Autism Spectrum Disorders and Inborn Errors of Metabolism: An Update

Abstract

Background

Autism spectrum disorder is characterized by social communicative deficits with restricted interests occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems, such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these conditions.

Method

A computer-assisted search was performed to identify the most common inborn errors of metabolism associated with autism.

Results

The following disorders were identified: phenylketonuria, glucose-6-phosphatase deficiency, propionic acidemia, adenosine deaminase deficiency, Smith–Lemli–Opitz syndrome and mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deficiency.

Conclusion

The risk of autistic features is increased in children with inborn errors of metabolism, especially in the presence of cognitive and behavioral deficits. We propose that affected children should be screened for autism.

Introduction

Autism spectrum disorder (ASD) is a behavioral syndrome characterized by social communication deficits with rigid restricted interests, occurring in about 1% of the population.1, 2 Although ASD and autism are often used interchangeably, the former more correctly refers to a group of disorders of varying degrees of severity. At least 10% of patients with ASD suffer from comorbid disorders, such as tuberous sclerosis and fragile X syndrome.³

ASD can also occur with inborn errors of metabolism, sometimes referred to as inherited metabolic disorders, which occur in 1 in 800 live births.⁴ These conditions, which have become increasingly important because of the progress made in their diagnosis and management,⁵ occur when an enzyme or a transport protein deficiency causes a block in a metabolic pathway resulting either in a harmful accumulation of the substrate behind the block or in a deficiency of the product. They can be divided into acute and chronic categories. The former group usually begins in the first 2-3 years of life and may present in metabolic crisis (intoxication), whereas the latter may come to medical attention at any time and have a more insidious course. Metabolic disorders with intoxication often present with acute encephalopathy associated with acidosis, hyperammonemia, and/or hypoglycemia.⁵ Several behavioral and neuropsychiatric abnormalities can occur in children with metabolic disorders.⁶ These stem from the involvement of the central nervous system and include learning disability, social deficits, hyperactivity, aggression, catatonia, psychosis, and depression.⁷ Because most metabolic disorders are autosomal recessive,⁸ they are more common in countries with high rates of consanguinity, where they are associated with a significant degree of morbidity and mortality.⁹

Increased awareness of both autism and of inherited metabolic disorders has increased the focus on the comorbidity between them. Although, the exact rate of autism in patients with inherited metabolic disorders is not known, the rate of the latter in patients with autism is said to be around 2%. For example, in a study of 222 Greek children with autism, 2.7% suffered from a metabolic disorder.¹⁰ However, given that the correct diagnosis of an inborn error of metabolism requires both clinical and technological expertise, this figure is probably closer to 5%.¹¹

There have been no recent reviews of the association of autism with metabolic disorders since the last review by Manzi and colleagues.¹² Since then, several new reports have described the occurrence of autism in patients with inherited metabolic disorders. For example, a novel metabolic entity (branched chain ketoacid dehydrogenase kinase deficiency) was recently described in multiple consanguineous families with autism, epilepsy, and intellectual disability.¹³ The aim of this review is to describe the association between the two conditions with particular reference to publications since the review by Manzi et al.¹²