Mitochondrial DNA Depletion is a Prevalent Cause of Multiple Respiratory Chain Deficiency in Childhood

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…A minority of affected individuals present initially in infancy or childhood with isolated hepatic disease, occasionally following a viral illness. Affected individuals with this form may develop mild hypotonia and renal involvement manifesting as proteinuria and aminoaciduria [2,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. More recently, DGUOK mutations have been reported in a neonate with clinical and autopsy findings consistent with neonatal hemochromatosis and mtDNA depletion [56], and in individuals with adult-onset mitochondrial myopathy and mtDNA multiple deletions in skeletal muscle [57].…”

“…An adequate amount of mtDNA is required for the production of key subunits of mitochondrial respiratory chain complexes and therefore for energy production. Therefore, mtDNA depletion results in organ dysfunction that is likely due to insufficient synthesis of respiratory chain components needed for adequate energy production [1][2][3].…”

Mitochondrial Disease in Childhood: Nuclear Encoded

“…Typical symptoms include progressive external ophthalmoplegia (PEO), ptosis, and proximal weakness, but can also involve other systemic symptoms, including peripheral neuropathy, ataxia, dementia, sensorineural hearing loss, and other ocular symptoms. Many of these are adult onset in nature [48][49][50][51][52][53][54].…”

“…Infantile onset is common, with symptoms of epilepsy, hypotonia, developmental delay or regression, and hepatic failure that can be provoked by valproic acid [49]. Milder variants are associated with higher levels of mtDNA copy number, but can be slowly progressive and involve symptoms similar to the more severe phenotypes [50][51][52]. The nuclear genes involved in the MDD disorders are DGUOK, MPV17, POLG, RRM2B, SUCLA2, SUCLG1, TK2, C10orf2 (Twinkle), and TYMP.…”

Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

“…Indeed, both patients presented with a moderate reduction of mtDNA copy number (20-30%), which retrospectively is likely due to a secondary MRCD rather than a primary genetic defect. The presence of mtDNA depletion syndrome with liver mtDNA copy number below 10% is highly suggestive of a primary genetic defect (Molleston et al 2013, Sarzi et al 2007. Nevertheless, in patients exhibiting mtDNA depletion syndrome with a less pronounced decrease in liver mtDNA copy number (10-40 %), a primary defect cannot be nd not determined *Normal values are given in parenthesis a Values after intravenous injection of vitamin K. GGT, gamma-glutamyl transferase; normal GGT range for age: 1 month (10 to 270 IU/L), 2 months (10 to 160 IU/L), 4 months (7 to 100 IU/L), >5 months (5 to 45 IU/L) b Normal alpha-fetoprotein range for age: 1 month (<5,600 IU/mL), 3 months (< 180 IU/mL), 5 months (<70 IU/mL), 6 months (<20 IU/mL), > 6 months (<7 IU/mL) a Surgical liver biopsies were performed in patients 1 and 2, at 6 and 5 months of age, respectively, when patients had liver failure (Table 1).…”