Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
This article includes discussion of disorders of mitochondrial DNA maintenance, mitochondrial neurogastrointestinal encephalomyopathy, mtDNA depletion syndromes, and mitochondrial instability. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
An increasingly large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both in critical tissues. The genes involved encode proteins belonging to at least 3 pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and biogenesis. In most cases, allelic mutations in these genes may lead to markedly different phenotypes associated with either mtDNA depletion or multiple deletions, or both.
• Disorders of mtDNA maintenance are Mendelian traits, ie, autosomal dominant or recessive disorders associated with the accumulation of molecular abnormalities of mtDNA, leading to a mitochondrial disease.
• Depletion or multiple deletions of mtDNA or a combination of both in critical tissues are the molecular hallmarks of these disorders.
• Depletion of mtDNA can predominantly affect skeletal muscle (myopathic form) or liver and brain (hepatocerebral form). Recessive mutations in different genes can give rise to different tissue-specific syndromes: mutations in TK2 are responsible for the myopathic form; mutations in MPV17, DGUOK, TWNK (Twinkle), and TFAM for the hepatocerebral form; Alpers-Huttenlocher syndrome, characterized by severe brain poliodystrophy with liver cirrhosis, is due to specific mutations in POLG, encoding Pol-gammaA; mutations in the gene encoding the p53-dependent subunit 2 of the ribonucleotide reductase (RRM2B) are responsible for a form of muscle and kidney mtDNA depletion: mutations in the SUCLA2 and SUCLG1 genes are associated with infantile encephalomyopathy.
• The accumulation of multiple deletions is usually restricted to skeletal muscle and possibly the brain, is typically associated with chronic progressive external ophthalmoplegia (CPEO), and can be due to dominant mutations in genes encoding the following mitochondrial proteins: ANT1 (the muscle-heart specific adenine nucleotide translocator), Twinkle (the mitochondrial helicase encoded by TWNK), Pol-gammaA (encoded by POLG), Pol-gammaB (encoded by POLG2), p53-dependent subunit 2 of the ribonucleotide reductase (encoded by RRM2B), MPV17, DNA2, OPA1, and MFN2. CPEO and parkinsonism in late stages of life have been described in association with dominant mutations in POLG, TWNK, and MPV17. Recessive mutations of POLG and, more rarely, RRM2B, TK2, OPA1, SPG7, CHCHD10, C20orf72/MGME1, or RNAseH1 genes have also been associated with syndromic CPEO, the most frequent being sensory ataxic neuropathy, dysphagia, ophthalmoplegia (SANDO). Recessive mutations in the SLC25A4 gene encoding ANT1 have been associated with myopathy and cardiomyopathy.
• Mutations in TYMP, the gene encoding thymidine phosphorylase, TP, an enzyme involved in the catabolic disposal of thymidine, are responsible for mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE), a multisystem disorder that combines accumulation of mtDNA deletions, point mutations, and depletion.
In addition to sporadic or maternally inherited disorders due to mutations of the mitochondrial genome, mitochondrial diseases can also be transmitted as Mendelian traits. Here, we shall focus on those Mendelian disorders that alter the stability and the integrity of mtDNA. In 1989, Zeviani and colleagues described an Italian family with adult-onset mitochondrial myopathy characterized by CPEO and inherited in an autosomal dominant fashion (118). Maternal inheritance was excluded because the male patients also transmitted the disease to their offspring. Since then, many additional autosomal dominant CPEO families have been described. A second group of syndromes, characterized by infantile myopathy or hepatopathy, was then associated with depletion of mitochondrial DNA in affected tissues (60). Multiple deletions and depletion of mitochondrial DNA were also found in skeletal muscle in a complex, multisystem syndrome combining muscle, brain, and gastrointestinal symptoms (mitochondrial neurogastrointestinal encephalomyopathy or MNGIE) (39). Finally, mutations in the gene encoding the DNA polymerase gamma, the master enzyme of mitochondrial DNA replication, were found in severe, early-onset neurologic disorders, namely Alpers-Huttenlocher hepatopathic poliodystrophy, sensory-ataxia neuropathy with dysarthria and ophthalmoplegia, and spinocerebellar ataxia-epilepsy syndrome (62).
Over the last decade, an increasing number of genes have been identified in association with mtDNA multiple deletions or depletion with variable phenotypes hallmarked by syndromic CPEO, encephalomyopathy, and cardiomyopathy. The vast majority of them involve proteins directly involved in the mtDNA replisome (POLG and POLG2, Twinkle, DNA2, MGME1, TFAM) and dNTP supply for mtDNA synthesis (TP, TK2, DGUOK, RRM2B, SUCLA2, SUCLG1, ABAT). A novel category of proteins involved in accumulation of mtDNA multiple deletions is represented by OPA1 and MFN2, which are part of the complex machinery regulating mitochondrial dynamics, specifically mitochondrial fusion; and paraplegin and AFG3L2, which play an important role in the protein quality control of mitochondria. For some of the identified genes, such as MPV17, the mechanism leading to mtDNA instability has not been clarified.
Autosomal disorders classified as defects of mtDNA maintenance due to disturbed nuclear-mitochondrial intergenomic communication can be associated with the accumulation of mtDNA large-scale rearrangements (mtDNA breakage syndromes) or by severe reduction of the mtDNA copy number (mtDNA depletion syndromes). The most frequent clinical presentations are:
(1) adult-onset encephalomyopathy, defined clinically by CPEO, genetically by autosomal dominant or recessive transmission, and molecularly by the presence of multiple deletions of mtDNA.
(2) an autosomal recessive multisystem disorder known as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), characterized by combined accumulation of multiple deletions and partial depletion of mtDNA.
(3) a spectrum of recessive neurologic syndromes ranging from typical infantile hepatopathic poliodystrophy (Alpers-Huttenlocher syndrome) to juvenile-onset sensory-ataxia neuropathy, dysarthria, and ophthalmoplegia (SANDO) to a combination of spinocerebellar ataxia and epilepsy with or without external ophthalmoplegia.
(4) early-onset, organ-specific autosomal recessive syndromes associated with profound mtDNA depletion.
