mitochondrial diseases in adults natural history
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Mitochondrial diseases in adultsnatural history
S.Servidei, G.Primiano, D.Sauchelli,
C.Cuccagna, D.Bernardo, C. Sancricca
Institute of Neurology Catholic University
Roma
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• 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
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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
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mutation A3243G - phenotypesmost common mutation of mtDNA
PEO MELASMELAS
diabetes/neurosensorial deafness
cardiomyopaty
myopathy >>>>CNS
mild
CNS>>>>myo pathy
myopathy >>>>CNS
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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
+
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PEO
MELAS
MERRF
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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
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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
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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.
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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?
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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
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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
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December 2014
Severe, diffuse atrophyDementia
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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
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MELAS
MERRF
PEO S-DEL
Progression of cerebral and cerebellar atrophy2006----------------------2015
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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
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cerebellum
basal ganglia
white matter
liquor
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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).
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Follow up
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MERRF: SLEs rare; normal LA in both normal and affected regions
ChoCr
NAA
Cho Cr NAA
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POLG1: SLEs common; peak of LA elevated in the affected brain regions, absent in the normal regions
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A8344G
large mtDNA deletion
A3243G
PEO, ataxia, ophthalmoplegia
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A8344G
A3243G
mtDNA deletions
Peo/myopathy
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Muscle involvement bilateral and symmetric
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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
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MERRF
PEO
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Cardiac MRI
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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.
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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