Ali Kanık, MD1, Marta Frigeni, MD2 , Kayı Eliaçık, MD1, Ali Rahmi Bakiler, MD1,Tijen Tanyalcin, MD PhD3 Mei Baker, MD FACMG4, Nicola Longo, MD PhD2
1Izmir Tepecik Teaching and Research Hospital, Department of Pediatrics, Izmir, Turkey
2Pediatric Medical Genetics, University of Utah, Salt Lake City, Utah, USA
3Tanyalcin Medical Laboratory Selective Screening and Metabolism Unit, Izmir, Turkey
4Co-Director, Newborn Screening Laboratory Wisconsin State Laboratory of Hygiene, Madison, Wisconsin, USA
Corresponding Author contact information: email@example.com, +90 53 26579230
INTRODUCTION: Dilated cardiomyopathy is characterized by left ventricular enlargement and a reduction in the myocardial force of contraction. A specific cause cannot be identified in about 50% of cases and many patients require a heart transplant to survive. In children, 5-10% of cardiomyopathies are caused by an inborn errors of metabolism. Primary carnitine deficiency (OMIM 212140, carnitine uptake defect, carnitine transporter deficiency or systemic carnitine deficiency) is caused by defective activity of the high-affinity carnitine transporter (OCTN2), encoded by the SLC22A5 gene and can result in impaired fatty acid oxidation. This report describes the symptomatic diagnosis of a 8 year-old girl with primary carnitine deficiency and dramatic response of her cardiac function to carnitine supplementation.
CASE: A-8-year-old girl was referred for a history of dilated cardiomyopathy first diagnosed at 9 months of age. She presented with fatigability, abdominal pain and respiratory distress. Her parents were first cousins. Physical examination indicated failure to thrive (weight at the 3rd centile) with normal height (50th centile). Cardiac exam was significant for a 3/6 systolic murmur best heard at the lower left sternal border together with cardiac failure. Echocardiogram indicated an enlarged left ventricle end-diastolic diameter (LVED=56 mm, normal 33-47 mm) with a decreased left ventriculer ejection fraction (LVEF= 44%, normal 56-78%) and reduced shortening fraction (SF=20%, normal 28-44%). A plasma acyylcarnitine profile indicated very low free carnitine (C0=0.57 uM, normal 8-50 uM) with very low levels to absent long-chain acylcarnitines (C16= 0.02 uM, C18=0 uM). The patient was treated with L-carnitine 100 mg/kg/day divided into 3 doses and after 12-month the cardiomyopathy resolved with normalization LVED at 46 mm, LVEF at 57%, and SF at 30% with mild mitral valve insuffiency (present before therapy). Failure to thrive also improved with weight above the 5th centile. Sequencing of the SLC22A5 gene indicated homozygosity for c.614T>G, p.M205R in exon 3. This amino acid is highly conserved and in silico analysis with Polyphen2 and SIFT suggested a pathogenic role of this change. Expression studies in Chinese Hamster Ovary cells confirmed that the M205R mutation completely abolished carnitine transport (0% of normal OCTN2 activity). Homozygosity for this mutation was consistent with parental consanguinity.
CONCLUSION: Identification of the underlying causes of cardiomyopathy with subsequent disease-specific treatments may lead to improved outcomes. Primary carnitine deficiency is one of the treatable causes of cardiomyopathy since complete resolution of the heart disease is possible with carnitine supplementation. We hope that with the advent of national expanded newborn screening in Turkey by tandem mass spectrometry (MS/MS) more patients will be diagnosed, before the onset of cardiomyopathy or irreversible complications.