Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

Abstract

Could 10–20% of autism be prevented? We hypothesize that nonsyndromic or “essential” autism involves extreme male bias in infants who are genetically normal, but they develop deficiency of carnitine and perhaps other nutrients in the brain causing autism that may be amenable to early reversal and prevention. That brain carnitine deficiency might cause autism is suggested by reports of severe carnitine deficiency in autism and by evidence that TMLHE deficiency – a defect in carnitine biosynthesis – is a risk factor for autism. A gene on the X chromosome (SLC6A14) likely escapes random X-inactivation (a mixed epigenetic and genetic regulation) and could limit carnitine transport across the blood-brain barrier in boys compared to girls. A mixed, common gene variant-environment hypothesis is proposed with diet, minor illnesses, microbiome, and drugs as possible risk modifiers. The hypothesis can be tested using animal models and by a trial of carnitine supplementation in siblings of probands. Perhaps the lack of any Recommended Dietary Allowance for carnitine in infants should be reviewed.

The association between newborn screening analytes and childhood autism in a Texas Medicaid population, 2010–2012

“…The suggestive findings for acylcarnitine analytes/ratios at birth are consistent with a growing body of literature linking mitochondrial disorders, propionic acidemia, and carnitine‐related compounds/pathways with ASD in rodents and patients (Beaudet, ; Celestano‐Soper et al, 2012; Frye, Melnyk, & Macfabe, ; Legido, Jethva, & Goldenthal, ; Longo, Frigeni, & Pasquali, ; Mostafa & Al‐Ayadhi, ; Rossignol & Frye, ; Rossignol et al, ; Witters et al, ; Xie, Jones, Deeney, Hur, & Bankaitis, ; Ziats et al, ). More specifically, carnitine deficiency (particularly in the brain) and genetic defects in carnitine synthesis and transport have been linked to autism (Beaudet, ; Ziats et al, ). Among the five significant acylcarnitine analytes or acylcarnitine ratios in the current study, two (methylmalonylcarnitine and adipylcarnitine, both of them analytes of inorganic acid disorders) were inversely associated with ASD.…”

Gene and environment interactions in autism risk: Reflections on the carnitine deficiency hypothesis by Beaudet (Comment on DOI 10.1002/bies.201700012)

“…Collectively, these studies support the conclusion of others that certain genetic anomalies (i.e., glutamatergic signaling and carnitine biosynthesis) may carry significance in ASD risk . However, these studies point to rare SNPs or inborn genetic errors, and given that no single gene has been identified in the preponderance of ASD cases, it is important to identify environmental exposures that may mimic or otherwise amplify the effects of these genetic variants to increase susceptibility to neurodevelopmental impairment.…”

“…Regardless, researchers have pinpointed many genetic variations , including genes involved in carnitine biosynthesis and glutamatergic transmission, which may augment susceptibility to neurodevelopmental disorders like ASD. Beaudet put forward the hypothesis that an inactive copy of the TMLHE gene may contribute to an insufficient endogenous supply of carnitine, thereby increasing ASD risk. I argue here that these genetic variants may increase ASD risk, not directly, but by compromising endogenous mechanisms required to mitigate the effects of environmental exposures that I have previously implicated in ASD etiology and related neuropathology.…”

“…N 2 O exposure is known to antagonize NMDA receptor activation, thus simulating many of the downstream signaling deficits attributed to specific, rare genetic variants in ASD . Moreover, I have highlighted how low dose N 2 O exposure may enhance opioidergic activity through induction of central dynorphin release, an endogenous ligand of the kappa opioid receptor (KOR), and contribute to altered behavioral stereotypy, abnormal gait, socio‐communicative deficits, as well as synesthesia experiences in ASD .…”

Metabolic etiologies in West syndrome

“…Carnitine deficiency may result in loss of these protective effects. In addition, the link between PCD and autism is investigated …”