Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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The diagnosis of Leigh syndrome refers to a neurometabolic disorder affecting the central nervous system, with effects on cognition, development, and motor skills. Leigh syndrome generally presents in infancy or childhood, though older ages of presentation are possible. Clinically, Leigh syndrome is often characterized by dramatic neurologic regression in a previously healthy baby or child with high morbidity and mortality. Pathogenic variants in a multitude of genes involved in mitochondrial energy production (mitochondrial respiratory chain, pyruvate dehydrogenase, etc.) have been reported to be causative for Leigh disease. Treatment of patients includes aggressive management of comorbidities, vitamin cofactor supplementation where appropriate (biotin, thiamine), and management of physiologic stress, among other management approaches. Genetic counseling of family members is also essential, including guidance on personal and reproductive/recurrence risks.
• Leigh syndrome is a genetic neurometabolic disorder resulting from defects in mitochondrial energy production that most often presents in infancy or childhood.
• Leigh syndrome affects children usually in early years of life, presenting an estimated average of 1 per 34,000 births during the preschool period (04).
• Symptoms may include failure to thrive, weakness/hypertonia, ataxia, oculomotor palsy, seizures, and episodes of lactic acidosis, among other features.
• The course of Leigh syndrome is usually relapsing, often in response to physiologic stress (ie, respiratory or gastrointestinal infections). The outcome is often fatal.
• The diagnosis can be made based on the neuroimaging presentation (see below), but genetic confirmation is recommended.
• The characteristic finding on MRI is T1 and T2 prolongation, with symmetrical involvement in the putamen, globus pallidus, caudate, thalami, substantia nigra, inferior olivary nuclei, periaqueductal gray matter, superior cerebellar peduncles, tegmentum of the brainstem, and less commonly, periventricular white matter and corpus callosum.
• Treatment may consist of high dose thiamine (> 10-100 mg/kg/day), biotin (> 5-10 mg/kg/day), and supportive measures. In some cases, other agents may be useful depending on the specific genetic mutation.
Subacute necrotizing encephalomyelopathy was first described in 1951 by Dr. Denis Leigh, a British neuropathologist who reported the case of an infant with developmental regression at 6.5 months that progressed rapidly and resulted in death over a 6-week period (78). On autopsy, Dr. Leigh described multiple bilateral foci of spongy degeneration and microscopic vascular proliferation in the brainstem tegmentum, basal ganglia, thalamus, cerebellum, optic nerves, and spinal cord. He noted the similarity between subacute necrotizing encephalomyelopathy (SNE) and Wernicke syndrome (which arises as a result of nutritional thiamine deficiency). Notably, thiamine is a cofactor of the pyruvate dehydrogenase complex, mutations in which are now known to be 1 cause of Leigh disease. Thus, the parallels in neuropathology between Wernicke disease and Leigh disease, at their core, share a similar cellular pathological mechanism.
An autosomal recessive mechanism for the inheritance of Leigh disease was reported in 1954 based on a report of 2 affected siblings with consanguineous parents (49). A more complete review of neuropathological findings in Leigh disease were described by Montpetit and colleagues who in 1971 presented an overview of 50 cases in infants and children (93). Lesions were described as bilateral, sharply delimited, and mainly affected nuclear regions such as basal ganglia (mostly the putamina), and brainstem nuclei. The cerebral cortex was involved only in 10% of cases. White matter was affected less often, with the internal capsule affected in about one third of cases. The spinal cord was affected in one third of the population, with involvement of both grey and white matter.
Since these early case and neuropathological reports, pathological genetic variants in many genes have been reported.
Leigh syndrome was first associated with lactic acidosis by Worsley and colleagues (134). The first detected mitochondrial enzyme deficiency reported by Farmer and associates was pyruvate dehydrogenase complex deficiency (47). Willems and colleagues in 1977 showed that Leigh syndrome was heterogenous in origin as well as having association with cytochrome C oxidase (COX) deficiency (133). Subsequent research proved associations of Leigh syndrome with smallest subunit of cytochrome c oxidase, COX8A (60) and hemizygous NDUFA1 mutation (92).
Clinical presentation. The median onset of disease presentation of Leigh disease is 7 months (116), with onset in 80% of children presenting before 2 years of age, 55% in the first year and the additional 25% by 14 months. An additional 17% have onset of the disease between 3 and 15 years of age, and about 2% after 15 years of age (85). Disease onset prior to 6 months of age, failure to thrive, brainstem lesions on imaging, and need for intensive care treatment are all associated with poorer survival (116).
After initial presentation, the disease may progress slowly, plateau, or (rarely) rapidly progress to death. A relapsing and remitting course is frequent in Leigh disease. The onset is often seemingly acute, in the setting of an illness (ie, respiratory or gastrointestinal infection) or after a seizure from which recovery is incomplete, prolonged, or associated with unexplained coma.
The most common clinical features are regression in motor symptoms followed by ocular findings (116). Early findings may be poor sucking ability, the loss of head control, loss of motor skills, vomiting, and irritability. This may progress to hypotonia and failure to thrive. Ataxia, cerebellar tremor, and incoordination may be evident in ambulatory children, and movement disorders reflective of basal ganglia involvement including dystonia or choreoathetosis are not uncommon (86).
Abnormalities of respiration, which may become fatal unless treated, are due to bilateral brainstem involvement and may consist of periodic hyperventilation, apnea, gasping, sighing, and irregular breathing.
Oculomotor palsies also typically result from the brainstem involvement in the disease, including supranuclear palsy of vertical or lateral gaze.
Other ophthalmologic presentations may include: strabismus (most common manifestation) (40.9%), then pigmentary retinopathy (22.5%), followed by optic atrophy (22.5%), ptosis (15.9%), and finally, nystagmus (13.6%) (61).
Variably, there may be additional cranial nerve involvement leading to dysphagia or deafness. Of note, specific genetic mutations have been associated with a higher risk of deafness in Leigh disease including mtDNA 10197G>A (79) and the p.Val213Phe variant in mitochondrial asparaginyl-tRNA synthetase (NARS2) (114).
