Mitochondrial DNA depletion syndromes encompass rare genetic disorders stemming from various gene defects, including encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), an autosomal recessive condition linked to FBXL4 gene variants. Although its prevalence is estimated at 1/100,000-400,000, the mechanism behind MTDPS13 remains incompletely understood. Recent studies suggest FBXL4 variants disrupt mitophagy, contributing to its pathogenesis. A 3-year and 4-month-old male presented with respiratory distress, diarrhea, and unconsciousness. His medical history revealed developmental delay and dysmorphic features. Physical examination unveiled characteristic dysmorphisms, while neurological assessment indicated abnormalities. Laboratory findings exhibited metabolic disturbances consistent with MTDPS13, confirmed by genetic analysis revealing a homozygous c.1555C>T FBXL4 variant. FBXL4 defects, found in approximately 0.7% of suspected mitochondrial disease cases, lead to varied phenotypes with nonspecific facial dysmorphisms. The patient's presentation aligned with reported features, including growth delay, hypotonia, and developmental delay. Notably, the diagnosis occurred later than typical onset, highlighting the variability in disease manifestation. Treatment focused on symptom management, with dichloroacetic acid effectively addressing lactic acidosis. This case underscores the importance of considering mitochondrial diseases, particularly FBXL4-related MTDPS13, in patients presenting with metabolic disturbances and dysmorphic features. Early recognition facilitates appropriate management and genetic counseling for affected families. The spectrum of propionic acidemia (PA) ranges from neonatal onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis (often through newborn screening) and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasions in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal-onset and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, and chronic kidney disease. Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency. PA is caused by deficiency of propionyl-coenzyme A carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Newborns with PA tested by expanded newborn screening (NBS) have elevated C3 (propionylcarnitine). Testing of urine organic acids in persons who are symptomatic or those detected by NBS reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid. Testing of plasma amino acids generally reveals elevated glycine. Confirmation of the diagnosis relies on detection of biallelic pathogenic variants in PCCA or PCCB by molecular genetic testing, or detection of deficient PCC enzymatic activity. In individuals with equivocal molecular genetic test results, a combination of enzymatic and molecular diagnostics may be necessary. Treatment of manifestations: The treatment of individuals with acutely decompensated PA is a medical emergency: treat precipitating factors such as infection, dehydration, vomiting; reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using intravenous carnitine, and when necessary nitrogen scavenger medications and/or extracorporeal detoxification; transfer to a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present. Prevention of primary manifestations: Individualized dietary management should be directed by an experienced physician and metabolic dietician to control the intake of propiogenic substrates and to guide increased caloric intake during illness to prevent catabolism, typically by using specialized medical food. Gastrostomy tube placement is an effective strategy to facilitate the administration of medications and nutrition during acute decompensations and to improve adherence in chronic management of PA. Medications may include L-carnitine supplementation to enhance excretion of propionic acid and oral metronidazole to reduce propionate production by gut bacteria. Orthotopic liver transplantation may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or poor growth. Prevention of secondary complications: Consistent evaluation of the protein prescription, depending on age, sex, level of physical activity, severity of disorder, and presence of other factors such as intercurrent illness, surgery, and growth spurts to avoid insufficient or excessive protein intake is necessary. Excessive protein restriction or overreliance on medical foods can result in deficiency of essential amino acids and impaired growth, as well as catabolism-induced metabolic decompensation. Surveillance: Monitor affected individuals with a catabolic stressor (fasting, fever, illness, injury, and surgery) closely to prevent and/or detect and manage metabolic decompensations early. Regularly assess: (1) growth, nutritional status, feeding ability, and psychomotor development; (2) vision and hearing; (3) cardiac function for signs of cardiomyopathy and prolonged QT interval; (4) metabolic status by monitoring routine chemistries, plasma ammonia, plasma amino acids, and plasma carnitine levels; (5) complete blood count; and (6) kidney function. Agents/circumstances to avoid: Avoid prolonged fasting, catabolic stressors, and excessive protein intake. Lactated Ringer's solution is not recommended in individuals with organic acidemias. In individuals with QT abnormalities, avoid medications that can prolong the QT interval. Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided. Evaluation of relatives at risk: Testing of at-risk sibs of an affected individual is warranted to allow for early diagnosis and treatment. PA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCCA or PCCB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the PCCA or PCCB pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.