Autosomal dominant chronic progressive external ophthalmoplegia (adCPEO). CPEO is frequent in mitochondrial disorders. The clinical hallmark is extraocular muscle involvement; all patients have ptosis, usually with limitation of eye movements. The first symptoms typically appear when patients are 20 to 40 years old. Generalized muscle weakness is frequently present. Additional features vary among families; they may include ataxia, sensorineural hearing loss, cataracts, hypogonadism, parkinsonism, and psychiatric abnormalities consisting of severe depression and avoidant personality. Dysphagia, dysphonia, weakness of facial muscles, and peripheral neuropathy may be prominent symptoms in some families. At rest, elevated levels of plasma lactate are detected only in severely affected patients. Symptoms seem to progress with age. Muscle biopsies show ragged-red fibers due to the subsarcolemmal accumulation of abnormal mitochondria. In addition, the histochemical reaction for cytochrome c oxidase is decreased or absent in scattered fibers, and neurogenic changes may also be observed. Biochemically, the activities of mtDNA-related respiratory complexes (complex I, III, IV, and V) in muscle homogenate can range from normal to about 50% of the normal mean (86). Presymptomatic patients appear normal but often have laboratory, electrophysiological, morphological, and biochemical features of a subclinical mitochondrial encephalomyopathy. Autosomal dominant optic atrophy has been reported in association with CPEO and multiple mtDNA deletions. Additional signs included deafness, ataxia, axonal sensory-motor polyneuropathy, and mitochondrial myopathy with cytochrome c oxidase negative and ragged red fibers (03; 41; 113).
Autosomal recessive chronic progressive external ophthalmoplegia (arCPEO). In 1989, Yuzaki and colleagues reported multiple mitochondrial DNA deletions in muscle specimens from 2 siblings with CPEO, optic atrophy, muscle weakness, and peripheral neuropathy (114). However, in contrast to adCPEO families, the 2 siblings were the only affected members of the pedigree and were born from consanguineous, apparently healthy parents. The suggested mode of transmission was autosomal recessive (58). Since then, multiple deletions of mitochondrial DNA have been reported in numerous sporadic CPEO cases or in families in which CPEO was clearly transmitted as a recessive trait (up to 11% in our series) (48).
Accumulation of multiple deletions has been occasionally found in cases of sideroblastic anemia and mitochondrial myopathy, periodic paralysis, familial dilated cardiomyopathy, Wolfram syndrome, and hypertrophic cardiomyopathy. The pathogenetic significance of the mitochondrial DNA lesions in these disorders is uncertain. Finally, the presence of multiple mitochondrial DNA deletions in inclusion body myositis has been confirmed in a large series of patients, raising the interesting possibility that the intranuclear alterations typical of inclusion body myositis may damage the same nuclear genes involved in autosomal dominant or recessive progressive external ophthalmoplegia.
Mitochondrial neurogastrointestinal encephalomyopathy. This is an autosomal recessive disease characterized by the unusual combination of 6 features: (1) progressive external ophthalmoplegia, (2) severe gastrointestinal dysmotility, (3) cachexia, (4) peripheral neuropathy, (5) diffuse leukoencephalopathy on brain MRI, due to altered blood-brain barrier, and (6) evidence of mitochondrial dysfunction (histological, biochemical, or genetic abnormalities of the mitochondria) (39). The mean age at onset is 19 years, and the mean age at death is 37.6 years. Gastrointestinal manifestations comprise the most prominent and debilitating feature; gastrointestinal dysmotility causes abdominal pain, gastroparesis, frequent diarrhea, and intestinal pseudo-obstruction. Skeletal muscle biopsies reveal neurogenic changes and occasional ragged-red and cytochrome c oxidase-deficient fibers, reflecting the neuropathy and mitochondrial myopathy. The peripheral neuropathy is predominantly demyelinating, but electrophysiological data have also shown evidence of axonopathy in about one half of the patients. In the gastrointestinal system, histological studies have revealed abnormalities of both the intestinal smooth muscle and the enteric nervous system, thus, accounting for the severe gastrointestinal problems. In particular, studies of postmortem tissues from MNGIE patients revealed a selective, profound mtDNA depletion, and marked atrophy of the external layer of the muscularis propria of the small intestine, consistent with a visceral myopathy leading to the prominent gastrointestinal involvement typical of this disorder (31; 30). Later-onset and longer survival mitochondrial neurogastrointestinal encephalomyopathy patients have been reported (56).
Alpers-Huttenlocher hepatopathic poliodystrophy; sensory-ataxia neuropathy, dysarthria and ophthalmoplegia; and spinocerebellar ataxia-epilepsy syndrome. In the past few years, a number of recessive syndromes have been associated with qualitative or quantitative mtDNA abnormalities. These syndromes are all characterized by an association with recessive mutations of POLG, the master gene of mtDNA replication. Alpers-Huttenlocher hepatopathic poliodystrophy is an early onset, fatal disease, characterized by hepatic failure and intractable seizures, evolving into epilepsia partialis continua and global neurologic deterioration. The liver dysfunction is usually progressive as well, evolving from microvesicular steatosis with bile duct proliferation into cirrhosis. Childhood-onset or juvenile-onset autosomal recessive, progressive sensory-ataxic syndromes, with or without epilepsy, have been reported in families from Northern European countries, including Belgium, Finland, and Norway. The association of sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) defines some of these families, but in other families, cerebellar signs, myoclonus, and seizures are additional prominent findings. The use of valproate to control epilepsy is contraindicated in these patients because of their exquisite sensitivity to valproate hepatotoxicity, which may lead to fatal acute hepatic failure (Naviaux et al 1999; 29; 16; 40; 63; 101).
Mitochondrial DNA depletion syndromes. In contrast to other types of mitochondrial DNA defects, mitochondrial DNA depletion syndrome is a quantitative abnormality: there is paucity of mitochondrial DNA, but the remaining mitochondrial DNA does not harbor any mutations or rearrangements. Mitochondrial DNA depletion syndrome is transmitted as an autosomal recessive trait and is phenotypically and genotypically heterogeneous.
Some children present with myopathy, others with liver failure in infancy, and some with multisystem involvement. Consistent with the different phenotypes, mitochondrial DNA depletion may affect either a specific tissue (most commonly muscle or liver and brain) or multiple organs, including heart, brain, and kidney.