Seizures occur in approximately 40% of patients with Leigh disease and are more often seen in early onset disease, where they may present as infantile spasms. The most common forms of seizures in Leigh syndrome are generalized tonic-clonic and complex partial, found in 11% of patients in 1 study of 60 patients (29). Patients who have a history of seizures from birth have a higher occurrence of disease relapse (68; 124; 116).
Sudden onset of Leigh disease with involvement of peripheral nervous system and spinal cord may closely mimic Guillain-Barré syndrome.
Other organ manifestations include: hypertrophic cardiomyopathy, renal tubulopathy, and fatty liver infiltration (01). Childhood moyamoya disease has also been reported in patients with Leigh syndrome (33), as has Fukuyama congenital muscular dystrophy (72).
Neuroimaging findings. The findings of Leigh disease on MRI are characteristic, and correspond to the neuropathologic findings (see below). MRI shows T1 and T2 prolongation with symmetrical involvement, most commonly in the putamen, globus pallidus, caudate, thalami, substantia nigra, inferior olivary nuclei, periaqueductal gray matter, superior cerebellar peduncles, tegmentum of the brainstem, and less commonly periventricular white matter and corpus callosum. CT scans have been less helpful than MRI but nevertheless may detect basal ganglia involvement. Magnetic resonance spectroscopy has demonstrated decreased N-acetylaspartate and increased lactate levels, which are most apparent in the areas showing abnormal enhancement on MRI (90; 14).
An increase of lactic acid and pyruvate in blood and cerebrospinal fluid is an important indicator for involvement of the pyruvate dehydrogenase complex or mitochondrial respiratory chain. However, the degree of these elevations is variable, and normal levels do not exclude Leigh syndrome in the presence of a clear history and typical MRI findings.
Neuropathology. Leigh syndrome is a neurodegenerative mitochondrial disorder with classical pathological findings including characteristic necrotizing basal ganglia and brainstem lesions (07). The microscopic aspects of the lesions in Leigh disease have the following characteristics: (1) they are sharply demarcated; (2) there is spongiosis of the “neuropil” (the tissue constituents between neuronal cell bodies mainly consisting of dendrites and axons); (3) the presence of capillary thickening and proliferation; and (4) reactive changes involving macrophages (early) and astrocytes (late) (35; 25).
In addition to the CNS findings, peripheral nerves may also show involvement (56; 65; 59; Chabrol et al 1994; 91). Some specific genetic etiologies may be associated with a subset of characteristic neurologic findings (91): SURF1 mutations can cause a demyelinating neuropathy, MTATP6 mutations can lead to axonal neuropathy, late onset disease due to POLG1 mutations typically leads to a predominant sensory neuropathy with ataxia, and PDHc deficiency may cause a mixed or axonal sensorimotor neuropathy. These findings emphasize the need to test peripheral nerve function in Leigh syndrome patients, especially because the clinical severity of brain disease may overshadow the symptoms of peripheral nerve involvement.
In contrast to many other mitochondrial disorders, muscle biopsies from individuals with Leigh disease generally show nonspecific myopathic changes with little or no abnormal appearance to the mitochondria.
The prognosis in Leigh disease is generally poor, but is generally dependent on the etiology and clinically correlates to the presence or absence of seizures. For infants whose disease has its onset before 24 months of age, death generally occurs within 2 years of onset. For childhood and adolescent Leigh disease, the prognosis is more variable, with death occurring 3 to 10 years after onset. Rarely, children at any age may have a fulminant course lasting only days to weeks (52). For those patients with thiamine-responsive forms, the prognosis may be better.
In general, there is not an effective therapy for most causes of Leigh syndrome. However, there are some genetic etiologies where specific interventions can improve the outcome, highlighting the importance of determining the underlying pathological genetic variants in every affected individual (75; 76). For example, Leigh syndrome due to defects in thiamine transporter-2 (SLC19A3) can be treated with injections of free thiamine to restore thiamine levels in CSF, leading to improvements in recovery (97). As a more universal therapeutic approach, EPI-743, a potent cellular oxidative stress protectant, has been shown in early studies to modify the natural course of Leigh syndrome (74).
Ultimately the knowledge of the specific underlying genetic etiology for each affected individual can play a pivotal role in discovering general or personalized treatment options based on the specifically affected genes and pathways (52).
An 18-month-old girl was referred for evaluation of global developmental delay, growth retardation, acquired microcephaly, hypotonia, and episodic hyperventilation and ataxia. She was born at 42 weeks’ gestation and weighed 2550 gm. The pregnancy was complicated only by hyperemesis requiring intravenous hydration. Labor, delivery, and the perinatal period were unremarkable. The infant did well until 3 months of age when she developed significant vomiting, which was treated with thickened feeds and antacids, to some improvement. However, by 9 months there was a decline in growth parameters, and she was intolerant of solid foods. At 18 months she developed hypotonia, tremulousness, and ataxia. On examination at that time, her weight was at the 50th percentile for a 12-month-old, her height at the 50th percentile for a 16-month-old, and her head circumference at the 50th percentile for a 10-month-old. She had global developmental delay, generally functioning at an 11- to 13-month level, microcephaly, normal deep tendon reflexes, mild hypotonia, intention tremor, and a wide-based gait. She exhibited some self-stimulating and self-injurious behaviors, poking at her eyes and banging her head on hard surfaces. A peculiar breathing pattern was noted, with episodes of hyperventilation. There was no history of injury or major illness, and she was an otherwise healthy child. There was no family history of similarly affected members.
Previous tests included a barium swallow, CT and MRI of the brain, EEG, karyotype, serum quantitative amino acids, urine organic and amino acids, serum ammonia, chemistries including glucose, biotinidase, and arterial blood gas measurement, all of which were normal. A serum lactate was elevated at 28.8 mmol/L (normal < 23); pyruvate and ophthalmological examination were normal.
