Leigh Syndrome

A number sign (#) is used with this entry because of extensive genetic heterogeneity in Leigh syndrome. Mutations have been identified in both nuclear- and mitochondrial-encoded genes involved in energy metabolism, including mitochondrial respiratory chain complexes I, II, III, IV, and V, which are involved in oxidative phosphorylation and the generation of ATP, and components of the pyruvate dehydrogenase complex.

Description

Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), or complex V deficiency (see 604273) (summary by Lake et al., 2015).

Genetic Heterogeneity of Leigh Syndrome

Mutations in complex I genes include mitochondrial-encoded MTND2 (516001), MTND3 (516002), MTND5 (516005), and MTND6 (516006), the nuclear-encoded NDUFS1 (157655), NDUFS3 (603846), NDUFS4 (602694), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA9 (603834), NDUFA10 (603835), NDUFA12 (614530), NDUFAF6 (612392), and NDUFAF5 (612360). Mutation in the MTFMT gene (611766), which is involved in mitochondrial translation, has also been reported with complex I deficiency.

A mutation has been found in a complex III gene: BCS1L (603647), which is involved in the assembly of complex III.

Mutations in complex IV genes include mitochondrial-encoded MTCO3 (516050) and nuclear-encoded COX10 (602125), COX15 (603646), SCO2 (604272), SURF1 (185620), which is involved in the assembly of complex IV, TACO1 (612958), and PET100 (614770).

A mutation has been found in a complex V gene: the mitochondrial-encoded MTATP6 (516060).

Mutations in genes encoding mitochondrial tRNA proteins have also been identified in patients with Leigh syndrome: see MTTV (590105), MTTK (590060), MTTW (590095), and MTTL1 (590050).

Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502).

The French Canadian (or Saguenay-Lac-Saint-Jean) type of Leigh syndrome with COX deficiency (LSFC; 220111) is caused by mutation in the LRPPRC gene (607544).

Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.

Clinical Features

This condition was first described by Leigh (1951) in a patient with foci of necrosis and capillary proliferation in the brainstem. Feigin and Wolf (1954) observed 2 affected sibs from a consanguineous mating. Because of similarity to Wernicke encephalopathy (277730), they suggested that a genetic defect in some way related to thiamine was present (see HISTORY). Ford (1960) referred to 2 affected sibs, and Clark (1964) pictured the histopathology of 1 of them. The main biochemical findings were high pyruvate and lactate in the blood and slightly low glucose levels in blood and cerebrospinal fluid. Hommes et al. (1968), who studied a family with 3 affected sibs, found absence of pyruvate carboxylase in the liver and concluded that gluconeogenesis was impaired. Clayton et al. (1967) demonstrated therapeutic benefit of lipoic acid. Montpetit et al. (1971) pointed out similarity in the distribution and histology of the lesions of SNE to those of Wernicke disease. They tabulated instances of affected sibs and consanguineous parents. Kohlschutter et al. (1978) reported 2 sisters and a brother born of consanguineous parents.

Gordon et al. (1974) noted that since oxidation of pyruvate is dependent on a multienzyme complex (the pyruvate dehydrogenase complex), it is likely that a number of apoenzyme and coenzyme deficiencies could lead to this disorder. Whereas Kustermann-Kuhn et al. (1984) had found that activity of the pyruvate dehydrogenase complex was not deficient in the brain of 3 autopsied cases of Leigh disease, Kretzschmar et al. (1987) reported a patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency who at postmortem examination was found to have the specific CNS pathologic changes of Leigh disease.

Gilbert et al. (1983) reported an infant with pyruvate carboxylase deficiency (266150). Pathologic studies showed extensive necrotic areas in the brain, which the authors considered to be consistent with Leigh disease.

Rutledge et al. (1981) pointed out that hypertrophic cardiomyopathy (CMH; see 192600) is a frequent associated finding. Of 12 autopsy cases, 7 (including a pair of sibs) had hypertrophic cardiomyopathy, and 4 of these had asymmetric septal hypertrophy. The authors suggested that this feature may be useful in premortem diagnosis.

