Carnitine-acylcarnitine translocase deficiency (CACTD) is a type of long chain fatty acid oxidation disorder (LCFAOD) characterized by severe cardiac dysfunction. It has the highest rate of cardiac arrhythmia and mortality among LCFAODs.
Until recently, only 68 cases of CACTD had been reported in the literature. This number increased to 87 with a recent publication by Ryder et al in the Journal of Inherited Metabolic Disease. The article revisited the clinical, biochemical, and molecular findings related to CACTD, as well as treatment of 23 patients with CACTD from metabolic centers in New Zealand, Australia, Canada, the UK, and Hong Kong.
Most (16/23) patients in Ryder’s study had severe classical disease (ie, a catastrophic collapse within 48 hours of birth). One of them was homozygous for the variant c.199-10T>G of the solute carrier family 25 member 20 (SLC25A20) gene and, therefore, was classified as severe despite manifesting the disease later (8 days after birth).
Late-onset CACTD had been previously reported in patients with the c.199-10T>G splice site variant. For instance, Chen et al described the case of a neonate in mainland China who developed symptoms 61 days after birth. She presented with a severe metabolic crisis that rapidly evolved leading to respiratory insufficiency, cardiac arrest, and death. “Early recognition of symptoms and timely and appropriate treatment are critical for improving the outcome of this highly lethal disorder,” Chen et al said.
However, even when disease recognition and treatment occur early, outcomes remain poor. In the following sections, we will address the main findings reported by Ryder et al regarding the presentation and management of CACTD patients with classical and attenuated versions of the disease.
Cardiac Manifestations in CACTD Patients
In Ryder et al’s classical cohort, patients presented with severe neonatal cardiac dysfunction (n=2) and arrhythmias (n=10), in particular supraventricular and ventricular tachycardia. Seven of the 10 patients with arrhythmias experienced cardiac arrest and required cardiopulmonary resuscitation (CPR). Except for one case, all classical untreated cases developed hypoglycemia. Four patients showed normal echocardiograms at presentation.
Ten patients with classical disease (age range, 5 months-11 years) were alive at the time of publication. The other 6 had died in the first week of life (n=2) or when aged between 6 months and 4 years (n=4). Ryder et al noticed a trend in patients who survived beyond the first year (n=11), with 9 of them showing either normal function or borderline to moderate left ventricular hypertrophy (LVH) without cardiac dysfunction. The remaining 2 patients developed dilated cardiomyopathy or hypertrophic cardiomyopathy.
The study by Ryder et al also included 7 patients with attenuated disease. Most (6/7) of them were homozygous for variant c.82G>T (p.Gly28Cys). Only 2 patients showed abnormal findings on echocardiogram at presentation—one had mild left ventricular hypertrabeculation and the other had LVH with impaired contractility and asystolic arrest that required CPR. At the time of publication, all of these patients were alive.
Beyond the Cardiac Symptoms
Except for 2 patients whose levels were not assessed, almost all (14/16) patients with classical disease presented with hyperammonemia (range 50-1142 μmol/L). Most (13/14) of them developed chronic hyperammonemia despite intensive therapy. In the patients with attenuated disease, only 1 patient developed hyperammonemia and none revealed the condition chronically.
“The preponderance and pathogenesis of severe acute cardiac compromise and hyperammonemia in CACTD, relative to other [fatty acid oxidation disorders], remains unexplained,” Ryder et al wrote.
Patients in the classical disease cohort who developed hyperammonemia responded well to high rates of dextrose administration (10-12 mg/kg/min) during the acute phase. In contrast, they did not show significant improvements when treated with ammonia scavenging medications (n=7) or carglumic acid (n=2). One patient improved after starting D,L-3-hydroxybutyrate and triheptanoin (C7) soon thereafter.
The levels of creatine kinase were evaluated in 14 patients with classical disease. Most (13/14) patients had increased levels of creatine kinase of up to >25,000 U/L. Moreover, 9 patients out of the 16 with classical disease had evidence of acute renal injury at clinical presentation. Chen et al reported a case of renal Fanconi syndrome developed during the neonatal period and 2 cases of proximal renal tubular acidosis developed later in life.
A few (3/16) patients in the classical group also developed unexplained chronic, severe diarrhea, which improved with metronidazole in one patient. Moreover, all surviving patients with classical disease showed liver echogenicity, which was consistent with steatohepatitis or hepatomegaly. No patient developed pancreatitis, but few developed gallstones (n=2) or liver fibrosis (n=1) later in life.
The management of CACTD patients is challenging. In Ryder et al’s experience, patients tend to respond well to treatment with high rates of glucose infusion during acute decompensation.
“Early detection and standard treatment with high rates of [intravenous] dextrose and [medium chain triglyceride] feeds may allow survival of the initial insult but long-term survival outcomes are suboptimal using current treatment strategies,” they wrote.
Findings from their study’s cohort pointed to a potential benefit of using greater energy delivery from sources such as proteins, D,L-3-hydroxybutyrate, and triheptanoin, but additional studies are still required. In contrast, prolonged fasting might lead to acute energy deficit, which frequently results in sudden cardiac death.
In conclusion, Ryder et al suggest that “Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation.”
Ryder B, Inbar-Feigenberg M, Glamuzina E, et al. New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches. J Inherit Metab Dis. 2021;44(4):903-915. doi:10.1002/jimd.12371
Chen M, Cai Y, Li S, et al. Late-onset carnitine–acylcarnitine translocase deficiency with SLC25A20 c.199-10T>G variation: case report and pathologic analysis of liver biopsy. Front Pediatr. 2020;8:585646. doi:10.3389/fped.2020.585646