SNE LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY, INCLUDED
NECROTIZING ENCEPHALOPATHY, INFANTILE SUBACUTE, OF LEIGH
LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX III DEFICIENCY, INCLUDED
LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX IV DEFICIENCY, INCLUDED
LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX V DEFICIENCY, INCLUDED
LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX II DEFICIENCY, INCLUDED
LS
Sporadic Leigh disease
Sporadic infantile subacute necrotizing encephalopathy
Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The ... Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation (Dahl, 1998). Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (252010), complex II deficiency (252011), complex III deficiency (124000), complex IV deficiency (cytochrome c oxidase; 220110), or complex V deficiency (604273).
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 ... 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.
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 ... 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.
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 ... 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.
Mitochondrial DNA-associated (mtDNA-associated) Leigh syndrome and NARP are part of a continuum of progressive neurodegenerative disorders observed in members of the same family caused by abnormalities of mitochondrial energy generation....
DiagnosisClinical DiagnosisMitochondrial DNA-associated (mtDNA-associated) Leigh syndrome and NARP are part of a continuum of progressive neurodegenerative disorders observed in members of the same family caused by abnormalities of mitochondrial energy generation.Leigh syndrome. Stringent diagnostic criteria for Leigh syndrome were defined by Rahman et al [1996]*: Progressive neurologic disease with motor and intellectual developmental delay Signs and symptoms of brain stem and/or basal ganglia disease Raised lactate concentration in blood and/or cerebrospinal fluid (CSF) One or more of the following:Characteristic features of Leigh syndrome on neuroradioimaging (see Testing) Typical neuropathologic changes: multiple focal symmetric necrotic lesions in the basal ganglia, thalamus, brain stem, dentate nuclei, and optic nerves. Histologically, lesions have a spongiform appearance and are characterized by demyelination, gliosis, and vascular proliferation. Neuronal loss can occur, but typically the neurons are relatively spared. Typical neuropathology in a similarly affected sibling *Note: Prior to the development of modern imaging techniques, definitive diagnosis of Leigh syndrome was based on characteristic neuropathologic features and thus could only be made post mortem.Leigh-like syndrome. The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and CSF lactate levels, or incomplete evaluation. NARP. Strict diagnostic criteria for NARP have not yet been established. Diagnosis of NARP is based on the following clinical features: Neurogenic muscle weakness. Electromyography (EMG) and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy). Ataxia. Cerebral and cerebellar atrophy may be noted on MRI. Retinitis pigmentosa. The ocular manifestations of NARP are extremely variable and range from a mild salt and pepper retinopathy to bull's eye maculopathy and classic retinitis pigmentosa with bone spicule formation [Ortiz et al 1993]. Ophthalmologic examination may reveal pigmentary retinopathy or optic atrophy. Electroretinogram (ERG) may reveal abnormalities (including small-amplitude waveform) or may be normal. ERG may demonstrate predominantly cone dysfunction in some pedigrees and mainly rod dysfunction in others [Chowers et al 1999]. In addition, neuropathy, seizures, and learning difficulties are usually present. TestingBlood and CSF lactate levelsLactate is usually elevated in blood, but this is not an invariant feature and tends to be more marked in post-prandial samples. Testing multiple blood samples to obtain a daily profile is more sensitive than testing a single random sample. Lactate elevation is more consistent in CSF samples than blood samples. Plasma amino acids may show elevated alanine concentration (formed from the transamination of pyruvate), reflecting persistent elevation of plasma lactate concentration. Low plasma citrulline concentration has been reported in individuals with the m.8993T>G mutation [Rabier et al 1998]. Urine organic acid analysis often detects lactic aciduria and is useful in excluding other organic acidurias (see Organic Acidemias Overview). Proton magnetic resonance spectroscopy (MRS) can also be useful in detecting regional elevations in brain lactate levels. Brain imaging Characteristic features of Leigh syndrome are bilateral symmetric hypodensities in the basal ganglia on computed tomography (CT) or bilateral symmetrical hyperintense signal abnormality in the brain stem and/or basal ganglia on T2-weighted magnetic resonance imaging (MRI) [Arii & Tanabe 2000, Rossi et al 2003]. Specific tracts have not been reported to be affected in mtDNA-associated Leigh syndrome; however, specific brain lesions (affecting the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum) appear to be characteristic of Leigh syndrome caused by mutations in the nuclear gene NDUFAF2, encoding an assembly factor for respiratory chain complex I [Ogilvie et al 2005, Barghuti et al 2008, Hoefs et al 2009, Herzer et al 2010]. In NARP, cerebral and cerebellar atrophy may be noted on MRI. Muscle biopsy. Usually, histologic examination shows only minimal if any changes, such as accumulation of intracytoplasmic neutral lipid droplets. Ragged red fibers (a hallmark of adult-onset mitochondrial diseases) are rarely, if ever, seen. Cytochrome c oxidase-negative fibers are occasionally found