Leigh syndrome …

Neurogenetic Disorders

Updated 09.04.2023
Released 07.30.1998
Expires For CME 09.04.2026

Leigh syndrome

Authors: Christopher Mario Inglese MD, Alexander Y Kim MD

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Editor: Bernard L Maria MD

Leigh syndrome

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Introduction

Overview

Leigh syndrome is a neurometabolic genetic condition that typically presents during infancy or childhood. It is clinically characterized by progressive neurodegeneration associated with specific neuroradiology or neuropathology findings (symmetric basal ganglia or brainstem abnormalities). Additional organ systems may be affected. Leigh syndrome has been described in association with many nuclear and mitochondrial DNA defects. Treatment includes proactive surveillance for and aggressive management of comorbidities, vitamin or cofactor supplementation when appropriate, and mitigation of physiologic stressors. Specific forms of Leigh syndrome may have particular treatment principles. Genetic counseling is essential.

Key points

	• Leigh syndrome is a progressive neurometabolic genetic condition and the most commonly encountered phenotype in patients with primary mitochondrial disease.
	• Leigh syndrome typically presents with neurodegeneration during infancy or childhood. However, there may be multisystem manifestations, and onset may occur later in life. It is typically associated with a relapsing-remitting course and an increased risk for mortality.
	• The characteristic brain MRI findings include symmetric T1 and T2 prolongation involving the basal ganglia or brainstem. However, other regions of the central nervous system may also be affected.
	• The diagnosis can be established based on characteristic clinical, biochemical, and neuroimaging (or histopathologic) findings. Confirmation with genetic testing is recommended because the results may inform management.
	• Leigh syndrome has been attributed to various genetic etiologies implicating the nuclear and mitochondrial genomes. A growing number of Leigh-like syndromes and overlap syndromes also have been described.
	• Treatment is predominantly supportive. Vitamin or cofactor supplementation may be considered. Some forms of Leigh syndrome may have more targeted approaches to management, which cannot be considered universally helpful and may be harmful in some cases.

Historical note and terminology

In 1951, British neuropathologist Denis Leigh first described subacute necrotizing encephalopathy in an infant with rapidly progressive and ultimately fatal neurodegeneration (47). Autopsy was notable for the finding of bilateral symmetric spongy degeneration with vascular and glio-mesodermal proliferation reminiscent of Wernicke encephalopathy. However, the growing experience with Leigh syndrome was less suggestive of acquired thiamine deficiency and more suggestive of an inborn error of metabolism instead (26). Subsequent reports associated it with lactic acidosis and then with deficiencies of several mitochondrial enzymes, including pyruvate dehydrogenase and cytochrome c oxidase (82; 25; 81). Consequently, it has been recognized for many years that Leigh syndrome may be attributable to various genetic etiologies.

In parallel, it has also been appreciated for many years that Leigh syndrome may present with various neurologic and extraneurologic findings. The characteristic neuropathological findings for 50 cases of Leigh syndrome were first reviewed in detail by Montpetit and colleagues in 1971 (54). However, not all patients for whom the diagnosis of Leigh syndrome is suspected will meet diagnostic criteria. Under these circumstances, the diagnosis of Leigh-like syndrome has been applied (63). For a subset of these cases, the finding of Leigh-like lesions may instead be suggestive of an alternative diagnosis, such as MEGDEL syndrome with the distinctive “putaminal eye” sign (27). Furthermore, some patients with Leigh syndrome may also have findings consistent with an additional diagnosis, such as MELAS (03).

Clinical manifestations

Presentation and course

Clinical presentation. Most patients with Leigh syndrome initially present with psychomotor abnormalities during infancy or early childhood, with onset by 2 years of age in 80.8% of cases (69). When considered in aggregate, there does not appear to be a significant difference in the age at onset or disease outcome for cases attributable to nuclear DNA defects versus those attributable to mitochondrial DNA defects (71). However, specific genetic etiologies may be more likely to present with particular clinical, biochemical, radiographic, and neuropathologic findings (eg, cardiac and ocular involvement with defective complex I structure and assembly, cytochrome c oxidase deficiency on muscle histopathology with SURF1 pathogenic variation).

Leigh syndrome manifestations

(Contributed by Dr. Alexander Y Kim.)

Formal diagnostic criteria for Leigh syndrome have been proposed and updated based on the ever-evolving understanding of this clinical entity (45). Initial stringent criteria included progressive neurologic disease, signs and symptoms of brainstem or basal ganglia involvement, elevated blood or cerebrospinal fluid lactate levels, and neuroimaging or neuropathologic findings characteristic of Leigh syndrome. Since then, it has been recognized that some patients may present with alternative biochemical or molecular genetic evidence of defective energy metabolism instead of elevated lactate levels. A high index of suspicion is required to recognize the suggestive pattern of findings and then investigate further. Cases not fulfilling diagnostic criteria may be considered to have a Leigh-like syndrome instead.

