Available online at www.sciencedirect.

com Current Opinion in

ScienceDirect Neurobiology

On the dynamic and even reversible nature of Leigh

syndrome: Lessons from human imaging and mouse
models
Melissa A. Walker1,2,3,a, Maria Miranda1,2,a,
Amanda Allred1 and Vamsi K. Mootha1,2

Abstract month old male infant with subacute onset of progres-

Leigh syndrome (LS) is a neurodegenerative disease charac- sive somnolence. He died at age 7 months, afebrile but
terized by bilaterally symmetric brainstem or basal ganglia le- diaphoretic with unreactive pupils, marked hypertonia,
sions. More than 80 genes, largely impacting mitochondrial with upgoing toes but absent deep tendon reflexes.
energy metabolism, can underlie LS, and no approved medi- Autopsy revealed bilateral, symmetric brainstem, basal
cines exist. Described 70 years ago, LS was initially diagnosed ganglia, and spinal cord gray matter lesions characterized
by the characteristic, necrotic lesions on autopsy. It has been by gliosis, vacuolation, capillary proliferation, and rela-
broadly assumed that antemortem neuroimaging abnormalities tive sparing of neurons within areas with severe necro-
in these regions correspond to end-stage histopathology. sis [2].
However, clinical observations and animal studies suggest that
neuroimaging findings may represent an intermediate state, As more cases of LS began to be recognized, there was
that is more dynamic than previously appreciated, and even growing appreciation that this is a metabolic disease.
reversible. We review this literature, discuss related conditions Acidosis, as indicated by low serum bicarbonate in pa-
that are treatable, and present two new LS cases with radio- tients in the 1950s and subsequently lactic acidosis
graphic improvement. We review studies in which hypoxia re- found in patients in the 1960s, was the first salient
verses advanced LS in a mouse model. The fluctuating and biochemical observation [3]. Defects in pyruvate
potentially reversible nature of radiographic LS lesions will be metabolism were subsequently documented in several
important in clinical trial design. Better understanding of this patients with LS. Although defects in pyruvate meta-
plasticity could lead to new therapies. bolism were initially thought to be related to pyruvate
carboxylase deficiency, this hypothesis was never
Addresses proven, and many of these cases were ultimately linked
1
Howard Hughes Medical Institute, Department of Molecular Biology,
to pyruvate dehydrogenase deficiency [4]. Cytochrome c
Massachusetts General Hospital, United States
2
Broad Institute of Harvard, MIT, United States oxidase deficiency became the first component of the
3
Department of Neurology, Massachusetts General Hospital, United electron transport chain (ETC) to be linked to LS in
States 1977 [5].
Corresponding authors: Walker, Melissa A (walker.melissa@mgh.
harvard.edu); Mootha, Vamsi K ([email protected])
Our diagnostic approach and molecular genetic under-
a
Co-first authors. standing of LS have dramatically improved over the past
few decades. LS was diagnosed based on autopsy find-
ings till the 1970s when the advent of brain contrast
Current Opinion in Neurobiology 2022, 72:80–90 tomography (CT) and, subsequently, magnetic reso-
This review comes from a themed issue on Neurobiology of Disease nance imaging (MRI) enabled antemortem diagnosis
Edited by Bart de Strooper and Huda Zoghbi [6e9]. With advances in biochemical and molecular
For a complete overview see the Issue and the Editorial
genetic testing, scores of mitochondrial biochemical and
genetic lesions were linked to LS. Today, LS is widely
Available online 14 October 2021
recognized as the most common pediatric manifestation
https://doi.org/10.1016/j.conb.2021.09.006 of mitochondrial disease, with greater than 80 genes d
0959-4388/© 2021 Published by Elsevier Ltd. mostly encoding proteins localized to mitochondria d
underlying this syndrome [1].

Introduction Lake et al. have most recently defined LS as i) a char-

Leigh syndrome (LS), also known as subacute necro- acteristic clinical presentation including psychomotor
tizing encephalomyelopathy, is the most common pe- retardation and/or regression with progressive neuro-
diatric manifestation of inherited mitochondrial logic decline, often in a stepwise fashion, with de-
disorders [1]. In 1951, Dennis Leigh described a 5- compensations, frequently with illness, ii) radiologic