in individuals with Leigh syndrome caused by certain mtDNA and nuclear gene mutations. Note: (1) Although muscle biopsy is only occasionally abnormal, when it is abnormal it can be as much of a contributor to diagnostic certainty as respiratory chain enzymes or molecular testing. (2) If an affected individual is having a muscle biopsy for enzyme testing, histologic examination should also be performed.Respiratory chain enzyme studies. Biochemical analysis of tissue biopsies or cultured cells often detects deficient activity of one or more of the respiratory chain enzyme complexes. Isolated defects of complex I or complex IV are the most common enzyme abnormalities observed and can help guide subsequent molecular genetic testing of mtDNA or nuclear genes. Biochemical results can also be normal, usually in individuals with mtDNA mutations affecting complex V subunits such as the mutations at mitochondrial nucleotides 8993 and 9176 (Table 5). Skeletal muscle is usually the tissue of choice for enzyme studies. Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts. Approximately 10%-20% of individuals with normal skeletal muscle respiratory chain enzymes may have an enzyme defect detected in liver or cardiac muscle, particularly if those tissues are involved clinically [Thorburn et al 2004]. Molecular Genetic TestingGenesMitochondrial DNA-associated Leigh syndrome. Mutations in the mitochondrial genes MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3 are associated with mtDNA-associated Leigh syndrome. NARP. MT-ATP6 is the only gene in which mutation is known to cause NARP. Clinical testing Targeted mutation analysis. Targeted mutation analysis can be performed in DNA extracted from leukocytes, since the following mutations are always present at high load in leukocytes from persons with maternally inherited Leigh syndrome or NARP. Mitochondrial DNA-associated Leigh syndrome. Approximately 10%-20% of individuals with Leigh syndrome have either the m.8993T>G or the m.8993T>C mutation in MT-ATP6 [Santorelli et al 1993, Rahman et al 1996, Makino et al 1998]. Approximately 10%-20% have mutations in other mitochondrial genes. NARP. The proportion of individuals with NARP who have a detectable mutation at MT-ATP6 nucleotide 8993 is not known but is likely to be greater than 50%, at least in individuals with elevated blood lactate concentration. m.8993T>G is most common; m.8993T>C has also been described [Rantamaki et al 2005]. However, in one study, only two of ten individuals with neuropathy, ataxia, and retinitis pigmentosa (the 'cardinal' features of NARP) had a MT-ATP6 nucleotide 8993 mutation [Santorelli et al 1997b]; detailed clinical features were not described for the other eight individuals in that study. Note: Most mtDNA mutations are 'heteroplasmic' (i.e., mutant mtDNA coexists with wild type mtDNA) and for some mutations, the mutation load may vary among different tissues and may increase or decrease with age. The m.8993T>G and m.8993T>C mutations do not appear to show any significant variation in mutation load among tissues [White et al 1999c], so white blood cells or any other tissue type can be used to test for these two mutations. Some mtDNA mutations tend to disappear from white blood cells with increasing age [Rahman et al 2001]. Thus, for individuals with milder symptoms and for asymptomatic maternal relatives, the pathogenic mutation may be undetectable in leukocytes and may only be detected in other tissues such as hair follicles, urine sediment cells, or skeletal muscle. Skeletal muscle is the most reliable tissue for detection of mtDNA mutations and recent studies indicate that urine sediment sediment cells are preferable to blood [McDonnell et al 2004, Shanske et al 2004].Sequence analysis of all/part of the mitochondrial genomeTable 1. Summary of Molecular Genetic Testing Used in Mitochondrial DNA-Associated Leigh Syndrome and NARPView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMitochondrial DNA-Associated Leigh Syndrome NARPMT-ATP6 2Targeted mutation analysis in leukocyte DNAm.8993T>G and m.8993T>C mutations of MT-ATP6 10%-20%50%ClinicalAny or all of the genes: MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-CO3Sequence analysis of complete mtDNA in muscleMany different mtDNA mutations 310%-20%0%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Panel varies by laboratory and may include testing for mutations associated with MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and/or MT-CO3 (see Mitochondrial Disorders Overview).3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.Testing Strategy To confirm/establish the diagnosis in a proband Clinical testing, including brain imaging and measurement of lactic acid concentration in body fluids Molecular genetic testing of blood (or other samples obtained in relatively non-invasive manner) for targeted mutation analysis of common mtDNA mutationsIf targeted mutation analysis in blood does not identify a disease-causing mtDNA mutation, muscle biopsy for histology, biochemistry (respiratory chain enzyme assays), and complete mitochondrial DNA sequence analysisEnzyme studies of other tissues including skin fibroblasts, white blood cells, liver, or cardiac muscle may be performed in some centers. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family; however, the use of molecular genetic test results to predict long-term outcome is difficult. Genetically Related (Allelic) DisordersMitochondrial DNA mutations can also be associated with a variety of disorders including MELAS, MERRF, Leber hereditary optic neuropathy (LHON), infantile bilateral striatal necrosis, progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness, or sudden (unexplained) death in infancy, childhood, or adulthood (see Mitochondrial Disorders Overview).