Van Erven et al. (1987) reported 4 sibs (1 male, 3 female) of unrelated parents with what the authors considered to be an autosomal recessive juvenile form of Leigh syndrome. They detected no abnormalities of pyruvate metabolism in urine and serum, but all patients had marked elevations of CSF pyruvate and lactate concentrations. Although the affected sibs lived to adulthood, they were severely affected and 1 of them died at age 17 years. The mother had the onset of neurologic signs and symptoms at age 56 years. The authors suggested a defect restricted to the brain.

Van Maldergem et al. (2002) reported 2 sisters with facial dysmorphism who had axial hypotonia and failure to thrive in infancy. Other phenotypic characteristics included mental retardation, abnormal gait, spasticity, hyperreflexia, muscle atrophy, elevated lactic acid, and hypersignals in the caudate and putamen in 1 patient. They were both given a diagnosis of Leigh syndrome. Supplementation with coenzyme Q10 (CoQ10) resulted in marked clinical improvement. Investigation revealed markedly decreased muscle CoQ10 levels: 5% in 1 sister before treatment and 60% in the other during treatment. Lymphoblasts from both sisters showed 50% reduction of CoQ10. Van Maldergem et al. (2002) suggested that CoQ10 deficiency (607426) can present as Leigh syndrome.

Leigh Syndrome Due to Complex IV Deficiency

Willems et al. (1977) described deficiency of complex IV, cytochrome c oxidase, in muscle of a child who died at age 6 years of Leigh syndrome. The patient had markedly higher levels of pyruvate and lactate in CSF compared with blood. Miyabayashi et al. (1983) reported 2 brothers with deficiency of cytochrome c oxidase which was demonstrated not only in biopsied skeletal muscle but also in liver, brain, and cultured fibroblasts. One of the brothers was well until age 5 when nystagmus and incoordination began. At age 8 he was hospitalized because of difficulty walking and truncal ataxia triggered by rubella. He had moderate elevation of blood lactate after mild exercise and histochemically biopsied muscle showed markedly low cytochrome c oxidase activity. The second brother developed normally until age 10 months when dysphagia, muscular hypotonia and abnormal eye movements appeared and became progressively worse. He died in respiratory arrest 6 months later. Autopsy showed the morphologic changes of Leigh encephalomyelopathy.

Glerum et al. (1987) reported a male infant with developmental delay, hypotonia, nystagmus, optic disc pallor, and episodic metabolic acidosis. Brain CT scan showed basal ganglia hypodensities and cerebral atrophy. Blood lactate and pyruvate levels were increased. The disorder followed a progressive course, and the patient died at 3.5 years of age. Biochemical studies showed a kinetically abnormal cytochrome oxidase complex. The authors hypothesized that reduced ATP production and chronic intracellular acidosis may have contributed to the observed pathology in oxidative areas of the basal ganglia and brainstem in this patient.

In a 4-year-old daughter of consanguineous Mauritanian parents, Ogier et al. (1988) described severe muscle cytochrome c oxidase deficiency without clear evidence of clinical muscle abnormality. The child had the de Toni-Fanconi-Debre renal syndrome and acute neurologic deterioration resembling Leigh syndrome. Metabolic studies showed elevated cerebrospinal fluid lactate values contrasting with normal blood lactate, and high 3-hydroxybutyrate/acetoacetate ratio with normal lactate/pyruvate ratio.

Molecular Genetics

DiMauro and De Vivo (1996) reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1, mutations in the mitochondrial MTATP6 gene, and defects in complex IV. Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive.

Rahman et al. (1996) investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Complex I deficiency (see 252010) was more common than had previously been recognized. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., 516060.0001) a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (590060.0001), which is common in MERRF syndrome (545000), and a mitochondrial deletion. In 6 of the 7 PDHC-deficient patients, mutations were identified in the X-linked E1-alpha subunit of PDHC (PDHA1; 300502). Rahman et al. (1996) found no strong correlation between the clinical features and basic defects. Parental consanguinity suggested autosomal recessive inheritance in 2 complex IV-deficient sibships. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided.

Morris et al. (1996) reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (516060.0001) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.

In a patient with E3 deficiency (238331) who later developed features of Leigh syndrome, Grafakou et al. (2003) identified compound heterozygosity for mutations in the DLD gene (238331.0007 and 238331.0008).

In a review of the mechanisms of mitochondrial respiratory chain diseases, DiMauro and Schon (2003) diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as 1 of their pathologic consequences.