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 The dynamic nature of Leigh syndrome Walker et al. 81

evidence of LS lesions in the basal ganglia or brainstem the differential diagnosis, but also promise to provide
nuclei, which appear hyperintense in T2-weighted MRI insight into the etiopathogenesis of LS.
sequences, iii) biochemical evidence of abnormal energy
metabolism, and iv) identification of a pathogenic The rare LS cases reporting both neuroimaging and
variant in a characteristic gene [1]. ‘Leigh-like’ disease subsequent autopsy findings are instructive and reveal
or “LS spectrum” is used to describe cases in which a histologic evidence of edema and capillary proliferation,
subset of these features including the radiographic or gliosis, and d to a lesser extent d inflammation. Kissel
histologic findings are fulfilled [1]. At present, the et al. [36] reported an apparent adult-onset LS case
precise sequence of events linking mutations in disease with progressive T2 prolongation signal changes of the
genes to end brain disease is not known. A better un- cerebral peduncles, periaqueductal gray, and basal
derstanding of this molecular pathogenesis is crucial as, ganglia with initial expansion, followed by contraction of
at present, there are no proven therapies. the latter. Microscopic evaluation on autopsy reviewed
capillary proliferation and gliosis in regions with relative
Here, we review the published literature, present two neuronal preservation, as well as lipid-laden macro-
new clinical cases, and integrate recent animal studies phages in areas of complete neuronal replacement by
that collectively suggest that the brain disease in LS cavitation and necrosis. All areas affected on histopath-
may be more plastic than previously appreciated. In ologic examination were also detected on MRI [36].
particular, we explore the question of whether the Koch et al. [7] reported a case of twin infants with LS
antemortem MRI abnormalities may not fully equate to where CT scan lesions observed in late stages also
end-stage pathology and that these radiographic findings correlated with loss of cellularity, vascular engorgement,
might instead reflect intermediate d potentially and gliosis on autopsy.
reversible d stages of this disease.
Resolution of radiographic brain lesions in patients
Radiographic brain lesions in Leigh syndrome with Leigh syndrome
Hyperintense signals on the T2-weighted MRI Serial imaging has at times demonstrated regression of
sequence can arise from multiple processes, making the some radiographic LS lesions. Indeed, as early as 1985,
origin of LS lesion signal abnormalities unclear. Tissues Koch et al. reported the aforementioned case of twins
such as cerebrospinal fluid (CSF) that typically have diagnosed with LS on head CT. In that study, some of the
high water content appear bright or white on T2- lesions appeared to regress on repeat imaging. Initial CT
weighted sequences, whereas brain matter appears in demonstrated hypodensities of the bilateral basal ganglia
shades of gray varying by composition. LS lesions are T2 and midbrain tegmentum at age 10 months. The basal
hyperintense, as they represent an uncharacteristically ganglia lesions were not, however, apparent on repeat
bright signal in affected regions [10]. What processes imaging at 17 months despite persistent decline in res-
typically produce T2 hyperintensity? Possibilities piratory function. Autopsy performed on one twin
include hemorrhage, ischemia, neoplasm, infection, and showed that the basal ganglia lesions that had resolved on
inflammation [10]. Reduced diffusivity on isotropic repeat imaging demonstrated no gross necrosis, only mild
diffusion mapping (thought to represent cytotoxic neuronal loss, capillary proliferation, and reactive astro-
edema) [11] has occasionally been reported in LS le- cytosis. However, in the brainstem, where imaging ab-
sions (e.g. the study reported by Bonfante et al. [9]). normalities had been persistent, there was ‘significant’
Notably, however, not all studies included this tech- loss of cells, vascular ‘engorgement,’ and ‘marked’ reac-
nique; and this abnormality can also represent an artifact tive astrocytosis [7]. These findings led the authors to
of high T2 signal. While the contribution of hemorrhage, hypothesize that ‘active lesions with vascular prolifera-
neoplasm, or infection to the T2 signal abnormalities in tion’ but without frank necrosis might appear and sub-
LS can be definitively excluded by autopsy and clinical sequently resolve [7,8]. Intriguingly, recent reports of
studies, the relative contributions of inflammation, arterial spin labeling in patients with LS indicate
edema, loss of plasma membrane integrity, and/or frank increased blood flow to LS regions during acute symp-
necrosis to high T2 signals remain unknown in both the tomatic crises [37]. Others have similarly observed
end-stage disease and antemortem intermediate states radiologic improvement of T2 signal abnormalities
in humans. without evidence of necrosis in various cohorts [9,38,39]
and in case report format (Table 2). These findings
Although LS lesions are quite distinctive, a small handful suggest that LS lesions that regress on repeat imaging
of hereditary conditions and a number of acquired con- potentially correspond to intermediate pathologic states
ditions d ranging from toxins, insults, nutritional de- rather than end-stage necrotic lesions.
ficiencies, infections d can lead to lesions with MRI
features resembling LS (Table 1) [1,12e35,54,56]. We report two new cases of transient LS brain lesions.
These mimetics are not only important considerations in Case 1 is a 10-year-old girl who first presented at age 9

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82 Neurobiology of Disease

Table 1

Radiographic differential diagnosis of Leigh syndrome brain lesions.

