Metabolic Disorders May Underlie Some Diagnosed Autism Cases

Genetic metabolic diseases, such as Sanfilippo syndrome, may underlie an autism spectrum disorder (ASD) diagnosis, especially when accompanied with additional symptoms, according to a case series in Turkey.

The data suggested that 3.3% of ASD cases may have a metabolism-related genetic cause, which in many cases can be attenuated or resolved with appropriate treatment.

It is therefore crucial that clinicians closely and carefully analyze ASD patients’ additional signs and symptoms, as well as their family medical history, to help them decide whether to test for metabolic diseases, the researchers noted.

The study, “Cases of inborn errors of metabolism diagnosed in children with autism,” was published in the journal Clinical Neuroscience.

ASD is a neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive or restrictive behaviors. It is estimated that one in 160 children worldwide and one in 54 in the U.S. have ASD.

Its underlying cause remains uncertain, but research suggests that it results from of a complex combination of genetic, molecular, and environmental factors. In the past decade, an increasing number of studies have shown a link between genetic disorders — including those causing metabolic abnormalities — and ASD.

Sanfilippo syndrome, also called mucopolysaccharidosis (MPS) type III, is one such genetic metabolism disorder that may result in ASD symptoms.

Notably, a previous review study found that the ASD profile in Sanfilippo patients consists of communication and social difficulties, with little evidence of repetitive or restricted behavior. It also suggested that clinicians should consider screening for Sanfilippo syndrome when their patients show ASD symptoms alongside other physical and developmental problems.

Now, researchers at the University of Health Sciences, in Turkey, set out to analyze the frequency and type of genetic metabolism disorders in children and adolescents diagnosed with ASD, followed at a single center.

They retrospectively analyzed the demographic, clinical, and laboratory data of 179 ASD patients with no signs of other underlying genetic/neurological diseases, who applied to their Pediatric Metabolism outpatient clinic between September 2018 and February 2020.

As a result of specific blood and urine metabolic tests, six (3.3%) ASD patients, with ages ranging from 5.5 to 17 years, were diagnosed with genetic metabolism disorders.

Two adolescent boys had classical phenylketonuria (PKU), two other boys were diagnosed with classical homocystinuria (HCU), one girl was diagnosed with Sanfilippo syndrome type D, and one boy had 3- methylcrotonyl Co-A carboxylase (3-MCC) deficiency.

Particularly, the seven-year-old girl with Sanfilippo showed learning disabilities, hyperactivity, and coarse facial features — which prompted the metabolic testing. Further evaluation revealed no eye or heart problems, but the presence of skeletal abnormalities were suggestive of an MPS.

Enzymatic testing showed that the girl, diagnosed with ASD 3.5 years before, had a deficiency in the N-acetylglucosamine-6-sulfatase enzyme, confirming a diagnosis of Sanfilippo type D. Since there are no available targeted therapies for the disease, she was given supportive care for her symptoms.

Notably, four cases, including the girl with Sanfilippo, were born of consanguineou (blood-related) parents, a factor known to increase the risk of genetic metabolic diseases.

For most of these disorders, a child must inherit two mutated copies of a certain gene (one from the mother and one from the father) to develop the disease — a more likely situation when the parents have similar genetic backgrounds. The rate of consanguineous marriage in Turkey is very high, the team noted.

The symptoms in three boys — one with PKU, one with HCU, and one with 3-MCC — lessened after appropriate treatment. In addition, family screening allowed the diagnosis of genetic metabolism disorders in two relatives, with one of them showing a reduction in symptoms after specific treatment.

“Careful evaluation of the history, physical examination and additional findings in patients diagnosed with autism spectrum disorder will guide the clinician in the decision-making process and [in choosing] the appropriate specific metabolic investigation,” the researchers wrote.

Notably, “an underlying inborn error of metabolism may be a treatable cause of autism,” the team wrote.

Among the study’s limitations, the researchers noted that the metabolic testing performed does not cover all metabolic diseases, meaning that some may have been missed in these pediatric patients with ASD. Also, no genetic tests were conducted in the cases diagnosed with genetic metabolism disorders.