New insights into carnitine‐acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches

Ryder, Bryony; Inbar‐Feigenberg, Michal; Glamuzina, Emma; Halligan, Rebecca; Vara, Roshni; Elliot, Aoife; Coman, David; Minto, Tahlee; Lewis, Katherine; Schiff, Manuel; Vijay, Suresh; Akroyd, R. M. D.; Thompson, Sandra A.; MacDonald, Anita; Woodward, Abigail J M; Gribben, Joanne E L; Grünewald, Stéphanie; Belaramani, Kiran; Hall, Madeleine; Haak, Natalie van der; Devanapalli, Beena; Tolun, Adviye A.; Wilson, Callum; Bhattacharya, Kaustuv

doi:10.1002/jimd.12371

Cited by 12 publications

(18 citation statements)

References 43 publications

(143 reference statements)

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“…There were two patients, 10 years and 16 months of age at the time of the publications who were compound heterozygous for the c.326 + 1delG variant in SLC25A20. Their phenotype was similar to our patient's phenotype [5]. Our sibling pair with CACT deficiency was compound heterozygous for the known p.Asn300Glnfs*24 variant in SLC25A20.…”

Section: Discussionsupporting

confidence: 79%

“…The Research Ethics Office, Health Research Ethics Board, University of Alberta (Study ID: Pro00108842) approved this retrospective cohort study. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).…”

Section: Supplementary Informationmentioning

confidence: 99%

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Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic

Ambrose

Sheehan

Bahl

et al. 2022

Orphanet J Rare Dis

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Background: Mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects are a group of inherited metabolic diseases. We performed a retrospective cohort study to report on the phenotypic and genotypic spectrum of mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects as well as their treatment outcomes. Methods:All patients with mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were included. We divided patients into two groups to compare outcomes of those treated symptomatically (SymX) and asymptomatically (AsymX). We reviewed patient charts for clinical features, biochemical investigations, molecular genetic investigations, cardiac assessments, neuroimaging, treatments, and outcomes.Results: There were 38 patients including VLCAD (n = 5), LCHAD (n = 4), CACT (n = 3), MAD (n = 1), CPT-I (n = 13), CPT-II (n = 3) deficiencies and CTD (n = 9). Fourteen patients were diagnosed symptomatically (SymX), and 24 patients were diagnosed asymptomatically (AsymX). Twenty-eight variants in seven genes were identified in 36 patients (pathogenic/likely pathogenic n = 25; variant of unknown significance n = 3). Four of those variants were novel. All patients with LCHAD deficiency had the common variant (p.Glu474Gln) in HADHA and their phenotype was similar to the patients reported in the literature for this genotype. Only one patient with VLCAD deficiency had the common p.Val283Ala in ACADVL. The different genotypes in the SymX and AsymX groups for VLCAD deficiency presented with similar phenotypes. Eight patients were treated with carnitine supplementation [CTD (n = 6), CPT-II (n = 1), and MAD (n = 1) deficiencies]. Thirteen patients were treated with a long-chain fat restricted diet and MCT supplementation. A statistically significant association was found between rhabdomyolysis, and hypoglycemia in the SymX group compared to the AsymX group. A higher number of hospital admissions, longer duration of hospital admissions and higher CK levels were observed in the SymX group, even though the symptomatic group was only 37% of the study cohort. Conclusion:Seven different mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were present in our study cohort. In our clinic, the prevalence of mitochondrial long-chain fatty acid oxidation and carnitine defects was 4.75%.

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Section: Discussionsupporting

confidence: 79%

Section: Supplementary Informationmentioning

confidence: 99%

Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic

Ambrose

Sheehan

Bahl

et al. 2022

Orphanet J Rare Dis

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“…This may be related to the less residual enzyme activity and the increased accumulation of carnitine-acylcarnitine ( 33 , 34 ). In our study, CACT deficiency due to the c.199–10T > G variation is a severe phenotype with a significantly higher mortality, arrhythmia, seizures, and hyperammonemia incidence than other variations, while CACT deficiency caused by the c.82G > T mutation is associated with milder phenotype ( 5 ). The most frequent mutation was a splicing site variation of c.199–10T > G.…”

Section: Discussionmentioning

confidence: 59%

“…CACT deficiency, encoded by the SLC25A20 gene on chromosome 3p21.31, is the cause of this condition ( 4 ). To shuttle long-chain fatty acids through the inner mitochondrial membrane and into the mitochondrial matrix, where mitochondrial β-oxidation takes place, CACT is an essential part of the carnitine cycle ( 5 ). Mitochondrial β-oxidation serves as the primary energy source for cardiac and skeletal muscles, while ketogenesis in the liver fuels brains tissue during prolonged fasting and exercise ( 1 , 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency

Shen²

2022

Front. Pediatr.

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BackgroundCarnitine-acylcarnitine translocase deficiency (CACT deficiency) is a rare and life-threatening autosomal recessive disorder of mitochondrial fatty acid oxidation caused by variant of SLC25A20 gene. The most prevalent missense variant in the SLC25A20 gene in Asia was c.199–10T > G. Due to the c.199–10T > G variant, CACT deficiency is a severe phenotype.Materials and MethodsHerein, we present a neonatal case with c.199–10T > G variant in China and analyze the clinical, biochemical, and genetic aspects of 78 patients previously identified with CACT deficiency.ResultsThe patient presented with a series of severe metabolic crises that rapidly deteriorated and eventually died 3 days after delivery. The sequencing of the patient's genome indicated that he was homozygous for the c.199–10T > G variant. 30 patients were found to have the c.199–10T > G mutation, of which 23 were Chinese and 22 were afflicted by the c.199–10T > G splicing variation. In China, c.199–10T > G allele frequency was 82.6%.ConclusionIn CACT deficiency, prompt recognition and treatment are critical. Our data suggested that c.199–10T > G may be a potential hotspot SLC25A20 gene mutation in the Chinese population. Detection of single nucleotide polymorphism is possible for high-risk patients and parents in China.

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“…As a consequence, the role of 3-HMG, 3-MGL, and 3-HIVA in the pathophysiology of these disorders must be better defined [ 8 , 31 , 34 , 35 ]. Traditionally, the hyperammonemia in organic acidemias has been thought to arise from inhibition of N-acetylglutamate synthase but may also arise from insufficiency of Krebs cycle intermediates, favoring α-ketoglutarate production from glutamate [ 36 , 37 , 38 ]. The Reye Syndrome phenotype is more typically associated with fat oxidation disorders, and this could arise from ketone body synthetic insufficiency in the context of hypoglycemia [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases

Thompson

Hertzog²,

Selvanathan³

et al. 2023

Nutrients

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3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. A retrospective chart and literature review of Australian patients over their lifespan, incorporating acute and long-term dietary management, was performed. Data from 10 patients contributed to this study. The index case of this disorder was lost to follow-up, but there is 100% survival in the remainder of the cases despite several having experienced life-threatening episodes. In the acute setting, five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids (delivering glucose above estimated basal utilization requirements). All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. Most patients take L-carnitine. Three children and none of the adults take nocturnal uncooked cornstarch. Of the cohort, there were two patients that presented atypically—one with fulminant liver failure and the other with isolated developmental delay. Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder.

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New insights into carnitine‐acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches

Cited by 12 publications

References 43 publications

Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic

Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic

One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency

Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases

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