Mitochondrial DNA-associated Leigh syndrome (subacute necrotizing encephalomyelopathy). Onset of symptoms can be from the neonatal period through adulthood but is typically between age three to 12 months, often following a viral infection. Later onset (i.e., after age one year, including presentation in adulthood) and slower progression occur in up to 25% of individuals [Goldenberg et al 2003, Huntsman et al 2005]. ...
Natural HistoryMitochondrial DNA-associated Leigh syndrome (subacute necrotizing encephalomyelopathy). Onset of symptoms can be from the neonatal period through adulthood but is typically between age three to 12 months, often following a viral infection. Later onset (i.e., after age one year, including presentation in adulthood) and slower progression occur in up to 25% of individuals [Goldenberg et al 2003, Huntsman et al 2005]. Leigh syndrome is a progressive neurodegenerative disorder. Initial features may be nonspecific, such as failure to thrive and persistent vomiting. Decompensation (often with raised blood and/or CSF lactate concentrations) during an intercurrent illness is typically associated with psychomotor retardation or regression. A period of recovery may follow the initial decompensation, but the individual rarely returns to the developmental status achieved prior to the presenting illness. Neurologic features include hypotonia, spasticity, dystonia, muscle weakness, hypo- or hyperreflexia, seizures (myoclonic or generalized tonic-clonic), infantile spasms, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Brain stem lesions may cause respiratory difficulty (apnea, hyperventilation, or irregular respiration), swallowing difficulty, persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia). Ophthalmologic findings include optic atrophy, retinitis pigmentosa, and eye movement disorders [Morris et al 1996, Rahman et al 1996, Tsuji et al 2003].Extraneurologic manifestations can be cardiac (hypertrophic cardiomyopathy [Agapitos et al 1997]), hepatic (hepatomegaly or liver failure [Leshinsky-Silver et al 2003a]), or renal (renal tubulopathy or diffuse glomerulocystic kidney damage [Yamakawa et al 2001, Tay et al 2005]). Table 2 lists the frequency of various clinical features in individuals with Leigh syndrome and Leigh-like syndrome, with and without mtDNA mutations. The data have been updated from those reported by Rahman et al [1996] by allowing for six of the original individuals in whom mtDNA mutations have subsequently been identified. Some features appear to be more common in individuals with mtDNA mutations, for example, bulbar problems and (although not specifically studied by Rahman et al [1996]) pigmentary retinopathy in up to 40% of individuals with mtDNA 8993 mutations [Santorelli et al 1993]. Not surprisingly, consanguinity is more common in individuals without mtDNA mutations; most of whom are likely to have an autosomal recessive disorder (see Differential Diagnosis). However, for most individuals with Leigh syndrome, the profile of clinical features in a particular individual is not strongly indicative of the likely genetic origin (mtDNA vs. nuclear gene mutation) of the disorder.Most affected individuals have episodic deterioration interspersed with "plateaus" during which development may be quite stable or even show some progress. The duration of these plateaus is variable and on occasion may be ten years or more. Death typically occurs by age two to three years, most often from respiratory or cardiac failure. In undiagnosed cases, death may appear to be sudden and unexpected. Table 2. Prevalence of Clinical Features in Leigh Syndrome and Leigh-Like Syndrome View in own windowClinical FeatureLeigh SyndromeLeigh-Like Syndrome13 individuals with mtDNA mutations identified 1 22 individuals without mtDNA mutations identified5 individuals with mtDNA mutations identified 2 27 individuals without mtDNA mutations identifiedMedian Age in Months at Onset (Range in Months) 6 (3-120)6 (1-42)9 (0-118)7 (0-102)% of Individuals in whom Feature was Present Consanguinity018030Family history46452056Male62556070Developmental delay10010010089Hypotonia92824070Spasticity62502052Reflexes increased69646052Reflexes decreased823022Weakness62556044Ataxia38368037Involuntary movements15362033Dystonia15272019Seizures3145067Nystagmus46452037Ophthalmoplegia/ squint54234056Optic atrophy3832015Ptosis15184015Cranial nerve palsies155015Bulbar problems693610044Peripheral neuropathy0907Respiratory disturbance85646056Poor feeding31556030Unexplained vomiting31364037Failure to thrive38556056Cardiac problems8507Adapted from Rahman et al [1996]1. These 13 individuals include four with the m.8993T>G mutation, two with the m.8993T>C mutation, one with the m.8344G>A mutation, and six individuals in whom mtDNA mutations have been identified subsequently: namely, two brothers with the m.14459G>A mutation [Kirby et al 2000], two unrelated individuals with the m.14487T>C mutation [unpublished data], and single individuals with the m.13513G>A mutation [Kirby et al 2003] and the m.12706T>C mutation [unpublished data].2. These five individuals include two with the m.8993T>G mutation, two with the m.8993T>C, and one with a mtDNA deletion.Table 3. Investigation Results in Leigh Syndrome and Leigh-Like SyndromeView in own windowInvestigationLeigh SyndromeLeigh-Like Syndrome13 individuals with mtDNA mutations identified 1 22 individuals without mtDNA mutations identified5 individuals with mtDNA mutations identified 2 27 individuals without mtDNA mutations identifiedMedian Age in Months at Onset (Range in