Summary:
Carnitine insufficiency can be the etiology of life-long seizures and debilitating fatigue. Ripples of metabolic effects are seen here in amino acid and fatty acid profiles, and the three urinary carnitine functional markers strongly suggest the true nature of the disorder.

History
A 48-year-old man started experiencing seizures as a child, but otherwise developed normally. At 39 years old the seizures had become severe, along with severe and disabling fatigue. Normal seizure-regulating medications were ineffective, so the ION metabolic profile was ordered from Metametrix.

Description of Results
The results will be described in the order that they were initially inspected, which will build from inconclusive to etiologic-defining observations.

Mildly abnormal findings:

The standard serum chemistry profile showed only moderately elevated cholesterol and triglycerides, with low HDL (37) and high LDL (181).

Even though the metabolic markers for vitamins B6, B12, and folate were all in normal ranges, homocysteine was elevated. An indication of impaired methionine metabolism is found in the mid-normal plasma methionine with low lysine, threonine, and tryptophan.

Serum b-carotene was undetectable while vitamin A was near the upper limit, indicating increased rate of b-carotene conversion or difficulty with transport. Also note that while a somewhat elevated lipid peroxides result indicates elevated membrane PUFA oxidation, the 8OHdG marker of DNA oxidative damage rate is barely detectable, so the oxidative damage seems specific to membrane lipids.

A strange pattern of fatty acids emerges:

Going from the top of the plasma fatty acid profile, the mystery continues as the n-3 family is generally depressed as frequently seen in simple dietary insufficiency of the n-3 oils. However, the pattern of n-6 fatty acids is bizarre. It is extremely rare to find such elevations of the GLA, DGLA, AA, and docosatetraenoic acids. Since LA is low-normal, the rate of desaturation and elongation is extremely elevated in this patient.

The elevated Mead acid confirms such a stimulation of desaturation. The Triene/Tetraene (Mead/AA) ratio is mid-normal because of simultaneous elevation of the both fatty acids.

Evidence of highly unusual fatty acid metabolic effects continues to be seen in the monounsaturated and saturated families. First, it is fairly common to find the pattern of slightly elevated stearic acid with high-normal palmitic and arachidic. This is typically found in patients with hyperinsulinemia. However, it is highly unusual to see such simultaneous elevations of palmitoleic, vaccenic, oleic, and 11-eicosenoic acids. These monounsaturated fatty acids are the products of n-7 or n-9 desaturation of the corresponding saturated fatty acids. Again, it looks like there is something stimulating desaturation. Another explanation is impairment in the rate of oxidation of oxidation of unsaturated fatty acids. We will now turn to the definitive finding in this series.

Recommendations

L-Carnitine or acetyl-L-carnitine should be started at an aggressive dosage. Carnitine use can be titrated to maximum metabolic effect, as indicated by normalization of the markers described above. Since there is strong evidence that this patient has a genetic carnitine dependency, he will probably need to continue maintenance-level supplemental carnitine indefinitely.

The n-3 fatty acid deficit must be improved, but the first order of intervention in that area is to improve antioxidant status so that further oxidative damage is avoided. Antioxidant supplementation for 3-4 weeks may be followed with introduction of fish oils, but it is important to check lipid peroxide levels after about 60 days of fish oil supplementation in this case. If the lipid peroxides are rising, then antioxidant use should be further increased and fish oil supplementation should be moderated.

One other area of metabolic maintenance is to anticipate increased amino acid utilization when fatty acid oxidation is improved. For this reason, a balanced formula of essential amino acids may be added as the carnitine dosage is stabilized.

Other Comments

The enzymes that transport fatty acids across the mitochondrial membranes are known to show a high prevalence of genetic polymorphism. Individuals bearing these traits show widely varying clinical responses because of the ubiquitous tissue requirement for energy production from fatty acids. Neurological disorders are the most frequent manifestation, showing the high susceptibility of cells of the CNS to such energetic deprivation. This man apparently has a relative mild from of acylcarnitine transferase deficiency that has allowed relatively normal development into adulthood.

In the data from this case we are able to observe multiple corresponding, and we might presume related, disturbances in amino acid and especially fatty acid metabolism. The pattern of elevation of n-6 fatty acids is extremely unusual, and it reveals a previously unreported specific class of fatty acid transfer impairment associated with a carnitine transport deficit. The enormous AA/EPA ratio elevation with concurrent multiple monounsaturated fatty acid elevations further illustrates how carnitine can impact fatty acid metabolism. We look forward to posting additional follow up data on this case.