CSF was normal except for an elevated lactate of 3.5 mmol/L (normal < 2.0). A repeat brain MRI was performed and showed characteristic, symmetrical increased T2-weighted signal in the putamina and tegmentum of the brainstem, supportive of the tentative diagnosis of Leigh disease. She was enrolled in an early intervention program where she received physical therapy, occupational therapy, and speech services. Over the next 2 years she had periods of worsening, and she developed seizures. She was treated empirically with B vitamins and coenzyme Q and given anticonvulsants for seizures. Despite a gastrostomy tube, she failed to gain weight adequately. She continued to deteriorate, becoming less alert and interactive and losing all language. She eventually died at 4 years of age of respiratory failure. No autopsy was performed.
Leigh syndrome represents the clinical and radiological expression of a group of inherited disorders of energy metabolism. Two major subgroups exist: (1) disorders of oxidative phosphorylation caused by dysfunction of components of the mitochondrial respiratory chain; (2) disorders of pyruvate oxidation through an impairment of the pyruvate dehydrogenase complex (PDHc). Debray and colleagues present a useful overview of its diverse etiologies (37).
Table 1 summarizes the mitochondrial and nuclear genes that have been associated with Leigh syndrome.
(A) Mitochondrial DNA
Large-scale deletions of mitochondrial DNA
Gene mutations affecting subunits and assembly factors: complexes I, III, IV, V
• Complex I: MT-ND1, ND6, MT-TK, TLI, TV, TW
• Complex IV: COX III
• Complex V: MTATP6 (ATPase 6 subunit)
Variable intrafamilial disease expression due to heteroplasmy
Most common: tRNALys
(B) Nuclear DNA
(1) Mutations affecting subunits, assembly factors and coenzyme Q
• Complex I: NDUFS1,2,3,4,7,8, NDUFV1, NDUFA1,2,10,11,12, NDUFAF2, C8ORF38, C20ORF7, FOXRED1, C12ORF65
• Complex II: SDHA (Fp subunit), SDHAF1
• Complex III: BCS1L, TTC19, UQCRQ
• Complex IV: SURF1, NDUFA4, COX10, COX15, SCO2, PET100
• Coenzyme Q: PDSS2
• ATP synthase: LRPPRC?
Nuclear encoded subunits summarized in (70; 105).
PET100 is found in Lebanese with Leigh syndrome
(2) Mutations affecting synthesis and translation of mitochondrial DNA.
Resultant defects may affect 1 or more complexes
translation of mtDNA transcript: TSFM, EFG1 (mitochondrial elongation factor), LRPPRC (posttranscription defect specifically affecting COX subunits), TACO1 (translation activator gene of COX1), formation of τm5(U) in anticodon wobble position: GTBPB3; methionyl-tRNA formyltransferase defect: MTF
LRPPRC mutation is found in French-Canadian Leigh syndrome
(3) Pyruvate dehydrogenase complex (PDHc)
PDHA1, PDHB, DLAT, DLD, PDHX
PDHA1 encoding E1 alpha located on the X-chromosome
(4) Thiamine pyrophosphokinase deficiency
(5) Thiamine transport deficiency
Biotin-thiamine-responsive basal ganglia disease mimics Leigh syndrome
(6) β-oxidation of fatty acids
ECHS1 (short chain enoyl coenzyme A hydratase, that catalyzes the second step of β-oxidation)
(7) Glycogen synthesis
GYG2: initiation of glycogen synthesis
An understanding of the biochemical etiology of Leigh syndrome began with the astute observation of common morphological features linking Wernicke disease, caused by acquired thiamine deficiency, to Leigh syndrome (78; 49). Deficiency of thiamine (vitamin B1), a cofactor of the pyruvate dehydrogenase complex, causes deficiency of acetyl-CoA, necessary to sustain the citric acid cycle, and leads to accumulation of pyruvate and lactate. Genetic deficiency of pyruvate dehydrogenase has the same biochemical consequences and represents a major underlying genetic etiology of Leigh syndrome. Currently, most of the known biochemical defects that cause Leigh syndrome are due to defects in oxidative phosphorylation. Inheritance of Leigh disease can include: matrilineal (mtDNA), autosomal dominant, X-linked, or autosomal recessive inheritance.
Dysfunction of single respiratory chain complexes. The mitochondrial respiratory chain is composed of 5 complexes (I-V) located on the inner mitochondrial membrane, which transports electrons supplied by the citric acid cycle and produces a proton gradient across the inner mitochondrial membrane. This gradient is reversed in a final step via backflow in a channel formed by complex V to drive phosphorylation of ADP to ATP. DiMauro and Schon provide an excellent review of the functioning of the respiratory chain (43).
Except for complex II, each complex of the mitochondrial respiratory chain is composed of nuclear and mitochondrial encoded components. Complex II is entirely nuclear encoded. Therefore, Leigh syndrome arising from genetic defects of the respiratory chain can follow mitochondrial or Mendelian inheritance. In the former case, (also known as MILS, or maternally inherited Leigh syndrome), the disease is transmitted through oocyte which contributes all of the mitochondria to the embryo, although mtDNA mutations may also arise de novo. Leigh syndrome with maternal inheritance may lead to a wide range of disease expression depending on the variability of the ratio between normal and affected mtDNA (heteroplasmy) in each individual. In the case of Mendelian inheritance, the mode of inheritance is autosomal recessive, with both parents heterozygous for the mutated gene or, X-linked.
A study carried out on 96 patients confirmed presence of phenotype-genotype correlations in those patients who were having genetically confirmed Leigh syndrome. Important differences between mtDNA and nDNA associated Leigh syndrome were identified and it was confirmed that their diagnosis would require thorough investigations including clinical and radiological evaluations in addition to laboratory and genetic testing (117).