Months)6 (3-120)6 (1-42)9 (0-118)7 (0-102)% of Individuals in whom Feature was Present Lactate not done05204Lactate normal05033Lactate raised100868063CT/MRI not done094015CT/MRI normal814033CT/MRI atypical006037CT/MRI typical9277015Postmortem diagnosis3841022Adapted from Rahman et al [1996] 1. These 13 individuals include four with the m.8993T>G mutation, two with the m.8993T>C mutation, and one with the m.8344G>A mutation plus six individuals reported in that study in whom mtDNA mutations have been identified subsequently, namely two brothers with the m.14459G>A mutation [Kirby et al 2000], two unrelated individuals with the m.14487T>C mutation [unpublished data], and single individuals with the m.13513G>A mutation [Kirby et al 2003] and m.12706T>C mutation [unpublished data].2. These five individuals include two with the m.8993T>G mutation, two with the m.8993T>C, and one with a mtDNA deletion.NARP. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. First described by Holt et al [1990], NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, pigmentary retinopathy, seizures, learning difficulties, and dementia. Other clinical features include short stature, sensorineural hearing loss, progressive external ophthalmoplegia, cardiac conduction defects (heart block) and a mild anxiety disorder [Santorelli et al 1997a, Sembrano et al 1997]. Visual symptoms may be the only clinical feature. One individual had obstructive sleep apnea requiring tracheostomy and nocturnal mechanical ventilation [Sembrano et al 1997].Individuals with NARP can be relatively stable for many years, but may suffer episodic deterioration, often in association with viral illnesses. Intermediate phenotypes in the continuum. Maternal relatives of individuals with Leigh syndrome or NARP can have any one or a combination of the individual symptoms associated with Leigh syndrome, NARP, or other mitochondrial disorders. These include mild learning difficulties, muscle weakness, night blindness, deafness, diabetes mellitus, migraine, or sudden unexpected death.
For most mtDNA mutations, it is difficult to distinguish a simple correlation between genotype and phenotype because clinical expression of a mtDNA mutation is influenced not only by the pathogenicity of the mutation itself but also by the relative amount of mutant and wildtype mtDNA (the heteroplasmic mutant load), the variation in mutant load among different tissues, and the energy requirements of brain and other tissues, which may vary with age. ...
Genotype-Phenotype CorrelationsFor most mtDNA mutations, it is difficult to distinguish a simple correlation between genotype and phenotype because clinical expression of a mtDNA mutation is influenced not only by the pathogenicity of the mutation itself but also by the relative amount of mutant and wildtype mtDNA (the heteroplasmic mutant load), the variation in mutant load among different tissues, and the energy requirements of brain and other tissues, which may vary with age. The m.8993T>G and m.8993T>C mutations probably show the strongest genotype-phenotype correlation of any mtDNA mutations. A notable feature is that they show very little tissue-dependent or age-dependent variation in mutant load [White et al 1999c] and have a strong correlation between mutant load and disease severity. These features allowed White et al [1999a] to generate logistic regression models that gave curves predicting the probability of a severe outcome in an individual based on their measured mutant load of m.8993T>G and m.8993T>C (Figure 1). However, it should be noted that in such retrospective studies it is not possible to completely avoid ascertainment bias, and the data should be regarded as broadly indicative rather than precise.FigureFigure 1. Estimated probability of a severe outcome (with 95% confidence intervals) for an individual with the mtDNA m.8993T>G or m.8993T>C mutation, based on the mutant load of the individual. A severe outcome is defined as severe symptoms (more...)m.8993T>G. Individuals with m.8993T>G mutant loads below 60% are usually asymptomatic, or have only mild pigmentary retinopathy or migraine headaches; however, asymptomatic adults with mutant loads of up to 75% have been reported [Tatuch et al 1992, Ciafaloni et al 1993]. As a generalization, individuals with moderate levels (~70%-90%) of the m.8993T>G mutation present with the NARP phenotype, while those with mutant loads above 90% have maternally inherited Leigh syndrome. Note: Overlap in mutant loads is observed between some asymptomatic individuals and others with NARP, and between some individuals with NARP and others with Leigh syndrome.m.8993T>C. m.8993T>C is a less severe mutation than m.8993T>G, and virtually all symptomatic individuals have m.8993T>C mutant loads of more than 90%. Genotype-phenotype correlations are much weaker for other mtDNA mutations detected in multiple unrelated cases of Leigh syndrome (e.g., m.3243A>G in MT-TL1, m.8344A>G in MT-TK, m.9176T>C in MT-ATP6, m.14459G>A and m.14487T>C in MT-ND6, m.10158T>C and m.10191T>C in MT-ND3, and m.13513G>A in MT-ND5). The presence of any of these mutations in individuals with symptoms of Leigh syndrome identifies the genetic cause of the disorder. However, unlike the m.8993T>G and m.8993T>C mutations, it is usually not possible to interpret the heteroplasmic mutant load to predict outcome (e.g., in asymptomatic family members or in prenatal diagnosis) unless the value is near 0% or near 100%. This situation should improve in the future, at least for some mtDNA mutations, as more data become available.