Leigh Syndrome Due to Complex I Deficiency

Morris et al. (1996) described complex I deficiency (252010) as an important cause of Leigh syndrome. Identified in 7 of 25 patients, it was the second most common biochemical abnormality after complex IV deficiency.

Loeffen et al. (1998) described the first mutations in a nuclear-encoded component of the respiratory chain complex I, NDUFS8 (602141.0001 and 602141.0002), in a patient with Leigh syndrome who died at age 11 weeks. In 2 male sibs with Leigh syndrome confirmed postmortem, Smeitink and van den Heuvel (1999) identified a mutation in the nuclear NDUFS7 gene (601825.0001), which encodes a subunit of complex I. One proband presented with feeding problems, dysarthria, and ataxia at age 26 months; the other presented with vomiting at 11 months. The course was progressive, especially after infection. Lactic acid concentration was normal in blood, urine, and cerebrospinal fluid (slight increase in cerebrospinal fluid). Magnetic resonance imaging showed symmetrical hypodensities in both sibs, who died at 3.5 years and 5 years, respectively.

In a patient with complex I deficiency resulting in Leigh syndrome, Petruzzella et al. (2001) identified a homozygous mutation in the NDUFS4 gene (602694.0004), a nuclear-encoded subunit of complex I. After birth, the girl showed failure to thrive, psychomotor delay, hypotonia, seizures, lactic acidosis, cardiomyopathy, and basal ganglia lesions on ultrasound. She died at 7 months of age from respiratory failure.

Taylor et al. (2002) reported a heteroplasmic missense mutation in the mtDNA-encoded subunit-5 of respiratory complex I (516005.0003) in a patient who died from Leigh syndrome due to complex I deficiency at the age of 24 years. There was no family history.

Sudo et al. (2004) identified an asp393-to-asn mutation in the MTND5 gene (D393N; 516005.0007) in 6 of 84 (7%) Japanese patients with Leigh syndrome. The proportions of mutant mtDNA in muscles were relatively low (42 to 70%). Ptosis and cardiac conduction abnormalities were frequently seen (83%). Sudo et al. (2004) suggested that this mutation is a frequent cause of Leigh syndrome and that patients with this mutation may have a characteristic clinical course.

In a male infant with Leigh syndrome, Ugalde et al. (2003) identified a heteroplasmic missense mutation in the MTND6 gene (516006.0007). The patient presented at 4 months of age with tonic-clonic seizures, and was later found to have motor retardation, hypotonia, deafness, pyramidal and extrapyramidal tract signs, and episodic brainstem events with oculomotor palsies, strabismus, and recurrent apnea. Laboratory studies showed lactic acidemia and basal ganglia lesions. He died at age 7 months.

In a patient with Leigh syndrome, Benit et al. (2004) identified compound heterozygosity for mutations in the NDUFS3 gene (603846.0001-603846.0002).

In a patient with Leigh syndrome, Hinttala et al. (2006) identified a heteroplasmic missense mutation in the MTND2 gene (516001.0006). The patient had progressive encephalomyopathy and died from respiratory failure at age 10 years.

In a Turkish boy with Leigh syndrome due to mitochondrial complex I deficiency, born of first-cousin parents, Hoefs et al. (2008) identified a homozygous splice site mutation in the NDUFA2 gene (602137.0001). He had hypertrophic cardiomyopathy and developmental delay from birth, and brain MRI showed cerebral atrophy and hypoplasia of the corpus callosum. After a varicella infection, he developed severe acidosis, seizures, and coma, and died of cardiovascular arrest at age 11 months. MRI just before death showed demyelinization of corticospinal tracts and subacute necrotizing encephalomyelopathy consistent with Leigh syndrome. The fibroblast and muscle complex I enzymatic activities were 36% and 20% of control values, respectively.