Several studies of larger cohorts have continued to emphasize the frequency of developmental delay, regression, hypotonia, and weakness in patients with Leigh syndrome (69; 04; 74; 38). A wide variety of additional neurologic findings may be observed, including seizures (eg, generalized, focal, spasms, status epilepticus, epilepsia partialis continua), spasticity, myoclonus, choreoathetosis, dystonia, ataxia, and neuropathy. Various ocular findings (eg, nystagmus, strabismus, visual impairment, optic atrophy, retinopathy, ptosis, ophthalmoplegia) and failure to thrive are also frequently encountered. Additional multi-organ system manifestations may include cardiac, hepatic, and renal dysfunction.

Beyond overall disease progression, certain clinical complications can cause death or increase the risk thereof. Respiratory failure may occur due to brainstem dysfunction or muscular weakness. Cardiomyopathy may be present at disease onset or develop later in the clinical course. There should be a low threshold for evaluating the possibility of these life-threatening medical problems.

It has also become increasingly important to appreciate the possibility of overlap syndromes meeting criteria for both Leigh syndrome and another condition, such as MELAS and MERRF (67; 03; 79). Based on the cases reported thus far, MELAS/LS overlap syndrome and other blended phenotypes may be more likely with a pathogenic variant in the mtDNA. Separately, dual diagnosis with Leigh syndrome and a comorbid condition (eg, moyamoya disease, Fukuyama congenital muscular dystrophy, mucolipidosis type II) has also been described (17; 42; 72). These unique cases call attention to potential pitfalls in the diagnosis of Leigh syndrome.

Neuroimaging findings. The characteristic MRI findings of Leigh syndrome correlate with the neuropathologic findings. MRI shows T1 and T2 prolongation with symmetrical involvement, most commonly of the putamina, globi pallidi, caudates, thalami, substantia nigra, inferior olivary nuclei, periaqueductal gray matter, superior cerebellar peduncles, tegmentum of the brainstem, and, less commonly, the periventricular white matter and corpus callosum. CT scans are considered less useful than MRIs but may nevertheless detect basal ganglia involvement. MRS may demonstrate decreased N-acetylaspartate and increased lactate levels, which are most apparent in the abnormally enhancing areas on MRI (52; 08).

Abnormal putaminal signal in Leigh disease (MRI) (1)

T1-weighted axial MRI of a 7-year-old girl with Leigh disease and dystonia, corticospinal tract dysfunction (progressive), with complex I deficiency. (Contributed by Dr. Richard Morse.)
Abnormal putaminal signal in Leigh disease (MRI) (2)

T2-weighted axial MRI of a 7-year-old patient with Leigh disease. (Contributed by Dr. Richard Morse.)
Abnormal signal in the midbrain in Leigh disease (MRI)

T2-weighted axial MRI of a 14-month-old infant with Leigh disease and apnea, oculomotor palsies, and developmental regression. (Contributed by Dr. Richard Morse.)
Abnormal symmetrical signal in the upper midbrain and lower thalamus in Leigh disease (MRI)

14-month-old infant with Leigh disease. (Contributed by Dr. Richard Morse.)

Alves and colleagues have provided a detailed description of the brain and spine MRI findings of Leigh syndrome organized by CNS location (03). Based on their results and those of other groups, the classic description of bilateral symmetrical brainstem or basal ganglia lesions may be an oversimplification. Furthermore, some lesions demonstrated by neuroimaging may be transient rather than permanent.

Neuropathology. Leigh syndrome was originally described as a neuropathological entity classically characterized by symmetric necrotizing basal ganglia and brainstem lesions (47; 54). Ongoing observations have substantiated the general description of the distinctive symmetric focal lesions as “vasculo-necrotic” and resembling the sequelae of infarction despite the absence of a clear relationship to major vessels (15; 44). Specific lesion subtypes have been described and are thought to reflect several factors, including lesion age, patient age, and disease duration. Even to the naked eye, there may be coexisting reddish-brown soft tissue and greyish firm gliotic scar thought to represent younger and older lesions, respectively, sometimes in juxtaposition suggestive of episodic damage to selectively vulnerable tissue. Histologically, the younger cellular lesions demonstrate vascular hypertrophy and congestion, macrophage and foam cell abundance, spongiosis of the neuropil, etc. In contrast, older hypocellular lesions predominantly demonstrate fibrous gliosis. Some regions may be selectively spared (eg, the inferior olivary nuclei during infancy), whereas others may be more consistently compromised (eg, the substantia nigra or the inferior colliculi). Similar lesions may be encountered in the setting of other primary mitochondrial diseases (eg, MELAS, MERRF, Kearns-Sayre syndrome), which may be distinguished from Leigh syndrome by the topography of involvement. However, individual cases may be characterized by significant overlap between diagnostic categories.

Additional regions of the central and peripheral nervous system may be affected beyond the classic pattern of basal ganglia and brainstem involvement. Spinal cord involvement is likely underappreciated (44). The possibility of peripheral neuropathy should also be considered (31; 53). Specific characteristics may suggest specific genetic etiologies (eg, demyelinating neuropathy and SURF1 pathogenic variation, axonal neuropathy and MT-ATP6 pathogenic variation, predominantly sensory neuropathy and POLG1 pathogenic variation). In contrast, histological examination of the muscle may only be notable for nonspecific changes. The absence of mitochondrial biochemical or morphological changes in muscle does not exclude the possibility of Leigh syndrome.

