Primary carnitine deficiency identified by whole exome sequencing

Interesting, but it seems like obtaining carnitine levels initially would have led to the diagnosis faster. In this setting primary carnitine deficiency would seem to be high on the differential.(Stanley CA, DeLeeuw S, Coates PM, Vianey-Liaud C, Divry P, Bonnefont JP, Saudubray JM, Haymond M, Trefz FK, Breningstall GN, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol. 1991 Nov;30(5):709-16.)

Lahrouchi N, Lodder EM, Mansouri M, Tadros R, Zniber L, Adadi N, Clur SB, van Spaendonck-Zwarts KY, Postma AV, Sefiani A, Ratbi I, Bezzina CR. Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death. Eur J Hum Genet. 2017 Mar 15. doi: 10.1038/ejhg.2017.22. [Epub ahead of print]

Abstract

Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death. 

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From the article

The proband was a 3-year-old girl of Moroccan descent who was born to a 25-year-old female at 39 weeks of gestation via caesarian section. She had normal development until the age of 2 years. In the months prior to admission, the parents noted progressive fatigue, shortness of breath and pallor. The patient had no learning difficulties or mental retardation. She was referred to a pediatric cardiologist and at the time of presentation was in a good overall condition. During physical examination, pallor of skin and conjunctivae were observed. No audible heart murmur was noted and the peripheral pulse was normal. She had normal neurological examination and no dysmorphic features were identified. Her electrocardiogram (ECG) revealed high voltage R and deep S waves in V5 and V2, respectively, suggesting left ventricular hypertrophy, tall peaked T-waves and a short QTc interval, (318 ms; Figure 1a). Trans-thoracic echocardiography revealed situs solitus levocardia with atrioventricular and ventricular arterial concordance. There was good systolic function with a shortening fraction of 36%. Severe concentric hypertrophy was observed without outflow or intra-cavity obstruction (Figure 1c). The left ventricular posterior wall and the interventricular septum were measured 8.3 mm (normal range (NR), 3.2–6.1; z-score,11 3.26; height, 102 cm; weight, 14 kg) and 10.5 mm, respectively (NR, 3.5–7.1; z-score, 3.45; Table 1). There was no mitral regurgitation and the rest of the heart was normal. Her creatine kinase level was 110 U/l (NR, 30–200) and hemoglobin level measured 7 g/dl (NR, 11–13). The patient lived in an isolated area of the south of Morocco with limited access to specialized clinical infrastructure and unfortunately biochemical testing for known treatable causes of pediatric cardiomyopathy was not performed at this stage. In addition, there is, at present, no nationwide newborn screening program in Morocco...

Because of a remarkable family history of two siblings dying suddenly at young age, she was referred for further investigation to the department of medical genetics in Rabat (Morocco). The pedigree of the family is shown in Figure 2. The proband (II-5) is the offspring of consanguineous parents. Her oldest brother (II-1) died suddenly at 6 months of age. Her sister (II-2) had a very similar clinical course as the proband with progressive fatigue and shortness of breath. She was seen by a pediatric cardiologist and diagnosed with severe hypertrophic cardiomyopathy at the age of 3 years. Unfortunately, she died suddenly shortly after the diagnosis was made. The third sibling (a boy, II-3) died at 20 weeks of gestation. His fetal ultrasound showed severe hypertrophic cardiomyopathy. The patient’s only living sibling (II-4) is 7 years old and is doing well. Considering the significant family history and heterogeneity of genetic causes of pediatric cardiomyopathy,12, 13 we performed WES to detect the potential underlying genetic cause to assist in the making of a definite diagnosis....

To follow-up on our genetic findings, we performed targeted tandem mass spectrometry analysis of plasma carnitine levels in the patient revealing complete absence of free carnitine (0 μmol/l; ref., 30–50 μmol/l) and a trace level of total carnitine (<1 μmol/l; ref., 43–65 μmol/l) further establishing the diagnosis of PCD.

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