrial disorders

FLAIR

DWI

ADC

MRA

rCBF

rCBV

MR @ 2 d MR @ 8 d MR @ 30 d MR @ 120 d

H1-MRS

T1 +C T1 +C

MELAS: lesions in supratentorial cortical and subcortical areas; non-vascular distribution and migrational behavior; increased perfusion; mixed pattern of increased (vasogenic edema) and restricted (cytotoxic edema) diffusion on ADC maps since the early stages. Some cortical lesions turn into pseudolaminar necrosis, gliosis and atrophy.

MELAS non-ischemic neurovascular cellular

mechanismparoxysmal events common at the onset of

SLEs • focal (mainly motor) or generalized

seizures in 44% of patients and in 74% of SLEs

• migrainous attacks in 50% of patients and in 64% of SLEs -> role of Cortical Spread Depression in SLEs in SLEs in posterior brain regions?

MELASPathophysiology of stroke-like:

theories1.ischemic mechanism based on a

mitochondrial microangiopathy, BBB dysfunction, vasogenic edema

2.primarily metabolic mechanism sustained by neuronal energetic dysfunction and toxic effect of lactic acid

3.non-ischemic neurovascular cellular mechanism

LA

NAA

DWIMRI

Cho Cr NAALA

•Very high incidence, compared with vascular strokes, of bilateral and symmetrical lesions

•36-year old: May 2004 auditory agnosia (severe difficulty comprehending speech and to process auditory stimuli)•MRI/DWI: acute, bilateral and almost symmetrical, abnormal signal intensity in both temporal lobes

December 2014

Severe, diffuse atrophyDementia

Cerebral and/or cerebellar atrophy exceeded by far the extension of SLEs in more than 50% of the patients

Two mechanisms involved in MELAS abrupt loss of function due to cell injury

followed by partial recovery (with coexistence of vasogenic and cytotoxic edema in acute lesions) and

an independent slowly progressive degenerative process that can precede by years SLEs

MELAS

MELAS

MERRF

PEO S-DEL

Progression of cerebral and cerebellar atrophy2006----------------------2015

proton magnetic resonance spectroscopic imaging (1HMRSI) assess metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-L-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine [Cr]) ), and 5) membrane biosynthesis and turnover (total choline [Cho])

A number of brain MRI and magnetic resonance spectroscopy signatures exist for different subtypes of mitochondrial disease

cerebellum

basal ganglia

white matter

liquor

MELAS

DWI and MRS spectra in a 15-year old boy with A3243G mutation one month before a SLE (a). During the SLE, involving cortical and subcortical white matter of right occipital lobe, a double LA peak is visible with marked reduction of NAA (b). After clinical resolution, one month later, LA disappeared and NAA normalized(c).

Follow up

MERRF: SLEs rare; normal LA in both normal and affected regions

ChoCr

NAA

Cho Cr NAA

POLG1: SLEs common; peak of LA elevated in the affected brain regions, absent in the normal regions

A8344G

large mtDNA deletion

A3243G

PEO, ataxia, ophthalmoplegia

A8344G

A3243G

mtDNA deletions

Peo/myopathy

Muscle involvement bilateral and symmetric

Atrophy and fat infiltration predominantly involved glutei and posterior thigh muscles (biceps femoris and adductor magnus). At level of the leg,the posterior compartment was more commonly involved with a prevalent impairment of soleus.

MERRF

MERRF

PEO

Cardiac MRI

Late Gadolinium Enhancement

• delayed enhancement in 38% of patients

• mostly in inferolateral segments of the left ventricle

• characteristic pattern of non-ischemic LGE

• may represent an early signCardiac MRI in MERRF

diffuse intramural LGE and global hypocinesia of the left ventricle (EF 28%) and depressed global systolic dysfunction of the right ventricle (EF 38%). The presence of mitochondrial abnormalities confirmed the mitochondrial origin of the cardiomyopathy.Implanted with implantable cardioverter-defibrillator at the age of 60 years.

ConclusionThe mitochondrial medicine has had a brief and intense history, but the best (including effective therapy) is yet to come (Billi Di Mauro)The appropriate use of reliable biomarkers may be helpfulfor diagnosis and disease monitoringin defining natural historyto characterize and better understanding mechanisms of mitochondrial dysfunction that lead to heterogeneous phenotypesto orient therapeutic strategies