Differential Diagnosis
FBXL4-related mtDNA depletion syndrome needs to be differentiated from other mtDNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g., TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (e.g., POLG and TWNK). The function of FBXL4 is not yet known. Mitochondrial DNA depletion syndromes are phenotypically classified into myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal forms . Myopathic forms present in infancy or early childhood with hypotonia, proximal muscle weakness, and feeding difficulty. Cognition is usually spared. Typically, there is rapid progression of muscle weakness with respiratory failure and death within a few years of onset. Encephalomyopathic mtDNA depletion syndromes present in infancy with hypotonia and developmental delay. Depending on the underlying defect, other features, including deafness, movement disorders, Leigh like syndrome, and renal disease, can be observed. Hepatocerebral forms present with early-onset liver dysfunction and neurologic involvement, including developmental delay, abnormal eye movements, and peripheral neuropathy. Neurogastrointestinal forms, the prototype of which is mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease, present in adolescence to early adulthood with progressive gastrointestinal dysmotility, cachexia, and peripheral neuropathy. Table 3. Mitochondrial DNA Depletion Syndromes
