Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

Strandqvist, Anna; Haglind, Charlotte Bieneck; Zetterström, Rolf; Németh, Antal; Döbeln, Ulrika von; Stenlid, Maria Halldin; Nordenström, Anna

doi:10.1007/8904_2015_505

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…Mitochondrial β-oxidation defects may be secondary to dysfunction of dependent processes, such as deficiencies of the carnitine fatty acid transporter system, or mitochondrial electron transfer flavoprotein system (multiple acyl-CoA dehydrogenase deficiency) (40). The occurrence of developmental delay, autistic-like behavior or ASD in genetic defects of mitochondrial β-oxidation (41) particularly VLCAD (42) and LCHAD (43) suggests that impaired mitochondrial β-oxidation may contribute to dysfunctional energetic metabolism in subsets of patients with ASD. Deletion of the TMLHE gene, which is the first step in carnitine synthesis pathway and located on the X chromosome, is found more often in males with non-dysmorphic autism suggesting that TMLHE deficiency is a risk factor for autism, albeit with low penetrance (estimated at 2–4%) (44).…”

Section: Discussionmentioning

confidence: 99%

A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses

et al. 2018

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Autism spectrum disorder (ASD) is currently diagnosed according to behavioral criteria. Biomarkers that identify children with ASD could lead to more accurate and early diagnosis. ASD is a complex disorder with multifactorial and heterogeneous etiology supporting recognition of biomarkers that identify patient subsets. We investigated an easily testable blood metabolic profile associated with ASD diagnosis using high throughput analyses of samples extracted from dried blood spots (DBS). A targeted panel of 45 ASD analytes including acyl-carnitines and amino acids extracted from DBS was examined in 83 children with ASD (60 males; age 6.06 ± 3.58, range: 2–10 years) and 79 matched, neurotypical (NT) control children (57 males; age 6.8 ± 4.11 years, range 2.5–11 years). Based on their chronological ages, participants were divided in two groups: younger or older than 5 years. Two-sided T-tests were used to identify significant differences in measured metabolite levels between groups. Näive Bayes algorithm trained on the identified metabolites was used to profile children with ASD vs. NT controls. Of the 45 analyzed metabolites, nine (20%) were significantly increased in ASD patients including the amino acid citrulline and acyl-carnitines C2, C4DC/C5OH, C10, C12, C14:2, C16, C16:1, C18:1 (P: < 0.001). Näive Bayes algorithm using acyl-carnitine metabolites which were identified as significantly abnormal showed the highest performances for classifying ASD in children younger than 5 years (n: 42; mean age 3.26 ± 0.89) with 72.3% sensitivity (95% CI: 71.3;73.9), 72.1% specificity (95% CI: 71.2;72.9) and a diagnostic odds ratio 11.25 (95% CI: 9.47;17.7). Re-test analyses as a measure of validity showed an accuracy of 73% in children with ASD aged ≤ 5 years. This easily testable, non-invasive profile in DBS may support recognition of metabolic ASD individuals aged ≤ 5 years and represents a potential complementary tool to improve diagnosis at earlier stages of ASD development.

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Section: Discussionmentioning

confidence: 99%

A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses

et al. 2018

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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%

“…The underlying mechanisms associated with the development of neurological and neuropsychological disorders secondary to FAOD remain unclear. However, it is known that energy deficiencies, unmetabolized intermediates, and docosahexaenoic acid deficiencies can all hinder brain development and may lead to some or all of the cognitive damage associated with these observed outcomes [50]. Importantly, LC-FAOD can also be associated with low docosahexaenoic acid levels due to dietary over-restrictions.…”

Section: Pathophysiologymentioning

confidence: 99%

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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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“…Carnitine biosynthesis is therefore sensitive to iron homeostasis. Clinical evidence to support this contention derives from studies where reduced serum carnitine levels are routinely detected in children suffering from iron deficiency anemias (60,61). Regarding NSC carnitine malnutrition, fetal iron deficiency follows maternal iron deficiency, and this syndrome is common.…”

Section: Tmlhe Mutations and The Phenotypic Penetrance Paradoxmentioning

confidence: 99%

The neural stem cell/carnitine malnutrition hypothesis: new prospects for effective reduction of autism risk?

Bankaitis

Xie

2019

Journal of Biological Chemistry

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Autism spectrum disorders (ASDs) are developmental neuropsychiatric disorders with heterogeneous etiologies. As the incidence of these disorders is rising, such disorders represent a major human health problem with escalating social cost. Although recent years witnessed advances in our understanding of the genetic basis of some dysmorphic ASDs, little progress has been made in translating the improved understanding into effective strategies for ASD management or minimization of general ASD risk. Here we explore the idea, described in terms of the neural stem cell (NSC)/carnitine malnutrition hypothesis, that an unappreciated risk factor for ASD is diminished capacity for carnitine-dependent long-chain fatty acid ␤-oxidation in neural stem cells of the developing mammalian brain. The basic premise is that fetal carnitine status is a significant metabolic component in determining NSC vulnerability to derangements in their self-renewal program and, therefore, to fetal ASD risk. As fetal carnitine status exhibits a genetic component that relates to de novo carnitine biosynthesis and is sensitive to environmental and behavioral factors that affect maternal circulating carnitine levels, to which the fetus is exposed, we propose that reduced carnitine availability during gestation is a common risk factor that lurks beneath the genetically complex ASD horizon. One major prediction of the NSC/carnitine malnutrition hypothesis is that a significant component of ASD risk might be effectively managed from a public policy perspective by implementing a carnitine surveillance and dietary supplementation strategy for women planning pregnancies and for women in their first trimester of pregnancy. We argue that this prediction deserves serious clinical interrogation. Autism spectrum disorders (ASDs) 2 are neurodevelopmental disorders characterized by core symptoms of impaired social interaction and communication and repetitive, restricted behaviors. Other deficits, such as intellectual disabilities and epilepsy, are also frequently on display. ASDs include autism, Asperger syndrome, and pervasive developmental disorder (not otherwise specified) and can be either dysmorphic or nondysmorphic. These disorders already affect 1.5%-3% of young children in the United States, Europe, and Australia. Moreover, ASD management extracts a heavy social cost. Current estimates are that the annual toll of ASD management in the United States alone will exceed $450 billion by the year 2025 (1, 2), and these estimates do not take into account the heavy emotional burden shouldered daily by caretakers of the afflicted. Unfortunately, ASD incidence, whether as a result of increased awareness/diagnosis or genuine increase in disease (3), is still climbing rapidly. Deciphering the mechanisms underlying ASDs and the associated risk factors is therefore an area of intense public and biomedical interest. Although it is generally accepted that ASD etiology includes both genetic and environmental factors (4, 5), effective strategies for treating core symptoms...

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Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

Abstract: Background: Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are scarce. We present results from neuropsy-

Cited by 12 publications

References 32 publications

A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses

A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses

Clinical manifestations and management of fatty acid oxidation disorders

The neural stem cell/carnitine malnutrition hypothesis: new prospects for effective reduction of autism risk?

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