Myopathic form. Typically, affected children are born after an uncomplicated pregnancy, although decreased fetal movements are noted in some cases. A few patients had arthrogryposis and clubfeet, but facial dysmorphic features are rare. The patient usually presents in the first year of life with feeding difficulty, failure to thrive, hypotonia, weakness, and occasionally progressive external ophthalmoplegia. Death is usually due to pulmonary insufficiency and infections, but some patients survive into their teens (60; 98). The clinical spectrum has now expanded to include spinal muscular atrophy type 3-like presentation, rigid spine syndrome, severe muscle weakness with marked dystrophic alterations, encephalopathy, and seizures (26), and a milder myopathic phenotype without motor regression and with longer survival (69). mtDNA depletion in muscle has been reported in patients with early-onset myopathy, lactic acidosis, and renal proximal tubulopathy with nephrocalcinosis (10). In patients with earlier onset and rapid courses, all muscle fibers have little or no immunoreactivity to DNA antibodies and are cytochrome c oxidase-deficient, whereas in later-onset patients the pattern of involvement is mosaic; some fibers appear normal, whereas others lack both COX activity and mtDNA. Proliferation of mitochondria (ragged-red fibers) is not a consistent feature, but their number can increase with age. Biochemical defects of all complexes containing mtDNA-encoded subunits are always present in muscle mitochondria. Patients with mtDNA depletion in muscle tend to have elevated serum creatine kinase levels, ranging from 2 to 30 times the upper limit of normal. This is an important clue for the diagnosis because increased serum creatine kinase is relatively uncommon in patients with other mitochondrial myopathies.
Encephalomyopathic forms. Two forms have been reported, both caused by a block of succinyl-CoA lyase activity in the Krebs cycle. The first is characterized by high lactate in blood, severe psychomotor retardation with muscle hypotonia, impaired hearing, and generalized seizures followed by knee and hip contractures, finger dystonia, and mild ptosis. Brain MRI is suggestive of Leigh syndrome. Moderate mtDNA depletion (about 32%) has been documented in skeletal muscle (20; 12; 71). Mutations in the gene encoding the ATP-dependent succinyl-CoA lyase activity, SUCLA2, are responsible for this form. The second, extremely severe form is due to mutations in SUCLG1, the gene encoding the GTP-dependent isoform SUCLG1 (see below) and is associated with combined muscle and liver mtDNA depletion, dysmorphic features, connatal lactic acidosis, and death in the first days of life (70). Both syndromes are hallmarked by methylmalonic aciduria, which accumulates because of impaired conversion into succinyl-CoA of propionyl-CoA, derived from the beta oxidation of odd-number fatty acids. A large cohort of patients with mutations in SUCLA2 and SUCLG1 has been described (13), showing significantly longer survival in SUCLA2 patients compared to SUCLG1 patients. Hypertrophic cardiomyopathy and liver involvement were exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations.
Finally, patients with mutations in the ABAT gene, encoding 4-aminobutyrate aminotransferase, have elevated levels of GABA along with severe psychomotor retardation, intractable seizures, hypotonia, and hyperreflexia, associated with profound mtDNA depletion (07). ABAT, besides its role in GABA biosynthesis, encodes another component of the SCS.
The mechanism of mtDNA depletion in mutations of the SCS components is unclear but could be related to the physical interaction of SCS with nucleoside diphosphate kinase, NDPK, an enzyme involved in the salvage pathway of mitochondrial nucleotides.
Hepatocerebral form. Mitochondrial DNA depletion is seen in some infants with liver failure (57). Onset of symptoms is between birth and 6 months; death usually occurs within 1 year of age. The most common symptoms and signs include persistent vomiting, failure to thrive, hypotonia, and hypoglycemia associated with progressive neurologic symptoms. Histological changes on liver biopsy include fatty degeneration, bile duct proliferation, fibrosis, and collapse of lobular architecture. Reduced cytochrome c oxidase histochemistry and decreased mitochondrial respiratory chain enzyme activities were found in the liver of a few patients. A variant form of hepatocerebral mitochondrial DNA depletion syndrome affects the Navajo people with a prevalence of 1 in 1600 live births, hence the term Navajo neurohepatopathy. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and “classical” forms of Navajo neurohepatopathy have been described (106).
Although autosomal dominant progressive external ophthalmoplegia is a relatively benign, slowly progressive condition, severe complications can arise during the course of the disease, including severe dysphagia with feeding difficulties, sensory-motor neuropathy, ataxia and parkinsonism, severe depression, diabetes mellitus, and multiple endocrine defects. These complications are more frequent in association with mutations of the POLG gene. Sensory-ataxia neuropathy, dysarthria, and ophthalmoplegia and spinocerebellar ataxia-epilepsy are also progressive disorders that may be complicated by development of ophthalmoplegia, cognitive impairment, status epilepticus, and global neurologic failure.
Mitochondrial neurogastrointestinal encephalomyopathy is a devastating disorder usually leading to death from complications due to malabsorption or progression of neurodegeneration. Likewise, mitochondrial DNA depletion syndrome is an invariably fatal disorder. In the myopathic form, more than 75% of patients have onset during the first year of life, and the disease is rapidly fatal. Only a minority of the cases has a more prolonged course and few survive into childhood. The hepatopathic form is usually fatal within the first year of life. The involvement of the central nervous system in mitochondrial DNA depletion is not uncommon. Approximately 30% of the patients can present central nervous system dysfunction during the disease course, including seizures and abnormal electroencephalographic discharges, but it is uncertain whether the seizures are due to mitochondrial DNA depletion in the brain or are secondary to hypoxia or electrolyte disturbances. Alpers-Huttenlocher hepatopathic poliodystrophy is also a fatal disease of infancy and childhood, although protracted cases reaching the second decade of life have occasionally been reported. These patients develop refractory myoclonic epilepsy, frequently evolving into epilepsia partialis continua. They usually die from complications of the latter or because of liver failure, which can be exacerbated by exposure to valproate. Valproate hepatotoxicity has been reported in several cases.
A 58-year-old woman suffered from PEO, as did her father, brother, and daughter. Onset was at 30 years of age, with slow progression. Ragged-red and cytochrome c oxidase negative fibers were found on a muscle biopsy taken when the patient was 48 years old. Multiple deleted species were detected by southern-blot analysis of muscle mitochondrial DNA.
Note the severe ptosis and bilateral weakness of facial muscles.
Autosomal dominant progressive external ophthalmoplegia is a genetically heterogeneous clinical entity. In different sets of families, linkage analysis identified loci responsible for autosomal dominant CPEO on chromosomes 10q (93), 4q (45), and 15q (102), but additional loci have been or remain to be identified because some families failed to map to any 1 of the known loci.