In a patient, born of consanguineous Kurdish parents, with Leigh syndrome due to mitochondrial complex I deficiency, van den Bosch et al. (2012) identified a homozygous mutation in the NDUFA9 gene (R321P; 603834.0001). After birth, the child developed respiratory and metabolic acidosis with increased serum lactate. Isolated complex I deficiency was found in muscle (29% of controls) and fibroblasts (11% of controls). He developed profound hearing loss, apneas associated with brainstem abnormalities, and retinitis pigmentosa. Brain MRI on day 6 showed diffuse loss of supratentorial white matter and brainstem volume with T2 hyperintensities of the basal nuclei, as well as a region of focal necrosis in the thalamus, all consistent with Leigh syndrome. He became increasingly hypertonic with choreodystonic movements, and died of respiratory insufficiency at age 1 month. Gel electrophoresis and Western blot analysis showed a significant decrease in mature complex I and in NDUFA9 in patient fibroblasts, and wildtype NDUFA9 restored complex I activity in patient fibroblasts, confirming that the mutation caused the disorder. The mutation was found by homozygosity mapping followed by candidate gene analysis.

In a 10-year-old girl, born of consanguineous Pakistani parents, with Leigh syndrome due to mitochondrial complex I deficiency, Ostergaard et al. (2011) identified a homozygous truncating mutation in the NDUFA12 gene (R60X; 614530.0001). The mutation was identified by homozygosity mapping followed by candidate gene sequencing. Patient muscle and fibroblasts showed an isolated defect of complex I activity, at 11 and 60% control values, respectively. Patient fibroblasts showed a complete absence of the NDUFA12 protein, although complex I was present at reduced levels. Transduction with wildtype NDUFA12 restored protein expression, complex I amount, and complex I activity. The patient had delayed motor development, with walking at age 20 months. From age 2 years, she showed progressive loss of motor abilities and developed scoliosis and dystonia. At age 10 years, she had poor growth, used a wheelchair, and had severe muscular atrophy and hypotonia. Hypertrichosis was noted. Vision and hearing were normal, and she attended a special school where she had learned to read and write. NDUFA12 mutations were not found in 122 patients with complex I deficiency, indicating that it is not a common cause of the disorder.

Haack et al. (2012) reported 2 unrelated patients with Leigh syndrome due to complex I deficiency associated with biallelic MTFMT mutations (611766.0001; 611766.0004). One had vertical gaze palsy, partial optic atrophy, mental retardation, spastic quadriplegia, and neurosensory bladder dysfunction. The other had developmental delay, hypotonia, ataxia, and periventricular white matter lesions.

Leigh Syndrome Due to Complex II Deficiency

In 2 sibs with complex II deficiency (252011) presenting as Leigh syndrome who were born from first cousins, Bourgeron et al. (1995) identified homozygosity for a mutation in the SDHA gene (600857.0001), which encodes the flavoprotein subunit of complex II. The authors noted that this was the first reported mutation in a nuclear gene causing a mitochondrial respiratory chain deficiency in humans.

Leigh Syndrome Due to Complex III Deficiency

In 2 unrelated patients with complex III deficiency (124000) born to unrelated parents, de Lonlay et al. (2001) identified the same homozygous mutation in the BCS1L gene (603647.0002), a nuclear gene that encodes a protein involved in the assembly of complex III. The patients had metabolic acidosis, hepatic involvement, neurologic deterioration, and brainstem and basal ganglia lesions consistent with a diagnosis of Leigh syndrome. One patient also had abnormal ventilation patterns and proximal renal tubulopathy. The patients died at 6 months and 2 years of age.

Leigh Syndrome Due to Complex IV (Cytochrome c Oxidase) Deficiency

Miranda et al. (1989) described an ingenious method for distinguishing between mitochondrial and nuclear mutations responsible for COX deficiency resulting in Leigh syndrome: a cell fusion system with prolonged cultivation of hybrids permitted preferential loss of mitochondrial DNA from 1 parent cell with demonstration that the COX defect was corrected by the nuclear DNA from that parent cell.

Tiranti et al. (1995) generated 2 lines of transmitochondrial cybrids. The first was obtained by fusing nuclear DNA-less cytoblasts derived from normal fibroblasts with mitochondrial DNA-less, i.e., rho(0), transformant fibroblasts derived from a patient with COX-deficient Leigh syndrome. The second cybrid line was obtained by fusing rho(0) cells derived from a human osteosarcoma cell line, with cytoplasts derived from the same patient. The first cybrid line showed a specific and severe COX-deficient phenotype, while in the second all the respiratory chain complexes, including COX, were normal. These results suggested to the authors that the COX defect in the patient was due to a mutation of a nuclear gene.