Prognosis and complications

Leigh syndrome has been associated with a wide array of clinical trajectories, ranging from fulminant progression resulting in early mortality to relatively static. A relapsing-remitting course has been frequently described because many patients experience acute exacerbations, particularly with intercurrent illnesses (28). Ultimately, understanding a specific patient’s prognosis should be informed by the genetic etiology and the clinical presentation.

Earlier onset and higher clinical severity (eg, elevated CSF lactate, failure to thrive, seizures, brainstem lesions on neuroimaging, illnesses requiring critical care) are thought to be predictive of poor prognosis with regard to acute exacerbations and survival (28). However, rapid progression to mortality has been described even with adult-onset Leigh syndrome. The leading cause of death is respiratory failure, whether attributable to brainstem dysfunction or respiratory muscle weakness. Cardiac failure has also been described as a cause of death. In general, peak mortality for Leigh syndrome occurs before 3 years of age. However, specific etiologies have been associated with expectations for either shorter lifespans (eg, NDUFS4 pathogenic variation, SURF1 pathogenic variation, MT-ND5 pathogenic variation, MT-ATP6 pathogenic variation, ALDH5A1 pathogenic variation) or longer lifespans (eg, SUCLA2 pathogenic variation, PET100 pathogenic variation, ECHS1 pathogenic variation, SLC19A3 pathogenic variation), and some may have specific treatments with the potential to meaningfully alter the natural history (45; 04; 49; 74). For example, rapid resolution of acute encephalopathy without recurrence has been described in a few patients with Leigh syndrome attributable to thiamine transporter 2 deficiency (56). It is important to keep in mind that the data are evolving and may be conflicting.

Clinical presentation with the specific sequence of primary developmental delay preceding neurodevelopmental regression has been associated with earlier onset and poor prognosis (77). Bilateral caudate changes have also been associated with poor outcomes (49).

Clinical vignette

An 18-month-old female was referred for the evaluation of global developmental delay, growth restriction, acquired microcephaly, hypotonia, episodic hyperventilation, and ataxia. Pregnancy was complicated by hyperemesis gravidarum, requiring intravenous fluids. She was born at 42 weeks gestation. Her birth weight was 2,550 grams. The perinatal course was uncomplicated. She developed feeding difficulties with vomiting at 3 months of age, which was initially improved by thickening her feeds and antacid administration. However, by 9 months of age, she was noted to be intolerant of solid foods, and her growth parameters demonstrated decline over time. She developed hypotonia, tremulousness, and ataxia by 18 months of age. There was no family history of similar presentation.

At the time of evaluation, her weight was at the 50th percentile for a 12-month-old, her height was at the 50th percentile for a 16-month-old, and her head circumference was at the 50th percentile for a 10-month-old. She had global developmental delay and functioned at the level of an 11- to 13-month-old. Additionally, she exhibited self-stimulating and self-injurious behaviors, such as poking her eyes and banging her head. Physical examination was notable for microcephaly, mild hypotonia, intact deep tendon reflexes, intention tremor, and wide-based gait. She also had a peculiar breathing pattern with episodic hyperventilation.

Her diagnostic evaluation included unremarkable barium swallow study, head CT, brain MRI, EEG, karyotype, plasma amino acids, urine amino acids, urine organic acids, ammonia, chemistries including glucose, biotinidase enzyme activity, arterial blood gas, and eye examination. Lactate was elevated at 28.8 mmol/L (upper limit = 23 mmol/L), whereas pyruvate was not. CSF studies were also notable for elevated lactate at 3.5 mmol/L (upper limit = 2 mmol/L). Repeat brain MRI demonstrated a characteristic symmetric increased T2-weighted signal within the putamina and the brainstem tegmentum, which supported the suspected diagnosis of Leigh syndrome.

Her clinical course was progressive. Over the next 2 years, she experienced episodic worsening of her condition and developed a seizure disorder. She was treated with antiepileptics, empiric B vitamin, and coenzyme Q10 supplementation. She had inadequate weight gain despite gastrostomy tube placement. She was enrolled in an early intervention program and received physical, occupational, and speech therapy services. However, she continued to deteriorate. She became less alert and interactive over time and lost all language. She eventually developed respiratory failure and passed away at 4 years of age. An autopsy was not performed.

Biological basis

Etiology and pathogenesis

Leigh syndrome is not a single disorder but rather the shared clinical, biochemical, radiographic, and neuropathologic expression of a diverse and growing group of inborn errors of energy metabolism. The number of known genetic etiologies has been steadily approaching 100 since the initial description of this clinical entity in 1951. These may be broadly subdivided based on whether the molecular genetic defect is located in the nuclear DNA (nDNA) or the mitochondrial DNA (mtDNA). According to the recent meta-analysis of 385 cases conducted by Chang and colleagues, 38% of cases were attributable to nDNA defects, whereas 32% were attributable to mtDNA defects (16). Subsequently published studies have reinforced the importance of investigating both possibilities with molecular genetic testing (46; 04; 74; 38).

