A 27-year-old woman presented to the hospital with severe fatigue and generalized muscle weakness that had progressively worsened over several months resulting in multiple falls and decreased oral intake. Her past medical history was pertinent for class III obesity (mass index, 40.0 kg/m2). She presented 5 months earlier to neurology clinic with fatigue and proximal muscle weakness primarily affecting her lower extremities. This had developed over a period of 6 months after she started a low carbohydrate, calorie restricted diet for weight loss. She developed severe vomiting after a week of being on the diet and she stopped it after a month having already lost 20 lbs (9.07 kg). Testing revealed a slightly elevated thyroid stimulating hormone (TSH) at 5.45 muIU/mL (reference range: 0.550-4.780 muIU/mL) with elevated thyroid peroxidase antibodies and creatine kinase (CK) (588.0 units/L, reference range: 34.0-145.0 units/L). She was started on Levothyroxine 25 mcg daily for presumed hypothyroid myopathy but her symptoms continued to worsen and her TSH was still high at 4.17 muIU/mL (reference range: 0.358-3.740 muIU/mL). Antibody testing for myositis (PL-7, PL-12, Jo-1, EJ, OJ, SRP, MI-2, TIF1gamma, MDA-5, NXP-2, PM/SCl, Ku, SS-A, U1-RNP, U2 snRNP, and U3 RNP antibodies; Esoterix Endocrinology), necrotizing myopathy (SRP IFA screen, HMG-CoA reductase antibody; Mayo Clinic Laboratories), myasthenia gravis (ACHR binding antibody, striated muscle antibody, Mayo Clinic Laboratories), and panel-based genetic testing for muscular dystrophies (Comprehensive Muscular Dystrophy Panel, Invitae) was normal. Electromyography suggested an inflammatory, genetic, or metabolic myopathy of her lower extremities. A vastus lateralis biopsy revealed vacuolated muscle fibers with lipid droplets suggestive of a lipid storage myopathy. A plasma acylcarnitine profile (Mayo Clinic Laboratories) revealed elevated small-, medium- and long-chain acylcarnitine species in a pattern suggestive of a defect in fatty acid oxidation. Urine organic acid analysis revealed elevated excretion of orotic acid (91 mmol/mol creatinine [Cr], reference range: <6 mmol/mol Cr) and 2-hydroxy glutaric acid (270 mmol/mol Cr, reference range: <50 mmol/mol Cr). Genetic testing was ordered; however, results were pending at the time of her presentation to the hospital.
She presented to the hospital with worsening weakness, multiple falls, and decreased oral intake. Neurological exam in the hospital revealed proximal greater than distal weakness of bilateral upper and lower extremities, neck weakness, and trace to absent lower extremity reflexes. She was also found to have a pulmonary embolism based on intraluminal filling defects in the segmental branches of the bilateral lower lobe pulmonary arteries. She was noted to have developed severe ketoacidosis with venous pH 7.00 (reference range: 7.32-7.43), beta hydroxybutyrate 5.67 nmol/L (reference range: 0.02-0.27 nmol/L), rhabdomyolysis with CK 4656 units/L (reference range: 34.0-145.0 units/L), and lactate peaking at 6.0 mmol/L (reference range: <1.3 mmol/L), prompting admission to the intensive care unit for treatment of acidosis. She was treated with sodium bicarbonate, normal saline, thiamine, dextrose, and heparin infusions, and improved within 24 hours. Her venous pH normalized to 7.45 (reference range: 7.32-7.43), CK improved to 245 units/L (reference range: 34.0-145.0 units/L), and lactate improved to 3.6 mmol/L (reference range: <1.3 mmol/L). She was empirically started on carnitine, riboflavin, cyanocobalamin, and coenzyme Q10 supplementation to treat a presumptive diagnosis of a riboflavin-responsive lipid storage myopathy such as MADD. She did, however, continue to have objective weakness with proximal greater than distal weakness of bilateral upper and lower extremities on physical examination. Her genetic testing results while not immediately available were expedited and ultimately revealed a heterozygous frameshift mutation, c.51dup;p.(A18Cfs*5), in the ETFDH gene likely pathogenic for MADD.
After recovery from her acute illness she was discharged to inpatient rehabilitation for physical and occupational therapy. She was maintained on carnitine, riboflavin, cyanocobalamin, coenzyme Q10, and thiamine supplementation along with a high carbohydrate, low-fat diet and discharged home to continue the same treatment. She was able to adhere to a diet with less than 25 g of fat per day and she was also advised to avoid prolonged fasting. Over the next few weeks she continued to have intermittent nausea requiring ondansetron, and neuropathic pain requiring pregabalin but overall her strength and energy started to improve. Her CK normalized, down to 36 units/L (reference range: 34.0-145.0 units/L) within 3 weeks after her presentation to the hospital (Fig. 1)
While her initial genetic testing revealed a single pathogenic variant in the ETFDH gene, she underwent additional testing including whole genome trio sequencing with no reportable sequence variants or copy number variants found that would be related to her condition (AR, ATN1, ATXN1, ATXN10, ATXN8OS, CACNA1A, CSTB, DIP2B, DMPK, FMR1, FXN, IL11RA, TBP, TCF4, Whole Genome Sequencing and Deletion/Duplication Trio Analysis, PerkinElmer Genomics), that is, did not find a second variant in the gene or evidence of genetic disorders that can mimic MADD. Karyotype and microarray revealed she was a carrier of a balanced translocation involving chromosomes 5 and 19; 46,XX,t(5;19)(p10;q10). Repeat plasma acylcarnitine profile on treatment showed a relative shift towards short- and medium-chain acylcarnitine species (Fig. 2). Repeat urine organic acid analysis was normal.
Over 4 months she gained nearly 30 lbs (13.61 kg) and metformin and eventually liraglutide were initiated in an attempt to help with weight loss. Her TSH was also noted to be as high as 21.58 muIU/mL (reference range: 0.550-4.780 muIU/mL) and her levothyroxine was increased slowly to 100 mcg daily. Nearly a year after her hospitalization she continues to feel well with improved strength and energy.