As a follow-up to the study by Tiranti et al. (1995), Munaro et al. (1997) performed studies demonstrating that a COX+ phenotype could be restored in hybrids obtained by fusing COX- transformant fibroblasts of 7 additional Leigh syndrome patients with cells lacking mitochondria. This result, like that of Tiranti et al. (1995), was explained by the presence of a mutation in a nuclear gene. In a second set of experiments, designed to demonstrate whether COX- Leigh syndrome is due to a defect in the same gene or in different genes, Munaro et al. (1997) tested several hybrids derived by fusing the original COX- cell line with each of 7 other cell lines. COX activity was evaluated in situ by histochemical techniques and in cell extracts by a spectrophotometric assay. No COX complementers were found among resulting hybrid lines. This result demonstrated that all 8 cases were genetically homogeneous, and suggested to the authors that a major nuclear disease locus is associated with several, perhaps most, of the cases of infantile COX- Leigh syndrome.

Of the 8 patients whose cells were studied by Munaro et al. (1997), 6 shared an apparently identical, rapidly progressive encephalopathy, characterized by early onset, generalized hypotonia with brisk tendon reflexes, truncal ataxia, ocular motor abnormalities including slow saccades, ophthalmoparesis or complex irregular eye movements, 'central' abnormalities of ventilation including episodes of apnea and irregular hyperpnea, and rapidly progressive psychomotor progression leading to death from central ventilatory failure. Some of the cells were from patients with affected sibs. In all patients, the CT scan or MRI revealed the presence of symmetric lesions scattered from the basal ganglia to the brainstem, including the cerebellum. In 1 case, necropsy examination showed necrotic lesions associated with glial and vascular proliferation, as typically described in subacute necrotizing encephalomyelopathy. In 2 of the patients the clinical features were considered atypical as described by Angelini et al. (1986). One patient showed later onset, predominantly myopathic signs, absence of 'central' abnormalities of ventilation, no signs of peripheral neuropathy, and mild or no abnormalities of eye movements. In all 8 patients, lactic acid was elevated in blood and urine and muscle biopsy examination showed a severe decrease in the histochemical reaction to COX. Ragged-red fibers were consistently absent, while lipid accumulation was a distinct feature of the muscle biopsies of the 2 atypical patients. In a patient with Leigh syndrome and cytochrome c oxidase deficiency, Adams et al. (1997) did not identify pathogenic mutations in any of the 13 structural subunits of the COX complex, including 10 nuclear-encoded and 3 mitochondrial-encoded genes.

Using microcell-mediated chromosome transfer and a functional complementation approach to COX deficiency in cell lines from patients with LS, Zhu et al. (1998) mapped the genetic defect in these patients to a 4.5-cM region on chromosome 9q34. Sequence analysis identified compound heterozygous mutations in the nuclear-encoded SURF1 gene (see, e.g., 185620.0001), a housekeeping gene. The authors suggested that SURF1 has a role in the assembly or maintenance of an active COX complex. Using functional complementation assays based on cell fusion studies, Tiranti et al. (1998) identified 8 homozygous or compound heterozygous mutations in the SURF1 gene in 9 families with LS (see, e.g., 185620.0006).

In 18 of 24 (75%) patients with COX-deficient LS, Tiranti et al. (1999) identified mutations in the SURF1 gene. A total of 13 different mutations were found, including frameshift, nonsense, and splice site mutations, which were predicted to result in loss of protein function. No missense mutations were identified. In addition, no SURF1 mutations were found in 6 patients with COX deficiency classified as 'Leigh-like' or in 16 patients with COX deficiency classified as 'non-LS.' Tiranti et al. (1999) concluded that SURF1 mutations are specifically associated with LS, and that SURF1 is the gene responsible for most of the COX-deficient cases of LS. Tiranti et al. (1999) reported monozygotic twin females who died from Leigh syndrome in the third year of life. A homozygous missense mutation in the SURF1 gene (185620.0006) was found in the affected twins. This mutation was also found in heterozygous state in their mother but not in their father. FISH analysis excluded deletion of the paternal allele, and haplotype analysis using 22 microsatellites confirmed uniparental disomy of chromosome 9.