Leigh syndrome may also be conceptually subdivided based on the mechanism by which energy metabolism is expected to be disrupted. Historically, it has been useful to consider whether oxidative phosphorylation or pyruvate metabolism is impaired. There are myriad mechanisms by which either biological process may be disrupted. Impaired oxidative phosphorylation may be characterized by either isolated or combined respiratory chain complex deficiencies. This, in turn, may be caused by subunit defects, cofactor transport or biosynthesis defects, mtDNA maintenance defects, mitochondrial membrane maintenance defects, and other pathophysiologies. Impaired pyruvate metabolism may be attributable to either primary or secondarily-induced pyruvate dehydrogenase complex deficiencies. It is important to remember that biochemical findings do not necessarily indicate specific genetic etiologies.

DiMauro and Schon have provided a useful review of the complex interplay between the nuclear and mitochondrial genomes as required for normal mitochondrial structure and function (23). For example, respiratory chain complexes consist of both nDNA-encoded and mtDNA-encoded components, with the exception of complex II, which includes only nDNA-encoded subunits. Selected nDNA and mtDNA defects are highlighted here as follows:

Table 1. Selected Nuclear DNA Defects

*PDHA1* pathogenic variation	Pyruvate hydrogenase deficiency was among the first enzymatic defects described in association with Leigh syndrome. It remains an important cause with a specific treatment strategy. The PDHA1 gene encodes the E1-alpha subunit of the pyruvate dehydrogenase complex. Pathogenic variation in this gene is a common cause of primary pyruvate dehydrogenase complex deficiency or Leigh syndrome. It should also be specifically considered with X-linked inheritance.
*ECHS1* pathogenic variation	The ECHS1 gene encodes mitochondrial short-chain enoyl-CoA hydratase 1, which catalyzes steps in both fatty acid oxidation and the valine catabolic pathway. It has been associated with secondarily-induced pyruvate dehydrogenase complex deficiency. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may benefit from a specific treatment strategy.
*HIBCH* pathogenic variation	The HIBCH gene encodes 3-hydroxyisobutyryl-CoA hydrolase, which catalyzes a step in the valine catabolic pathway. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may benefit from a specific treatment strategy.
*SLC19A3* pathogenic variation	The SLC19A3 gene encodes a thiamine transporter. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may specifically benefit from thiamine (and biotin) supplementation to good effect.
*TPK1* pathogenic variation	The TPK1 gene encodes thiamine pyrophosphokinase, which catalyzes the conversion of thiamine to the active cofactor thiamine pyrophosphate. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may specifically benefit from thiamine (and biotin) supplementation to good effect.
*ACAD9* pathogenic variation	The ACAD9 gene encodes a mitochondrial flavoenzyme that catalyzes a step in fatty acid oxidation and participates in mitochondrial complex I assembly. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may specifically benefit from riboflavin supplementation.
*PDSS2* pathogenic variation	The PDSS2 gene encodes a subunit of decaprenyl diphosphate synthase, which catalyzes the first step of the coenzyme Q10 biosynthetic pathway. Pathogenic variation in this gene has been recognized as a cause of Leigh syndrome that may specifically benefit from coenzyme Q10 supplementation.
*SURF1* pathogenic variation	The SURF1 gene encodes an assembly factor of mitochondrial complex IV (cytochrome c oxidase). Pathogenic variation in this gene has been identified as a leading cause of Leigh syndrome as a whole (particularly in association with complex IV deficiency or hypertrichosis) and is one of the most common nDNA-defects encountered. There is a growing body of evidence that it may be associated with an unfavorable prognosis, albeit with some conflicting data.
*SUCLA2* pathogenic variation	The SUCLA2 gene encodes the beta-subunit of succinyl-CoA ligase, which is a mitochondrial matrix enzyme that catalyzes a step in the canonical tricarboxylic acid cycle. Pathogenic variation in this gene has been associated with Leigh syndrome at a high frequency in the Faroe Islands as a consequence of a founder effect. It is also uniquely characterized by elevated methylmalonic acid.
*LRPPRC* pathogenic variation	The LRPPRC gene encodes a leucine-rich pentatricopeptide repeat-containing protein involved in regulating mitochondrial posttranscriptional gene expression. Pathogenic variation in this gene has been associated with French-Canadian variant of Leigh syndrome at a high frequency in the Saguenay-Lac Saint-Jean region near Quebec, Canada as a consequence of a founder effect. A subset of cases has also been uniquely characterized by frequent acute metabolic or neurologic crises with severe complex IV deficiency in the brain and liver.
*DNM1L* pathogenic variation	The DNM1L gene encodes a protein belonging to the dynamin superfamily involved in mitochondrial and peroxisomal fission. Pathogenic variation in this gene has been associated with the only known form of autosomal dominant Leigh syndrome.
*NDUF* pathogenic variation	The various NDUF genes encode subunits of mitochondrial complex I (NADH dehydrogenase). Pathogenic variation in these genes has been associated with Leigh syndrome and mitochondrial complex I deficiency either in isolation or in combination with another mitochondrial complex deficiency. Additionally, data have suggested a higher likelihood of cardiac involvement with mitochondrial complex I deficiency.

With the mtDNA defects, it is worth considering the potential contributions of matrilineal inheritance, the mitochondrial bottleneck, heteroplasmy, threshold effects, and random mitotic segregation in producing the protean presentations of Leigh syndrome. For example, the same m.8993T>C variant may be associated with neuropathy, ataxia, and retinitis pigmentosa (NARP) or with Leigh syndrome, depending on the heteroplasmy level (33).