Complex I (NADH:ubiquinone oxidoreductase). Complex I, the largest complex, accounts for up to 30% of mitochondrial disorders in childhood (48). It comprises 7 subunits encoded by mitochondrial DNA and 38 encoded by nuclear genes. Complex I deficiency may cause diverse mitochondrial syndromes, including progressive leukoencephalopathy, cardiomyopathy, and severe lactic acidosis. The most common association, however, is Leigh disease. As complex I is assembled from mitochondrial- and nuclear-encoded subunits, both Mendelian inheritance and mitochondrial inheritance are involved. In complex I dysfunction, the frequency ratio of mitochondrial and nuclear gene defects diagnosed is about equal. Among the mitochondrial genes encoding complex I, pathogenic variants in ND5, are particularly associated with Leigh disease (31).
Heteroplasmy, ie, the presence of a normal and a mutated set of mitochondria in an individual due to maternal (mitochondrial) inheritance plays a major role in the expression of disease. The importance of heteroplasmy as a cause of variable expression within a single pedigree is illustrated by the report of van Karnebeek and colleagues of a family with ND5 mutation with MELAS (mitochondrial inherited lactic acidosis and stroke like episodes) in a 10-year-old female and a fatal neonatal course in a younger sister (129).
The first nuclear gene encoding a respiratory chain subunit, NDUFS8, a subunit of complex I, was identified in 1998 (82). By 2012, mutations in 16 nuclear genes mostly encoding subunits and assembly factors of complex I were associated with Leigh syndrome (70). Mortality is high, with 75% dying before the age of 10 years. It should be noted that 1 complex I gene, NDUFA1, is encoded on the X-chromosome and is associated X-linked Leigh syndrome (50).
Complex II, succinate-ubiquinone oxidoreductase. Complex II is composed of 4 subunits, encoded on nuclear DNA. Reports on complex II deficiency and Leigh syndrome are rare. Bourgeron and colleagues reported siblings with Leigh disease, complex II deficiency, and a mutation in the flavoprotein (Fp) subunit (19). Brockmann and colleagues reported elevated succinate by MR spectroscopy of affected white matter (21), which offers an interesting approach to the detection of complex II deficiency in brain. Interestingly, SDHA mutations have also been found in paragangliomas and pheochromocytomas, and therefore in the rare instance a patient is diagnosed with Leigh syndrome due to CII defect, specifically SDHA, tumor screening should be considered (103).
Coenzyme Q (CoQ) and complex III (ubiquinol cytochrome c reductase). Complex III is made up of 11 subunits of which 10 are encoded by nuclear genes. CoQ transfers electrons from complexes I and II to complex III. Indirect enzymatic methods measuring I+III and II+III do not distinguish between deficiencies of CoQ and complex III. Leshinsky-Silver and colleagues reported a neonate with severe lactic acidosis, hyperammonemia, and a brain MRI compatible with Leigh disease (80). In liver severely reduced activities of II+III and I+III were restored in vitro by CoQ. In another study Q10 (coenzyme Q) administration ameliorated clinical findings in an adult with Leigh disease, deficient succinate:cytochrome c oxidoreductase (complex II-III) and decreased CoQ levels in tissues and CSF (130). A gene defect affecting the synthesis of CoQ leading to Leigh syndrome and nephropathy was first identified in 2006 by Lopez and colleagues (84). Mutations were found in the PDSS2 subunit gene of CoQ.
Complex III has rarely been associated with Leigh disease. De Lonlay and colleagues reported mutations in a complex III nuclear encoded subunit (BCS1L) in patients with a multisystem disorder affecting liver, kidney, and brain (40). MRI characteristics were compatible with Leigh syndrome.
TTC19 gene mutation in a patient with Leigh syndrome was reported and believed to cause either a loss of protein function or mRNA decay. TTC19 encodes tetratricopeptide 19, a CIII assembly factor on the inner mitochondrial membrane, thus affecting CIII function (08).
Complex IV (cytochrome c oxidase, COX). Human COX comprises 13 subunits: 3 are mtDNA-encoded, whereas the remaining are encoded by nuclear genes, including major causes of Leigh disease—pathogenic variants in SURF1 and in COX genes.
In a large retrospective study of 180 patients diagnosed with complex IV deficiency from Eastern Europe, 47 had pathogenic variants in SURF1 (18), all of whom had Leigh syndrome. Interestingly, defects in SURF1 may show distinctive MRI abnormalities with predominant abnormalities in MR involvement of the subthalamic nuclei, medulla, inferior cerebellar peduncles, and substantia nigra (46; 104). Defects in SURF1 have been associated with hypertrichosis in Leigh syndrome, and according to the group who studied this relationship, should prompt a work-up for SURF1 mutation (10).
Mutations usually lead to mitochondrial syndromes other than Leigh disease (113); however, several published reports associate COX assembly factor COX10 and COX15 with Leigh disease (06; 32; 96; 23). mtDNA pathogenic variants as a cause of biochemical COX deficiency are relatively rare. Tiranti and colleagues reported a mutation in the mitochondrial COX III gene in a patient with Leigh disease (123).
Pathogenic variants in LRPPRC are attributed to complex IV deficiencies due to defects in the subunit specific mitochondrial translation process (108) as it is for TACO1 (131). LRPPRC mutations are associated with the French-Canadian variant of Leigh syndrome, a severe early-onset type with involvement of the liver, also known as Saguenay-Lac-Saint-Jean cytochrome c oxidase deficiency (SLSJ-COX) (38). The role of LRPPRC protein in mRNA stabilization has been well documented at this point (108; 109), and these findings may need further exploration.
SCO2 (synthesis of cytochrome c oxidase) pathogenic variations have also been reported to cause Leigh syndrome. Chadha and colleagues propose that the documented variants of SCO2, which encodes for an assembly factor, transport copper ions into the COX complex and alter the structure of the protein, thus leading to functional COX deficiency (26). NDUFA4 mutations, originally believed to cause complex I defects, have now been shown to be associated with complex IV instead. Using polyacrylamide gel analysis, Pitceathly and colleagues showed that NDUFA4 is a subunit of COX and defect can lead to disease (101). PET100 was shown to encode a complex IV biogenesis factor that is located on the inner mitochondrial membrane and forms a subcomplex with complex IV subunits. Pathogenic variants in this gene have been reported in 8 Lebanese individuals with Leigh syndrome (81).
