*5.3.4 Disorders of* γ*-aminobutyric acid metabolism*

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of GABA metabolism that results from a mutation in both ALDH5A1 genes. Neurological manifestations may include seizures, and ASD features among others.

## *5.3.5 Disorders of pyrimidine and purine metabolism*

Children with ASD and comorbid seizures have been described to have disorders of purine and pyrimidine metabolism. Patients show a variable combination of mental retardation, epilepsy, ASD features, and cerebellar vermis hypoplasia.

#### *5.3.6 Disorders of amino acid metabolism*

Disorders in the metabolism of phenylalanine, have been described in children with ASD and comorbid epilepsy. Phenylketonuria is an autosomal recessive inborn error of phenylalanine metabolism resulting from deficiency of phenylalanine hydroxylase secondary to a mutation in the PAH gene on chromosome 12q23.2. Children with PKU who go untreated or who do not adhere to the diet adequately may demonstrate poor growth, poor skin pigmentation, microcephaly, seizures, spasticity, ataxia, aggressive behavior, hyperactivity, ASD features, global developmental delay, and/or severe intellectual impairment. Recently an inactivating mutation in the branched-chain ketoacid dehydrogenase kinase was described to be associated with autism, epilepsy, and intellectual disability in three families with two children each who were products of first-cousin consanguinity.

#### *5.3.7 Mitochondrial dysfunction associated with epilepsy in ASD*

A recent meta-analysis found that 5% of children with ASD met the criteria for classic mitochondrial disease, while as many as 30% of children with ASD may manifest mitochondrial dysfunction.

Prevalence of abnormal mitochondrial function in immune cells derived from children with ASD is exceedingly high.

A meta-analysis found that, overall, 41% of children with ASD and documented mitochondrial disease are reported to have seizures.

Mitochondrial dysfunction has also been reported in many genetic syndromes associated with ASD and epilepsy. For example, in Rett syndrome, Phelan– McDermid syndrome, 15q11-q13 duplication syndrome, Angelman syndrome and Down syndrome, mitochondrial dysfunction may underlie the phenotype of ASD with epilepsy, regardless of the underlying cause**.**

Abnormalities in mitochondrial function can lead to abnormal development in brain circuits, resulting in both neurodevelopmental disorders and epilepsy through several mechanisms. Abnormalities in mitochondrial biomarkers have also been found in the brains of individuals with ASD. Thus, it is very likely that changes in mitochondrial function in the brain affect neural transmission and function in children with ASD. Neural synapses that are areas of high energy consumption and are especially dependent on mitochondrial function may be one of the mechanisms for developing these developmental disorders. Recent studies have suggested that oxidative stress may be involved in the development of epilepsy.

Studies have found connection between reactive oxygen species and mitochondrial dysfunction in brain tissue from individuals with ASD. This may be another mechanism where mitochondrial dysfunction can lead to the development of epilepsy in ASD.

Immune dysfunction is found to be implicated in the development of epilepsy, and evidence of cellular and humoral immune dysfunction has also been implicated in ASD. Thus, studies suggest abnormalities in immune cell function result in seizures in ASD.

Another physiological abnormality that is becoming increasingly recognized in both ASD and epilepsy is the dysregulation of calcium [81]. On the other hand, epilepsy may be a common symptom of metabolic disorders and be a clue that a metabolic disorder may be the underlying etiology of the neurodevelopmental abnormalities in children with epilepsy and ASD. One advantage of investigating and diagnosing metabolic disorders is that treatments for many of these metabolic disorders are available.
