Over the years, I have got into the habit of requesting plasma acylcarnitines in subjects with raised CK. As a rheumatologist, one sees one's share of subjects with high CK. Most of them have muscle pain, some have fatigue and exercise intolerance. Largely they look well, and investigations are unrewarding.
The European Federation of Neurological Societies recommends that CK levels above the following thresholds be investigated:
Caucasian female- 325 U/l
Caucasian male- 503 U/l
Afro-Caribbean female- 600 u/l
Afro-Caribbean male- 1200 U/l
The girl in question was Caucasian, in her early twenties, and was referred with a diagnosis of ?Fibromyalgia. As physicians all over the world will be aware, this has become a popular and somewhat lazy diagnosis in almost anybody with pain, particularly in primary care. However, this particular girl had had a few admissions with vomiting and abdominal pain. Looking back through one such episode, I found that her CK was ~1500 and 800 on 2 occasions, but had not been repeated.
So I repeated her CK- it was normal. A few days later, however, her plasma acylacarnitines were reported as at least moderately raised for all fatty acid lengths- short chain, medium chain and long chain fatty acids.
So what did she have?
The most likely diagnosis in an adult with raised CK and increase in plasma acylcarnitines of all lengths is Multiple Acyl Co-A Dehydrogenase Deficiency (MADD). This is a condition that is quite responsive to riboflavin in 98% of cases and is therefore important not to miss.
MADD is just one of a number of lipid storage myopathies- the others being Neutral Lipid Storage Disorder Myopathy (NLSD-M), Primary Carnitine Deficiency (CD), and Carnitine Palmitoyl Transferase-II (CPT2) deficiency. More about those others later.
MADD is autosomal recessive, caused by deficiency of one of 3 enzymes- Electron Transfer Flavoprotein Dehydrogenase (ETFDH), or the two isoforms of ETF itself- A&B. Ninty-three percent of cases are due to ETFDH deficiency. When the deficiency is severe, such as with 2 null alleles, you get the most severe form of the disease, with congenital abnormalities (Type I) or without (type II). Such subjects present as neonates with metabolic decompensation such as vomiting, metabolic acidosis, non-ketotic hypoglycaemia, and hepatic failure with hyperammonemia, as seen in Reye's syndrome.
Type 3, with delayed onset presentation in teenage or adulthood, is the form most of us will come across. In 2014, Grunert reported that 350 such cases had been published (of all types), but it is likely that a vast majority of cases with milder phenotypes remain undiagnosed and unpublished.
Most subjects with delayed onset MADD have chronic muscle pain, muscle fatigue, subjective proximal muscle or neck weakness and exercise intolerance. A small minority have episodes of rhabdomyolysis. Subjects can remain asymptomatic. A minority present with acute metabolic decompensation with abdominal pain, vomiting, and acidosis, more commonly seen in types 1 & 2, often after episodes of stress such as fever, infection, fasting, pregnancy or labour. Chronic & acute forms can co-exist in 20% of cases.
The screening test is plasma (or serum) acylcarnitines, which will show a rise across all fatty acid lengths, i.e short, medium and long chain fatty acids (C6-C18). Corroboration can be had by measuring urinary organic acids (spot sample in non-acidified container), specifically that of glutaric acid, 2-hydroxy glutaric acid, ethylmalonic acid, 3-hydroxyisovaleric acid, adipic, suberic and sebacic acids and glycine conjugates (acylglycines). These will be raised. Hence MADD is also known as type-2 glutaric aciduria. Since the plasma acyl-coA is all bound to carnitine, serum free carnitine will be low. However, some subjects have raised plasma acylcarnitines and high urinary organic acid excretion only during periods of stress.
The confirmatory test is sequencing of the ETFDH gene, looking for mutations or null alleles. This will yield the diagnosis in 93% of cases. Muscle biopsy will show lipid containing vacuoles adjacent to normal looking mitochondria on Oil Red-O stain, but does not contribute anything extra if molecular techniques are available.
Once diagnosed, it is important to start these subjects on riboflavin in a dose of 200 mg daily. In most reported case series, riboflavin has been co-prescribed with either carnitine (3g daily) or co-enzyme A, but not both. Many subjects respond within a month, with normalisation of raised CK alongside clinical improvement of pain, fatigue and muscle power, but others may need longer.
Other lipid storage myopathies have different phenotypes. Neutral Lipid Storage Disorder Myopathy (NLSD-M) presents in adults with myopathic features, but in addition is accompanied by cardiomyopathy, fatty liver, transaminitis, high tryglycerides & VLDL, and type 2 diabetes mellitus. There may be parental consanguinity. The putative defect is in the PNPLA2 gene, with a deficit in the enzyme Adipose Triglyceride Lipase (ATGL), which catalyses the first step in the breakdown of intracellular triglycerides. Leucocytes show characteristic tryglyceride accumulation, called "Jordan's anomaly". The only effective treatment is medium chain fatty acids (these enter the mitochondria directly for beta-oxidation, without needing to be conjugated to carnitine).
Primary carnitine deficiency (CD) presents early in life, can be fatal, but is treatable if diagnosed. It presents with myopathy, cardiomyopathy, nonketotic hypoglycaemia and Reye's syndrome type hepatic failure with hyperammonemia. The defect is in the Carnitine Organic Cation Transporter gene, OCTN2. Treatment is Carnitine, in a dose of 3g daily.
CPT2 deficiency is seen in young adults or teenagers, who present with a characteristic history of recurrent rhabdomyolysis, often after exercise, fasting or fever. Some subjects develop renal failure due to myoglobinuria. Unlike the other lipid storage myopathies described above, fat accumulation in the form of lipid droplets is largely absent in muscle biopsy samples on Oil Red-O staining. Recently, bezafibrate has been shown to improve lipid shuttle in these patients in fibroblasts by activating PPAR-gamma, but clinical trials have failed to show benefit.