Complex V (ATP synthase). Complex V is comprised of approximately 16 subunits, of which 2 are encoded by mitochondrial DNA; the remaining are encoded on nuclear genes. A point mutation, affecting m.8993 at more than 90% heteroplasmy within the ATPase 6 subunit, is associated with Leigh disease (107; 24; 03; 66; 94). Two other mitochondrial disorders associated with the ATPase 6 gene are NARP (neuropathy-ataxia-retinitis pigmentosa) and familial bilateral striatal necrosis. In the first patient with NARP, Holt and colleagues discovered the heteroplasmic m.8993 point mutation that was subsequently found also to cause Leigh disease (62; 107). It is remarkable that the same m.8993 mutation causes different disorders, Leigh syndrome and NARP, dependent on the degree of heteroplasmy. Familial striatal necrosis is mainly expressed as late infantile or juvenile onset dystonia with putaminal lesions and a slowly progressive course. The MRI lesions are stable and do not proceed to involvement of the brainstem as seen in Leigh disease. In this disorder different point mutations in the ATPase 6 gene have been found (41).
Disease caused by defective tRNA genes. Twenty-two tRNA genes are encoded in the mitochondrial genome. Commonly found in MELAS and MERRF, pathogenic variants in mitochondrial tRNA are rare causes of Leigh disease (120; 34; 125), the most common affecting tRNALys (110).
tRNA pathogenic variants affect overall respiratory chain functioning rather than specific complexes, often resulting in combined decreases of activities of complexes I and IV together with a decrease in overall ATP production. Different phenotypes are caused by mitochondrial DNA mutations. The outcome of such mutations depends on the heteroplasmic load and tissue susceptibility. Several excellent reviews reflect on these aspects (43; 110; 137).
Occasionally, homoplasmic single-base mtDNA mutations may occur that affect both a mother and all children, but with different degrees of illness, despite the fact that all carry the same mutation load. An impressive example reported by McFarland and colleagues describes a mother and her 6 children, who all carried the same mt-tRNA Val mutation, which resulted in mild symptoms in the mother and lethal disease in all 6 children, including a case of Leigh syndrome (89).
In rare instances, large-scale deletions of mitochondrial DNA may cause Leigh disease. This contrasts with adult-onset progressive external ophthalmoplegia in which large-scale mutations of mtDNA are commonly found (136).
mtDNA depletion as a cause of Leigh syndrome. A growing group of mitochondrial disorders involves pathogenic variants in nuclear genes involved in mitochondrial DNA synthesis and maintenance, leading to depletion of mitochondrial DNA. mtDNA depletion has various clinical effects that may include Leigh syndrome. Defects in POLG, which encodes polymerase-gamma (part of the mitochondrial DNA replication machinery), most commonly lead to Alpers disease, a progressive disease affecting liver and cerebral cortex, but may result in Leigh disease (121). Leigh disease can also be caused by defects in SUCLA2, which encodes 1 subunit of the citric acid cycle enzyme succinyl-CoA ligase. Its role in mitochondrial nucleotide synthesis is not solved completely, but defects in this gene causes depletion of mtDNA and a reduction of respiratory chain complexes I, III and IV along with increased excretion of methylmalonic acid, formed from succinyl-CoA (44; 98).
Large-scale mtDNA mutations as a cause of Leigh syndrome. Chae and colleagues report a heteroplasmic large-scale deletion of mtDNA resulting in Leigh syndrome, renal tubulopathy, and hypoparathyroidism (27).
Defects in mitochondrial DNA translation. Another emerging group of disorders with impairment of multiple respiratory chain complexes is due to mutations in nuclear genes that encode proteins involved in the translation of mitochondrial RNA transcripts. This subgroup of nuclear genes that affect mitochondrial protein translation processes includes mitochondrial elongation factor (EFG1) associated with infantile onset encephalopathy with characteristics of Leigh syndrome (126). Ahola and associates found that defects in mitochondrial translation elongation factor Ts (EFTs) were responsible for infantile mitochondrial cardiomyopathy that progressed to juvenile Leigh syndrome in 2 siblings (02). The mutation was found in the TSFM gene that encodes for mitochondrial EFTs, leading to protein instability and mitochondrial translation defect. Interestingly, a high carrier frequency of 1:80 for this mutation was found in a Finnish population of 35,000 with no homozygotes, likely because it is homozygous lethal.
DiMauro and Garone thoroughly review the impact of genetic mitochondrial disorders on the fetus and newborn (42).
Further support of the need for proper translational of mitochondrial DNA came from the work by Kopajtich and associates (73). They showed that individuals carrying compound heterozygous or homozygous mutations in GTPBP3 had combined respiratory chain complex deficiencies in skeletal muscle, lactic acidosis, hypertrophic cardiomyopathy, neurologic symptoms, and MRI involvement of the thalamus, putamen, and brainstem. These mutations resulted from mitochondrial translational defects due to the role of GTPBP3 in forming τm5(U) in the anticodon wobble position of 5 mitochondrial tRNAs.
Mitochondria rely on the N-formylation of initiator methionyl-tRNA (Met-tRNA) by mitochondrial methionyl-tRNA formyltransferase (mt-MTF) for initiation of translation. Sinha and colleagues showed that compound heterozygous mutations within the nuclear genome for mt-MTF resulted in reduced mitochondrial translation efficiency and combined oxidative phosphorylation deficiency leading to Leigh syndrome (115). It is not known if this mutation causes reduced mitochondrial translation because of the reduced activity of the mt-MTF or because of reduced levels of the mutated mt-MTF.