Differential DiagnosisNARP Neurogenic weakness and neuropathy (see Charcot-Marie-Tooth Hereditary Neuropathy Overview) Ataxia (see Hereditary Ataxia Overview) Retinitis pigmentosa (see Retinitis Pigmentosa Overview) Leigh syndrome. In most individuals with Leigh syndrome, the disease is not caused by a mtDNA mutation but by an autosomal recessive or X-linked disorder of mitochondrial energy generation. It was previously thought that mtDNA mutations caused only a very small proportion of Leigh syndrome [Morris et al 1996]. However, in most reports on large series of individuals with Leigh syndrome, the proportion caused by mutations of mtDNA is found to be 10%-30% [Santorelli et al 1993, Rahman et al 1996, Makino et al 1998]. Further analyses of a large series of 67 individuals with Leigh or Leigh-like syndrome reported by Rahman et al [1996] have now identified pathogenic mtDNA mutations in 27% of the entire group and 37% of the individuals with a stringent diagnosis of Leigh syndrome (Table 2) [Author, personal communication]. Mutations in nuclear genes that result in respiratory chain complex deficiencies and Leigh syndrome are summarized in Table 4. Table 4. Leigh Syndrome Caused By Nuclear Gene Mutations Resulting in Respiratory Chain Complex DeficienciesView in own windowRespiratory Chain Complex DeficiencyNameGenesReferencesI (NADH-coenzyme Q reductase)Complex I-deficient Leigh syndromeNDUFV1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA1, NDUFA2, NDUFA10, NDUFAF2, C8orf38, C20orf7, FOXRED1 Loeffen et al [2000], Benit et al [2001], Benit et al [2004], Fernandez-Moreira et al [2007], Hoefs et al [2008], Pagliarini et al [2008], Hoefs et al [2009], Calvo et al [2010], Gerards et al [2010], Tuppen et al [2010], Hoefs et al [2011] Other unknown genesII (succinate-ubiquinone reductase)Complex II-deficient Leigh syndromeSDHA Bourgeron et al [1995], Pagnamenta et al [2006]IV (cytochrome c oxidase)Cytochrome c oxidase-deficient Leigh syndromeSURF1, COX10, COX15 Pequignot et al [2001], Antonicka et al [2003], Oquendo et al [2004] French-Canadian or Saguenay-Lac Saint Jean typeLRPPRC Mootha et al [2003] Other unknown genesII+III (succinate cytochrome c reductase)Coenzyme Q10 deficiencyPDSS2, other unknown genesVan Maldergem et al [2002] , López et al [2006]I, III + IV (multiple respiratory chain enzyme deficiencies)Mitochondrial DNA depletion syndromePOLG, SUCLG1, other unknown genesTaanman et al [2009], Van Hove et al [2010]I, III + IV (multiple respiratory chain enzyme deficiencies)Mitochondrial translation defectC12orf65, other unknown genesAntonicka et al [2010]Other disorders that cause or resemble Leigh syndrome include:Pyruvate dehydrogenase deficiency, usually caused by mutations in the X-linked gene PDHA1, which encodes the E1alpha subunit [Rahman et al 1996, Lissens et al 2000]. Mutations in PDHB encoding the E1beta subunit and PDHE3BP encoding the E3 binding protein have also been associated with Leigh syndrome [Schiff et al 2006, Quintana et al 2009].Dihydrolipoamide dehydrogenase (E3) deficiency [Grafakou et al 2003] Biotinidase deficiency [Mitchell et al 1986] Bilateral striatal necrosis [De Meirleir et al 1995, Thyagarajan et al 1995]. Autosomal recessive infantile bilateral striatal necrosis may be caused by mutations in NUP62, encoding a component of the nuclear pore [Basel-Vanagaite et al 2006].Acute necrotizing encephalopathy, which may be triggered by viral infections. Recently mutations in RANBP2, encoding another nuclear pore component, have been linked to infection-triggered familial acute necrotizing encephalopathy [Neilson et al 2009].Viral encephalopathies [Suwa et al 1999] Other neurodegenerative disorders with similar changes on neuroimaging including pantothenate kinase-associated neurodegeneration, neuroferritinopathy [Curtis et al 2001], and organic acidemias. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Leigh syndromeNARP
To establish the extent of disease in an individual diagnosed with mtDNA-associated Leigh syndrome or NARP, the following evaluations are recommended:...
