Phenotypic manifestations of the OCTN2 V295X mutation: Sudden infant death and carnitine-responsive cardiomyopathy in Roma families

In two non‐consanguineous Hungarian Roma (Gypsy) children who presented with cardiomyopathy and decreased plasma carnitine levels, we identified homozygous deletion of 17081C of the SLC22A5 gene that results in a frameshift at R282D and leads ultimately to a premature stop codon (V295X) in the OCTN2 carnitine transporter. Carnitine treatment resulted in dramatic improvement of the cardiac symptoms, echocardiographic, and EKG findings in both cases. Family investigations revealed four sudden deaths, two of them corresponded to the classic SIDS phenotype. In postmortem tissue specimens available from three of them we could verify the homozygous mutation. In liver tissue reserved from two patients lipid droplet vacuolization could be observed; the lipid vacuoles were located mainly in the peripherolobular regions of the acini. In the heart tissue signs of generalized hypertrophy and lipid vacuoles were seen predominantly in the subendocardial areas in both cases; some aggregates of smaller lipid vacuoles were separated, apparently by membranes. Review of all OCTN2 deficiency cases reported so far revealed that this is the first presentation of histopathology in classic familial sudden infant death syndrome (SIDS) with an established SLC22A5 mutation. In addition to the two affected homozygous cardiomyopathic children and three homozygous sudden death patients, the genetic analysis in 25 relatives showed 14 carriers. The mutant gene derived from five non‐consanguineous grandparents, each of them having 6–14 brothers and sisters. This alone suggests a wide ancestral spread of the mutation in certain Roma subpopulations. © 2004 Wiley‐Liss, Inc.