Autism and metabolic diseases – more treatable ‘autisms’ hiding in plain sight?

What are inborn errors of metabolism?

Inborn errors of metabolism (IEM), sometimes called inherited metabolic diseases, are rare genetic disorders in which a single genetic mutation affects one or more biochemical pathways, that is, specific sequences of chemical reactions, that are involved in metabolism.

The disorders are usually caused by errors in specific enzymes that help break down parts of food. A food product that is not broken down and converted into energy can become toxic, and can build up in the body over time affecting the functioning of many organs, including the brain.

There are currently over 700 known IEMs, and new ones are being discovered constantly through technological diagnostic advances, and through more widespread use of whole genome sequencing.

The latest estimates show that IEMs occur in approximately 1 in 1000 people.

There are different types of IEMs, according to what types of metabolic process they affect, for example purine and pyrimidine disorders, lysosomal or glycogen storage disorders, organic acidemias, fatty acid oxidation disorders, urea cycle disorders, and many others.

Lots of IEMs cause severe symptoms and can often be fatal, but there are others that cause mild and/or unspecific symptoms that overlap with more common disorders.

“Non-classic or variant-type inborn errors of metabolism may be manifested at any age and may not show all or even any of the features usually associated with the classic descriptions of these disorders. The practitioner must maintain an index of suspicion in the approach to diagnosis of any of these disorders, especially when the patient is out of infancy.” (Chinsky & Steinter 2009)

Signs and symptoms of inborn errors of metabolism

Symptoms of IEMs are often present from birth or early childhood, but in some cases they can become noticeable only much later, in late childhood and even in adult life.

Possible signs in newborns/babies include:

• neonatal seizures
• lethargy
• vomiting
• abnormal breathing
• hypotonia (underdeveloped muscle tone) or hypertonia (overdeveloped muscle tone)
• poor feeding
• failure to thrive
• jaundice
• slow development or developmental regression
• abnormal eye movements
• dysmorphic (abnormal) features of the face and head
• abnormal body or urine odour
• abnormal hair or skin texture

Some symptoms, like dysmorphic facial features, may not be obvious at birth, but they become more pronounced over time.

Later in a child’s life, or even in adolescence or adulthood, some other problems may become more prominent, such as:

• movement and motor difficulties
• intellectual disability
• psychiatric symptoms (such as anxiety or aggression)
• strokes or stroke-like episodes
• seizures or other symptoms triggered by specific activities such as fasting or change in physical activity level.

Inborn errors of metabolism in autism – overlooked symptoms and missed diagnosis?

Autism frequently occurs in some types of inborn errors of metabolism, usually alongside intellectual disability and some degree of motor impairment.

Although it is often estimated that less than 5% of autism is due to underlying metabolic disease, it is possible that some of the cases are being missed and that the true prevalence of IEM in autism could be slightly higher.

A study by Spilioti and colleagues published in 2013 examined 187 Greek children with autism for the presence of metabolic abnormalities. It was discovered that:

“Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%)….Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet.” (Spilioti 2013)

In a recent study by İnci and colleagues the hospital records data of 247 children with autism were examined in order to investigate possible missed cases of IEM. After detailed investigation, six patients were each diagnosed with a previously undiagnosed inborn error of metabolism: phenylketonuria, cerebral creatine deficiency, hypobetalipoproteinemia, glycogen storage disease type IX-a, dihydropyrimidine dehydrogenase deficiency, and succinic semialdehyde dehydrogenase deficiency.

Cakar and Yilmazbas reported similar findings from their investigation. In a group of 179 Turkish patients with autism who presented to their clinic, and as a result of specific metabolic examinations performed, six (3.3%) patients were diagnosed with inborn errors of metabolism. Two  patients were diagnosed with classical phenylketonuria, two with classical homocystinuria, one with mucopolysaccharidosis type 3D (Sanfilippo syndrome) and one with 3-methylchrotonyl Co-A carboxylase deficiency.