Leigh and Leigh-like syndrome

Mutations in >80 disease genes related to T2 hyperintense bilaterally symmetric brainstem nuclei or basal ganglia lesions; [1]
mitochondrial energy metabolism (e.g., lesions are frequently also found in the cerebellum and spinal cord.
PDH, OXPHOS)
Genetic defects in thiamine transport/ T2 hyperintensities of bilateral basal ganglia, deep gray nuclei; SLC19A3- [54,56]
processing (SLC19A3 and TPK1) related disease also involves cortical and subcortical white matter
Organic acidurias, GM1 and GM2 May at times present with T2 hyperintense bilaterally symmetric brainstem [26–28]
gangliosidoses, guanidinoacetate nuclei or basal ganglia lesions, often in addition to more canonical white
methyltransferase deficiency matter or other intracranial disease
Acquired neurologic insult
Hypoxic ischemic injury (HII) MRI may present with T2 hyperintense lesions of the bilateral putamina and [12,23]
thalami ± bilateral globi pallidi lesions and white matter lesions. HII after the
neonatal period tends to spare the thalami.
Hypoglycemic ischemic encephalopathy Classically involves the occipital cortex in addition to basal ganglia, thalami. T2 [29]
lesions preceded by diffusion restriction may evolve into encephalomalacia.
Refractory status epilepticus Typically involves pulvinar (+/− cortex), accompanied by diffusion restriction, [30]
histopathology similar to Wernicke-Korsakoff lesions.
Toxic/metabolic
Wernicke-Korsakoff Syndrome (thiamine Uniformly involves mammillary bodies in addition to structures affected in LS; [31]
deficiency) basal ganglia involvement is rare in classical (alcohol use disorder-
associated) disease but can occur in pediatric and nonalcohol use disorder-
associated adult cases; histology differs from LS in that petechial
hemorrhage is often observed.
Kernicterus (CNS bilirubin toxicity) T2 hyperintense basal ganglia lesions have been reported as late as 1 year; [32]
some reports involve T1 hyperintense lesions.
Osmotic myelinolysis Most commonly occurs in individuals with comorbid alcohol use disorder, cases [33]
with thalamic and striatal T2 signal changes have been reported.
Carbon monoxide poisoning Bilateral globi pallidi are uniformly T2 hyperintense; cerebral cortex, cerebral [34]
white matter, cerebellum, midbrain may also be involved. In rare cases, T2
and T1 hyperintensity of the globi pallidi have been observed. Lesions may
regress with time.
Metronidazole encephalopathy Lesions mostly commonly occur in the brainstem and/or cerebellar dentate [35]
nuclei, although basal ganglia are rarely involved. Metronidazole
encephalopathy is more common in individuals with comorbid alcohol use
disorder.
Fedratinib toxicity Reported as rare side effect in individuals being treated for myeloproliferative [13]
disorders. T2 hyperintense lesions were observed in the bilateral caudate
nuclei, lenticular nuclei, and thalami but not in the mammillary bodies. Clinical
and radiographic improvements were reported after thiamine
supplementation.
Disulfiram toxicity Bilateral globi pallidi and putamina are affected. Most occurrences in individuals [14]
with alcohol use disorder being treated with disulfiram; however, one case
reported in a child after accidental ingestion.
Carbon disulfide toxicity This industrial solvent is metabolized by cytochrome P450 enzymes to [15]
thiocarbamide, 2-mercapto-2-thiazolinone-5, and 2-thiothiazolidine-4-
carboxylic acid, the latter of which conjugates to glutathione. Chronic
exposure leads to encephalopathy, parkinsonism, and neuropathy. Imaging
features may be suggestive of a microangiopathy.
Vigabatrin exposure Lesions occur in ~30% of patients with epilepsy treated with vigabatrin (a GABA [16]
transaminase inhibitor) and are diffusion restricting as well as T2
hyperintense. Lesions resolve with discontinuation of therapy.
Infection-related
Hemolytic-uremic syndrome (HUS) Lesions often involve splenium of the corpus callosum in addition to structures [17]
typically affected in LS, were diffusion-restricting and T2 hyperintense, and
resolve in most cases. Edema, necrosis, spongiosis, gliosis, hemorrhages,
and thrombotic microangiopathy have all been reported on histology.
Flavivirus (West Nile, Murray Valley Lesions occur in a significant proportion of patients and may be diffusion [18]
Encephalitis) restricting and T2 hyperintense or diffusion restricting (and resolving) only,
with the latter seeming to confer a better prognosis.
Variant Creutzfeldt-Jakob disease (bovine Pulvinar most commonly affected, dorsomedial thalamic nuclei, caudate head, [19]
spongiform encephalopathy) and periaqueductal gray matter may also be involved. Lesions may regress.
Histology is characterized by spongiform change, neuronal loss,
astrocytosis, and deposition of partially protease-resistant prion protein.