Pyruvate dehydrogenase complex deficiency. Pyruvate dehydrogenase complex (PDHc) deficiency is an important cause of progressive and relapsing inherited neurodevelopmental disorders, including Leigh disease, as well as brain malformations including callosal dysgenesis, gyral abnormalities, and periventricular cysts. PDHc is a mitochondrial enzyme complex that links glycolysis to the citric acid cycle via conversion of pyruvate into acetyl CoA. Thus, it is a central control point determining the balance of energy generation from carbohydrates, fatty acids, and amino acids (22).
The brain in its early developmental stage is mainly dependent on glycolysis for bioenergetic function. Therefore, PDHc deficiency affects the developing brain at the embryo-fetal stage (as opposed to respiratory chain defects where the time of onset is usually around birth or later). This explains the unique malformative effects of PDHc deficiency. When Leigh disease and brain malformations are seen together, PDHc deficiency is highly likely to be the cause.
The PDHc enzyme complex is located in the mitochondrial matrix. It is made up of up 3 subunits: E1, E2, and E3, (pyruvate dehydrogenase E1, dihydrolipoamide acetyl transferase E2, and lipoamide dehydrogenase E3).
E1, pyruvate dehydrogenase, is a tetramer constructed from 2 units E1alpha and 2 units E1beta. Thiamine pyrophosphate acts as its coenzyme. The E1alpha subunit is encoded on the X-chromosome by the PDHA1 gene, the E1beta subunit by PDHB, E2 by DLAT, E3 by DLD, E3-binding protein by PDHX and PDH-phosphatase by PDP1. PDH activity is regulated by a kinase and a phosphatase that act as on-off switches for the complex, and the X-protein or E3 binding protein, which bind E2 to E3.
With the exception of PDH-kinase, each of these genes has been associated with metabolic disorders. Four neurologic subtypes have been described in association with PDHc dysfunction (15): (1) neonatal encephalopathy with lactic acidosis, (2) nonprogressive “infantile encephalopathy”, (3) Leigh syndrome, and (4) recurrent ataxia. Leigh syndrome was diagnosed in 8 males. Cerebral malformations diagnosed by MRI were found in both PDHA and PDHX mutations, consisting of periventricular pseudocysts, gyral abnormalities, polymicrogyria, and total or partial callosal agenesis.
In a retrospective analysis of 371 published PDHc cases, patients with a defect in the X-linked E1alpha subunit (PDHA1) were the largest subgroup with the ratio between females and males close to equal (99). Although E1alpha is encoded on the X-chromosome, affected females are symptomatic because of non-random X-inactivation favoring the affected X-chromosome. Neuroimaging of PDHc deficient patients showed lesions compatible with Leigh syndrome in 27% of available studies (n=186). The most common manifestation was ventriculomegaly. Hypogenesis or agenesis of the corpus callosum was found in 31%, the latter finding typically found in E1alpha deficiency. Lethality was high, with most of the deaths in early childhood.
Defects in E3 represent a distinct subclass of PDHc deficient disorders because this enzyme subunit participates in 2 other reactions besides PDH: 2-oxoglutarate dehydrogenase and breakdown of branched-chain amino acid. Deficiency of E3 therefore causes an increase in the excretion of 2-oxoglutarate and an increase of plasma branched-chain amino acids (57).
Thiamine transporter defect. In 2013, Gerards and colleagues described the SCL19A3 mutation resulting in Leigh syndrome. SCL19A3 is a low affinity, high capacity transporter and 1 of 2 known thiamine transporters (the other being SCL19A2) that transports thiamine into the cell (53). Though defects in this gene have been reported previously, Gerards and colleagues showed that Leigh syndrome developed in Moroccan patients because of a nonsense c.20C>A mutation leading to complete absence of the protein. These patients showed response to thiamine administration.
Thiamine pyrophosphokinase (TPK) deficiency. A defect in thiamine pyrophosphokinase was found to be present in a patient with Leigh syndrome-like features including progressive, early-onset developmental delay. TPK produces thiamine pyrophosphate once thiamine is transported into the cell, and is a cofactor for pyruvate dehydrogenase, transketolase, 2-ketoglutarate dehydrogenase, and branched chain α-keto acid dehydrogenase. In this case, Banka and colleagues reported that lactic acidosis may not be present and 2-ketoglutaric aciduria may be the only marker present (13). Unlike patients with typical TPK deficiency or thiamine transporter defects, this patient was not responsive to early thiamine supplementation.
Fatty acid oxidation and valine catabolism defects. Short chain enoyl coenzyme A hydratase is a key enzyme in multiple pathways including β-oxidation of short- and medium-chain fatty acids and catabolism of isoleucine and valine from methacrylyl-CoA. Compound heterozygous mutations in the ECHS1 gene were found in a 21-month-old boy with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed in this patient (106). Accumulation of methacrylyl-CoA and acryloyl-CoA was attributed to 2 siblings with fatal Leigh syndrome (100). Deficiency of ECHS1 can also result in wrinkled, nonelastic, and sagging skin—a Leigh-like syndrome with cutis laxa (12).
Glycogen synthesis. Two male siblings were investigated with findings of Leigh syndrome and ketonemia without elevation of lactate and pyruvate. X-linked recessive mutations were found in GYG2. GYG2 encodes glycogenin-2 protein, which is involved in glycogen synthesis initiation. The mutation was found to alert the protein structure, resulting in destabilization and malfunction (64).
The incidence of Leigh disease is approximately 1 in 40,000 births, though this is highly population specific. A genetic isolate in Quebec, Canada has been found to have an incidence of 1 in 2000 births, and a Faroese population has been found to have an incidence of 1 in 2500 births. In another study of the northern European population, the incidence was found to be 1 in 32,000 (105).
Based on the effectiveness and safety of pronuclear transfer, it has also been considered as a reproductive option to prevent the inheritance of mtDNA encoded disorders (139). An important study has been carried out on a Leigh syndrome female carrier who achieved pregnancy successfully by spindle cell transfer. This mitochondrial replacement therapy was potentially an important development in achieving pregnancy in a Leigh syndrome carrier without transmission of mtDNA from oocytes to preimplantation embryos (05; 138).
