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Key Points

  • Disease summary:

    • Primary carnitine deficiency (OMIM 212140) is a disorder of the carnitine cycle that impairs fatty acid oxidation. It is caused by mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter. Primary carnitine deficiency has a frequency of about 1:40,000, with 1% of the population being carrier for this condition. It has a very high frequency in the Faroe Islands (prevalence 1:1300 people, incidence 1:720) due to a founder effect.

    • The lack of the plasma membrane carnitine transporter results in urinary carnitine wasting, low serum carnitine levels (0-5 μM, normal 25-50 μM), and decreased intracellular carnitine accumulation. Affected patients can have a predominant metabolic (hypoglycemia, hepatic encephalopathy) or cardiac (cardiomyopathy, arrhythmia) presentation. Some people remain asymptomatic for long time, but are at risk for sudden cardiac death.

  • Hereditary basis:

    • Primary carnitine deficiency is transmitted as an autosomal recessive disorder caused by mutations in the SLC22A5 gene on 5q31.1. Penetrance in affected individuals is thought to be very high, although quite a few people are identified as adults due to expanded newborn screening.

  • Differential diagnosis:

    • Primary carnitine deficiency needs to be differentiated from secondary carnitine deficiency. This can occur in disorders of the carnitine cycle (carnitine-acylcarnitine translocase [CACT] or carnitine palmitoyl transferase 2 [CPT-2] deficiency) and fatty acid oxidation (MCAD, VLCAD, LCHAD, TFP deficiency), organic acidemias (propionic, methylmalonic, isovaleric, and glutaric acidemia, 3-methylcrotonylglycinuria, multiple carboxylase deficiency, and other more rare), renal disease (renal Fanconi syndrome, chronic renal failure, dialysis), lysinuric protein intolerance (LPI), chronic ketosis or ketogenic diet, extreme prematurity, prolonged use of intravenous nutrition not supplemented by carnitine, and drug therapy (valproic acid, phenobarbital, phenytoin, carbamazepine, drugs containing pivalic acid).

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

At least one of the following

  • Markedly reduced plasma free and total carnitine (usually free carnitine <10 mM and total carnitine <15 mM)

  • Low long-chain acylcarnitines (C16, C18, C18:1) in the plasma acylcarnitine profile

  • Low-normal plasma free carnitine levels while receiving carnitine supplements

And the absence of

  • Abnormal acylcarnitine species indicative of other fatty acid oxidation defect or organic acidemia

  • Abnormal urine organic acid with prominent ketonuria or metabolites suggestive of an organic acidemia

  • Clinical history (prematurity, use of specific drugs, intravenous hyperalimentation, renal disease, etc) suggestive of secondary carnitine deficiency

  • Maternal disease causing carnitine deficiency (in breast-fed infants): maternal primary carnitine deficiency, glutaric acidemia type 1, medium-chain acyl CoA dehydrogenase (MCAD) deficiency, cystic fibrosis

Clinical Characteristics

Deficiency of carnitine can impair fatty acid oxidation at time of fasting. Typically, symptoms are triggered by fasting, an infection, fever, or an acute gastroenteritis, increasing the requirement of calories from fatty acid oxidation. Carnitine deficiency can remain asymptomatic for long time if patients are not stressed. Patients can present with a predominant metabolic or cardiac presentation or with both (Table 96-1). ...

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