ManagementEvaluation Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with mtDNA-associated Leigh syndrome or NARP, the following evaluations are recommended:Developmental assessmentNeurologic evaluation, MRI, MRS [Takahashi et al 1999], EEG (if seizures are suspected) ,and nerve conduction studies (if neuropathy is suspected) Metabolic evaluation, plasma and cerebrospinal fluid lactate and pyruvate concentrations, urine organic acids Ophthalmologic evaluation Cardiac evaluation Treatment of ManifestationsNo specific treatment for mtDNA-associated Leigh syndrome and NARP exists. Supportive management includes treatment of the following:Acidosis. Sodium bicarbonate or sodium citrate for acute exacerbations of acidosis Seizures. Appropriate antiepileptic drugs tailored to the type of seizure under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002]. Dystonia Benzhexol, baclofen, tetrabenezine, and gabapentin may be useful, alone or in various combinations; an initial low dose should be started and gradually increased until symptom control is achieved or intolerable side effects occur. Botulinum toxin injection has also been used in individuals with Leigh syndrome and severe intractable dystonia. Cardiomyopathy. Anticongestive therapy may be required and should be supervised by a cardiologist. Regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients and feeding management is indicated.Psychological support for the affected individual and family is essential.Prevention of Primary ManifestationsNo specific preventative treatment for primary manifestations of mtDNA-associated Leigh syndrome and NARP exists. SurveillanceAffected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression and the appearance of new symptoms. Neurologic, ophthalmologic, and cardiologic evaluations are recommended.Agents/Circumstances to AvoidSodium valproate and barbiturates should be avoided because of their inhibitory effect on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002]. Anesthesia can potentially aggravate respiratory symptoms and precipitate respiratory failure, so careful consideration should be given to its use and to monitoring of the individual prior to, during, and after anesthetic procedures [Shear & Tobias 2004]. Dichloroacetate (DCA) reduces blood lactate by activating the pyruvate dehydrogenase complex. Anecdotal reports have suggested that DCA may cause some short-term clinical improvement in mtDNA-associated Leigh syndrome [Takanashi et al 1997, Fujii et al 2002]. A double-blind, placebo-controlled trial of DCA in a different mitochondrial disease, MELAS, found no benefit and in fact documented a toxic effect of DCA on peripheral nerves [Kaufmann et al 2006]. A more recent report described the results of long-term administration of DCA to 36 children with congenital lactic acidosis (randomized control trial followed by an open label extension) [Stacpoole et al 2008]. This study concluded that oral DCA is well tolerated in young children with congenital lactic acidosis and that it was not possible to determine whether the peripheral neuropathy associated with long-term DCA administration is attributable to the drug or to the underlying disease process. It therefore appears prudent for individuals with mtDNA-associated Leigh syndrome or NARP to avoid DCA, in view of the underlying risk of peripheral neuropathy caused by the disease itself in these conditions. Evaluation of Relatives at RiskMolecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutation loads and are thus at risk of developing symptoms. However, no proven disease-modifying intervention exists at present.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAntioxidants, including coenzyme Q and analogs such as idebenone, can enhance the function and viability of cultured cells from individuals with the m.8993T>G mutation [Geromel et al 2001, Mattiazzi et al 2004], but have no proven efficacy in treatment of Leigh syndrome. Newer mitochondrial-targeted antioxidants (such as mitoQ) that show much greater protection against oxidative stress in cultured cell and animal models [Jauslin et al 2003, Adlam et al 2005] are being investigated as potential therapies for a range of oxidative stress-related disorders. Gene therapy provides a potential approach to decreasing the proportion of mutant mtDNA in the cells of an individual. Studies in cultured cells have shown that a mitochondrially targeted restriction endonuclease can recognize and degrade mtDNA containing the m.8993T>G mutation found in NARP and mtDNA-associated Leigh syndrome, while leaving wild-type mtDNA intact [Tanaka et al 2002]. A more recent study used an adenoviral vector to deliver the restriction endonuclease to the mitochondrion and showed that there was no evidence of nuclear DNA damage in treated cells [Alexeyev et al 2008]. However, such approaches are clearly still a long way from clinical applicability.Promising results have been obtained using a similar proof-of-principle approach in a mouse model of mtDNA heteroplasmy to shift the mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses [Bayona-Bafaluy et al 2005]. This strategy could potentially prevent disease onset or reverse clinical symptoms in individuals harboring certain heteroplasmic mutations in mtDNA.