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.
Courtesy of ResearchGate
