**Background:** Inherited metabolic disorders (IMDs) are rare, and co-occurrence of two distinct IMDs is exceptionally uncommon. Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM #201475) is caused by pathogenic variants in ACADVL, leading to impaired mitochondrial oxidation of long-chain fatty acids (C14-20). It presents with a spectrum of phenotypes: severe early-onset (cardiomyopathy, arrhythmias, hypoglycemia), mild (hypoketotic hypoglycemia, hepatomegaly), and late-onset (myopathy, rhabdomyolysis). Encephalomyopathic mitochondrial DNA depletion syndrome 13 (MTDPS13; OMIM #615471) is an autosomal recessive disorder due to biallelic FBXL4 variants, causing mtDNA instability and depletion. Clinically, it features encephalopathy, hypotonia, failure to thrive, lactic acidosis, developmental delays, and dysmorphic features. No prior case of combined VLCAD deficiency and MTDPS13 has been reported.
**Methods:** Peripheral blood samples were collected from the patient and his parents with written consent. Whole-exome sequencing was performed at CENTOGENE (Rostock, Germany). Genomic DNA was fragmented, and target regions (approximately 41 Mb of the human coding exome, >98% of coding RefSeq from GRCh37/hg19, plus mitochondrial genome) were enriched using DNA capture probes. Sequencing was done on an Illumina platform with at least 20× coverage depth for >98% of targeted bases. An in-house bioinformatics pipeline aligned reads to GRCh37/hg19 and the revised Cambridge Reference Sequence (rCRS) of human mtDNA (NC_012920). Variants with minor allele frequency <1% in gnomAD and disease-causing variants in HGMD, ClinVar, or CentoMD were evaluated. Variants were classified per ACMG guidelines.
**Key Results:** A 33-day-old Saudi male infant, born to consanguineous healthy parents, presented with severe failure to thrive, recurrent hypoglycemia, and positive newborn screening for VLCAD. Birth weight was 2.10 kg (third percentile), height 31.5 cm (third percentile), head circumference 44.05 cm (50th percentile). He had dysmorphic features: small head, elongated face, bitemporal narrowing, epicanthal folds, downslanting palpebral fissures, thick eyebrows, micrognathia, and low-set ears. Postnatally, he was in the NICU for poor sucking and severe hypoglycemia, discharged on special formula and mitochondrial cocktails. He was readmitted at 33 days with lethargy, hypoglycemia, and persistent lactic acidosis. Despite ICU management (dichloroacetic acid, sodium bicarbonate, dextrose 10%, riboflavin, thiamine, biotin), his condition deteriorated, requiring mechanical ventilation, and he expired. Laboratory findings: venous blood gas pH 7.37, pCO2 1.5 mm Hg, HCO3 15.4 mmol/L, lactate 6.9 mmol/L (normal 2 mmol/L), ammonia 81.6 μmol/L (normal 40 μmol/L), alanine aminotransferase 721 U/L (normal 41 U/L), aspartate aminotransferase 515.2 U/L (normal 40 U/L). Tandem mass spectrometry showed significant elevation of C14:1 (3.744 μmol/L), indicating VLCAD deficiency. Urine GC-MS revealed elevated lactic acid and acetoacetate. Chest radiography showed increased cardiothoracic ratio and mild cardiomegaly; echocardiography revealed a small atrial septal defect with increased left ventricular thickness and normal systolic function, consistent with hypertrophic cardiomyopathy. Transcranial ultrasound was unremarkable. Whole-exome sequencing identified two homozygous pathogenic variants: ACADVL c.134C>A p.(Ser45*) (nonsense) and FBXL4 c.1698A>G p.(Ile566Met) (missense). Parental testing confirmed carrier status.
**Clinical Implications:** This is the first reported case of co-occurring VLCAD deficiency and MTDPS13. The patient's severe phenotype—including early-onset failure to thrive, recurrent hypoglycemia, persistent lactic acidosis, hypertrophic cardiomyopathy, and dysmorphic features—likely resulted from the combined energy deficit from both disorders. The FBXL4 variant (c.1698A>G) has been previously associated with developmental delay and lactic acidosis; the ACADVL variant (c.134C>A) is known to cause VLCAD deficiency. The case underscores the importance of considering multiple genetic diagnoses when clinical features are atypical or severe, especially in consanguineous populations. It also highlights the need for comprehensive genetic testing (e.g., whole-exome sequencing) in patients with complex metabolic presentations. Preventive measures such as prenatal diagnosis and preimplantation genetic diagnosis are crucial in high-consanguinity settings like Saudi Arabia to reduce the incidence of such rare disorders.