Pantethine therapy dramatically rescues end-stage failing heart in a patient with deficiency of coenzyme A biosynthesis

Abstract

The phosphopantothenoylcysteine synthetase (PPCS) deficiency is a rare genetic autosomal disorder responsible of a defect in Coenzyme A (CoA) synthesis from vitamin B5 (pantothenate).^1-3 Only few human cases have already been described and none severe form has been successfully treated. We report the case of an infant with an end-stage heart failure who spectacularly improved with treatment by pantethine.

This first child of consanguineous parents was born after a full-term and uneventful pregnancy, with normal birth measurements. He presented at the age of 3 days after a symptom-free interval, a neurological deterioration with lethargy, axial hypotonia contrasting with limb hypertonia. Initial biological investigations revealed ketoacidosis (pH 7.43, bicarbonate 11 mmol/L [N: 22–26], anion gap 26 mmol/L [N: 14–16], β-hydroxybutyrate 4.8 mmol/L [N < 0.25]) and hyperammonaemia (301 μmol/L [N < 80]), suggesting an inborn error of metabolism. However, metabolic workup (blood amino acid, acylcarnitine, and urinary organic acid profiles) remained unspecific and the patient recovered with a symptomatic treatment (high energy intake and temporary removal of natural protein from the diet, nitrogen scavenger treatment, carnitine and vitamin supplementation). He was discharged at home after 3 weeks with a suspected ketolysis defect and the instructions to avoid fasting.

At the age of 3.5 months, during a viral infection, he presented a progressive distress with a brief cardiorespiratory arrest requiring resuscitation. Initial biological workup showed lactic acidosis (pH 7.10, lactate 11 mmol/L [N: 0.5–2.2]), hyperammonaemia (350 μmol/L [N < 60]), increased levels of creatine kinase (63 500 U/L [N < 310]), and transaminases (SGOT: 16N and SGPT: 3N), with low partial thromboplastin time (41% [N > 70]). Echocardiography revealed a severe dilated hypokinetic cardiomyopathy (left ventricular end-diastolic diameter, LVEDD, 32 mm, +4.2 SD for body area, and left ventricular ejection fraction, LVEF 22%). Blood levels of NT-proBNP (17 245 ng/L [N < 125]) and of troponin T (258 ng/L [N < 14]) were severely increased. Cardiac MRI confirmed the dilated cardiomyopathy, without argument for a viral myocarditis. Coronary angiography was normal. A respiratory chain deficiency was then suspected, and muscle and liver biopsies were performed. The examination of the muscle biopsy under electron microscopy demonstrated morphological alterations of the mitochondria, with almost exclusively degenerative forms with poorly preserved matrix and/or mitochondrial cristae, consistent with a mitochondrial cytopathy (Figure 1). The histological examination of the liver biopsy was unspecific with only a mild paleness of the hepatocytes, which might suggest a minimal microsteatosis. Further analyses showed a mild decrease of complex IV activity around 65% of control in the skeletal muscle and 90% in the liver (methods used for measurement of respiratory chain complex activities are given in Data S1). Western blot analysis was in favour of complex IV assembly impairment. Despite intensive pharmacological cardiac support [epinephrine, norepinephrine, angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, diuretics, milrinone and repeated infusions of the calcium sensitizer levosimendan], cardiac situation remains precarious (Figure 2) and the patient experienced 2 months later a second cardiac arrest successfully resuscitated. Heart transplantation was refuted because of multisystem organ involvement, including transitory liver failure, rhabdomyolysis episodes, feeding difficulties and recurrent deep venous thromboses.

Between the ages of 3.5 and 6.5 months, the patient remained admitted in ICU and presented recurrent episodes of deep venous thrombosis despite low-molecular-weight heparin therapy, revealing an antiphospholipid antibody syndrome (APS) for which preventive vitamin K antagonist therapy was initiated. Plasma levels of creatine kinase (median value 908 U/L, range 250–114 830, N < 310) and of ammonia (median value 85 μmol/L, range 26–129, N < 40) remained fluctuating. The baby developed eating disorders necessitating enteral nutrition. Because of recurrent vomiting, a gastroparesis was confirmed by gastric scintigraphy and jejunal tube feeding was required. Neurological development was considered as subnormal with only a persistent global hypotonia and a normal brain MRI. Finally, exome sequencing led to the identification of a new homozygous mutation in the PPCS gene (c.727G > C, p. Ala243Pro) categorized as highly deleterious by prediction tools. Both parents were heterozygous for this variant and were asymptomatic. This variant has never been reported before and was classified as likely pathogenic according to ACMG criteria (PM2, PM1_S, PP4 and PP3_M) using prediction tools results, population databases frequency and clinical data. Indeed, the dramatic reversal of disease progression, notably the failing heart, just a few days of starting pantethine treatment is a strong argument to the reality of the suspected disease due to PPCS deficiency. Nevertheless, functional validation studies to demonstrate its functional impact are still in progress.

