A physically fit, 39-year-old Norwegian woman arrives at the hospital complaining of generalized muscle weakness. She informs the resident that her symptoms began 3 days earlier after experiencing flu-like symptoms and a sore throat. Her weakness has progressed to the point where she needs help walking and she indicates that her arms feel heavy and tired. She has a dull pain in her lower back, chest, and proximal muscles of both her arms and legs when she moves. She does not have any abdominal or urinary issues, sensory disturbances, or difficulties breathing or coughing. There is no history of drug or alcohol abuse; she doesn’t smoke or take prescription medications. She can’t recall having any insect bites and occasionally travels in Europe for business.
Upon further investigation, a similar incident was discovered from 7 years prior. She had been hospitalized for 2 weeks due to muscle weakness that was preceded by a case of acute tonsillitis. However, a diagnosis was never made and she was discharged. She also remembers recurring episodes after prolonged exercise as a child. On one occasion, her parents had to carry her home after an afternoon cross-country skiing trip. Although these instances were disconcerting, they were attributed to childhood hip dysplasia, which was surgically corrected at age 18.
A physical exam revealed possible tonsillitis, a temperature of 100.5oF, and her pharynx was red with swollen white tonsils. Marked symmetrical weakness of both arms and legs was confirmed during the neurological workup. She was unable to raise her legs and had difficulties abducting her shoulders. She appeared to have more strength in her hands and feet than the proximal muscles of her arms and legs. Palpitation of the muscles revealed no pain and reflexes were normal.
Laboratory tests were ordered. A marked increase in white cells, neutrophils, and CRP (14.72 mg/dL) was observed, potentially indicating a bacterial infection. Both liver and troponin tests fell within normal ranges. However, creatine kinase (CK) levels were exceedingly high (8336 U/L), coupled with increased aspartate aminotransferase and lactate dehydrogenase levels that suggest rhabdomyolysis. More tests were ordered (chest X-ray, ECG, virological screenings for Borrelia and Syphilis) but the results were unremarkable. Throat cultures did indicate a Streptococcus infection and she was started on amoxicillin/clavulanate and intravenous fluids.
Her CK levels peaked after the first day and gradually fell over the following days. Incidents of electrolyte imbalances were observed, presenting with high potassium levels and concurrent low calcium and phosphate levels. Proteins in urine were observed as well, but renal failure never occurred. By the third day, all tests were normal, including serum myoglobin levels, nerve conduction, and myography. However, the underlying pathology was undetermined. A quadriceps muscle biopsy was performed and revealed type II muscle atrophy and fat droplets in type I and type II muscle fibers. Muscle biochemistry indicated abnormal CPT content and carnitine levels. DNA analysis revealed a point mutation on exon 3 (Ser113Leu) and a variant mutation on exon 2 (Ala67Gly) of the carnitine palmitoyltransferase II (CPT-II) gene, a positive test for the adult form of CPT-II deficiency.
The carnitine palmitoyltransferase (CPT) system at a quick glance:
The CPT-II gene is responsible for encoding an enzyme of the same name. The CPT-II enzyme plays an essential role in the production of ATP and ketone bodies. Without the CPT system and its ability to oxidize lipids, it is difficult to meet the energy needs of the brain and skeletal muscle. Unlike short- or medium-chain fatty acids that upon activation can freely diffuse through the mitochondria membrane, long-chain fatty acids (LCFA) must be transported through both the outer and inner membranes. In the cytosol, the LCFA is activated by coenzyme A (CoA), forming acyl-CoA. The activated acyl-CoA (fatty acid with the CoA substrate) is transported through the outer membrane by the CPT-I enzyme to the inner-membrane space. Once inside, carnitine acylcarnitine translocase (CACT) exchanges carnitine with the CoA substrate and then CPT-II transports the carnitine fatty acid across the inner membrane. Inside the mitochondrial matrix, the CPT-II enzyme replaces the carnitine substrate with CoA and β-oxidation can occur. The 2 main products are acetyl-CoA, a necessary precursor in the Krebs cycle, and ketone bodies.
CPT-II deficiency drilled down:
There are more than 40 mutations attributed to the various forms of CPT-II deficiency. This deficiency results in either a partial or total inability to oxidize LCFAs for energy consumption. CPT-II deficiencies are generally divided into 3 categories: neonatal, infantile, and adult. The neonatal variety is uniformly fatal and consists of either deletions or insertions in the CPT-II gene. To date, there are a reported 18 families with this horrible mutation. Various missense mutations are responsible for both the infantile and adult forms.
CPT-II deficiency is an autosomal recessive disorder. The chances of inheriting it from parents who carry the mutation are as follows: 25% of being affected, 50% chance of being a carrier, and 25% chance of not being affected at all. The infantile form has an early onset and typically manifests in the first year of life. It is characterized by liver failure, cardiomyopathy, seizure, hypoketotic hypoglycemia, peripheral myopathy, abdominal pain, and headaches. The infantile form has a high associated mortality rate. There are a reported 28 families with this form, of which, many are the products of incest.
The adult form is the most common, and the most common mutation is in p.Ser113Leu, seen in approximately 60% of cases. The adult form is also the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria. It is characterized by recurrent myalgia coupled with myoglobinuria, weakness, and elevated serum CK levels. During attacks, 60% of individuals have reported muscle weakness and some report cramping. Myoglobinuria and brown-colored urine have been described in 75% of cases. End-stage renal disease has also been reported in some cases. The age of onset varies but approximately 70% of cases begin in childhood while the reminder manifest during adulthood. Attacks are often preceded by intensive exercise, but there are reports about moderate exercise initiating an attack. Exercise is the most common trigger, followed by infection, and finally fasting. Cold, general anesthesia, and sleep deprivation have also been reported as triggers. Any condition where the body relies on increased lipid metabolism for muscle function can trigger an attack.
There is no cure for CPT-II. Since 1973, there have been approximately 300 reported cases of the adult form. This form appears to have a gender component to it, affecting males at a 2:1 rate, with some accounts as high as 5:1. The reason behind this disparity is unknown. Avoidance of triggers is the main therapeutic concern and includes exercise, fasting, valproic acid, general anesthesia, ibuprofen, and high doses of diazepam. Dietary restrictions may also help manage this condition. It is imperative to maintain high glucose levels; therefore, a diet rich in starches is generally recommended (70% glucose and under 20% fats). In severe cases, carnitine replacement therapy may be necessary. During an attack of rhabdomyolysis and myoglobinuria, it is important to keep the patient well hydrated to prevent renal failure. As a preventative measure, glucose infusion may be necessary to prevent catabolism during infections, and frequent meals may help avoid low glucose levels and lipolysis.
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