Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

Goetzman, Eric S.

doi:10.1007/s40142-017-0125-6

Cited by 20 publications

(23 citation statements)

References 102 publications

(95 reference statements)

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“…Countless environmental exposures and triggers have been shown to modify the fatty acid oxidation pathway, including the use of statins and nutritional supplements, aspirin, or viral infection. 64 Depending on the pathogenic variant and genes involved, such factors can modify residual fatty acid oxidation and/or trigger symptoms. Distinct combinations of environmental exposures and pathogenic variants have the potential to interact differently, making it challenging to definitively identify genotype–phenotype correlations, especially given the small patient population with FAODs.…”

Section: Genotypic and Phenotypic Spectrum Of Faodmentioning

confidence: 99%

Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders

Marsden

Bedrosian

Vockley

2021

Genetics in Medicine

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Fatty acid oxidation disorders (FAODs) are potentially fatal inherited disorders for which management focuses on early disease detection and dietary intervention to reduce the impact of metabolic crises and associated spectrum of clinical symptoms. They can be divided functionally into long-chain (LC-FAODs) and medium-chain disorders (almost exclusively deficiency of medium-chain acyl–coenzyme A dehydrogenase). Newborn screening (NBS) allows prompt identification and management. FAOD detection rates have increased following the addition of FAODs to NBS programs in the United States and many developed countries. NBS-identified neonates with FAODs may remain asymptomatic with dietary management. Evidence from numerous studies suggests that NBS-identified patients have improved outcomes compared with clinically diagnosed patients, including reduced rates of symptomatic manifestations, neurodevelopmental impairment, and death. The limitations of NBS include the potential for false-negative and false-positive results, and the need for confirmatory testing. Although NBS alone does not predict the consequences of disease, outcomes, or management needs, subsequent genetic analyses may have predictive value. Genotyping can provide valuable information on the nature and frequency of pathogenic variants involved with FAODs and their association with specific phenotypes. Long-term follow-up to fully understand the clinical spectrum of NBS-identified patients and the effect of different management strategies is needed.

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Section: Genotypic and Phenotypic Spectrum Of Faodmentioning

confidence: 99%

Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders

Marsden

Bedrosian

Vockley

2021

Genetics in Medicine

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“…Further research investigated other tissues such as skeletal muscle, which also can be profoundly affected by potentially life-threatening complications, such as rhabdomyolysis. Additional organ systems whose dysfunction generally is not life threatening are included in Table 2 [41][42][43][44][45][46][47][48][49][50][51][52]…”

Section: Clinical Manifestations Of Faodmentioning

confidence: 99%

Clinical manifestations and management of fatty acid oxidation disorders

Merritt

MacLeod

Jurecka

et al. 2020

Rev Endocr Metab Disord

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Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy–requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities.

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“…Therapies to overcome deficit in ACSL5 function are currently unknown and were not assessed in this research. In humans, therapies for disorders disrupting lipid digestion and absorption, involve removing lipids from the diet or replacing them with those that bypass the genetic block 61 , 62 . The disorder described in this study chiefly impacts the metabolism of LCFA.…”

Section: Discussionmentioning

confidence: 99%

A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed

O’Brien

Beijerink

Sansom³

et al. 2020

Sci Rep

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Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (Praw = 2.87E−06) was discovered and validated in a closely related population (Praw = 1.75E−45). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.

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Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

Cited by 20 publications

References 102 publications

Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders

Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders

Clinical manifestations and management of fatty acid oxidation disorders

A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed

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