Assessment of the outcome and biochemical characteristics of infants with abnormal NBS for systemic primary carnitine deficiency and its the carrier frequency in the US

Kimihiko Oishi, MD, Lissette Estrella, NP, Ashley H. Birch, PhD, Ruth Kornreich, PhD, Lisa Edelmann, PhD, Pankaj Prasun, MD, George A. Diaz, MD, PhD

Departments of Genetics & Genomic Sciences, and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA

Corresponding Author: Kimihiko Oishi, MD

Email:   Phone: 1-212-241-2848


Systemic primary carnitine deficiency (CDSP) is an autosomal recessive condition caused by mutations in the SLC22A5 gene that encodes the high-affinity carnitine transporter in various tissues. CDSP can be treated with L-carnitine but it results in hypoketotic hypoglycemia, skeletal myopathy, cardiomyopathy or heart failure if untreated, while many patients with CDSP remain asymptomatic even without treatment unless they are under metabolic stress. Recent introduction of the expanded newborn screening (NBS) has been successful to identify CDSP patients who are at risk for life-threatening heart failure. A previous study indicated that NBS detects not only infants with CDSP but also carriers of this condition or affected mothers. To assess the outcome

and biochemical characteristics of infants with abnormal NBS suspecting CDSP, we performed a single-center retrospective analysis of the patients who were referred to the Program for Inherited Metabolic Diseases of Mount Sinai Hospital from the New York State NBS Program between Jan 2012–May 2017. We also evaluated carrier frequency of CDSP in the US using an NGS carrier screening test performed at the Mount Sinai Genetic Testing Laboratory.

A total of 32 patients were evaluated for low C0 levels detected by the NBS program. Patients who persistently required L-carnitine supplement to maintain normal free carnitine levels and/or who had two pathogenic or likely pathogenic variants in SLC22A5 were diagnosed with CDSP. Among those 32 patients, nine patients had CDSP (28%). The etiologies of the remaining patients included eleven cases of premature birth earlier than 30 weeks gestational age (PB) (35%), ten cases of maternal carnitine deficiency (MD) (31%), and two others. There was no significant difference in initial NBS C0 levels between the groups. Plasma free carnitine levels at the initial evaluation were significantly

lower in the CDSP group compared to the other groups (CDSP; 7.6±2.89, MD; 14.8±6.44, PB; 50.0±17.8μM (mean±SD), CDSP vs MD p<0.01, CDSP vs PB p<0.0001). Urine free carnitine level in CDSP at the initial evaluation was significantly higher than that of MD (p<0.0001) but lower than that of PB (CDSP; 765.1±302.99, MD; 23.2±24.42, PB; 2853.4±2503.1μM (mean±SD)).

Sequencing of SLC22A5 was performed for the patients in the CDSP (5/9 cases) and MD (8/10 cases) groups. In all five cases of CDSP, two variants were identified, including two novel variants, c.761G>A, p.R254Q and c.1088T>A, p.L363H. Of interest, 50% of cases from the MD group that were sequenced (4/8 cases) were found to be carriers of CDSP, and one of the mothers of these carriers was confirmed to have CDSP.

Among the 32,908 individuals screened, we detected 42 different pathogenic or likely pathogenic variants in SLC22A5 in 243 heterozygous and one compound heterozygous individuals. Based on these findings, we estimated a carrier frequency of 1/135 for CDSP in an unselected US population. The four most frequent variants identified were c.641C>T, p.A214V (18.4%), c.136C>T, p.P46S (17.6%), c.1345T>G, p.Y449D (13.5%), and c.1400C>G, p.S467C (8.2%).

Our findings suggested that high urine free carnitine excretion in a setting of very low plasma free carnitine at the initial evaluation is a strong predictor for CDSP among NBS positive infants. It was also confirmed that NBS is a tool to identify carriers of CDSP or mothers who have asymptomatic CDSP as previously described. According to the estimated carrier frequency, CDSP may be underdiagnosed, particularly in populations who were born before introduction of expanded NBS.

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