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

Abstract

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.

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

“…Data from human deficiencies in FA oxidation and rodent models with genetically or chemically impaired FA oxidative capacity support the interpretation that reduced FA oxidation causes cardiac hypertrophy. For example, in humans, defects in the Na ϩ -carnitine cotransporter (Na ϩ -driven organic cation transporter 2 [OCTN2]) cause a cardiomyopathy characterized by cardiac lipid accumulation and hypertrophy (34). Similarly, mice with juvenile visceral steatosis (JVS) mouse mimics human systemic carnitine deficiency because mice with JVS have a spontaneous deficiency of OCTN2 that results in cardiac lipid accumulation and hypertrophy, as well as a 2-fold increase in cardiac mitochondrial area (45).…”

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

“…After therapy all cases had increase in their hemoglobin levels. In the literature, anemia was noted in some cases of primary carnitine transporter deficiency (Cano et al 2008;Komlósi et al 2009;Lamhonwah et al 2002;Melegh et al 2004;Tein and Di Mauro 1992). Carnitine is known to have a role in red blood cell metabolism: it stabilizes the cellular membrane and raises the red blood cell osmotic resistance (Evangeliou and Vlassopoulos 2003).…”

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

“…This results in low carnitine plasma levels due to decreased intracellular carnitine accumulation and increased carnitine excreted in the urine. Homozygous deletion of 17081C of the SLC22A5 gene results in a frameshift mutation at R282D, which leads to a premature stop codon in the OCTN2 carnitine transporter, as observed in Hungarian Roma (Gypsy) infants who present with cardiomyopathy and decreased plasma carnitine levels ( 183 ). The affected children present with feeding diffi culties, upper respiratory tract infections, hepatomegaly with abnormal liver function tests, hypoglycemia, and mildly elevated creatine kinase ( 170 ).…”

“…Acquired disorders, such as alcoholic cirrhosis, renal failure as a result of chronic hemodialysis, and epilepsy treated with valproic acid, also have been associated with secondary carnitine defi ciency (192)(193)(194). However, the exact mechanism for carnitine defi ciency and the possible benefi ts of carnitine replacement under these conditions need further study ( 183,189,190,195 ).…”

“…The affected children present with feeding diffi culties, upper respiratory tract infections, hepatomegaly with abnormal liver function tests, hypoglycemia, and mildly elevated creatine kinase ( 170 ). A residual carnitine transport activity has been observed in some OCTN2 mutations, and in such situations, life-long replacement of L-carnitine and decreased intake of dietary fat are considered the major treatment options for primary carnitine defi ciency (182)(183)(184). In untreated patients, the defi ciency of carnitine can progress to hypertrophic cardiomyopathy and weakness of skeletal muscles ( 185 ).…”