Table 2. Selected Mitochondrial DNA Defects

*MT-ND* pathogenic variation	The various MT-ND genes encode subunits of mitochondrial complex I (NADH dehydrogenase). Pathogenic variation in these genes has been specifically associated with cortical involvement or presentation with MELAS/LS overlap syndrome. Additionally, data have suggested a higher likelihood of cardiac involvement with mitochondrial complex I deficiency.
*MT-CO3* pathogenic variation	The MT-CO3 gene encodes a subunit of mitochondrial complex IV (cytochrome c oxidase). Pathogenic variation in this gene should be considered in patients with Leigh syndrome and complex IV deficiency not attributable to nDNA-defects.
*MT-ATP6* pathogenic variation	The MT-ATP6 gene encodes a subunit of mitochondrial complex V (ATP synthase). Pathogenic variation in this gene has been identified as a leading cause of Leigh syndrome as a whole and is one of the most common mtDNA-defects encountered. The m.8993T>G and m.8993T>C variants specifically have been frequently found in association with Leigh syndrome.
*MT-TK* *and MT-TL1* pathogenic variation**	The MT-TK and MT-TL1 genes encode the mitochondrial tRNAs for lysine and leucine, respectively. Pathogenic variation in these genes has been associated with multiple primary mitochondrial disease phenotypes, including overlap syndromes.
Single large-scale mitochondrial DNA deletion (SLSMD)	SLSMDs are a rare cause of Leigh syndrome.

Differential diagnosis

The differential diagnosis for Leigh syndrome depends on the age of onset, clinical course, pattern of neurologic involvement, and associated clinical findings. The “classic” presentation is subacute encephalopathy with bilateral basal ganglia or brainstem involvement. However, this is an oversimplification of the phenotype. The presence of spinal cord or white matter involvement does not exclude the possibility of Leigh syndrome. Furthermore, the protean manifestations of primary mitochondrial diseases, including Leigh syndrome, typically require that the differential diagnosis remains broad. A few key considerations are as follows.

Characteristic clinical course. In the pediatric population, stepwise neurologic deterioration has been specifically described with the vanishing white matter leukodystrophies. Historically, the presence of cavitation was thought to distinguish this group of disorders from Leigh syndrome. However, cavitation on neuroimaging has been reported with the latter as well (03). In contrast, basal ganglia involvement is not expected with the vanishing white matter leukodystrophies as it is with Leigh syndrome. A variety of primary mitochondrial diseases, including MELAS/LS overlap syndrome (meeting criteria for both MELAS and Leigh syndrome), may also present with stepwise neurologic deterioration (79).

Characteristic bilateral basal ganglia involvement. It is important to consider the possibility of specifically actionable mimics of Leigh syndrome, including biotin-thiamine responsive basal ganglia disease attributable to thiamine transporter deficiency, defects of thiamine processing, and acquired thiamine deficiency (05). It may not be possible to differentiate between these diagnostic considerations and Leigh syndrome without molecular genetic testing, so empiric biotin and thiamine supplementation is often considered, given the potential for dramatic improvements. Some inborn errors of metabolism, including the organic acidemias (eg, methylmalonic acidemia, propionic acidemia, glutaric acidemia type I), may be characterized by increased risk for bilateral striatal necrosis in the setting of acute metabolic crisis. Biochemical screening may demonstrate derangements specific to these organic acidemias. Other inborn errors of metabolism, including the lysosomal storage disorders (eg, GM1 gangliosidosis) and the several forms of neurodegeneration with brain iron accumulation (eg, pantothenate kinase-associated neurodegeneration), may present more insidiously or with characteristic findings (58). For example, progressive visceromegaly may be noted with GM1 gangliosidosis, whereas the classic “eye of the tiger” sign may be noted with pantothenate kinase-associated neurodegeneration. Isolated striatonigral degeneration with progressive dystonia has been reported in association with complex V, nuclear pore, and phosphoinositide regulation defects (22; 09; 48). Inborn errors of immunity, including the type I interferonopathy known as Aicardi-Goutieres syndrome, may present with bilateral basal ganglia involvement in the setting of subacute encephalopathy and multi-organ system dysfunction (13).

Characteristic combination of bilateral basal ganglia and brainstem involvement. This pattern of neurologic involvement has been recently described in a patient with a phosphoinositide regulation defect associated with VAC14 pathogenic variation (36). The possibility of a primary mitochondrial disease like Leigh syndrome could only be excluded after establishing the actual underlying diagnosis via whole exome sequencing.

Ordinarily, classic cases of Leigh syndrome may be distinguished from those of other primary mitochondrial diseases with bilateral brainstem involvement (eg, DARS2 pathogenic variation) based on distinctive topographies of involvement (75). However, atypical presentations have been described.

The presence of lactic acidosis is neither necessary nor sufficient for establishing the diagnosis of Leigh syndrome. It is also a nonspecific finding that may be attributable to various intrinsic genetic and extrinsic environmental factors, including other primary mitochondrial diseases and spurious elevation attributable to improper sample collection. Lactic acidosis with a normal (or low) lactate-to-pyruvate ratio is suggestive of pyruvate dehydrogenase complex deficiency, which may be primary or secondary (eg, mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, acquired thiamine deficiency).