Genetic counseling and prenatal diagnosis are extremely important to help families understand the risks of recurrence of Leigh syndrome. Due to tissue heteroplasmy in mtDNA encoded disorders, it is particularly difficult to predict the clinical outcome of potentially affected offspring.
The age of presentation and the pattern of neurologic involvement in Leigh disease are highly variable. The usual presentation is a subacute encephalopathy, often with brainstem involvement. The most encountered finding on MRI is bilateral involvement of basal ganglia, the brainstem, or both. The spinal cord may be involved initially as well. Bilateral basal ganglia involvement may be seen in several other inborn errors besides Leigh disease, including organic acidemias.
The clinical presentation of stepwise regression is seen in vanishing white matter disease, an autosomal recessive disorder. However, in this disorder the basal ganglia is not involved and the white matter proceeds to cavitation.
Isolated involvement of the caudate nucleus and putamen combined with progressive dystonia during childhood is seen in infantile striatal necrosis, an autosomal recessive disorder. Associated gene defects have been found in mitochondrial ATPase 6 gene (41) and in the nuclear pore gene nup62 (16).
It is worth addressing biotin responsive and biotin-thiamine responsive basal ganglia disease, as these fully imitate in clinical and imaging findings. As such, it is important to treat these as Leigh syndrome for all intents and purposes. Thus, it is suggested that all patients with suspected Leigh syndrome should receive thiamine and biotin (11).
Lactic acidosis may be seen in other disorders including biotinidase deficiency, holocarboxylase synthetase disease, disorders of gluconeogenesis, and occasionally in congenital disorders of glycosylation including congenital disorder of glycosylation type Ia (20).
Presentation and course are highly variable (102); however, there are characteristic clinical presentations that often precede diagnostic workup for Leigh disease.
(1) Stepwise, subacute neurologic regression, often following an infectious period, often involving the brainstem.
(2) MRI findings of bilateral involvement of basal ganglia, mostly the putamina, eventually also involving the brainstem nuclei and white matter are characteristic of Leigh disease of various genetic etiologies. Patients with complex I deficiencies have bilateral brainstem lesions and anomalies of the putamen. Supratentorial stroke-like lesions were found only in patients with mitochondrial DNA complex I deficiencies. Patients with MT-TLI and PDH deficiencies may have stroke-like images or corpus callosum malformations, respectively, which are not usually seen in complex I deficiencies (77). Proton MR-spectroscopy may show elevated lactate in the most affected areas (eg, basal ganglia).
(3) A positive family history including evidence of individuals with mild phenotypic expression. There may be a history of parental consanguinity, similar cases, or recurrent miscarriages (11). The family history may also help to establish the mode of inheritance. A pedigree supporting mitochondrial (maternal) inheritance may greatly aid in the molecular genetic approach (mitochondrial vs. nuclear genes).
(1) Lactate and pyruvate in plasma and in CSF. The lactate/pyruvate (L/P) ratio, which reflects the cytoplasmic NADH/NAD+ content, has characteristic associations with specific mitochondrial defects. An L/P over 20 in blood or CSF may indicate dysfunction of the respiratory chain (although sometimes this ration can be normal). An increase of lactate with retained normal or low ratio is typically seen in PDHc deficiency (99). Proton magnetic resonance spectroscopy combined with MRI is a safe method to detect intracerebral lactate increase. The finding of an increase of succinate in affected white matter is a strong indication for complex II involvement (21; 95).
(2) Lactate determination in blood is less reliable, unless sufficient measures are taken to avoid stasis from the use of a tourniquet. An indwelling venous catheter or arterial sampling will avoid these artefacts and can be combined with other samples such as alanine and ketone bodies. Fasting and loading tests are of limited usefulness and may occasionally precipitate crises (37). It is important to note that normal lactate and pyruvate levels do not exclude the diagnosis of Leigh disease.
(3) Organic acids and amino acids should be screened to exclude other inborn errors that may occasionally result in phenotypic patterns that mimic oxidative phosphorylation or PDHc deficiencies. Increased excretion of 3-methylglutaconic acid has been associated with a number of mitochondrial disorders including MEGDEL (3-methylglutaconic aciduria, deafness, and Leigh syndrome) (135). Increased excretion of methylmalonic acid in a patient with Leigh syndrome may be caused by mutation of SUCLA2 (98). Low plasma citrulline has been associated with the m8993T>G mitochondrial mutation (36).
(4) Screening for concomitant cardiac, hepatic, and renal involvement (multisystem disorder) is mandatory in all suspected cases of oxidative phosphorylation disorder.
(5) Respiratory chain studies should preferably be performed in a muscle biopsy. Ideally, biopsy should be performed under general anesthesia as local anesthesia may contaminate the sample (11). When trying to assess the entire oxidative phosphorylative system, the biopsy needs to be processed promptly (11). The outcome of muscle histology and histochemistry may be completely normal in Leigh disease, especially in children and, therefore, does not rule out the need for such studies (39).
The positive finding of microscopic mitochondrial enzyme changes on muscle histochemistry, eg, an increase of cytochrome c oxidase negative fibers, should be followed by such studies anyway. Enzymatic analysis involves determination of activity of respiratory chain (RC) complexes (typically: I, II, I+III, II+III, IV). Positive criteria for an RC defect have been formulated by Bernier and colleagues encompassing children and adults (17):
• Less than 20% activity of any RC complex in a tissue
• Less than 30% activity of any RC complex in a cell line
• Less than 30% activity of the same RC complex activity in 2 or more tissues
• Functional: Fibroblast ATP synthesis rates greater than 3 SD below mean.
A tool for the assay of the amount of each respiratory chain complex is blue native polyacrylamide gel electrophoresis (BN-PAGE). This allows quantification of respiratory chain complexes in small amounts (127). It may be necessary to examine more than 1 tissue because tissue-specific expression or variable levels of heteroplasmy in the case of mitochondrial mutations may cause normal results in 1 tissue and specific abnormalities in another tissue from the same patient.