Following this diagnosis of CoA synthesis deficiency, a therapeutic trial with oral pantethine, a potential source for CoA de novo biosynthesis that bypasses the PPCS step (Figure 3), was initiated at 7 months of age.^{3, 4} The dosage was initiated at 7 mg/kg/day in four oral doses per day and progressively increased (+7 mg/kg/day every 4 days) in 12 days up to 28 mg/kg/days. A spectacular improvement was associated with the introduction of pantethine therapy. In a week, the LVEF, LVEDD and NT-proBNP levels were normalized (Figure 2), allowing discontinuing cardiovascular drugs in several weeks, except ACE inhibitor. A video of echocardiography before and after 6 months of treatment with pantethine is available in Supplementary information files (see Videos S1 and S2 in Supporting Information). LVEF and LVEDD remained normal 2 years later with the continuation of pantethine treatment and ACE inhibitor. Similarly, plasma levels of ammonia and creatine kinase quickly normalized and remained normal thereafter. Improvement of gastroparesis was more progressive and a moderate psychomotor delay persisted at the age of 3 years (he can stand-up and walk, with a persistent mild axial hypotonia and speech delay). His current treatment includes pantethine supplementation (28 mg/kg/day), vitamin K antagonist and ACE inhibitor.

Coenzyme A (CoA) is a fundamental cofactor in all living organisms. It is the predominant acyl carrier in mammalian cells and a cofactor that plays a key role in energy and lipid metabolism. CoA biosynthesis from pantothenate involves five enzymatic steps catalysed by four enzymes that are highly conserved from prokaryotes to eukaryotes (Figure 2). Pathogenic mutations of all of these enzymes have been previously reported with various presentations.

Currently, six patients from three unrelated families have been reported with PPCS deficiency, all of them with a predominantly cardiac presentation including dilated cardiomyopathy and various degrees of heart failure.^{3, 5} Two of these patients had a severe neonatal presentation, very similar of our patient. Besides dilated cardiomyopathy, both experienced acute life-threatening events with heart failure, recurrent episodes of increased plasma levels of creatine kinase, hyponatremia and hypokalaemia, and finally died at 3 and 4 months of age. Digestive difficulties were also constantly reported with, as in our case, gastroparesis and feeding difficulties. The four other patients are all from the first reported family and seem to have a milder form of the disease with mainly cardiac symptoms, including a dilated cardiomyopathy diagnosed after a course of several months or years (4 months, 12 months, 23 months and 20 years), and a better outcome. Two of them died from heart failure at the age of 2 and 3 years, and the others are still alive at the age of 10 and 21 years, respectively.

Recently, two sisters have been reported with a phosphopantothenoylcysteine decarboxylase (PPCDC) deficiency, the next step of CoA biosynthesis, with an almost similar presentation including a dilated cardiomyopathy, axial hypotonia, feeding difficulties, lactic acidosis, elevated creatine kinase level, and fatal outcome at the age of 4 months.⁶ These clinical presentations contrast with those of other enzymatic defects in the pathway of CoA synthesis (pantothenate kinase 2 and CoA synthase deficiencies) that present as a neurodegenerative disease with brain iron accumulation and no cardiac involvement.⁷ This suggests a major role of 4-phosphopantetheine synthesis (catalysed by PPCS and PPCDC reactions) in the heart compared to brain.

Therapy with pantethine, a dietary supplement that bypasses PPCS deficiency for CoA biosynthesis (Figure 3) using another direct PANK way, induced a spectacular improvement of cardiomyopathy, suggesting its contribution to the restoration of the CoA pool and improvement of cardiac energy production. The dramatic efficacy of this treatment contrasts with the previously treated patients for whom only a mild or no improvement of their cardiac function was reported, possibly due to a longer course of the disease for the first two patients³ with possibly irreversible damages such as necrosis, apoptosis and fibrosis, or a too late initiation of the treatment for the third patient who died several days later.⁵ Other explanations could be the number of daily doses, which was one dose per day in the previous publications^{3, 5} compared to four daily doses in our study, and the total daily dosing per patient that was very different (from 60 to 1800 mg/day) because adjusted for body weight (≈ 24 mg/kg/day in all the patients). Whatever facilitating CoA synthesis could also improve cardiac function in other situations of heart failure, in which energy deprivation seems to contribute to cardiac dysfunction remains to be studied.^{8, 9}

This case report emphasizes the major role of PPCS enzyme for cardiac energy metabolism and function. The potential benefits of pantethine as metabolic therapy should be examined in other situations of heart failure.¹⁰

FL reports consulting fees from AlfaSigma, Biomarin and Sanofi Genzyme, outside the submitted work. The other authors reported no conflict of interest.