ANT1 mutations. The gene responsible for the autosomal dominant progressive external ophthalmoplegia form linked to the 4p locus (SLC25A4) encodes the muscle-specific isoform of the mitochondrial adenine nucleotide translocator ANT1 (44). ANT1 is also abundant in heart and brain. Dominant missense mutations have been found in families with autosomal dominant progressive external ophthalmoplegia and in sporadic patients with mild, slowly progressive myopathy and few or no extramuscular symptoms. In 2005, Palmieri and colleagues reported the first recessive mutation in the SLC25A4/ANT1 gene in a patient who presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance, ragged-red fibers, and lactic acidosis, but no ophthalmoplegia. Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA, and virtually no ATP uptake was measured in proteoliposomes reconstituted with protein extracts from muscle of this patient (72). A 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an ANT1 frameshift null mutation (c.523delC, p.Q175RfsX38) was later reported (91). Interestingly, the variable severity of cardiomyopathy in this family depended on the mtDNA haplogroup inherited from the mother, with patients carrying the haplogroup U suffering a more rapid and severe cardiomyopathy than those with haplogroup H (91). ANT1 mutations are responsible for approximately 7% of the adCPEO cases in our series. Both dominant and recessive mutations lead to the accumulation of multiple mtDNA deletions, and their clinical course is relatively benign. However, de novo dominant mutations in SLC25A4 have been identified by whole exome sequencing in 7 patients presenting with profound congenital hypotonia and muscle weakness, leading to death in the neonatal period. Profound mtDNA depletion and impairment of ATP transport capacity is the hallmark of this early onset form of ANT1-related disease (96). However, the reason why both recessive and dominant mutations in a monomeric protein (04) give rise to similar phenotypes is still unknown.
TWNK (Twinkle) mutations. The gene responsible for the autosomal dominant progressive external ophthalmoplegia form linked to the 10q locus encodes the mitochondrial DNA and RNA helicase involved in replication of the mitochondrial genome (87). The mutations cluster in a region believed to be involved in protein-to-protein interactions. Mutations in TWNK may be of variable severity, ranging from late-onset “pure” progressive external ophthalmoplegia to more severe clinical presentations including, beside progressive external ophthalmoplegia, proximal muscle and facial weakness, dysphagia and dysphonia, mild ataxia, and peripheral neuropathy (personal observation). Symptoms are much more severe in a few homozygous mutant patients described in consanguineous families. Twinkle mutations are responsible for approximately 30% of the autosomal dominant progressive external ophthalmoplegia cases in our series. A specific, recessive Twinkle mutation causes infantile onset spinocerebellar ataxia, IOSCA (64), which is part of the Finnish disease heritage. Onset usually is between 1 and 2 years of age. Patients suffer from a combination of ataxia, athetosis, areflexia, muscle hypotonia and severe epilepsy. Other features such as ophthalmoplegia, hearing loss, and optic atrophy appear later in the disease course. Some patients show reduced mental capacity, and hypergonadotropic hypogonadism may occur in girls. Morphologic studies reveal sensory axonal neuropathy and progressive atrophy of the cerebellum, brainstem and spinal cord (47). Besides infantile onset spinocerebellar ataxia, an Alpers-like clinical phenotype has also been associated with recessive mutations in TWNK (35; 85).
Pol-gamma mutations. The mitochondrial DNA polymerase (pol-gamma) is essential for mitochondrial DNA replication and proofreading-based repair. It is composed of a 140-kDa catalytic subunit (pol-[gamma]A) and a 55-kDa accessory subunit (pol-[gamma]B), which functions as a DNA binding factor, increasing the processivity of the polymerase holoenzyme. The holoenzyme works as an ab2 heterotrimer. The catalytic subunit is encoded by POLG on chromosome 15q25, whereas the accessory subunit is coded by POLG2 on chromosome 17q. Over the last 5 years, it has become clear that mutations of POLG are a major cause of human mitochondrial disease. So far more than 100 mutations in pol-gamma have been reported (website: NIEHS Human DNA Polymerase Gamma Mutation Database). This gene is the most frequent cause of autosomal dominant progressive external ophthalmoplegia (50% of the cases in our series) (102; 48). In autosomal dominant progressive external ophthalmoplegia due to POLG mutations, prominent features are severe dysphagia and dysphonia and, occasionally, a movement disorder including parkinsonism, cerebellar dysfunction, or chorea (52). Cognitive decline, depression, hypogonadism (including precocious menopause), and gastrointestinal dysmotility may be additional findings (23; 52). The severity of the syndromes varies in relation to the type of mutation.
Recessive mutations of POLG are also responsible for a variety of other syndromes, including most of the autosomal recessive progressive external ophthalmoplegia cases (48) and the apparently sporadic progressive external ophthalmoplegia cases associated with the accumulation of multiple mitochondrial DNA deletions (01). Recessive POLG mutations have been described in Alpers-Huttenlocher syndrome (62; 16; 21) associated with mitochondrial DNA depletion. Mutations in POLG are also responsible for SANDO (104) and for the spinocerebellar ataxia and epilepsy syndromes identified in Northern Europe (103; 109; 40). In several instances, the same POLG mutations have been reported in these different syndromes, suggesting that they form a continuum of “POLG-related,” severe, recessive disorders. Two mutant alleles determining amino acid changes in the spacer region of the POLgamma-A protein (A467T and S748W) are recurrent in all these conditions, which may help the diagnostic workout in suspected cases. A few heterozygous dominant mutations have been identified in POLG2, in patients with adult-onset CPEO, cardiac conduction defect, and increased creatine kinase (51; 107; 111).
MGME1, DNA2, and RNASEH1 mutations. In addition to the main constituents of the mitochondrial replisome, ie, Pol-gamma A and B and the helicase Twinkle, several genes have been identified which encode proteins involved in maturation of the newly synthesized mtDNA strands and may also take part in some mechanisms of mtDNA repair, notably long-patch base-excision repair (LP-BER). Some of these gene products, such as the DNA flappase MGME1, are exclusively localized within mitochondria. Others have a double localization, in both the nucleus and mitochondria: for instance DNA2 and FEN1, which are also involved in the processing of 5’ flap structures occurring in DNA replication and LP-BER, and RNAseH1, which specifically digests the RNA component of RNA/DNA hybrids, formed during RNA priming of DNA templates. Recessive mutations in MGME1 (46), DNA2 (80), and RNASEH1 (79) have been identified in patients with CPEO and accumulation of multiple mtDNA deletions. Whilst MGME1 and RNASEH1 mutations are inherited as recessive traits, DNA2 mutations are dominant. The onset is usually in adulthood, more rarely in childhood, and CPEO is frequently complicated by prominent weakness of the respiratory muscles, leading to ventilatory insufficiency, ataxia with cerebellar atrophy, and additional signs indicating the involvement of the central and peripheral nervous systems.
