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Alternative titles; symbolsMITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED▼ DescriptionMitochondrial DNA depletion syndrome-2 is an autosomal recessive disorde...

Alternative titles; symbols


▼ Description
Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (Oskoui et al., 2006).

For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

▼ Clinical Features
Boustany et al. (1983) reported a female infant with a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. Electron microscopy of skeletal muscle in the proband showed marked proliferation of enlarged mitochondria, many containing concentric rings of cristae, and biochemical studies showed severely decreased cytochrome c oxidase activity (less than 1% of normal). Mitochondria from kidney, liver, heart, lung, and brain examined postmortem had normal cytochromes and preserved cytochrome c oxidase activity. A second cousin, related through the maternal grandfather, died at 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement, consistent with the hepatocerebral form of the disorder. In the second cousin, liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. In an addendum, the authors noted that a sister of the proband presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. Findings of electron microscopy and biochemical analysis of muscle and liver biopsy specimens were identical to those in the proband.

In tissue samples from the original proband and second cousin reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA restricted to skeletal muscle (2% of control values) in the proband, and involving liver (12% of control values) in the second cousin. A third unrelated patient had mtDNA deficiency in muscle only (3% of control values), and a fourth in muscle and kidney only (17% control values in both tissues). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients.

Tritschler et al. (1992) reported 5 children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity associated with a decreased amount (2 to 34% of normal) of muscle mitochondrial DNA.

Vila et al. (2003) described an unusual case of a 14-year-old boy with the myopathic form of the disorder who was a compound heterozygote for mutations in the TK2 gene. Symptoms were manifest since birth, and muscle examination at ages 3 and 8 years showed ragged-red fibers, deficiency of cytochrome c oxidase, and severe depletion of mtDNA. Activities of mitochondrial respiratory chain enzymes at that time were normal. Reexamination at age 14 years showed progression of the disease and muscle biopsy showed severe muscle atrophy, no mtDNA depletion, and decreased activities of all respiratory chain enzymes. Vila et al. (2003) noted that the patient had an unusually long survival time and suggested that mtDNA-depleted muscle fibers had become atrophic or died over time, while fibers with normal mtDNA had survived. Respiratory enzyme deficiency was attributed to accumulation of somatic mitochondrial mutations.

In a study of skeletal muscle fibers from 2 sibs with mtDNA depletion myopathy due to TK2 mutations, who were previously reported by Mancuso et al. (2002), Durham et al. (2005) determined that muscle fiber mtDNA density of 0.01 mtDNA per cubic micrometer was the minimal amount of mtDNA required to maintain residual cytochrome c oxidase (COX) activity.

Oskoui et al. (2006) reported 4 unrelated patients with the myopathic form of mtDNA depletion syndrome due to TK2 mutations. There was significant clinical variability: 1 patient had a rapidly progressive course with death at age 19 months, whereas the others showed a more protracted course. One died at age 6 years and another at age 16 years. The fourth child was alive at age 9 years and could walk independently with lumbar lordosis and toe walking. She had facial diplegia, decreased muscle mass, diffuse muscle weakness, and normal pulmonary function.

Paradas et al. (2013) reported a 22-year-old man, born of consanguineous parents, with genetically confirmed MTDPS2 (T108M; 188250.0003) and a somewhat protracted course. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity.

Clinical Variability

Behin et al. (2012) reported 3 unrelated patients with genetically confirmed MTDPS2 who had a milder course and slower progression than usually associated with this disorder. Although all patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood, all presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and 1 could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal in all patients. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. However, there were no genotype/phenotype correlations, as 2 patients were homozygous for a previously reported mutation (T108M; 188250.0003) that had been observed in children with a more severe form of the disorder.

▼ Molecular Genetics
In patients with the myopathic form of mtDNA depletion syndrome, Saada et al. (2001) identified mutations in the mitochondrial thymidine kinase gene, H90N and I181N, now H163N (188250.0001) and I254N (188250.0002), respectively.

To further characterize the frequency and clinical spectrum of the causative mutations, Mancuso et al. (2002) screened 20 patients with myopathic mtDNA depletion syndrome. No patient had mutations in the deoxyguanosine kinase gene (DGUOK; 601465), but 4 patients from 2 families had TK2 mutations. Two sibs were compound heterozygotes for a previously reported H163N mutation (188250.0001) and a novel T77M mutation (now T150M; 188250.0003). Another pair of sibs harbored a homozygous I22M mutation (now I95M; 188250.0004), and 1 had evidence of lower motor neuron disease. Thus, the clinical expression of TK2 mutations is not limited to myopathy. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28 to 37% of controls).

In a family originally described by Tritschler et al. (1992) in which 3 sibs had myopathic mtDNA depletion syndrome, Mancuso et al. (2003) identified homozygosity for the T150M mutation. The patients had 80 to 90% mtDNA depletion in muscle biopsy specimens, and all died by age 40 months. The authors noted that exon 5 is a hotspot for TK2 mutations.