It is important to consider the possibility of Leigh syndrome in the differential diagnosis for demyelinating (eg, neuromyelitis optica spectrum disorder, anti-MOG associated disease), ischemic, and infectious disease processes given its potential to serve as a mimic (03). Patients with Leigh syndrome mimicking these diseases may not present with all of the expected findings, follow the expected clinical courses, or demonstrate the expected treatment responses. Under these circumstances, the possibility of specifically actionable mimics, including CNS-isolated hemophagocytic lymphohistiocytosis, should also be considered (11; 59).

Diagnostic workup

If the possibility of Leigh syndrome is suspected, the diagnostic evaluation should include studies that will generate evidence of defective energy metabolism as required to fulfill diagnostic criteria. Historically, measurement of blood or cerebrospinal fluid levels was considered necessary. However, the absence of lactic acidosis does not exclude the diagnosis; alternative biochemical indicators of defective energy metabolism and molecular genetic results have been considered acceptable more recently. The characteristic pattern CNS involvement also may be demonstrated with neuroimaging instead of postmortem histopathology. Assessment of additional organ system (eg, cardiac, hepatic, renal) involvement should be considered, given the increased risk for morbidity or mortality with certain complications.

Genetic testing. The ever-expanding list of genetic etiologies, including several with specific treatment considerations, has increased the importance of pursuing molecular genetic testing. Single-variant testing may be pursued when there is a known familial variant or established founder effect (eg, French-Canadian type Leigh syndrome in the Saguenay-Lac Saint-Jean region, Leigh syndrome in the Faroe Islands). Single-gene testing may be pursued when a distinctive clinical finding suggests a specific genetic etiology (eg, hypertrichosis and SURF1 pathogenic variation). Multi-gene panel testing assessing the nuclear DNA or the mitochondrial DNA may be pursued when the possibility of Leigh syndrome or other primary mitochondrial disease is generally considered. Whole exome or genome sequencing may be pursued when the differential diagnosis may not be reasonably restricted to the possibilities assessed by multi-gene panel testing. If these molecular genetic studies are nondiagnostic, it is important to consider genetic testing using an orthogonal methodology (eg, chromosomal microarray analysis) or a different tissue type for mtDNA testing.

Neuroimaging. Brain MRI is considered the mainstay neuroimaging study for evaluating possible Leigh syndrome and is expected to demonstrate bilateral symmetrical brainstem or basal ganglia lesions. The presence of unexpected findings (eg, white matter lesions with cavitation) does not exclude the diagnosis (03). Furthermore, recent recognition of the high frequency of spinal cord involvement also suggests the importance of spine MRI. Advanced techniques, such as arterial spin labeling perfusion and magnetic resonance spectroscopy, are not considered necessary or sufficient for establishing the diagnosis.

Biochemical testing. Measuring cerebrospinal fluid lactate levels requires lumbar puncture but may be more reliable than measuring blood lactate levels. The latter is prone to spurious elevations unless specific measures are taken (eg, avoiding the use of a tourniquet, avoiding active muscle contraction, putting the sample on ice immediately, and processing the sample immediately). The usefulness of calculating the lactate-to-pyruvate ratio increases as the degree of lactic acidosis does (19). A range of cut-offs (generally 20 to 25) have been proposed for considering the ratio elevated. In the setting of lactic acidosis, an elevated lactate-to-pyruvate ratio is thought to suggest respiratory chain dysfunction, whereas a nonelevated ratio is thought to suggest pyruvate dehydrogenase deficiency instead. However, it is important to remember that both types of lactic acidosis may occur as secondary phenomena.

Oxidative phosphorylation may also be assessed by measuring respiratory chain complex activities, typically performed using muscle tissue and in conjunction with detailed histopathologic assessment. If pursued, it is important to ensure that the requirements for reliable results are met (05). The muscle biopsy is ideally performed under general anesthesia because local anesthetic use has been associated with false-positive findings. The sample should be promptly processed. Both isolated and combined complex deficiencies may be observed in the setting of Leigh syndrome. Specific criteria for oxidative phosphorylation disorders have been proposed (12). However, these biochemical findings are ultimately nonspecific. Furthermore, the absence of oxidative phosphorylation or histopathologic abnormalities in muscle does not exclude the possibility of Leigh syndrome (21).

Specific genetic etiologies may be suggested by specific biochemical abnormalities, such as elevated methylmalonic acid for Leigh syndrome associated with SUCLA2 pathogenic variation and reduced citrulline for cases associated with the m.8993T>G pathogenic variant (57; 18). Additional assessment of amino or organic acids may be informative.

Management

In general, the treatment of Leigh syndrome is predominantly supportive, which is the case for most primary mitochondrial diseases. However, specific types of Leigh syndrome may be associated with a higher probability of benefit (or harm) with particular diets, supplements, medications, etc. Therefore, it is imperative to establish a precise molecular genetic diagnosis for an informed approach to management.