OPA1 and MFN2 mutations. OPA1 is a dynamin-like GTPase located in the inner mitochondrial membrane involved in mitochondrial fusion, cristae organization, and control of apoptosis. OPA1 mutations are linked to nonsyndromic autosomal dominant optic atrophy (DOA), a condition characterized by slowly progressive visual loss starting in childhood, first described by the Danish ophthalmologist Paul Kjer in 1959. However, a few missense mutations, clustered in the GTPase domain, are responsible for a non-syndromic autosomal dominant optic atrophy “plus” syndrome, consisting of a combination of DOA with CPEO, peripheral neuropathy, ataxia, deafness (03; 41), and multiple sclerosis-like illness or spastic paraplegia (113). These patients have ragged-red and cytochrome-c-oxidase negative muscle fibers, with paracrystalline inclusions filling abnormally shaped mitochondria. Remarkably, all patients harbored multiple mtDNA deletions and OXPHOS deficiency in their skeletal muscle (50). The mechanisms leading to the accumulation of multiple mtDNA deletions in this condition are still unknown but indicate that mitochondrial shape and mtDNA integrity are linked, possibly through a mechanism controlling the structure and function of nucleoids (115). A study showed that specific isoforms of OPA1, including exon 4b, lead to partial depletion of mtDNA and disorganization of nucleoid distribution throughout the mitochondrial network (19).
Interestingly, a single family with DOA plus phenotype without CPEO has been reported in association with a MFN2 heterozygous missense mutation (c.629A> T, p.D210V); these patients showed accumulation of mtDNA multiple deletions in skeletal muscle (82). A second report described a child with an early-onset progressive multi-systemic disorder carrying another MFN2 missense mutation (c.628G> T, p.D210Y), which affected the same aspartate residue but with a different change; this child had mitochondrial DNA depletion in skeletal muscle (78). Studies of skeletal muscle from a mouse model with conditional deletion of the mitofusins MFN1 and MFN2, both mitochondrial GTPases essential for mitochondrial fusion, revealed that mitochondrial genomes rapidly accumulate point mutations and deletions (15). Thus, impaired fusion due to mutations in both OPA1 and MFN2 proteins may lead to mtDNA instability and depletion through novel mechanisms, which are still under investigation.
RRM2B, TK2, DGUOK, and MPV17 mutations. Linkage analysis in a single family with adCPEO mapped the disease locus to chromosome 8q22.1-q23.3, and a heterozygous RRM2B mutation was found to co-segregate with the phenotype (100). RRM2B encodes the small (regulatory) subunit of p53-inducible ribonucleotide reductase, involved in the de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates. Screening of a large series of patients with adCPEO showed that dominant RRM2B mutations are relatively frequent (24). Recessive mutations affecting the RRM2B are typically found in infantile cases of mtDNA depletion syndrome with renal proximal tubulopathy (10), but a single family was associated with a recessive form of CPEO (95). A clear correlation between the clinical phenotype and the underlying genetic defect was found in a relatively large cohort of patients (75). Myopathy, bulbar dysfunction, and fatigue were prominent symptoms, often associated with sensorineural hearing loss and gastrointestinal disturbance. Severe multisystem neurologic disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype.
A report showed that recessive mutations in the TK2 gene, encoding the mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, previously associated with mtDNA depletion syndrome, may also cause CPEO with mtDNA multiple deletions (99). Further studies have reported a handful of adult myopathic cases characterized by slowly progressive weakness and respiratory failure, associated with recessive TK2 mutations; in these cases, multiple mtDNA deletions in skeletal muscle coexisted and were more prominent than mtDNA depletion (06; 73; 02).
A similar scenario has also been reported for another gene initially associated only with mtDNA depletion (ie, DGUOK encoding the mitochondrial deoxyguanosine kinase). Recessive DGUOK mutations were found by exome sequencing in adult patients with a spectrum of clinical phenotypes ranging from mitochondrial myopathy with or without CPEO, recurrent rhabdomyolysis, and adult-onset lower motor neuron syndrome with mild cognitive impairment (81). These patients had accumulation of mtDNA multiple deletions in skeletal muscle.
Also, mutations in MPV17, another gene typically associated with mtDNA depletion, have been associated with mtDNA multiple deletions and recessive adult-onset mitochondrial myopathy with CPEO, parkinsonism, and leukoencephalopathy (08; 28).
Thus, genes initially associated with mtDNA depletion syndromes may also harbor allelic mutations that lead to adult-onset disorders associated with mtDNA multiple deletions, in most cases CPEO syndromes.
GFER mutations. A homozygous mutation in the human GFER gene, coding for a sulfhydryl oxidase (DRS) of the mitochondrial intermembrane space, has been reported in an inbred Moroccan family (18). Three siblings were affected by congenital cataract, progressive muscular hypotonia, sensorineural hearing loss, and developmental delay. Muscle biopsy showed scattered COX deficiency and mtDNA multiple deletions. DRS is a protein involved in 1 of the mitochondrial protein import pathways. The pathogenic link between DRS mutation and mtDNA multiple deletions is presently unknown.
SPG7 mutations. In 2014, two papers reported the occurrence SPG7 recessive mutations associated with CPEO and mitochondrial myopathy with accumulation of mtDNA multiple deletions (74; 108). SPG7 encodes for paraplegin, a component of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (68). Originally, it was associated with autosomal recessive spastic paraplegia (14). Typically, the clinical phenotype developed in mid-adult life with either CPEO/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were also common, but urinary symptoms were rare, despite the spasticity. The mechanism leading to multiple deletions remains unclear, but secondary dysregulation of OPA1 has been proposed to mediate clonal expansion of mtDNA deletions, driven by compensatory mitochondrial biogenesis.
AFG3L2. Two patients with indolent ataxia and CPEO with 2 different heterozygous mutations in AFG3L2 were identified (33). AFG3L2 encodes another subunit of m-AAA protease which interacts with paraplegin, and was originally associated with spinocerebellar ataxia. Also, in this case, the mechanism leading to mtDNA instability is unknown.
CHCHD10 mutation. In 2014, a dominant mutation in the CHCHD10 gene was reported in association with the unusual phenotype of mitochondrial myopathy, cerebellar ataxia and fronto-temporal dementia and ALS-like motor neuron disease (05). CHCHD10 is a mitochondrial protein located in the intermembrane space enriched at the cristae junctions, of unknown function. Overexpression of the mutant allele leads to disturbed mitochondrial dynamics and disruption of cristae organization.
