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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 411

hypotonia [306] . There are two isoforms of AGC: one synthesized by SLC25A12 and expressed mostly in
muscle and nervous tissue, and the other isoform by SLC25A13. SLC25A12 encodes the solute carrier
AGC1, which catalyzes the unidirectional exchange between intra-mitochondrial asparate and cytosolic
glutamate. AGC1 is a component of the malate-aspartate shuttle. Variants in SLC25A12 are associated
with severe hypotonia, arrested development, seizures, and global cerebral hypomyelination [307,308] . Variants
in the SLC25A13 gene encoding AGC2 induce adult onset type II citrullinemia, due to the specific loss
of liver argininosuccinate synthetase [309] . Variants in SLC25A15 produce a disorder of the urea cycle,
hyperornithinemia-hyperammonemia-homcitrulluria, due to reduce transport of ornithine by the carrier
ORC1 [310] . SLC25A16 protein is located in the IMM and is thought to transport coenzyme A, but this has
not been conclusively demonstrated. Recessive variants in SLC25A16 are associated with severe fingernail
dysplasia [311] . SLC25A20 encodes the carnitine-acylcarnitine translocase that is responsible for the transport
of long-chain fatty acids from the cytoplasm to the matrix for b-oxidation, via the carnitine shuttle. The
translocase is embedded in the IMM and transfers acylcarnitine from carnitine palmitoyltransferase I
in the OMM to carnitine palmitoyltransferase II in the IMM. Recessive variants induce an early infancy
lethal condition manifested by hypoketotic hypoglycemia, cardiomyopathy, hepatopathy, and muscle
weakness [312,313] . The protein transporter of 2-oxoadipate and 2-oxoglutarate across the IMM is SCL25A21.
Biallelic variants in SCL25A21 inhibit the degradation of tryptophan and lysine, which in turn alters the
generation of NADH and acetyl-CoA, with corresponding elevations in intracellular quinolinic acid and
oxopate, and together they induce a neuropathy with a spinal muscular atrophy-like disease [314] . In addition
+
to SCL25A12, glutamate and associated proton (H ) is transported into the intermembrane space and into
the matrix by SLC25A22 (GC1) and SLC25A18 (GC1). Once in the matrix, glutamate is converted into
a-ketoglutarate and ammonia [315] . Biallelic loss of function variants in SLC25A22 result in severe early
onset malignant partial migrating seizures of infancy and early epileptic encephalopathy [316,317] . SLC25A24
encodes one of the five ATP-Mg/Pi carriers. APC1 (mitochondrial ATP-Mg/Pi carrier isoform 1), whose
main function is the exchange of ATP-Mg or ADP for phosphate across the IMM, is modulated by extra-
mitochondrial Ca 2+[318] . Biallelic variants induce a rare syndrome of bone dysplasia of the skull and fingers,
distinctive facial dysmorphology, and prenatal and postnatal growth retardation with early demise due to
decreased mitochondrial ATP synthesis [319] .

S-adenosylmethionine (SAM) is required for methylation of target proteins. The mitochondrial SAM
carrier is encoded by SLC25A26 and is the sole entry mechanism into mitochondria. Methylation is
required for nucleic-acid modifications and ETC functioning. Variants in SLC25A26 induce a range of
phenotypes, from neonatal early death to acute episodes of cardiopulmonary failure and progressive
muscle weakness [320] . The gene SLC25A32 encodes the flavin adenine dinucleotide (FAD), which transports
FAD into the mitochondria, needed for ETC activity and FAD-dependent cofactor requiring enzymatic
activity [321] . Recessive variants induce a wide range of disease, from recurrent muscle exercise intolerance to
early onset ataxia, myoclonia, dysarthria, and muscle weakness [322] . The SLC25A42 carrier is responsible for
the importation of coenzyme A across the inner membrane in exchange for deoxyadenine nucleotides and
ADP. Recessive variants in SLC25A42 induce a variety of clinical features and range from isolated myopathy
to movement disorders, encephalopathy, seizures, and developmental regression in other patients [247] .
Increased iron deposition in the basal ganglia was reported in the globus pallidi and substantia nigra.

Nuclear-encoded mitochondrial sideroblastic anemias demonstrate ringed sideroblasts in erythroid
precursor cells with pathologic iron deposits within mitochondria. Two mitochondrial specific genes, one
X-linked, ALAS2, and one autosomal recessive, SLC25A38, represent two etiologies. ALAS2 encodes the
first enzyme in heme synthesis in the condensation of glycine and succinyl-CoA to form ALA, while the
solute carrier SLC25A38 is hypothesized to be the transporter of glycine across the IMM [323] . As noted
above, other mitochondrial localized gene products SLC19A2, PUS1, ABCB7, and GLRX5 also produce
siderobastic anemia, but without intra-mitochondrion iron deposits.