Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disorder of lipid metabolism presenting as a childhood to adult-onset metabolic myopathy. ^{Reference Grünert1} Patients present with a chronic myopathy with exercise intolerance, myalgias, variable proximal weakness and risk of rhabdomyolysis. There are characteristic elevations in multiple serum acylcarnitine species (especially long and medium chains) due to impaired function of multiple enzymes involved in fatty acid beta-oxidation, often with concurrent baseline elevations of creatine kinase (CK). Muscle pathology typically demonstrates a lipid storage myopathy, with the presence of lipid droplets in muscle fibers and a variable degree of mitochondrial pathology. ^{Reference Pennisi, Garibaldi and Antonini2} MADD is classically caused by autosomal recessive variants in the ETFDH gene in the late-onset myopathic type, while variants in the ETFA and ETFB genes are more common in the severe infantile types. Rare genetic defects in riboflavin metabolism (e.g. FLAD1) can present as a “MADD-like” disorder. Riboflavin at a typical dose of 300 mg daily is an effective treatment for MADD, improving muscle symptoms and reversing the biochemical and muscle pathology abnormalities, making it an important condition to recognize. Emerging reports have recently identified an acquired form of MADD associated with sertraline. ^{Reference Sunebo, Appelqvist, Häggqvist and Danielsson3–Reference Sunebo, Nilsson and Engvall6} Herein, we describe a patient with sertraline-associated MADD.

A 26-year-old female was assessed for persistently elevated CK levels. A peak elevation of CK at 8,251 U/L was initially found during an admission for embolic stroke of unknown source (ESUS) 3 years prior without any associated muscle pain or weakness. CK decreased to 557 U/L with fluids, and she was discharged without further repeat CK at that time. However, CK levels over subsequent years demonstrated persistent elevations ranging between 469 and 2,238 U/L. CK was normal 6 years prior but was not checked in the time interval between.

She reported 3 years of non-disabling muscle fatigue and mild weakness predominantly affecting her proximal lower extremities in activities such as climbing stairs while carrying heavy objects. She denied any upper limb or bulbar weakness, dyspnea, myalgias and cramps. She never experienced exercise-induced rhabdomyolysis, myoglobinuria, or metabolic decompensation from illness requiring hospitalization. In childhood, she had no limitations to physical activity and was a competitive dancer. Birth and developmental history were non-contributory.

Past medical history was significant for recurrent ESUS, with no residual neurologic deficits following acute endovascular therapy. The etiology of her large vessel strokes was evaluated extensively without an identified cause. Other history included livedo reticularis, migraine with aura, anxiety, obesity (body mass index 42 kg/m², no ultrasound evidence of fatty liver disease), dyslipidemia (recent triglycerides 2.25 mmol/L [normal < 1.70], low-density lipoprotein 2.19 mmol/L [normal < 3.50 mmol/L]) and recurrent nephrolithiasis.

Medications included rosuvastatin 40 mg daily, started after her first admission for stroke (CK was elevated prior to drug start) and recently held for 4 months without any change in CK. Sertraline was started 6 years prior, titrating up to 100 mg daily. She was also taking apixaban, perindopril, semaglutide, vitamin B12 and vitamin D2. Family history was non-contributory with no history of consanguinity.

Neurologic exam was normal, with preserved muscle bulk and strength. Routine nerve conduction studies were normal; however, needle EMG demonstrated a proximal myopathy without fibrillation potentials.

Investigations for her myopathy included a normal autoimmune myositis antibody panel (including anti-HMGCR antibodies). She had previous echocardiogram and Holter monitoring which were normal. Serum acylcarnitine profile demonstrated elevations in several long- and medium-chain acylcarnitines, suggestive of MADD (Supplemental Table). Muscle biopsy of the vastus lateralis confirmed a lipid storage myopathy (Figures 1 and 2). Whole exome sequencing, which had been sent to evaluate both cryptogenic stroke and myopathy, did not identify pathogenic variants, likely pathogenic variants, or variants of uncertain significance in genes associated with MADD, MADD-like disorders, or other causes of lipid storage myopathy.