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 The dynamic nature of Leigh syndrome Walker et al. 83

Table 1 (continued )

Influenza A, B associated encephalopathy/ Involvement of the splenium of the corpus callosum is often reported in addition [20]
Reye syndrome to the gray matter structures affected by LS.
Cerebral malaria Lesions of gray and white matter have been reported with some authors [21]
interpreting the gray matter lesions as resulting from vasogenic edema.
Other genetic disorders
Wilson disease (ATP7B) The MRI brain may be normal, but the most common abnormality is a T2 [22]
hyperintense signal in the lateral rim of the bilateral putamina. T2
hyperintensity of the caudate, globi pallidi, and thalami were seen only when
putaminal lesions were absent. Rarely, T1 hyperintensity may be seen in the
thalami. Response of brain lesions to copper chelation remains unclear.
Menkes disease (ATP7A) T2 hyperintense lesions of the caudate nuclei, lenticular nuclei, and globi pallidi [24]
have been reported. Isolated T2 hyperintensities of the parieto-occipital white
matter and isolated cerebral atrophy have also been reported.
Juvenile Huntington disease (HTT) Caudate atrophy, similar to adult patients, was observed in addition to T2 signal [25]
abnormalities of the caudate, which is not a feature of adult-onset disease.
Interestingly, juvenile onset HD mostly typically presents with Parkinsonism,
although adult-onset disease is characterized by chorea.
Dentatorubral-pallidoluysian atrophy (ATN1) T2 hyperintensity of the globi pallidi and thalami are present with atrophy of the [26]
tegmentum, other deep gray nuclei, and cerebellum. Histopathology
demonstrates characteristic neuronal intranuclear inclusions.

MRI, magnetic resonance imaging; OXPHOS, oxidative phosphorylation; GABA, Gamma-Aminobutyric Acid; HD, Huntington Disease; CNS, central nervous
system.

months with failure to thrive and stridor. The MRI brain confirmed diagnosis. Eight patients carried mitochon-
obtained at that time revealed T2 hyperintense bilateral drial DNA (mtDNA) mutations, 13 had nuclear gene
lesions of the caudate nuclei and putamina, thalami, and defects, with only two of these occurring in genes
red nuclei. CSF lactate was elevated at w5 mM. DNA functioning outside of the mitochondrion (SLC19A3
sequencing revealed compound heterozygous mutations [54,55] and TPK1 [56]). Transient lesions were located
in mitochondrial complex I (CI) assembly factor either in the basal ganglia (18/30), the brainstem (1/30),
NDUFAF3 (c.489_490delTG and p.Y11D). She began or in multiple brain regions (basal ganglia and the
taking a-Tocotrienol quinone in a clinical trial as a brainstem [4/30], basal ganglia and thalami [1/30], basal
toddler and continues on this medication. At age 4 years, ganglia and the cerebellum [4/30], the brainstem and
she was nonambulatory but had made significant thalami [2/30]). Although most cases describe bilateral
developmental progress, with 2e3 spoken words and the regression of lesions, asymmetric resolution of caudate
ability to point to multiple people or body parts on lesions was observed in two patients. Transient lesions
command. The T2 half-Fourier single-shot turbo spin- often recurred in the setting of illness or metabolic
echo (HASTE) brain sequence demonstrated the crises, which are well known to be preciptants of disease
decreased total area of T2 hyperintensity of the basal progression [40,41,48]. Among published cases, 16 pa-
ganglia lesions and apparent regression of basal ganglia, tients’ improved MRIs coincided with clinical
thalami, and red nuclei signal abnormalities (Figure 1A). improvement at the time of publication [8,38,40,42e
Case 2 is a 9-year-old boy who initially presented at age 46,48,49,52e54]. In some cases, this improvement was
16 months with ataxia, decreased arousal, and seizures. coincident with a treatment including ketogenic diet
The MRI brain at that time demonstrated bilateral, [38,44], rapamycin/steroids/n-acetylcysteine [52], co-
symmetric T2 hyperintensities of the dentate nuclei, enzyme Q10 [49], or biotin and thiamine supplemen-
and lactate peaks on magnetic resonance spectroscopy. tation [54,57]. Critically, no contemporaneous histology
Enzyme and genetic testing confirmed defects in the has been reported for these intermediate states in which
pyruvate dehydrogenase complex subunit PDHA1 T2 hyperintensity had been observed but had later
(hemizygous p.L5P), and ketogenic diet was initiated. regressed, and the availability of associated clinical data
The repeat MRI brain at age 4 years showed interval is variable making it difficult to correlate imaging find-
decrease in T2 hyperintense lesions (Figure 1B). At age ings with clinical course.
8 years, he speaks in full sentences and ambu-
lates independently. Inherited or acquired thiamine deficiency: a special
case of treatable lesions in humans
We identified more than 32 published cases of LS with Owing to shared features in the disease mechanism
radiographic resolution of some or all lesions [7e9,38e (Table 1), clinical presentation, radiographic, and his-
50,52e54] (Table 2). Age of onset ranged from birth tological findings, comparison of LS to Wernicke
to 22 years. Twenty-one patients carried a genetically Korsakoff syndrome (WKS) d which is often reversible