▼ Pathogenesis
The human mitochondrial transcription factor A (TFAM; 600438) is a 25-kD protein that may be an important regulator of both transcription and replication of mtDNA. Deficiency of the yeast homolog, ABF2, is associated with loss of mtDNA. This prompted Poulton et al. (1994) to investigate both protein and mRNA levels for this factor in cell lines experimentally depleted of mtDNA and in patients with myopathic mtDNA depletion to determine whether these conditions are associated with a deficiency of TFAM. They found that the ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle from the 3 patients and in other tissues in 1. Furthermore, TFAM was low in cells depleted either permanently or transiently of mtDNA, and this reduction roughly paralleled mtDNA levels. They concluded that deficiency of TFAM may be a marker of, or possibly a cause of, mtDNA depletion in some patients with this condition.

Wang et al. (2003) found that recombinant human TK2 with either the H163N (188250.0001) or the I254N (188250.0002) mutation, which they called H121N and I212N, respectively, had a similar subunit structure compared with wildtype TK2. The I212N mutant enzyme showed less than 1% activity compared with wildtype TK2 with all deoxynucleosides. The H121N mutant enzyme had normal Km values for thymidine and deoxycytidine, but 2- and 3-fold lower Vmax values, respectively, compared with wildtype TK2 and markedly increased Km values for ATP, leading to decreased enzyme efficiency. Competition experiments revealed that thymidine and deoxycytidine interacted differently with the H121N mutant compared with wildtype TK2.

▼ Animal Model
Akman et al. (2008) created mice harboring a his126-to-asn (H126N) mutation in the Tk2 gene, which is homologous to the H163N mutation (188250.0001) in humans. Homozygous mutant mice (Tk2 -/-) were obtained at the expected mendelian frequency and appeared normal at birth. However, at postnatal day 10, they showed several defects relative to wildtype and heterozygous mutant littermates, including growth retardation, reduced spontaneous activity, generalized coarse tremor, and impaired gait. They rapidly developed weakness, leading to severe stress or death by 2 weeks of age. Tk2 -/- animals showed reduced Tk2 activity in all tissues analyzed, with activity reduced to 1.7% of wildtype in brain, the most severely affected tissue. In Tk2 -/- mice, brain mitochondria had a dTTP concentration about 20% of wildtype, and liver mitochondria showed reduced levels of both dTTP and dCTP. The content of other dNTPs in these tissues was unchanged, and dNTP levels in other tissues were not affected. Depletion of mtDNA was most prominent in brain, where it was 12.5% of wildtype, and only brain showed decreased activities of respiratory chain enzymes, primarily complexes I and IV, and reduced ATP levels and ATP/ADP ratios. Spinal cord neurons had abnormal vacuolar changes, and the white matter of spinal cord and cortex showed evidence of activated glial cells. Akman et al. (2008) concluded that, in contrast to the muscle-specific phenotype observed in patients with the H163N mutation, mice homozygous for the H126N mutation showed a rapidly progressive encephalomyelopathy.

Bartesaghi et al. (2010) demonstrated that in vivo loss of Tk2 activity in mice led to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In Tk2-deficient cerebellar neurons, these abnormalities were associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure, and degeneration of selected neuronal types.

Lopez-Gomez et al. (2021) evaluated the effects of AAV gene therapy with and without pyrimidine deoxynucleoside (deoxycytidine (dC) and thymidine (dT)) treatment in a mouse model of Tk2 deficiency. AAV9 delivery of TK2 cDNA (AAV9-TK2) to the mutant mice on postnatal day 1 rescued Tk2 activity in liver, brain, and muscle but not in kidneys. The treated mutant mice had delayed disease onset and longer lifespan compared to untreated mutant mice. When the mice were treated with sequential AAV dosing, a dose of AAV9-TK2 on postnatal day 1 and then a dose of AAV2-TK2 on day 29, vector induction was not increased in the kidneys and vector genomes per nucleus were decreased in the brain and muscle compared to the mice treated with only AAV9-TK2. However, survival of the AAV9-TK2/AAV2-TK2 treated mice was significantly increased compared to the AAV9-TK2 treated and untreated mutant mice. Growth curves, motor function, and strength were similar in the AAV9-TK2/AAV2-TK2 treated mice and the AAV9-TK2 treated mice, and neither treatment cohort developed head tremors. The mutant mice were also treated with sequential AAV9-TK2/AAV2-TK2 dosing and with oral dC and dT from postnatal day 21 and had improved growth, survival, and mtDNA copy number in liver and kidneys compared to the other treatment cohorts of mutant mice. Lopez-Gomez et al. (2021) concluded that dC and dT supplementation enhances the effects of TK2 gene therapy and supports the potential for future combination therapy in patients with TK2 deficiency.

Tags: 16q21