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.Other A range of vitamins and other compounds are often used in the hope of improving mitochondrial function. Most commonly these include riboflavin, thiamine, and coenzyme Q10 (each at 50-100 mg/3x/day) [Panetta et al 2004]. A high-fat diet, providing 50%-60% of daily caloric intake from fat, may be prescribed to individuals with Leigh syndrome resulting from complex I deficiency, although currently there is no evidence supporting this therapeutic rationale in this particular disorder. Biotin, creatine, succinate, and idebenone have also been used. Some of these agents may show partial efficacy in some individuals with milder mitochondrial disorders, but sustained therapeutic response in NARP or Leigh syndrome has not been described.Several recent studies have investigated whether upregulation of mitochondrial biogenesis may provide an effective therapeutic approach for mitochondrial respiratory chain diseases. This approach involves using agonists such as bezafibrate or resveratrol to stimulate the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) pathway. Bezafibrate treatment of a mouse model of muscle-specific complex IV deficiency resulted in increased complex IV activity and improved survival [Wenz et al 2008]. A second study showed promising results in fibroblasts from patients with a range of respiratory chain enzyme defects; nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient respiratory chain enzyme after bezafibrate treatment [Bastin et al 2008]. These data are likely to prompt clinical trials but no data have yet been reported to show that such approaches will be effective in persons with mitochondrial disorders.A recent study explored the use of alpha-ketoglutarate and aspartate in transmitochondrial cybrids heteroplasmic for the m.8993T>G mutation [Sgarbi et al 2009]. The rationale was that these substrates would increase flux through the citric acid cycle, thereby increasing ATP production independently of oxidative phosphorylation (so-called ‘substrate level phosphorylation’). Initial results were promising, but further studies are needed before clinical applications can be considered.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Mitochondrial DNA-Associated Leigh Syndrome and NARP: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameMT-ND6MitochondriaNADH-ubiquinone oxidoreductase chain 6MT-ND4MitochondriaNADH-ubiquinone oxidoreductase chain 4MT-ND1MitochondriaNADH-ubiquinone oxidoreductase chain 1MT-TKMitochondriaNot applicableMT-TWMitochondriaNot applicableMT-ATP6MitochondriaATP synthase subunit aMT-ND5MitochondriaNADH-ubiquinone oxidoreductase chain 5MT-TL1MitochondriaNot applicableMT-TVMitochondriaNot applicableMT-CO3MitochondriaCytochrome c oxidase subunit 3MT-ND2MitochondriaNADH-ubiquinone oxidoreductase chain 2MT-ND3MitochondriaNADH-ubiquinone oxidoreductase chain 3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Mitochondrial DNA-Associated Leigh Syndrome and NARP (View All in OMIM) View in own window 256000LEIGH SYNDROME; LS 516000COMPLEX I, SUBUNIT ND1; MTND1 516001COMPLEX I, SUBUNIT ND2; MTND2 516002COMPLEX I, SUBUNIT ND3; MTND3 516003COMPLEX I, SUBUNIT ND4; MTND4 516005COMPLEX I, SUBUNIT ND5; MTND5 516006COMPLEX I, SUBUNIT ND6; MTND6 516050CYTOCHROME c OXIDASE III; MTCO3 516060ATP SYNTHASE 6; MTATP6 551500NEUROPATHY, ATAXIA, AND RETINITIS PIGMENTOSA 590050TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 1; MTTL1 590060TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK 590095TRANSFER RNA, MITOCHONDRIAL, TRYPTOPHAN; MTTW 590105TRANSFER RNA, MITOCHONDRIAL, VALINE; MTTVNormal allelic variants. All mtDNA genes lack introns and are transcribed as large polycistronic transcripts that are processed into monocistronic mRNAs. Protein-coding genes are then translated by the mitochondrial-specific translational machinery. Mitochondrial DNA is highly polymorphic and information on known polymorphisms can be obtained at MITOMAP: A Human Mitochondrial Genome Database, which provides a compendium of polymorphisms and mutations of the human mtDNA The highly polymorphic nature of mtDNA means that special care must be taken in molecular genetic testing to distinguish pathologic variants from polymorphisms, particularly when using common PCR-RFLP assays. For example, several polymorphisms introduce or abolish a restriction site such that fragments produced by restriction digest viewed on a Southern blot may suggest a false positive or false negative result [Johns & Neufeld 1993, Kirby et al 1998, White et al 1998]. Positive results generated by such methods should always be confirmed by an independent method such as sequencing.Pathologic allelic