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84 Neurobiology of Disease

Table 2

Published cases of Leigh syndrome reporting radiographic improvement.

Gene or biochemical defect Age initial Age repeat imaging Reversing lesion(s) References
imaging

n/r 10mo 17mo Basal ganglia [7]

n/r 10mo 17mo Basal ganglia [7]
n/r 22mo 30mo Right caudate, midbrain [7]
n/r 10yr 11mo 11yr 7mo Left caudate [8]
n/r 3yr 3.5yr Basal ganglia [43]
PDHC deficiency 1yr 2yr Globus pallidus, cerebellum [44]
Complex I deficiency n/r n/r Basal ganglia [42]
PDHC deficiency 4yr 7mo 4yr 9mo Basal ganglia [42]
n/r n/r n/r Upper brainstem [39]
Partial COX deficiency 22yr 22yr Basal ganglia, thalami [45]
n/r 14mo 27mo Globi pallidi [46]
PDHA1 3yr 7yr Basal ganglia, inferior olivary nuclei [48]
PDHA1 n/r n/r Basal ganglia, cerebellum [41]
MT–ND5 n/r n/r Midbrain [41]
MT-ATP6 n/r n/r Basal ganglia [41]
HIBCH (c.287C > A) 14mo 24mo Basal ganglia [47]
MT–ND3 (m.10197G > A) 16yr 17yr Thalamus, cerebral peduncle, pons, [49]
medulla oblongata
PDHA1 1yr 8mo 6yr 8mo (multiple) Basal ganglia (initially improved, then [40]
progressed)
SLC19A3 2.5yr 3yr Basal ganglia [54]
MT-ATP6 (m.8689G > A) n/r n/r Putamen [9]
MT–ND3 (m.10158T > C) n/r n/r regression reported, lesion location not [9]
detailed
MT-ATP6 (m.9176 T > C) n/r n/r regression reported, lesion location not [9]
detailed
TPK1 21mo 29mo, 3yr 2mo, Basal ganglia, dentate nuclei [56]
3yr 5mo, 6yr 1mo
SUOX (c.1096C > T; c.1376G > A) 1yr 2yr, 6.5yr Globi pallidi, substantia nigra [53]
SUOX (c.1096C > T; c.1376G > A 1yr 2mo 2yr 8mo Globi pallidi, substantia nigra [53]
SUOX (c.1096C > T; c.1376G > A) 1yr 4mo 3yr 10mo Globi pallidi, substantia nigra [53]
NDUFS4 (c.355G > C) 1yr 2yr 5mo Thalami, brainstem (f/u MRI showing [52]
3yr 9mo new abnormal signal in medulla)
MT-ATP6 (m.8993T > G) n/r 32mo later Putamen [50]
MT–ND4 (m.11778G > A) n/r n/r Brainstem and basal ganglia lesions at [50]
MT–ND6 (m.14484T > C) baseline; only oculomotor nuclei in
the f/u study
MECR n/r n/r Brainstem and basal ganglia at [50]
baseline; mildly evident basal
ganglia in the f/u study
PDHA1 (c.1132C > T) 16mo 28mo Globi pallidi [38]
PDHA1 (c.615C > G) 1yr 9mo 4yr 1mo Globi pallidi [38]
NDUFAF3 9mo 5yr Caudate, putamen, thalami, red nuclei Case 1
PDHA1 16mo 4yr Dentate nuclei Case 2

