Fever, Fasting, and Rhabdomyolysis in an Adult Male
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.279697
Source of Support: None, Conflict of Interest: None
Keywords: CPT II deficiency, myopathy, myoglobinuria, rhabdomyolysisKey Messages: Thermolability of the mutant CPT II enzyme rather than its actual deficiency, explains triggering of muscle symptoms by prolonged exercise, infections, febrile episodes, or exposure to cold.
A 34-year-old man spent several hours doing yard work on a weekend. Overnight, he experienced fever, rhinorrhoea, and some upper airway discomfort. The following day, he felt nauseous and experienced generalized muscle aches and difficulty walking. Over the next several hours, the leg weakness progressed to arm, neck, and jaw muscles. He had difficulty in chewing, speaking, and swallowing. He passed dark colored urine. The rest of the review of systems was unremarkable. He had no allergies. He was nonalcoholic. He had significant family history nor a history of steroid and statin use.
Beginning around age 6, he had frequent muscle cramps and soreness after long play hours. They used to resolve spontaneously in a day or so after rest, and hence never brought to medical attention. At 14, an episode of severe generalized muscle weakness and myalgia, triggered by prolonged sustained physical exertion, left him largely bedridden for 3–4 days.
Neurology examination showed generalized muscle tenderness and slightly edematous proximal limb muscles. Muscle strength was MRC grade 3/5 in the proximal and 4/5 in distal groups of the upper and lower extremities. Neck flexion and extension strength was MRC grade 4/5. The rest of the examination was normal including vitals, mentation, cranial nerves, cerebellar, tone, bulk and sensations.
At the outside hospital, a CT scan of the chest showed bibasilar infiltration. He received empiric antibiotics and Oseltamivir. Serum CK level was 40,000 U/L which increased to 118,000 U/L over the next 12 h. Serum creatinine, liver functions, thyroid profile, and complete metabolic panel including sodium, potassium, chloride, phosphate, and calcium were normal.
The clinical presentation characterized childhood onset of exercise intolerance and a triggered, episodic, symmetrical proximal myopathy. Prolonged physical activity, presumed viral illness, and avoidance of regular meal due to nausea might have all contributed as triggers. Based on these features, a metabolic myopathy was suspected. This includes disorders of carbohydrate, lipid (mainly fatty acid oxidation defects), and adenine nucleotide metabolism as well as some mitochondrial myopathies. Extremely elevated CK and dark urine during acute episode suggest rhabdomyolysis and myoglobinuria. [Table 1] outlines the differences between carbohydrate and lipid metabolism disorders. Based on this, we suspected a lipid metabolism disorder. Of these, fatty acid oxidation (and transport) defects are the principle ones.,
CK levels peaked to 130,000 U/L before dropping to 800 U/L after 96 h. Myoglobin was elevated to 6921 ng/ml (normal 28–72 ng/ml) confirming rhabdomyolysis. Serum ionized calcium was 1.08 mmol/L (normal >1.13 mmol/L). AST was 2000 U/L at admission and 116 U/L at discharge and ALT 800 U/L at admission and 526 U/L at discharge. Serum lactate and urine organic acids were normal making mitochondrial myopathy less likely.
We deferred the forearm exercise test because its yield in “screening” a metabolic myopathy is less when rhabdomyolysis appears to occur sporadically, on a delayed basis after more protracted exertion, or following fasting. (as in our case). Its yield is greatest only when rhabdomyolysis is provoked by brief periods of intense exercise (suspected carbohydrate metabolism disorder, see [Table 2]). During rhabdomyolysis, muscle biopsy is usually reserved for cases with recurrent episodes where etiology is indeterminate and exercise forearm testing and genetic analysis for carnitine palmitoyl transferase (CPT) have been unremarkable. CPT I and II are enzymes in the carnitine cycle. CPT II deficiency is the most common cause of muscle fatty acid metabolic disorder and recurrent myoglobinuria in adults. Carnitine and several enzymes in this cycle work in tandem to transport acetylated long-chain hydrophobic fatty acids from the cytosol into the mitochondrial matrix for the production of energy via β-oxidation.
Genetic testing from the patient's saliva sample showed a homozygous pathogenic variant in CPT2 gene [c.338C>T (p. Ser113Leu)] confirming the presence of metabolic myopathy from carnitine pamitoyl transferase 2 deficiency. At the coding region 338 of CPT II gene exon, a change of nucleobase from cytosine to thymine resulted in corresponding change of 113th amino acid from serine to leucine on the translated protein.
Ser113Leu is the most common mutation observed in adult cases with CPT II deficiency. In approximately, 90% cases, the molecular basis is a Ser113Leu in homozygous or heterozygous state with an allele frequency of approximately 65%.,
Among the three phenotypes of CPT II deficiency syndromes, the adult myopathic form is relatively milder with onset often in childhood. On the contrary, lethal neonatal and severe infantile forms are multiorgan severe fat metabolism disorders. The clinical spectrum seems to be related to the type of CPT II gene mutation. In terms of complications, myoglobinuria may lead to acute renal failure, respiratory insufficiency, or disseminated intravascular coagulation. Fulminant rhabdomyolysis can be associated with hyperkalemia and hypocalcaemia leading to cardiac arrhythmias.
The conundrum of Ser113Leu-related CPT II mutation and its sensitivity to fasting, cold exposure, and raised body temperature has not been clearly understood. Since Ser113Leu mutation is a single amino acid transition, the protein transcript is of normal length. Correspondingly, in patients with Ser113Leu mutation, muscle CPT II protein has been reported normal, as demonstrated by immunohistochemistry and western blot. Furthermore, in transfected COS cells [C V-1 (simian) in O rigin carrying the S V40 virus genetic material] with the Ser113Leu mutation, a normal synthesis but impaired catalytic activity of the enzyme is postulated. Interestingly, in a study of fibroblast culture from patients with Ser113Leu mutation, thermal instability of CPT II enzyme and reduced fatty acid oxidation at 40°C and 45°C were demonstrated. The thermolability of the mutant enzyme might explain why muscle symptoms in Ser113Leu CPT II deficiency are triggered by prolonged exercise, infections, febrile episodes, or exposure to cold.
Patients with adult CPT II deficiency can generally lead a normal life with some restrictions. Prolonged aerobic exercise, fasting, and cold exposure are to be avoided. Medium-chain fatty acids like triheptanoin can be helpful as they do not require the carnitine shuttle. Extra carbohydrate intake before sustained exercise may improve exercise tolerance.
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[Table 1], [Table 2]