variants. Pathologic mtDNA mutations that have been shown to cause Leigh syndrome, Leigh-like syndrome, or NARP are listed in Table 5. Table 5. Selected Pathologic Allelic Variants in Mitochondrial DNA-Associated Leigh Syndrome and Leigh-Like SyndromeView in own windowMitochondrial DNA Nucleotide ChangeGene SymbolProtein Amino Acid Change Reference Sequencesm.3243A>G MT-TL1Not applicable m.3460G>AMT-ND1p.Ala52Thrm.3481G>Ap.Glu59Lysm.3890G>Ap.Arg195Glnm.5523T>GMT-TWNot applicablem.5537insTNot applicablem.5559A>GNot applicablem.8344A>G MT-TKNot applicablem.8363G>ANot applicablem.8851T>CMT-ATPp.Trp109ArgAC_000021.2m.8993T>Gp.Leu156Argm.8993T>Cp.Leu156Prom.9176T>C p.Leu217Prom.9176T>Gp.Leu271Argm.9185T>Cp.Leu220Prom.9191T>Cp.Leu222Prom.9478T>CMT-CO3p.Val91Alam.9537insCFrameshiftm.10158T>C MT-ND3p.Ser34Prom.10191T>C p.Ser45Prom.10197G>Ap.Ala47Thrm.10254G>Ap.Asp66Asnm.11777C>AMT-ND4p.Arg340Serm.11984T>Cp.Tyr409Hism.T12706T>CMT-ND5p.Phe124Leum.13513G>A p.Asp393Asnm.13514A>Gp.Asp393Glym.14484T>CMT-ND6p.Met64Valm.14459G>A p.Ala72Valm.14487T>C p.Met63Valm.1624C>TMT-TVNot applicablem.1644G>TNot applicablem.4681T>CMT-ND2p.Leu71ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). See MITOMAP for details of mitochondrial genome and allelic variants. See Table 2 and Table 3 for phenotype information.Note: See Table 6 (pdf) for mutations and percentages associated with Leigh syndrome only. Normal gene product. Human mtDNA encodes 37 genes, including 13 genes encoding protein subunits of the mitochondrial respiratory chain and oxidative phosphorylation, 22 tRNA genes, and two rRNA genes. The mitochondrial-specific translational machinery is required because translation of mtDNA-encoded genes is physically separated from the cytosolic translational machinery and because the mtDNA genetic code differs from the universal genetic code in several codons.Abnormal gene product. For mtDNA mutations associated with the NARP and Leigh syndrome (mtDNA mutations) continuum, there is at best a partial understanding of the molecular genetic pathogenic mechanism. In most cases, a strong correlation exists between heteroplasmic mutant load and severity of the biochemical phenotype in cultured cells. In some cases, such as m.8993T>G and m.8993T>C, a strong correlation also exists between heteroplasmic mutant load and severity of the clinical phenotype in affected individuals. However, it cannot yet be explained why some mtDNA mutations cause a phenotype such as Leigh syndrome, while others cause myopathy, deafness, or diabetes mellitus. Molecular genetic pathogenic mechanisms for mtDNA mutations causing the NARP and Leigh syndrome (mtDNA mutations) continuum fall into two major classes, namely tRNA genes and protein-coding genes. Not surprisingly, tRNA mutations cause decreased mitochondrial protein synthesis by mechanisms that appear to involve abnormalities in both base modification and aminoacylation of the mutant tRNA and in some cases processing of the polycistronic mtRNA transcript, as discussed elsewhere (see MELAS and MERRF). Mutations in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part. The mutation for which the molecular pathogenesis is best understood is the most common mtDNA mutation in the NARP and Leigh syndrome (mtDNA mutations) continuum, the MT-ATP6 m.8993T>G mutation. The m.8993T>G mutation changes a conserved leucine to an arginine (p.Leu156Arg) in subunit 6 of the mitochondrial F1F0 ATP synthase. ATP synthase (or complex V) uses the proton gradient generated by respiratory chain complexes I to IV to drive ATP synthesis. Subunit 6 forms part of the F0 proton channel of the ATP synthase and the p.Leu156Arg amino acid substitution appears to block proton translocation and inhibit ATP synthesis [Tatuch & Robinson 1993]. The mutation may also interfere with assembly or stability of the ATP synthase [Garcia et al 2000, Nijtmans et al 2001]. Inhibition of ATP synthesis by the m.8993T>G mutation is expected to increase mitochondrial membrane potential and lead to increased production of superoxide, perhaps triggering increased cell death [Geromel et al 2001, Mattiazzi et al 2004]. These pathogenic mechanisms must contribute to the specific pattern of tissue involvement and cell loss seen in the NARP and Leigh syndrome (mtDNA mutations) continuum. The MT-ATP6 m.8993T>C mutation changes p.Leu156Pro rather than an arginine, and presumably results in less severe interference with proton translocation and a milder clinical phenotype than the m.8993T>G mutation [Santorelli et al 1996]. The MT-ND6 m.14459G>A and m.14487T>C mutations result in a dramatic decrease in the steady-state amounts of fully assembled complex I [Kirby et al 2003, Ugalde et al 2003]. There are few data on the molecular genetic pathogenesis of other mtDNA subunit mutations associated with the NARP and Leigh syndrome (mtDNA mutations) continuum, but most presumably cause either (1) a catalytic defect or (2) instability of the subunit and complex in which it is incorporated, or both.