A potential pathogenic role of oxalate in autism

doi:10.1016/j.ejpn.2011.08.004

European Journal of Paediatric Neurology

Volume 16, Issue 5, September 2012, Pages 485-491

https://doi.org/10.1016/j.ejpn.2011.08.004 Get rights and content

Abstract

Background

Although autistic spectrum disorders (ASD) are a strongly genetic condition certain metabolic disturbances may contribute to clinical features. Metabolism of oxalate in children with ASD has not yet been studied.

Aim

The objective was to determine oxalate levels in plasma and urine in autistic children in relation to other urinary parameters.

Method

In this cross-sectional study, plasma oxalate (using enzymatic method with oxalate oxidase) and spontaneous urinary calcium oxalate (CaOx) crystallization (based on the Bonn-Risk-Index, BRI) were determined in 36 children and adolescents with ASD (26 boys, 10 girls) aged 2–18 years and compared with 60 healthy non-autistic children matched by age, gender and anthropometric traits.

Results

Children with ASD demonstrated 3-fold greater plasma oxalate levels [5.60 (5th–95th percentile: 3.47–7.51)] compared with reference [(1.84 (5th–95th percentile: 0.50–4.70) μmol/L (p < 0.05)] and 2.5-fold greater urinary oxalate concentrations (p < 0.05). No differences between the two groups were found in urinary pH, citraturia, calciuria or adjusted CaOx crystallization rates based on BRI. Despite significant hyperoxaluria no evidence of kidney stone disease or lithogenic risk was observed in these individuals.

Conclusions

Hyperoxalemia and hyperoxaluria may be involved in the pathogenesis of ASD in children. Whether this is a result of impaired renal excretion or an extensive intestinal absorption, or both, or whether Ox may cross the blood brain barrier and disturb CNS function in the autistic children remains unclear. This appears to be the first report of plasma and urinary oxalate in childhood autism.

Introduction

The autism spectrum disorders (ASD), including classical autism, are regarded as a group of complex developmental disorders associated with life-long disability, of which prevalence during growth is considerably greater than previously thought.¹ This may reflect an increasing incidence of this condition.2, 3 Despite decades of research and high level of evidence, the etiology of ASD remains unclear, and biological causes are poorly understood.4, 6

Research has emphasized that ASD is strongly a genetic disorder.1, 4, 7, 8, 9 A wide range of abnormalities in central nervous system has been reported in autistic patients, including changes in brain size and reduced neurons in certain specific brain regions,6, 10, 11, 12, 13 and at least some of these features may be due to earlier deterioration of brain formation.¹³ Various theoretical approaches to autism have been discussed. Independent of the genetic background, a number of additional pathways, interactions between genetic and environmental factors and also co-morbidities have been reported in autism, including advanced maternal age and parity,¹⁴ environmental contribution to the condition, altered neurochemistry (in particular high peripheral serotonin levels), immunoexcitotoxic mechanisms, altered oxidative–reductive capacity, disturbed sulfur chemistry and behavioral symptoms, food allergies, intestinal dysbiosis, recurrent infections and possible altered immune response.1, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Among others, a high prevalence of gastrointestinal symptoms is frequently reported in ASD children which may be alleviated using dietary intervention or elimination diet.¹⁷ Some hypotheses appear regarding the pathogenic role of nutrients or trace elements in ASD, however, the level of evidence is not sufficient. The alterations in nutritional metabolism in the development of childhood ASD have been widely studied but the results are conflicting.

Metabolism of oxalate in children with autism has not been confirmed by laboratory tests. Thus, we hypothesized that oxalate may contribute to, or at least play a role in neuropsychiatric damage and behavioral dysfunction in ASD. The objective of this study was to determine oxalate levels in plasma and urine in children with autism in relation to other urinary parameters (calciuria, citraturia) and spontaneous urinary calcium oxalate crystallization.