n/r, not reported; f/u, follow up; PDHC, pyruvate dehydrogenase complex; COX, cytochrome C oxidase; MRI, magnetic resonance imaging.

with treatment and comparatively well-understood d encephalopathy) with hearing loss in addition to the
merits special attention. WKS results from dietary classic triad of confusion, oculomotor dysfunction, and
deficiency of and is treated with supplementation of ataxia, although hearing impairment is not a feature of
the essential vitamin thiamine (B1), which is a coen- alcohol use disorder-related disease [58]. In WKS, T2
zyme component for several mitochondrial enzymes, hyperintensities are found in the bilateral mammillary
including the pyruvate dehydrogenase complex, a bodies, thalami, tectal plate, and periaqueductal gray
known genetic cause of LS [1]. It is increasingly matter. Notably, nonalcohol use disorder patients d
recognized that WKS has two phenotypes: one arising who are more frequently pediatric d may additionally
purely from nutritional deficiency; and a nutritional have signal abnormalities of the basal ganglia, particu-
deficiency in the setting of alcohol use disorder [31]. larly the putamina [31]. The mammillary bodies are
The former presents in the acute phase (Wernicke uniformly affected in WKS but never to our knowledge

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 The dynamic nature of Leigh syndrome Walker et al. 85

Figure 1 thiamine metabolism (Table 1), raising the possibility of

shared pathogenesis between WKS and LS. LS-linked
genes SLC19A3 and TPK1 encode the plasma mem-
brane and cytosolic proteins required for thiamine
transport into cells and its processing, respectively. In
contrast to WKS, mutations in these genes lead to le-
sions in brain regions entirely consistent with LS and
comprise the very small subset of treatable forms of LS
that exhibit reversibility with high doses of thia-
mine [56,61].

Improvement of Leigh syndrome brain disease in a

mouse model
The best-characterized animal model of LS is the
mitochondrial CI accessory subunit Ndufs4 knockout
(Ndufs4
/
) mouse developed by the Palmiter laboratory
[62]. CI deficiency is a common cause of LS, and mu-
tations in NDUFS4 can, rarely, cause LS in humans [63].
Ndufs4
/
mice are born at term and show little or no
apparent disease till about 5 weeks when they develop
progressive encephalopathy and die around 7 weeks
[62]. The Ndufs4
/
have reduced body weight and
temperature, ataxia, seizures, lethargy, blindness, and
irregular breathing [62,64,65]. These mice typically
develop bilateral symmetric gray matter lesions in the
brainstem (vestibular nuclei), cerebellum, and olfactory
bulb. Although the neuroanatomy of these lesions is
consistent with the aforementioned definition of LS [1],
vestibular nuclei lesions have also specifically been re-
ported in humans [68], and cerebellar lesions are a
common feature in patients with LS, it is notable that
these mice do not exhibit lesions in the basal ganglia
[62]. Similar to humans, the Ndufs4
/
lesions are
characterized by gliosis with prominent microglial acti-
vation, vascular proliferation, neuronal loss, and vacuo-
lation [64]. Furthermore, the lesions identified by
T2-weighted MRI showing resolution of lesions. (a) Patient 1 basal ganglia
histopathology correlate with T2-weighted MRI hyper-
and thalamic lesions at age 9 months with resolution of thalamic lesions at
age 4 years (top) and red nuclei lesions at 9 months with resolution at age intensities [65]. Other murine mitochondrial encepha-
4 years (bottom). (b) Patient 2 demonstrates improvement of dentate lopathy models have been reported [69e72], but the
nuclei hyperintensities at age 16 months with marked improvement at age correlation of the histopathology with radiologic findings
4 years. MRI, magnetic resonance imaging. has only been firmly established for the Ndufs4
/
.