The treatment of primary pyruvate dehydrogenase complex deficiency is an illustrative example of how specific forms of Leigh syndrome may be rationally targeted. When the constituent enzyme activities are adequate, the pyruvate dehydrogenase complex links glycolysis to the tricarboxylic acid cycle by converting pyruvate to acetyl-CoA. When deficient instead, energy extraction from carbohydrates beyond the initial conversion of glucose to pyruvate is impaired. In theory, treatment with the ketogenic diet bypasses the biochemical block by shifting to fats as the primary energy source. In practice, growing experience in treating primary pyruvate dehydrogenase complex deficiency with the ketogenic diet suggests that it is both safe and effective (70). Supplementation with thiamine, which serves as an essential enzymatic cofactor (in the form of thiamine pyrophosphate), has been associated with beneficial effects in responsive patients (78). Treatment with dichloroacetate inhibits pyruvate dehydrogenase kinase, which catalyzes the inactivating phosphorylation of the pyruvate dehydrogenase complex. It has been shown to be well-tolerated and capable of producing biochemical improvements (73). Further study is required to determine whether it is capable of producing clinical improvements.

When the specific type of Leigh syndrome does not have a particular treatment or management approach, the broadly applicable consensus-based recommendations of the Mitochondrial Medicine Society, with more recent updates by Barcelos and colleagues, may be referenced (61; 07). Supervised exercise should be pursued to prevent or address deconditioning. Patients with baseline exercise intolerance should start with particularly low-intensity physical activities and then advance as able to higher-intensity ones. Prior cardiac screening is advised. The purpose of exercise treatment is to promote the proliferation of healthy mitochondria. A wide variety of vitamins and cofactors (eg, alpha-lipoic acid, folinic acid, L-carnitine, L-creatine, vitamin C, vitamin E, B-complex vitamins) have been (and continue to be) considered for the treatment of patients with primary mitochondrial diseases like Leigh syndrome (60; 61). Tiet and colleagues have recently provided a valuable review of targeted therapies that have been considered for genetic conditions that may present with Leigh syndrome (76). Selected treatment considerations are also highlighted here as follows:

Table 3. Selected Treatment Considerations

Ketogenic diet	Beyond its general utility for the treatment of epilepsy, the ketogenic diet specifically treats pyruvate dehydrogenase deficiency by bypassing the biochemical block. It has been shown to be safe and effective for primary pyruvate dehydrogenase complex deficiencies (70). However, inadequate effect or potential harm have been reported in the setting of inborn errors of metabolism characterized by secondary pyruvate dehydrogenase complex deficiencies, such as mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (10).
Valine-restricted diet	Leigh syndrome has been associated with the inborn errors of valine metabolism 3-hydroxyisobutyryl-CoA hydrolase deficiency and mitochondrial short-chain enoyl-CoA hydratase 1 deficiency. A valine-restricted diet could be considered a rational treatment for these conditions. Thus far, stabilization or improvement of clinical, biochemical, or radiographic findings has been reported in a few cases of Leigh syndrome attributable to these enzymatic defects (01).
Thiamine (vitamin B1)	Thiamine administration increases the availability of an activating cofactor (in the form of thiamine pyrophosphate) for the pyruvate dehydrogenase complex. It has been shown to be both safe and effective when applied for this specific purpose (78). High-dose supplementation at greater than 400 mg/day may be required, and very high-dose supplementation at greater than 1,200 mg/day has been reported in a few cases of primary pyruvate dehydrogenase complex deficiency as well.
	As expected, thiamine administration addresses the deficiency that occurs with thiamine transporter 2 deficiency. Rapid resolution of acute encephalopathy and prevention of recurrence has been reported in several patients treated with thiamine at 10 to 40 mg/kg/day (55; 56). This was administered in combination with biotin at 1 to 2 mg/kg/day.
	Sustained clinical improvement, including the prevention of additional episodes of encephalopathy or regression has been reported in a few patients with thiamine pyrophosphokinase deficiency treated with high-dose thiamine (06; 65). One patient was treated with 750 mg/day divided into four doses (for approximately 60 mg/kg/day) in combination with 300 mg/day of magnesium divided into two doses (for approximately 24 mg/kg/day) and 200 mg/day of biotin divided into two doses (for approximately 16 mg/kg/day). Resolution of radiographic abnormalities has been reported. It is postulated that thiamine administration overcomes the enzymatic defect.
Riboflavin (vitamin B2)	Riboflavin administration increases the availability of flavin adenine dinucleotide for various flavoproteins, thus improving catalytic function or structural stability. Clinical and biochemical response has been described in a few patients with isolated complex I deficiency associated with ACAD9 pathogenic variation (29). These patients were treated with 300 mg/day.
Dichloroacetate	Dichloroacetate administration is thought to relieve inhibition of the pyruvate dehydrogenase complex by pyruvate dehydrogenase kinase. It has been shown to be well-tolerated (73). However, further study is required to determine whether clinical improvements may be produced.
Coenzyme Q10 (ubiquinone, ubiquinol)	Coenzyme Q10 administration is expected to specifically address the deficiency that occurs with primary coenzyme Q10 deficiencies. However, treatment response is not guaranteed, and further study is required to determine whether this is determined by the genetic etiology, the dose, the dosing form, etc. Lack of treatment response was reported in a patient with early-onset Leigh syndrome and primary coenzyme Q10 deficiency associated with PDSS2 pathogenic variation (50).
	Coenzyme Q10 is the most commonly used supplement for primary mitochondrial diseases as a whole (61). It is available in various forms, including ubiquinone and ubiquinol. The latter requires adjusted dosing because it has higher bioavailability. Use of the synthetic coenzyme Q10 analogue idebenone has also been considered, given its higher bioavailability (28). Coenzyme Q10 administration is often considered, given its participation in the electron transport chain, its antioxidant properties, and other proposed mechanisms for ameliorating mitochondrial health.
EPI-743 (vatiquinone)	EPI-743 is an experimental para-benzoquinone analogue with structural similarities to coenzyme Q10 and idebenone but designed for improved pharmacologic potency (24). Initial results from an open-label study were promising (51). Some recovery of spontaneous breathing was reported in a patient treated initially with 30 mg/kg/day and subsequently with 45 mg/kg/day (43). Additional clinical, biochemical, and radiographic improvements were also observed. The long-term safety and efficacy are currently being studied.
Pyruvate	Clinical improvements have been reported in a patient with primary pyruvate dehydrogenase complex deficiency treated with sodium pyruvate at 0.5 g/kg/day divided into there doses (40). The mechanisms of action proposed by the authors included reduction of NADH/NAD ratio for stimulation of glycolysis, inhibition of pyruvate dehydrogenase kinase for activation of pyruvate dehydrogenase, and scavenging of hydrogen peroxide. Improved exercise tolerance, lactate level, and cardiac function have been reported in a patient with Leigh syndrome associated with cytochrome c oxidase deficiency and indeterminate genetic etiology (41). This patient was also treated with sodium pyruvate at 0.5 g/kg/day.
mTOR Inhibition	The potential salutary effects of mTOR inhibition were first suggested by a study of rapamycin administration in a Ndufs4-knockout murine model of Leigh syndrome (35). Rapamycin-treated mice demonstrated improved survival and health. Based on these promising experimental findings, a patient with NDUFS4 pathogenic variation was treated with everolimus (66). The dose was adjusted to maintain goal trough levels between 5 and 10 ng/mL. The patient no longer required tracheostomy or gastrostomy after 19 months of treatment and gained the abilities to walk independently and speak in sentences.