Similarly, investigation by Shi and colleagues published in 2019 revealed that out of 277 Chinese children with autism, over 5% were suffering from an underlying, previously missed metabolic disorder:

“Three cases of phenylketonuria, one case of homocysteinemia, one case of propionemia, one case of methylmalonic acidemia, one case of glutaric acidemia, one case of isovaleric acidemia, one case of argininemia, one case of citrullinemia I and four cases of primary carnitine deficiency were confirmed by genetic testing, which yielded an overall diagnostic rate of 5.1% (14/277). … Our result has provided further evidence for the co-occurrence of ASD and IEM. Tandem mass spectrometry has a great value for the diagnosis and treatment of ASD in childhood.” (Shi et al. 2019)

“Currently, the patient can share a smile, has good eye contact, and understands gestures. She has interest in peers and maintains social interaction (this interaction was previously brief and inappropriate)” (Marquez‑Caraveo et al. 2020)

The authors noted however that one limitation of their study was that the screening test that was used here  

only allowed the detection of amino acid diseases, organic acidemias and fatty acid oxidation disorders. Other IEMs involving large molecules (such as lysosomal disorders) that could be the cause of neurodevelopmental symptomatology were not included, and therefore ‘the number of cases with other IEMs may be even greater.’

Phenylketonuria (PKU) is an inherited metabolic disorder in which amino acid called phenylalanine cannot be broken down by the normal metabolic processes and instead builds up in the body. High levels of phenylalanine can damage the central nervous system and cause intellectual disability, seizures, anxiety, depression and behavioural problems.

Although the exact prevalence rate of autism in PKU is unknown, the relationship between autism and PKU is well documented, and it is thoughts that the toxic levels of phenylalanine play a significant role in the development of autism symptomatology.

Numerous published case reports and case series studies have repeatedly revealed late diagnosis and/or untreated PKU causing autism-related symptoms. In most cases those patients would show reduction in autism symptoms and improved mental functioning after commencing a PKU-specific, low-phenylalanine diet.

“The possibility of a metabolic disorder including PKU should be considered in any child presenting with symptoms of autism, learning or speech problems and PKU should be tested unless the newborn screening results are available. Even late diagnosed patients benefit from a restricted diet, as in this case who might have had a milder form of PKU and achieved normal school performance.” (Yıldız et al. 2020)

“This case illustrates that because the majority of autism cases are idiopathic, an occasional patient with a metabolic disorder might be overlooked especially in the era of newborn screening. We also…wish to draw attention to the possibility of cases missed in the screening program because of less than 100% coverage or insufficient food intake before blood sampling. Clinicians should keep in mind the possibility of treatable disorders in children with autism even when such disorders appear unlikely.” (Mazlum et al. 2016)

In addition to PKU, another type of IEM that has been reported to be a missed cause of autism in children is creatine transporter deficiency, or brain creatine deficiency.

A case study published in 2018 reported a case of creatine transporter deficiency (CDT) in two brothers with Autism Spectrum Disorder, diagnosed when the brothers were aged 17 and 12. The authors report that both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine upon CDT diagnosis, which partially improved their behavioral and autism-related symptoms.

“Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify Creatine Transporter Deficiency in children with autistic behavior and language disorders.” (Aydin 2018)

“Cerebral creatine deficiency should be included in the differential diagnosis in children with autistic symptoms, seizures, movement disorders, developmental delay, and language impairment.” (Yildiz et al. 2020)

Some of the other IEMs with frequently occurring autism symptoms include:

• disorders of branched-chain amino acids
• biotinidase deficiency, mitochondrial disorders (e.g. mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes—MELAS syndrome)
• disorders of folate transport and metabolism (cerebral folate deficiency, methylenetetrahydrofolate reductase deficiency)
• urea cycle disorders, disorders in purine metabolism (adenosine deaminase deficiency, adenylosuccinate lyase deficiency, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies)
• organic acidurias (such as propionic academia, 3-methylcrotonyl-CoA carboxylase deficiency and pyridoxine dependency)
• succinic semialdehyde dehydrogenase deficiency
• glucose 6-phosphate dehydrogenase deficiency
• lysosomal storage disorders (Niemann-Pick disease type C, Sanfilippo syndrome, neuronal ceroid lipofuscinoses)
• brain iron accumulation diseases
• disorders of copper metabolism (Wilson disease).