Thymidine phosphorylase mutations in MNGIE. Mapping of the MNGIE trait on chromosome 22q13.32-qter (36) has led to the identification of mutations in the gene encoding thymidine phosphorylase (TYMP) as the cause of the disease (66). Thymidine phosphorylase is involved in the catabolism of pyrimidines by promoting the phosphorolysis of thymidine into thymine and deoxyribose-phosphate. Defects of thymidine phosphorylase result in systemic accumulation of its substrates - thymidine and deoxyuridine (88; 55). In vitro studies have demonstrated that excess of thymidine and deoxyuridine leads to deoxynucleotide pool imbalance (22), which in turn can cause mitochondrial DNA instability (77). This is reflected by the molecular phenotype of mitochondrial neurogastrointestinal encephalomyopathy, which is characterized by both multiple deletions and partial depletion of muscle mitochondrial DNA. More than 80% of mtDNA mutations found in tissues from MNGIE patients are T-to-C transitions preceded by a short run of As. This signature mutation suggests a “next-nucleotide effect” caused by the more common misinsertion T:dGMP, which is quickly extended by the elevated dTTP concentration resulting from TYMP deficiency in the mitochondria of MNGIE cells (65). HeLa cells grown in media supplemented with 50 μM thymidine demonstrated mtDNA deletions and elevated mitochondrial pools of dTTP and dGTP, a result that recapitulated many of the genetic effects seen in MNGIE. An alternative hypothesis has been proposed, which implies dCTP depletion, secondary to dNTP unbalance due to excess of thymidine and deoxyuridine, is the cause of altered replication and impaired integrity of mtDNA in MNGIE (32).
Mitochondrial DNA depletion syndromes. Only 15% to 20% of mitochondrial deletion syndrome cases have been linked to mutations in 10 genes. Mutations in the gene encoding mitochondrial thymidine kinase (TK2) have been associated with the myopathic form of the disease (83). Since the first description, 20 mutations of TK2 have been reported in a total of 20 patients, with a prevalence of about 20%. A more generalized encephalomyopathic form of mitochondrial deletion syndrome has been associated with mutations in SUCLA2, the gene encoding the beta-subunit of the adenosine diphosphate-forming succinyl coenzyme A synthetase ligase, whereas deficiency of the alpha subunit of succinate-CoA ligase (SUCLG1) causes fatal infantile acidosis with a combined muscle and liver mtDNA depletion (70). Mutations in p53-dependent ribonucleotide reductase (RRM2B) have been described in children with mtDNA depletion in muscle and renal proximal tubulopathy (10). Mutations in POLG are a common cause of mitochondrial DNA depletion, especially of the hepatocerebral variants known as Alpers syndrome. However, an Alpers-like phenotype has also been associated with recessive mutations in TWNK, encoding Twinkle (35; 85).
A fraction of cases with hepatocerebral mitochondrial deletion syndrome has been associated with mutations in 2 additional genes, namely DGUOK and MPV17. DGUOK is the gene encoding the mitochondrial deoxyguanosine kinase (dGK) (54; 84; 94), whereas MPV17 encodes a small mitochondrial membrane protein of unknown function. Depletion of mitochondrial DNA has been documented only in liver, whereas the amount of mitochondrial DNA was normal in muscle and fibroblasts, and brain was not investigated. However, it is likely that the neurologic abnormalities found in these patients are a direct consequence of oxidative phosphorylation failure in the brain, rather than the result of brain damage due to liver insufficiency. Remarkably, the same pathogenic mutation in MPV17 that was previously identified in an Italian family (90) was later found to be responsible for Navajo neurohepatopathy (43), raising the possibility of a common founder effect. Haplotype analysis of the MPV17 locus in the Italian mtDNA depletion syndrome and in several Navajo neurohepatopathy families demonstrated that the mutation occurred independently in the 2 populations (89).
A homozygous mutation in the human GFER gene, coding for a sulfhydryl oxidase (DRS) of the mitochondrial intermembrane space, has been reported in an inbred Moroccan family (18).
As previously mentioned, a single case with a heterozygous MFN2 mutation has been reported in association with mtDNA depletion, widening the etiologic spectrum of these syndromes (78).
The most recent gene associated with early onset encephalopathy with mtDNA depletion is FBXL4 (09; 25). Patients with recessive mutations in FBXL4 were characterized by early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. FBXL4 is targeted to mitochondria, and it localizes in the outer membrane/intermembrane space. Its function is currently under investigation, but pathogenic mutations were associated with mitochondrial respiratory chain deficiency in muscle or fibroblasts, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. Substantially decreased mtDNA content was also observed in both muscle and fibroblasts from patients.
TFAM. A homozygous mutation in TFAM has been found in 2 siblings with a severe neonatal hepatic syndrome (92) and profound mtDNA depletion in liver and skeletal muscle. The mutation (c.533C> T) affects proline 178 (p.Pro178Leu), which is important for the interaction with the mtDNA minor groove. As a consequence of the mutation, the interaction of TFAM with mtDNA is impaired, TFAM undergoes degradation, and nucleoids are reduced in number and aggregate to form perinuclear clusters.