Media

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Christopher Mario Inglese MD

Dr. Inglese of Johns Hopkins All Children's Hospital has no relevant financial relationships to disclose.
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Alexander Y Kim MD

Dr. Kim of Johns Hopkins All Children's Hospital received a consulting fee from Alexion Pharmaceuticals, Inc.
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Editor

Bernard L Maria MD

Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.
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Former Authors

Mohammed Almuqbil MD
Hilary J Vernon MD PhD
Richard Morse MD (original author), Peter G Barth MD PhD, Redi Rahmani BA, Brandon Root MD, and Robert J Singer MD

Patient Profile

Age range of presentation: Typical: Early infancy to 2-3 years of age

Atypical: Wide age range of presentation from neonatal-onset to adult-onset
Sex preponderance: No sex preponderance
Heredity: Autosomal recessive inheritance characterizes many cases

Matrilineal inheritance characterizes many cases

X-linked inheritance characterizes cases of pyruvate dehydrogenase E1-alpha deficiency and a few other genetic etiologies

Autosomal dominant inheritance has been described for a single form of Leigh syndrome
Population groups selectively affected: More frequently encountered in the Faroe Islands as a consequence of founder effect

More frequently encountered in the Saguenay-Lac Saint-Jean region of Canada as a consequence of founder effect
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Leigh disease: 330.8
ICD-10: Leigh disease: G31.8
OMIM: Leigh syndrome: #256000

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Leigh syndrome

Associated Disorders

Mitochondrial disorders

Differential Diagnosis

Aicardi-Goutieres syndrome
Anti-MOG associated disease
Biotin-responsive basal ganglia disease
Biotin-thiamine responsive basal ganglia disease
CNS-isolated hemophagocytic lymphohistiocytosis
- Demyelination
- Glutaric acidemia type I
- GM1 gangliosidosis
- Inborn error of immunity
- Infection
- MELAS
- MELAS/LS overlap syndrome
- Methylmalonic acidemia
- Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
- Neuromyelitis optica spectrum disorder
- Nuclear pore defect
- Organic acidemia
- Phosphoinositide regulation defect
- Propionic acidemia
- Thiamine deficiency
- Thiamine pyrophosphokinase 1 deficiency
- Thiamine transporter 2 deficiency
- Vanishing white matter disease

Also Relevant

Coenzyme Q10
Complex II deficiency
Epilepsy in mitochondrial disorders
Hyperammonemia not caused by liver failure
Ketogenic diet in the treatment of epilepsy
- MELAS
- Mitochondrial disorders
- Neurogenetics and genetic and genomic testing
- Neuromuscular pathology: overview
- Thiamine deficiency
- White matter abnormalities in the brain

Leigh syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Selected Nuclear DNA Defects

Table 2. Selected Mitochondrial DNA Defects

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Table 3. Selected Treatment Considerations

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pyruvate carboxylase deficiency

Metal neurotoxicity

Pelizaeus-Merzbacher disease

Vascular cognitive impairment

Vanishing white matter disease

Addictive disorders

Automatic-voluntary dissociation

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