For a more comprehensive list see paper ‘Inborn Errors of Metabolism Associated With Autism Spectrum Disorders: Approaches to Intervention’ by Zigman et al.)

It should be noted that the IEM with the highest incidence of autism is Smith-Lemli-Opitz syndrome (SLOS), which is caused by an abnormality in cholesterol metabolism. SLOS is characterized by distinctive facial features, growth restriction, intellectual disability, small head size (microcephaly), feeding and gastrointestinal issues, and behavioral problems (irritability, sensory hyperreactivity, sleep disturbances). About half of children with SLOS also have autism. Dietary therapy and cholesterol supplementation often lead to developmental, cognitive and behavioural improvements in these children.

Testing and diagnosis

Many IEMs are tested for routinely at birth, but the precise number and types of tests, and the number of IEMs that are targeted through those tests, varies from country to country.

In the UK babies are screened at birth for only six IEMs, or inherited metabolic diseases. These are:

• phenylketonuria (PKU)
• medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
• maple syrup urine disease (MSUD)
• isovaleric acidaemia (IVA)
• glutaric aciduria type 1 (GA1) and
• homocystinuria (pyridoxine unresponsive) (HCU)

Some, but not all, IEMs can be accompanied by structural brain anomalies and/or by specific EEG changes. Brain MRI can sometimes aid the correct diagnosis of an IEM, or it can be used to flag a possible issue and signpost towards more detailed urine/blood/genetic tests.

In the absence of, or before a full genetic screening, abnormal values in the following metabolic tests can raise suspicion of IEM:

• Acidosis
• Respiratory alkalosis
• Hypoglycemia
• Elevated or low-absent urine ketones
• Urine reducing substances (in absence of glucosuria)
• Hyperammonemia
• Low blood urea nitrogen (especially with appearance of dehydration)
• Lactic acidosis
• Hyperuricemia
• Low uric acid
• Low cholesterol

“The addition of a serum ammonia level to the laboratory evaluation …will identify many children with inborn errors of metabolism.” (Denmark, 2006)

“Especially during the recent years, significant achievements have been gained for the biochemical and genetic diagnosis of inborn errors. Techniques such as tandem mass spectrometry and gas chromatography for biochemical diagnosis and microarrays and next-generation sequencing for the genetic diagnosis have enabled rapid and accurate diagnosis.” (Egzu, 2016)

Treatments

Many IEMs are treatable. Approximately 200 IEMs have a specific treatment that can prevent or reduce neurobiological damage and disability. The treatment is specific to the particular gene or a specific metabolic pathway that is affected in each case, and consists of restoration of the disrupted pathway.

The most common treatments consist of dietary modification, in other words avoiding foods that are affected by the dysfunctional metabolic pathway. One such example is PKU, which can be treated with a restricted phenylalanine diet.

In some cases the treatment consists of replacement of the missing enzyme, metabolite or cofactor (for example, creatine or biotin). Enzyme replacement therapy is now a well-established treatment for some IEMs, for example Gaucher disease. In some rare cases the treatment options will include the removal of toxic metabolite from the body, or even organ transplantation.

“Given their frequency and potential for treatment, the clinician should be aware of this group of conditions and learn to identify the typical manifestations of the different inborn errors of metabolism.” (Ferreira & van Karnebeek, 2019)

“Clinicians should think of metabolic testing with urine-blood aminoacid chromatography, or tandem mass spectrometry in cases with autism or learning difficulties even in the absence of intellectual disability and even in the era of newborn metabolic screening in order not to overlook treatable conditions.” (Mazlum et al. 2016)

“Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM.” (Yildiz et al. 2020)

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