Figure 1.

Light microscopy, muscle biopsy of the right vastus lateralis. (A) H&E demonstrating moderate fiber size variability, few rounded atrophic fibers and mildly increased internalized nuclei. Many muscle fibers show numerous small accumulations of basophilic structures. (B) Oil Red O showing a markedly increased number of lipid droplets of variable size in most muscle fibers. (C) Gomori trichrome showing punctate blue staining. (D) NADH-reacted section highlighting punctate aggregates of increased reactivity and size variability, suggestive of mitochondrial proliferation. Some fibers show small focal areas of decreased activity in the sarcoplasm. (E) COX-SDH stain similarly demonstrating punctate aggregates of COX reactivity, intermixed with small areas of decreased activity. (F) ATPase 4.6 highlighting fiber size variability in both type 1 (dark stain) and type 2 fibers (pale and intermediate stain) due to atrophy.

Figure 2.

Electron microscopy, muscle biopsy of the right vastus lateralis. (A) Small and large sarcoplasmic accumulations of edematous mitochondria, lipid droplets and glycogen and subsarcolemmal areas of mitochondrial proliferation (black arrow). Mitochondria can be seen co-localizing with accumulations of lipid droplets (red arrows). (B) Clusters of sarcoplasmic lipid droplets (arrows), glycogen and edematous mitochondria with multifocal myofibrillar disruption and subsequent destruction of sarcomeres. No paracrystalline or other inclusions are present in the mitochondria.

An acquired form of MADD due to sertraline use was suspected. Sertraline was switched to an alternative antidepressant, and she was started on riboflavin 300 mg daily. CK levels and acylcarnitine profiles both normalized within 2 months of treatment, and exertional fatigue improved.

This case highlights the importance of including MADD in the differential diagnosis of chronic myopathy with elevated CK and exercise intolerance. In the era of accessible first-line genetic testing for muscle disease, it is equally important to recognize the potential for acquired causes of metabolic myopathies. Sertraline was recently recognized to be associated with an acquired form of MADD. ^{Reference Sunebo, Appelqvist, Häggqvist and Danielsson3,Reference Jones, Mirman, Milone and Liewluck5} In the largest retrospective population study to date, ^{Reference Sunebo, Nilsson and Engvall6} Sunebo et al. identified 40 patients using sertraline at the time of MADD diagnosis. Only 5 patients carried a heterozygous ETFDH variant, and no patients carried two disease-causing variants to suggest a genetic mechanism. In their population, the incidence of sertraline-associated MADD was more common than the genetic form. As with genetic MADD, patients improved with riboflavin, with further improvements seen after sertraline discontinuation as evidence for a causal role of the medication. The mechanism of sertraline-induced MADD remains uncertain, although sertraline-associated impairment of mitochondrial oxidative phosphorylation is proposed as a potential contributor. ^{Reference Hedberg-Oldfors, Lindgren and Visuttijai4} There may be an unidentified genetic mechanism, with the shared association with sertraline use potentially suggestive of a pharmacogenomic factor. Of note, associations with MADD are not described with other SSRIs, and patients can be safely switched to an alternative.

In our patient, screening blood work with acylcarnitine profile suggested MADD; however, broad genetic testing was negative. While elevated BMI may be associated with modest increase in free carnitine and acylcarnitine levels, ^{Reference Mihalik, Goodpaster and Kelley7} the elevation is not expected to be above the upper limit of normal nor to the degree in MADD where multiple acylcarnitine species are significantly elevated. Increased intramyofiber lipid droplets on muscle biopsy can occur in obesity; however, associated mitochondrial proliferation in this setting is suggestive of a defect of fatty oxidation with secondary mitochondrial proliferation. ^{Reference Dubowitz, Sewry, Oldfors and Dubowitz8} With discontinuation of sertraline and treatment with riboflavin, our patient’s symptoms improved and CK and acylcarnitine profile normalized. We propose that in patients on sertraline with elevated CK and exercise intolerance, myalgias, or weakness, an acylcarnitine profile be performed to evaluate for acquired MADD as a potential treatable cause of myopathy.