The progressive external ophthalmoplegia phenotype is commonly associated with single mitochondrial DNA deletions in sporadic patients (59; 117). A pathogenetic role of multiple mitochondrial DNA deletions in autosomal dominant or recessive progressive external ophthalmoplegia is supported by the evidence of tight segregation of the molecular lesions with the onset and severity of the disease. For instance, Lamantea and colleagues have reported that, in a series of POLG1-positive progressive external ophthalmoplegia families, homozygous individuals appeared more severely affected and showed the presence of much higher amounts of multiple mitochondrial DNA deletions in muscle than their heterozygous relatives (48). Moslemi and colleagues have demonstrated close correlation between the accumulation of deletions and the segmental ragged-red cytochrome c oxidase-negative transformation of muscle fibers. These authors showed that within a single cytochrome c oxidase-deficient muscle fiber segment, only 1 single deletion could be detected. However, different deletions were identified in different segments. These results indicate clonal expansion of a single deleted mitochondrial DNA in each cytochrome c oxidase-deficient muscle fiber segment. A 2-hit mechanism can, therefore, be hypothesized, consisting of the combination of a nuclear factor that somehow predisposes to mitochondrial DNA deletions, followed by clonal expansion of each deleted mitochondrial DNA molecule in muscle and other stable tissues (61). Deletions are absent in cultured fibroblasts, peripheral blood cells, and cultured myoblasts but can be detected in stable tissues, including (besides skeletal muscle) brain, heart, and in lesser amount, kidney, and liver. Rearranged mitochondrial DNA molecules similar if not identical to those found in the multiple deletions syndromes are present at low levels (from less than 0.1 copies per cell to greater than 100 copies per cell) in the stable tissues of normal adult individuals (42). In normal conditions, rearranged and wild-type molecules seem to coexist in an equilibrium, in which rearrangements are continuously lost and reformed but never accumulate to physiologically damaging levels (except under highly abnormal conditions). These abnormal conditions may include (1) enhancement of the processes by which rearrangements are continuously generated, (2) inhibition of the processes by which they are usually lost, and (3) a (possibly transient) alteration in their selective value, whether at the level of phenotype or replicative advantage. In support of the first mechanism, the genes responsible for mitochondrial neurogastrointestinal encephalomyopathy and for a form of autosomal dominant progressive external ophthalmoplegia (TYMP and SLC25A4 [ANT1]) are both involved in nucleotide metabolism. Disturbances of the nucleotide pool available for mitochondrial DNA replication, as well as abnormalities in either the mitochondrial helicase or DNA polymerase, are likely to affect the rate or process of DNA replication, which could ultimately lead to the exaggerated production of rearranged mitochondrial DNA molecules (34). In addition to large-scale rearrangements, increased frequency of mitochondrial DNA point mutations have been reported in both familial progressive external ophthalmoplegia and MNGIE. In progressive external ophthalmoplegia cases due to mutations in the proof-reading region of POLG, low levels of somatic mutations were confined to the D-loop noncoding region but were absent in a coding region of mitochondrial DNA (17). The pathogenic significance of this finding is unclear. A more persuasive role of somatic point mutations in the pathogenesis of the disease has been demonstrated in MNGIE (65). Several somatic mutations, mostly T>C transitions preceded by 5'-An sequences, were scattered throughout the mitochondrial DNA molecule of tissues and cultured cells from MNGIE patients. Some mutations were clearly pathogenic, as they predict loss or abnormal function of mitochondrial DNA-encoded proteins or tRNA. The accumulation of these mutations is likely to be due to next-nucleotide effects and dislocation mutagenesis, as a consequence of increased levels of mitochondrial deoxy-thymidine and deoxy-uridine pools. Finally, the mitochondrial DNA damage caused by POLG1 mutations in Alpers-Huttenlocher syndrome, SANDO, and ataxia-epilepsy syndrome is unclear. Depletion of mitochondrial DNA or accumulation of multiple point mutations are likely possibilities, but more investigation is needed to prove these hypotheses.
Balance and control of the mitochondrial deoxynucleotide pools are essential for the maintenance of mitochondrial DNA copy number. Perturbation of this homeostatic control, as determined by defects of dGK and TK2, and possibly of thymidine phosphorylase, RRM2B, and SLC25A4 as well, can lead to mitochondrial DNA depletion or multiple deletions. These enzymes are involved in the salvage pathways of mitochondrial deoxynucleotides, which constitute the major source of mitochondrial DNA precursors in stable tissues such as liver, brain, and muscle.
A defect in the last step of the mitochondria dNTPs salvage pathway has been postulated in the pathogenesis of the SUCLA2 mutations (20) and SUCLG1 (70) because SCS-A and SCS-G are associated with nucleoside diphosphate kinase (NDPK), which also contributes to the homeostasis of ribonucleotides and deoxyribonucleotides in mitochondria.
The function of MPV17 and its role in the pathogenesis of mitochondrial DNA depletion syndrome is still unknown, but studies on its yeast ortholog, SYM1, suggest this protein has a role in the cellular response to metabolic stress (90).
The identification of OPA1 mutations as a cause of mtDNA multiple deletions in skeletal muscle, which is now extended to the cognate mitochondrial fusion protein MFN2 (82), points to the role played by mitochondrial network dynamics in mtDNA maintenance (115; 112). Impaired mitochondrial fusion in cells and in recombinant mouse models is indeed associated with mtDNA instability and worsening of the phenotype effects of mtDNA mutations (15).
Approximately 15% of the progressive external ophthalmoplegia cases are associated with multiple, instead of single, mitochondrial DNA deletions. A clear-cut familiarity is found in approximately one half of the cases. In our experience, mutations in ANT1, Twinkle, or POLG1 account for approximately 87% of familial progressive external ophthalmoplegia cases, including those in which an autosomal recessive or a co-dominant mode of transmission are suspected. No epidemiological data are available for mitochondrial neurogastrointestinal encephalomyopathy. More than 25 distinct mutations of the thymidine phosphorylase gene have been identified in 52 ethnically diverse patients with the disease (67; 38). Mitochondrial DNA depletion syndrome is not an uncommon clinical entity. In 1 series, 10% of young children (younger than 2 years old) referred for weakness, hypotonia, and developmental delay had mitochondrial DNA depletion (53).
The identification of the genetic defects in mitochondrial neurogastrointestinal encephalomyopathy, and in the prevalent forms of autosomal dominant progressive external ophthalmoplegia, makes prenatal diagnosis possible in these conditions. Likewise, prenatal diagnosis is also possible now for the recessive disorders associated with POLG1 mutations, including autosomal recessive progressive external ophthalmoplegia, SANDO, spinocerebellar ataxia-epilepsy syndrome, and Alpers-Huttenlocher poliodystrophy. In mitochondrial DNA depletion syndromes, TK2, dGUOK, or MPV17 mutations can also be screened for in at risk families. Because the genetic defect is not known, prenatal diagnoses for rarer forms of either autosomal dominant or recessive progressive external ophthalmoplegia and for mitochondrial DNA depletion syndrome are not possible at this time. The achievement of the correct genetic diagnosis is especially important in individuals with epileptic syndromes, such as Alpers-Huttenlocher poliodystrophy or spinocerebellar ataxia-epilepsy syndrome, because administration of valproate for seizures control can trigger a fulminant liver failure in these patients.