Section snippets

Study participants

The study was conducted in 36 Caucasian children and adolescents with autism (26 boys, 10 girls) aged 2–18 years (median 5.6 yrs; 5th percentile – 2.4 and 95th percentile – 14.6). These patients were recruited from different specialized centers, including our teaching hospital, and were followed in the departments and clinics (developmental neuropsychology, psychiatry, gastroenterology, metabolic, pediatric nephrology) of the University Children’s Hospital in Bialystok (Poland). They presented

Methods

Oxalate levels were determined in blood plasma samples after a night break without taking food (10–12 h) using enzymatic method with oxalate oxidase derived from 10-days old barley seedling adding oxalate to stabilize the endogenous plasma oxalate.²⁸ This method has been previously validated in children and has provided a comprehensive reference database.²⁹

In this study, spontaneous urinary calcium oxalate (CaOx) crystallization was assessed with the Bonn-Risk-Index (BRI) using the method by

Results

The plasma oxalate levels were found to be 3-fold greater in the autistic children [5.60 (5th–95th percentile: 3.47–7.51)] compared with reference [1.84 (5th–95th percentile: 0.50–4.70) μmol/L (p < 0.05)]. Our results showed that children with autism demonstrated over 2.5-fold greater urinary oxalate levels compared with healthy peers: 1.07 (5th–95th percentile: 0.48–2.14) mmol/1.73m²/24 h vs. 0.41 (5th–95th percentile: 0.11–0.46) mmol/1.73m²/24 h (p < 0.05). Patients with autism had also a

Discussion

The complex and multifactorial etiology of early neurodevelopmental damage in ASD is an essential issue in the consideration of the disease and, so far, there is no consensus about the neurological pathophysiology of ASD.³² Multiple combinations of genes are now being proposed to lead to the underlying mechanisms of autistic phenotype, and these combinations of genes may contribute to metabolic disorders found in children with ASD and be responsible for clinical symptoms.33, 34 Nevertheless,

Conclusions

In summary, hyperoxalemia and hyperoxaluria may be involved in the pathology of autistic spectrum disorders in children, although data is insufficient to determine its relevance, if at all, to pathogenesis. Some treatment options such as low oxalate diets, probiotic treatment (e.g. with Oxalobacter formigenes), supplementation with recombinant enzymes, modification of intestinal oxalate secretion or perhaps oxalate binding treatments may be helpful in these children. Whether improvement of

Acknowledgments

The two first authors (JK and TP) contributed equally to this work.

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We were unable to find reports describing other crystal-related brain conditions and their consequences on the brain. A recent paper by Konstantynowicz et al. speculated that hyperoxalemia and hyperoxaluria may be involved in the pathology of autistic spectrum disorders in children.6 Renal failure is considered the main clinical feature of PH type I. US is a remarkable detector of abnormalities and deposition of oxalate in kidneys and other organs.
Genetic deficiencies in enzymes involved in glyoxylate metabolism lead to primary hyperoxaluria (PH) type I, typically characterized by deposition of oxalate crystals in kidneys. A 2-month-old infant was admitted, and was diagnosed with renal failure. Abdominal ultrasound images revealed enlarged and hyperechoic kidneys. Additionally, on cerebral ultrasound (CUS) hyperechoic changes of thalami and basal ganglia were noted, reminiscent of perinatal hypoxic-ischemic brain damage. However, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, in particular putamen, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts. Moreover, macular crystals were detected at ophthalmoscopy. Our case report shows the potential of US imaging to detect deposition of crystals not only in kidneys but also in brain mimicking, perinatal asphyxia.

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Original articleA potential pathogenic role of oxalate in autism

Abstract

Background

Aim

Method

Results

Conclusions

Introduction

Section snippets

Study participants

Methods

Results

Discussion

Conclusions

Acknowledgments

Lancet

Lancet

Am J Hum Genet

Int J Dev Neurosci

J Pediatr

J Pediatr

Lancet

Lancet

Biol Psychiatry

Semin Nephrol

Toxicol Appl Pharmacol

Prostaglandins Leukot Essent Fatty Acids

Biol Psychiatry

Neuropsychopharmacology

J Urol

Endocrinol Metab Clin North Am

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Leg Med (Tokyo)

Epidemiology of autistic disorder and other pervasive developmental disorders

J Clin Psychiatry

What’s new in autism?

Eur J Pediatr

Neuropsychology of autism: a report on the state of the science

J Autism Devel Disord

Autism, regression, and the broader autism phenotype

Am J Med Genet

Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism

Am J Med Genet B Neuropsychiatr Genet

Minicolumnar pathology in autism

Neurology

Brain structural abnormalities in young children with autism spectrum disorder

Neurology

Neuropathological findings in autism

Brain

Original article
A potential pathogenic role of oxalate in autism