Multiple therapeutic approaches have been tested in

in LS (Table 1). The radiographic appearance and the Ndufs4
/
mouse. Recent gene therapy strategies to
postmortem histology of WKS and LS are similar, with re-express mouse Ndufs4 systemically restored lifespan
both characterized by relative neuronal sparing and and healthspan in the Ndufs4
/
[73]. Repletion of
striking gliosis, but unlike LS, WKS often also dem- nicotinamide adenine dinucleotide (NADþ) provided
onstrates evidence of prior hemorrhage [59]. With moderate extension of the the Ndufs4
/
lifespan from
prompt thiamine supplementation [31], most patients 60 to 100 days [74,75]. Interestingly, ectopic expression
with WKS will experience significant clinical recovery, of the yeast NADH dehydrogenase NDI1 in the brain
and resolution of brain lesions after treatment has been rescued the lifespan of the brain-specific Ndufs4
reported [60]. knockout, but the mice still had severe ataxia [76]. It is
unclear whether the beneficial effect of NDI1 is specific
Intriguingly, although most LS disease genes encode to restoring NADþ redox balance or of other down-
mitochondrial proteins involved in energy metabolism, stream effects of electron transport chain inhibition (i.e.
two of the genetic causes of LS involve perturbations of redox of the coenzyme Q pool, oxygen consumption,

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86 Neurobiology of Disease

proton pumping by downstream complexes, or mito- and histology are all ameliorated by hypoxia even when
chondrial ATP). Surprisingly, targeting reactive oxygen it is implemented at very advanced disease stages and
species with a potent antioxidant (KH176) [77] or does not restore the primary CI biochemical defect in
transgenic expression of metallothionein 1 [78] had no the Ndufs4
/
[83].
effect on lifespan. Rapamycin and doxycycline improved
healthspan and doubled the lifespan of Ndufs4
/
Radiographic improvement in lesions in the Ndufs4
/
has
[79e82]. also been achieved experimentally with other in-
terventions that reduce brain oxygen delivery including
The most powerful intervention to date in this model, anemia and administration of sublethal carbon monoxide
comparable to gene therapy, has been chronic, contin- but not with constitutive activation of the hypoxia-
uous exposure to mild hypoxia (11% oxygen), which led inducible factor (HIF) pathway [87]. Ndufs4
/
mice
to a dramatic extension of lifespan and healthspan, with exhibit a high partial pressure of brain oxygen, and
these mice now living for more than 270 days. Moreover, hyperoxia worsens disease, potentially reflecting reduced
radiologic (T2 MRI signal abnormalities) and histologic oxygen extraction by brain mitochondria [87], a finding
staining of neuroinflammatory microglial marker ionized reminiscent of the decreased oxygen utilization observed
calcium binder adaptor moleculare-1 (IBA1) show no in patients with mitochondrial myopathies [88].
evidence of the lesions in hypoxia-treated mice [83,84].
Although rapamycin, doxycycline, and hypoxia prevent Future outlook
neuroinflammation, anti-inflammatory drug tacrolimus In the 70 years since the initial description of LS, the
had no beneficial effect [79] suggesting that the field has made tremendous progress both in antemortem
mechanism(s) of action of successful interventions go diagnosis enabled by MRI imaging and in defining more
beyond blocking inflammation. To our knowledge, than 80 genetic causes for this disease. Although we
spontaneous recovery or reversal d partial or complete, typically think about LS as being a uniformly progressive
by imaging or histology d has never been documented and lethal disease, as we have discussed, there are a
in this mouse model. growing number of clinical case reports and now mouse
models that support the notion that some of the ante-
Treatment of Ndufs4
/
with hypoxia (11% oxygen) mortem imaging abnormalities observed in LS may not
initiated at advanced disease (7 weeks), when the mice represent end-stage disease but may in fact represent an
present advanced symptoms including radiologic abnor- intermediate state in the disease that is far more dy-
malities and are close to fulfilling humane euthanasia namic and even reversible. In particular, mouse studies
criteria, clinically reverses disease and rescues the mice
by improving their overall body weight and motor func- Figure 2
tion, as well as substantially extending their lifespan.
Given the uniformly progressive nature of the disease in
this mouse model and that neurodegeneration has been
reported at this timepoint [64], this dramatic improve-
ment was surprising. Remarkably, in addition to clinical
improvement, T2 MRI hyperintensities progressively
decrease till they become almost undetectable after one
month of hypoxia treatment, which correlates to a sub-
stantial reduction of neuroinflammation in histopathol-
ogy at this age [84] (Figure 2).