Progressive external ophthalmoplegia and Kearns-Sayre syndrome can be due to the presence of single mitochondrial DNA deletions that occur sporadically in single individuals (116; 59). The histological and biochemical abnormalities of skeletal muscle are identical to those found in autosomal dominant progressive external ophthalmoplegia and mitochondrial neurogastrointestinal encephalomyopathy. However, absence of transmission of the trait and southern-blot analysis of muscle mitochondrial DNA can distinguish these forms from autosomal dominant progressive external ophthalmoplegia caused by multiple mitochondrial DNA deletions. Gastrointestinal symptoms are prominent in mitochondrial neurogastrointestinal encephalomyopathy, whereas they are uncommon and usually mild in the other mitochondriopathies. Progressive external ophthalmoplegia and dominant transmission are also features of oculopharyngeal dystrophy, which can be easily distinguished from autosomal dominant progressive external ophthalmoplegia because of the late onset and the different muscle morphology. However, complaints of dysphagia and dysphonia are frequent in progressive external ophthalmoplegia cases, especially those due to mutations in POLG. Progressive external ophthalmoplegia can also occasionally be confused with myasthenia gravis, especially in the initial phase of the disease. Mitochondrial neurogastrointestinal encephalomyopathy can be confused with other causes of malabsorption and intestinal subocclusion, but the concomitant presence of progressive external ophthalmoplegia and peripheral and central neurologic symptoms can orient toward the correct diagnosis. The myopathic form of mitochondrial DNA depletion syndrome may mimic severe (type 1) spinal muscular atrophy (76; 69) or Duchenne muscular dystrophy (105). The presence of severe lactic acidosis suggests mitochondrial DNA depletion syndrome and is an indication for muscle biopsy. The hepatopathic form of mitochondrial DNA depletion syndrome can be confused with other severe hepatopathies of infancy, in which mitochondrial DNA depletion in liver may be present as a secondary phenomenon. Morphologic abnormalities (histochemical cytochrome c oxidase deficiency), respiratory chain enzyme defects, exclusion of other hepatopathies of infancy, and absence of drugs such as zidovudine that may induce mitochondrial DNA depletion, are the additional criteria that help differentiate primary mitochondrial DNA depletion syndrome of liver from a secondary phenomenon. Alpers-Huttenlocher syndrome must be differentiated from other forms of early-onset refractory epilepsy. Sensory-ataxia neuropathy, dysarthria, and ophthalmoplegia and ataxia-epilepsy syndrome should be differentiated from other recessive ataxias, especially Friedreich ataxia and ataxia-telangiectasia.
Specific diagnosis is based on examination of muscle and, in the hepatopathic form of mitochondrial DNA depletion syndrome, liver biopsies. In all syndromes associated with multiple deletions, it is essential to have definite evidence of the mitochondrial DNA abnormalities in muscle. Southern-blot analysis of “linearized” muscle mitochondrial DNA from symptomatic and presymptomatic individuals shows the presence of numerous hybridization bands of different size, including a major 16.5 kb band, corresponding to wild-type mitochondrial DNA, as well as several smaller bands, corresponding to deleted mitochondrial DNAs. In mitochondrial DNA depletion syndromes, the residual mitochondrial DNA amount in affected tissues, which can be measured by either quantitative Southern-blot or real-time polymerase chain reaction analyses, must be less than 30% to 35% of control, and multiple deletions must be absent. In addition, there must be histological evidence of ragged-red and cytochrome c oxidase-negative fibers in multiple deletions syndromes. The latter are also present in mitochondrial DNA depletion, whereas the former are usually absent. Specific diagnosis is now possible for mitochondrial neurogastrointestinal encephalomyopathy via the identification of mutations in the gene encoding thymidine phosphorylase or the measurement of its activity in peripheral leukocytes (88; 55). Likewise, screening for mutations in the genes encoding the adenine nucleotide translocator, Twinkle and POLG, should also be performed in all cases of progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. When Alpers-Huttenlocher syndrome, sensory-ataxia neuropathy, dysarthria, and ophthalmoplegia, or ataxia-epilepsy syndrome are suspected, analysis of the POLG1 gene is mandatory. In children with an Alpers-like phenotype with normal POLG1, analysis of Twinkle is recommended. The association of optic atrophy and ophthalmoplegia must orient the investigation on the OPA1 gene.
In general, no effective treatment exists for mitochondrial disorders. Coenzyme Q, ascorbate, L-carnitine, and riboflavin have been administered in various combinations to patients with mitochondrial encephalomyopathies, with disappointing results. Surgical correction of ptosis or the use of mechanical devices can help maintain open eyelids in severe progressive external ophthalmoplegia. Correction of severe metabolic acidosis and mechanical continuation of ventilation are necessary during the progression of mitochondrial DNA depletion syndrome. Allogenic stem cell (bone marrow) transplantation resulted in partial restoration of thymidine phosphorylase activity and reduction of plasma levels of dThd and dUrd in 1 patient (37), but the clinical efficacy of this treatment remains unproven. In MNGIE and progressive external ophthalmoplegia with severe dysphagia, feeding conditions can be improved by appropriate dietetic regime and, in severe cases, nutrition via gastric gavage. As already mentioned, the presence of POLG1 mutations in epileptogenic syndromes is an absolute contra-indication for the use of valproate, which can precipitate a hepatic failure. Interestingly, there are potential treatments for MNGIE. Hemodialysis (110) and repeated platelet infusions (49) have been shown to transiently reduce thymidine levels in blood. Allogeneic stem cell transplantation has had some success in restoring TYMP activity and lowering plasma thymidine levels (37). Both administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach and the liver AAV-mediated delivery of TYMP to restore nucleoside and nucleotide homeostasis in a murine model of MNGIE casted hope for more efficient therapy in these patients (11; 97). Similarly, deoxypyrimidine monophosphate bypass therapy has been proposed for TK2 deficiency-related phenotypes (27).
Pregnancy is not affected by autosomal dominant progressive external ophthalmoplegia. No information is available for mitochondrial neurogastrointestinal encephalomyopathy. Pregnancy is not applicable for mitochondrial DNA depletion syndromes and the severe recessive syndromes associated with POLG1 mutations.
Massimo Zeviani MD PhD
Dr. Zeviani of the National Neurological Institute “C Besta” in Milan, Italy and Medical Research Council at, Cambridge, United Kingdom, has no relevant financial relationships to disclose.See Profile
Carlo Viscomi PhD
r. Viscomi of the University of Cambridge has no relevant financial relationships to disclose.See Profile
Salvatore DiMauro MD
Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Childhood Degenerative & Metabolic Disorders
Jun. 10, 2021
X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can also affect girls. Diagnostic
Mar. 24, 2021
Mar. 21, 2021
This article discusses pyridostigmine, the most commonly used first-line therapy for myasthenia gravis. The article addresses the pharmacology, indications, contraindications, treatment goals, dosing, special considerations, interactions, and adverse effects to be considered in the use of this cholinesterase inhibitor.
Mar. 12, 2021
Mar. 06, 2021
In this article, the author discusses caring for children with various types of chronic neuromuscular disease. The updated article includes discussion
Feb. 24, 2021
Neuromuscular syndromes of the paraspinal muscles comprise the dropped head syndrome and the bent spine syndrome (camptocormia). Although these phenotypes
Feb. 15, 2021
Myasthenia gravis (MG) is a neuromuscular disease that causes muscle weakness and fatigue, affecting the ocular, bulbar, and limb muscles. Symptoms are worsened by muscle activity and improved by rest. They are caused by an autoimmune attack on acetylcholine receptors (AChR) or other components of the neuromuscular junction (NMJ).
Feb. 15, 2021