SULM – Schweizerische Union für Labormedizin | Union Suisse de Médecine de Laboratoire | Swiss Union of Laboratory Medicine

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Ch. Vianey-Saban

1Hôpital Debrousse, Service de Biochimie Pédiatrique, 69322 Lyon cedex 05, France

Cardiac muscle works almost exclusively in aerobic conditions and high amounts of ATP are needed for cardiomyocyte contraction. These cells are the richest in mitochondria of the body. Physiologic studies have shown that prenatally lactate and pyruvate predominate as energy sources for the heart, while postnatally there is an switch to fatty acid oxidation and ketone bodies. Cardiomyopathy is a condition of predominant cardiac failure with a chronic evolution. They are defined as primary when they are not the consequence of a cardiovascular disease. Their prognosis can be severe and lead to cardiac insufficiency or sudden death due to arrhythmia. Since cardiomyopathy can be the leading symptom in several inborn errors of metabolism (IEM), looking closer at the underlying biochemical disorders might help to understand their pathophysiology.

Two different situations can be distinguished:

- The cardiac affection is only one of the symptoms of the disease and it is integrated in an evocative clinical context. This is the case for some storage disorders like mucopolysaccharidoses (Type I, II, VI), mucolipidosis type II, fucosidosis, glycogenoses type III and IV, or neurogenerative disorders (Friedreich ataxia, Steinert disease) …

- In contrast cardiomyopathy can be the predominating (leading) symptom of the IEM. Cardiomyopathy is usually hypertrophic or hypokinetic. My talk is focussed on this last group of diseases; these include:

Glycogenosis type II: Pompe disease
It is due to acid maltase (?-1,4 glucosidase) deficiency. Cardiomyopathy appears in early infancy and is associated with severe muscle hypotonia and macroglossia. Cardiomegaly is remarkable and ECG changes are characteristic. Urinary oligosaccharide profile or, more specifically, measurement of urinary Glc4 (by tandem mass spectrometry) allows to suspect the diagnosis. This must be confirmed by measuring enzyme activity. Prognosis is severe; recent therapeutic trials using recombinant human maltase open new hopes.

Respiratory chain disorders
Oxidative phosphorylation (i.e. ATP production) is impaired which has a direct impact on the cardiomyocytes which depend heavily on the mitochondrial energy supply. Cardiomyopathy is hypertrophic in neonates and infants or can be dilated in childhood or adulthood. The cardiac affection can even be present antenatally. Screening tests include the determination of lactate, pyruvate, ketone bodies and their ratio in plasma, before and 1 hour after meal throughout the day or after a glucose loading test. The diagnosis has to be confirmed by the assay of respiratory enzyme activities in tissues. Some respiratory chain disorders are tissue-specific and are expressed only in myocardium. Unfortunately, therapies proposed so far are not really successful.

Mitochondrial fatty acid oxidation defects
At least 9 defects, which impair oxidation of long-chain fatty acids, affect the heart. The deficiency in ketone body production most probably explains why heart is a major target organ. Whether the accumulation of intermediate metabolites of fatty acid oxidation is a further pathogenic factor is still debated.
- Primary carnitine transporter deficiency (CTD) : cardiac failure is the major presenting manifestation and occurs only in CTD. The age of onset varies from 12 months to 7 years. The sodium-dependent active transport system of L-carnitine is defective. This results in very low levels of plasma L-carnitine plasma ( < 5µmol/L for free and total carnitine). Treatment with L-carnitine improves dramatically the cardiac function.
- CPT 2, CAT, VLCAD, LCHAD and TFP deficiency as well as multiple acyl-CoA dehydrogenase deficiency can present in the neonatal period or early in life with cardiac arrest or ventricular arrhythmia. Surviving patients can develop hypertrophic cardiomyopathy often associated with hypoketotic hypoglycaemia. The diagnostic investigation relies on plasma acylcarnitine profile. In all cases, the diagnosis has to be confirmed by the measurement of the defective enzyme activity. Treatment includes glucose infusion with carnitine and medium-chain triglyceride (MCT) supplementation. An attempt of treatment with odd-MCT supplementation seems promising.

In conclusion, diagnosis of IEM is important, even if the disease is not treatable, for allowing appropriate genetic counselling in these families. For a specific diagnosis, biological samples must be collected as soon as possible, including urine, plasma (heparined, for metabolite analyses), whole blood (EDTA, for enzyme determination and/or DNA extraction), and skin and tissue biopsies when the prognosis seems severe. A specialist of IEM must rapidly be contacted for counselling the investigations and the specific therapeutic attempts.


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