Although the mechanism of LS lesion improvement in

the Ndufs4
/
remains unknown, partial reversibility in
WKS disease rodent models has been reported. In a
thiamine-deficient mouse model, thiamine treatment
prevented further neuroinflammation and neuronal
death only when administered before extensive
neuronal loss occurs [85], indicating that treatment
halts disease progression but does not fully reverse it,
suggesting that inflammation preceding necrosis may be
amenable to intervention. Differences in the ‘lesion age’
may explain why thiamine treatment in the analogous
rat model normalized radiologic hyperintensities in the Radiologic and histopathologic reversal of lesions in the Ndufs4−/− mouse
after hypoxia treatment. Top: T2 MRI; red arrows indicate hyperintensities
thalamus and colliculi but not in mammillary nuclei and in vestibular nuclei. Bottom: immunohistochemistry of coronal section la-
lateral ventricles [86]. Unlike thiamine rescue in WKS beling microglia with IBA1 and the nuclear counterstain DAPI (40 ,6-
models, pathologic phenotype, imaging abnormalities, diamidino-2-phenylindole). MRI adapted from Ferrari et al., 2017.

Current Opinion in Neurobiology 2022, 72:80–90 www.sciencedirect.com

 The dynamic nature of Leigh syndrome Walker et al. 87

suggest that neuroinflammation is one of the features understood, it could imply that we can identify risk
that is reversible and correlates with phenotypic and factors to be avoided and hopefully new medicines that
radiographic improvement. directly target this biology for treating the scores of
patients. Although such interventions may not fix the
At present, we do not have a clear understanding of how proximal genetic lesion, they could be very powerful in
inherited mutations in any of greater than 80 different preventing disease progression. Mitochondrial diseases
genes can lead to radiographically supported LS. Key are extremely rare and heterogeneous, and although
open questions are as follows: (1) which are the dynamic interventions in the past have been coincident with
neuropathological features of LS lesions evidenced by recovery in LS, we emphasize that most of the cases of
T2 MRI (e.g. neuroinflammation, edema)? (2) in addi- radiographic improvement that we have reviewed here
tion to neuroinflammation, which aspects of interme- (Table 2) occurred spontaneously (e.g. studies re-
diate disease are reversible? (3) why do infections or ported by Koch et al. [7], Koch et al. [8], Arii and
illness precipitate these lesions on imaging? (4) is there Tanabe [39], Sofou et al. [41], Roig et al. [43], and
a critical treatment time window before irreversible Alves et al. [50]). This underscores the need for proper
tissue damage sets in? (5) is improvement caused by natural history studies and rigorous control arms in
removal of pathogenic drivers (e.g. excess oxygen), by clinical trials [89].
halting neuropathological effects of mitochondrial
dysfunction (e.g. neuroinflammation), or instead by
activating brain repair pathways? Patient cases
Written consent to publish case information was ob-
The answers to these important questions remain un- tained from patients.
known, but a detailed study of the human and mouse
model literature yields a handful of common themes. As Funding
expected, repletion of cofactor deficiencies such as thia- The authors acknowledge support from the NIH
mine correlates temporally with brain lesion improvement K08NS117889 (MAW), Deutsche Forschungsgemein-
in humans and rodents. It has also been shown that in- schaft 431313887 (MM), the Marriott Foundation
terventions to either buffer consequences of oxidative (VKM), the Howard Hughes Medical Institute (VKM),
phosphorylation defects (e.g. redox imbalances) or reduce and the MacCurtain family (VKM).
energetic demands (e.g. via mechanistic target of rapa-
mycin (mTOR) inhibition) can delay brain disease and Conflict of interest statement
extend life in the mouse. Finally, capillary proliferation on The authors declare the following financial interests/
histopathology and hyperperfusion of lesions during crises personal relationships which may be considered as po-
in humans supports a role for brain microvasculature in LS tential competing interests: VKM is listed as a coinventor
irrespective of genetic etiology. Strikingly, the radio- on a patent on the therapeutic uses of hypoxia for mito-
graphic differential diagnosis for LS lesions (Table 1) in- chondrial diseases. VKM is on the Scientific Advisory
cludes multiple processes in which pathogenic vasogenic Board of 5am Ventures and Janssen Pharmaceuticals.
edema d which may be associated with inflammation d
has been implicated. These findings are of course insuf- Acknowledgements
ficient to determine if hyperperfusion or any of its resul- The authors thank Darryl DeVivo, Mel B. Feany, and Lance Rodan for
valuable feedback.
tant effects d notable excess oxygenation d is causal or
merely secondary findings in LS. However, bench research
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