Rahman et al. (2001) described a 2-year-old girl, born of healthy, consanguineous Bengali parents, who presented with failure to thrive, global neurodevelopmental regression, and lactic acidosis. MRI of the brain showed leukodystrophy with involvement of the corticospinal tracts. There were no basal ganglia necrotic lesions characteristic of Leigh syndrome. Respiratory chain enzyme assays on biopsied muscle revealed a severe isolated deficiency of COX. Sequence analysis of the SURF1 gene showed homozygosity for a 2-bp deletion at nucleotides 790-791 (185620.0011). The patient's parents were heterozygotes. The authors suggested assaying respiratory chain enzymes in patients with leukodystrophy and lactic acidosis and sequencing SURF1 in patients with isolated COX deficiency. In a letter concerning the report by Rahman et al. (2001), Savoiardo et al. (2001) noted that lack of basal ganglia involvement can be observed in LS and appears to be a rather frequent feature of LS SURF1 patients.

In a patient with a 'Leigh-like syndrome' and COX deficiency characterized by neurologic abnormalities, severe lactic acidosis, and lesions in the putamen, Tiranti et al. (2000) identified a mutation in the mitochondrial-encoded subunit III structural gene of complex IV (MTCO3; 516050.0005). Expression studies showed defective COX assembly.

Dahl (1998) reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome.

Salviati et al. (2004) described a 10-year-old boy with an unusually mild clinical course of Leigh syndrome in whom they found a heterozygous 4-bp insertion in exon 6 (185620.0013) associated with a common polymorphism (573C-G) on the same allele. The patient also had a 10-bp deletion/2-bp insertion in exon 4 (185620.0003). His mother harbored the exon 4 mutation and his father carried the exon 6 mutation. At age 39 months, the patient had no MRI lesions; at 8 years of age, MRI showed only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei. Salviati et al. (2004) concluded that the spectrum of MRI findings in Leigh syndrome is variable and that SURF1 mutations should be considered in patients with encephalopathy and COX deficiency even when early MRI findings are negative. The authors noted that this patient, still alert, interactive, and able to communicate verbally at age 10, probably represented the longest reported survival to date.

In a patient with Leigh syndrome due cytochrome c oxidase deficiency, Oquendo et al. (2004) identified homozygosity for a mutation in the COX15 gene (603646.0001).

Bugiani et al. (2005) reported a 16-year-old Italian boy with Leigh syndrome who was compound heterozygous for a nonsense mutation (S151X; 603646.0003) and a missense mutation (S344P; 603646.0004) in the COX15 gene. The patient failed to thrive in infancy, with poor sucking and feeding difficulties, and was noted to have severe psychomotor delay at 4 months of age, with diffuse hypotonia, muscle wasting, and weakness. MRI at 18 months of age showed symmetric signal changes in the posterior part of the putamina and bilateral cerebellar white matter abnormalities. Plasma lactate and pyruvate levels were markedly elevated. Symptoms worsened thereafter with virtual arrest of body growth, progressive loss of postural control, and onset of dystonic postures in the upper limbs, whereas cognitive functions remained relatively better preserved. Clinical features remained grossly unchanged thereafter, and apart from central nervous system and skeletal muscle, the patient showed no abnormality in other tissues or organs, including the heart, gastrointestinal tract, liver, kidneys, or hematopoietic system.

Ostergaard et al. (2005) reported 3 unrelated patients with Leigh syndrome due to COX deficiency caused by mutations in the SURF1 gene. All 3 patients carried the common 10-bp deletion/2-bp insertion (185620.0003); 1 was homozygous, and the others were compound heterozygous with another SURF1 mutation. In addition to Leigh syndrome, all showed hypertrichosis at ages 8 months, 12 months, and 3 years, respectively. Hypertrichosis was on the forehead and extremities of 2 patients and on the forehead, extremities, and trunk in the third patient. Ostergaard et al. (2005) stated that 5 patients with SURF1 mutations and hypertrichosis had been reported in the literature (see, e.g., Moslemi et al., 2003; Rahman et al., 2001), and suggested that it be considered a clinical sign in patients with Leigh syndrome caused by SURF1 mutation.

Weraarpachai et al. (2009) identified a homozygous mutation in the TACO1 gene (472insC; 612958.0001) in affected members of a family with childhood-onset and slowly progressive Leigh syndrome due to mitochondrial complex IV deficiency. Synthesis of the MTCO1 subunit (516030) was decreased by approximately 65%, and there was a greatly reduced steady-state level of fully assembled complex IV. Expression of wildtype TACO1 rescued the MTCO1 assembly defect and complex IV activity.