Array-comparative genomic hybridization (a-CGH) screening may prove of some utility, especially in complex defects, and Lombardo and colleagues suggest it in all cases of patients with metabolic disorders of unknown etiology (83).
(6) Genetic diagnosis. Molecular testing (ie, including next-generation sequencing) has emerged as the primary method of diagnosis in Leigh syndrome (04). Molecular testing approaches include: targeted single gene or single variant testing (if the pathogenic familial variant is known), a multigene panel, or whole-exome sequencing (sequencing the whole DNA coding region). Whole-exome sequencing is particularly efficient in the investigation of patients with widely variable phenotypes. These techniques are effective in diagnosing rare mitochondrial diseases with higher accuracy and lower cost as compared to other diagnosis techniques (118). Whole-exome sequencing has also been claimed as very effective in identifying genetic cause of Leigh syndrome (51; 60; 63). Whole-exome sequencing findings can be verified by using other sequencing techniques such as Sanger sequencing if findings are technically ambiguous (114).
Specific treatments are available only in a small proportion of cases. Most treatments are given to activate a deficient enzyme by supplying its cofactor (as in the case of thiamine for PDHc), to bypass deficient complexes or to scavenge oxygen radicals.
According to a useful overview by Chinnery and Turnbull, the following oral treatments are available to the patient with mitochondrial disease (30):
(1) Quinone derivatives:
(a) Ubiquinone (Q10). Ubiquinone is clinically proven to be effective only in isolated ubiquinone deficiency; subjective improvement has been reported in other mitochondrial disorders. Ubiquinol, which is the reduced form of CoQ10, is often recommended for supplementation over the ubiquinone form due to possible improved bioavailability (52). There is a case report of a patient with the m.10197 G>A mutation in which Q10 supplementation ameliorated symptoms of Leigh syndrome (28).
(b) Idebenone acts as a free radical scavenger and bypasses complex I. No uniform results.
(2) Vitamin supplements:
(a) Thiamine (B1). High doses of thiamine should be started in all patients with suspected Leigh syndrome (54), with suggested started doses reported in literature of more than 10 to 100 mg/kg/day. PDHc deficiency has also been shown to be responsive to thiamine with suggested starting doses of more than 400 mg/day (128).
(b) Biotin (B7). May be beneficial in patients with Leigh syndrome due to thiamine transporter defect as per above, reported ranges of initial starting doses are greater than 5 to 10 mg/kg/day.
(c) Riboflavin (B2). Occasional therapeutic value in complex I and complex II deficiency. Although its therapeutic effect is unknown, it is worth considering in complex I dysfunction due to a mutation in ACAD9 encoding the very-long-chain-acylCoA dehydrogenase gene (55).
(d) Ascorbate (C) and menadione (K3). Antioxidants and bypass of complex III
(3) Metabolic supplement:
(a) Succinate. Donates electrons directly to complex II, bypassing complex I
(b) Creatine. Enhances pool of muscle phosphocreatine
(c) Carnitine. Alleviates secondary carnitine deficiency
(4) Dichloroacetate. Inhibits PDH kinase, thereby activating PDHc and reducing lactic acidosis. May cause neuropathy on prolonged treatment. A therapeutic trial established biochemical, but not clinical, benefit. The treatment was well tolerated (119).
(5) Corticosteroids. No consistent results reported; danger of exacerbation of metabolic encephalopathy.
(6) Ketogenic diet. Ketogenic diet has the potential of a rational treatment for PDHc deficiency, but has not been evaluated on a large scale (132). It has also been reported that treatment of a patient having Leigh syndrome and compound heterozygous mutations in the gene HIBCH can show significant improvements in neurologic status by adopting a valine-restricted diet (118).
(7) Pyruvate. Pyruvate, 0.9 g/kg/day resp. 0.5 g/kg/daily given orally as sodium pyruvate appeared to be beneficial in 2 patients so far: (1) a patient with Leigh syndrome and cardiomyopathy had improved quality of life and nonprogression of MRI abnormalities after 2 years of treatment despite continuing high levels of pyruvate and lactate (122) and (2) in a patient with Leigh syndrome due to due to a mutation in the E1alpha gene of the PDHc complex a decrease in pyruvate and lactate was recorded (71).
(8) EPI-743. EPI-743 is an experimental drug, with a quinone ring and an isoprene tail, making it structurally related to coenzyme Q, and the drug idebenone, was used so far in 2 open studies for treatment of mitochondrial disorders (45) and Leigh syndrome (87). The initial results appear promising.
(9) Acetazolamide. Acetazolamide may be considered for some patients with Leigh syndrome due to MT-ATP6 related mutations as it been shown to provide some benefit for episodic weakness in MELAS patients from such defects (09).
(10) Rapamycin. Mammalian target of rapamycin (mTOR) inhibitors are currently being investigated for the management of Leigh syndrome. One study found that NDUFS4-deficient mice that were administered rapamycin had delayed on set of neurologic symptoms and lesions (67).
The French-Canadian variant of Leigh syndrome can be associated with premature ovarian failure.
In maternally inherited Leigh syndrome (MILS), a mildly affected or clinically healthy mother may have a more or less severely affected child, dependent on the degree of heteroplasmy, ie, the relative amount of mutated versus normal mitochondria per cell line.
Given the risk of apnea and brainstem involvement in Leigh disease, patients should be considered at increased risk for anesthesia. There have been several reports regarding anesthesia use in patients with Leigh disease that describe the special considerations necessary in management (58; 88; 111; 112; 69).
In other mitochondrial disorders there are increased risks of adverse responses to anesthetic agents, and this risk should be assumed in the Leigh disease patient. If a cardiomyopathy is present, this would carry an additional risk. Arterial blood pressure monitoring, along with frequent blood gases, glucose, and lactate is recommended.
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.See Profile
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