Leigh Syndrome Due to Complex V Deficiency

In a female infant with Leigh syndrome characterized by lactic acidemia, hypotonia, neurodegeneration, and brain lesions, Tatuch et al. (1992) identified a heteroplasmic mutation (8993T-G; 516060.0001) in the mitochondrial-encoded ATP6 subunit (MTATP6) of ATP synthase (complex V). The patient had more than 95% abnormal mtDNA in fibroblasts, brain, kidney, and liver. In a family with multiple affected members, Shoffner et al. (1992) identified the same mutation. In the family reported by van Erven et al. (1987) in which the mother and all 4 children were affected with Leigh syndrome, de Vries et al. (1993) identified a heteroplasmic mutation in the MTATP6 gene (516060.0002).

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family G008, they identified homozygosity for a missense mutation (185620.0015) in the SURF1 gene in 2 sibs with mild intellectual disability, ataxia, short stature, and facial dysmorphism, diagnosed as a mild form of Leigh syndrome. The first-cousin parents were heterozygous for the mutation and had 2 healthy children.

Associations Pending Confirmation

For discussion of a possible association between a neurodegenerative disorder with clinical features of Leigh syndrome and variation in the GYG2 gene, see 300198.0001.

For discussion of a possible association between Leigh syndrome and variation in the IARS2 gene, see 612801.0002.

Clinical Management

Ma et al. (2015) generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A-G (590050.0001), causing MELAS, and 8993T-G (516060.0001) and 13513G-A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wildtype or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T-G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wildtype mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wildtype mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. Ma et al. (2015) concluded that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wildtype mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease.

Population Genetics

In 3 sibs, born of Ashkenazi Jewish parents, with Leigh syndrome due to complex I deficiency, Anderson et al. (2008) identified a homozygous mutation in the NDUFS4 gene (462delA; 602694.0006). The mutation was identified by linkage analysis followed by candidate gene sequencing. The sibs all had classic neurodegenerative features of the disorder, with encephalopathy, lesions on brain MRI, and lactic acidosis. The patients presented in the first months of life, and all died by age 10 months. The NDUFS4 mutation resulted in the loss of the cAMP-dependent protein kinase phosphorylation consensus site, which is important for activation of complex I. Skeletal muscle biopsy of 1 patient showed a mild decrease in complex I activity. The carrier frequency of the mutation, ascertained from 5,000 controls of Ashkenazi Jewish descent, was found to be 1 in 1,000, consistent with a founder effect in this population. Based on the results, Anderson et al. (2008) used prenatal testing in this family to help the parents produce an unaffected child.

History

Denis Leigh was a registrar in the Department of Neuropathology, Institute of Psychiatry, Maudsley Hospital, London, at the time he described this condition and named it subacute necrotizing encephalomyelopathy, or SNE (Leigh, 1951). He pronounced his name 'Lee,' not 'Lay'(McHugh, 1993).

It was originally suggested that the biochemical defect in Leigh syndrome was a block in thiamine metabolism. Cooper et al. (1969, 1970) found that patients with SNE elaborate a factor, found in the blood and urine, that inhibits the synthesis of thiamine triphosphate (TTP) in brain tissue. The enzyme responsible for TTP synthesis is called thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase. TTP was completely absent in postmortem brain. They suggested that an assay for the inhibitor of TTP synthesis could be performed on urine or blood for diagnostic purposes. In the urine of obligatory or presumptive heterozygotes, Murphy (1973) found an inhibitor of thiamine triphosphate synthesis in vitro. Pincus et al. (1969) had described the inhibitor in untreated patients. Thiamine derivatives in therapy were studied by Pincus et al. (1973). By direct examination of amniotic fluid for the inhibitor of TTP synthesis, Murphy et al. (1975) suggested that Leigh syndrome could probably be diagnosed antenatally. Plaitakis et al. (1980) studied the family of a patient who died at age 21 years. The patient came from an isolated Greek island with a population of 1,200. Studies of the family showed inhibitor of adenosine triphosphate-thiamine diphosphate phosphoryltransferase in several members of the family and many of these had a chronic neurologic illness compatible with Leigh disease. Several sibships had more than 1 affected member and the parents were demonstrably consanguineous in several instances.