METABOLIC ETIOLOGIES

Overview

Metabolic epilepsies are conceptualized as having a distinct metabolic abnormality that has been demonstrated to be associated with a substantially increased risk of developing epilepsy in appropriately designed studies. Metabolic disorders have genetic origin; however, as we currently understand it, the metabolic abnormalities are a separate disorder interposed between the genetic defect and the epilepsy.

Metabolic epilepsies, that are important to recognize (particularly those where epilepsy is the predominant condition and early treatment optimizes outcome), are presented in this section of EpilepsyDiagnosis.org:

• Biotinidase and holocarboxylase synthase deficiency
• Cerebral folate deficiency
• Creatine disorders
• Folinic acid responsive seizures
• Glucose transporter 1 deficiency syndrome (GLUT1DS)
• Mitochondrial disorders
• Peroxisomal Disorders
• Pyridoxine-Dependent (ALDH7A1)-DEE and Pyridox(am)ine 5’-Phosphate Oxidase (PNPO) Deficiency

BIOTINIDASE AND HOLOCARBOXYLASE SYNTHASE DEFICIENCY

In biotinidase deficiency, the endogenous recycling of biotin is impaired. Epilepsy is frequent, often starting after the first 3 or 4 months of life, and often as epileptic spasms; optic atrophy and hearing loss are also often seen. Clues to the diagnosis are alopecia and dermatitis. The refractory seizures respond promptly to small doses of biotin. In holocarboxylase synthase deficiency, symptoms start during the neonatal period. Seizures are less frequent, occurring in 25-50% of all children. Biotin also is effective in this disorder.

CEREBRAL FOLATE DEFICIENCY

Cerebral folate deficiency is defined as a neurological syndrome associated with low CSF 5-methyltetrahydrofolate (5MTHF), the active folate metabolite, in the presence of normal folate metabolism outside the nervous system. Cerebral folate deficiency can result from either disturbed folate transport or from increased folate turnover within the central nervous system. Typical features manifest from 4 months of age, with irritability, sleep disturbance, developmental delay, cerebellar ataxia, spastic paraplegia, deceleration of head growth, progressive hearing and visual impairment, dyskinesia and epilepsy (seen in one third of children). Neuroimaging shows progressive atrophy and demyelination. Causes include pathogenic variants in receptor-mediated folate receptor protein 1 (FR1), folate antagonists (irreversible binding or antibodies that block folate binding to FR1) and other causes of functional impairment in FR1. Secondary forms of cerebral folate deficiency have been recognized during chronic use of anti-folate (including anti-seizure) medications and in various conditions such as Rett syndrome and Aicardi-Goutieres syndrome. Treatment is with folinic acid, to normalize CSF 5MTHF values.

CREATINE DISORDERS

Disorders of creatine metabolism comprise three different defects: impaired creatine transport into the brain in the X-linked creatine transporter defect and impaired creatine synthesis in GAMT (guanidinoacetate methyltransferase) and AGAT (arginineglycine amidinotransferase) deficiencies. Only GAMT deficiency is regularly associated with epilepsy, which is often refractory to conventional treatment. Creatine supplementation alone frequently leads to improvement. Several seizure types may occur. Infants can present with infantile epileptic spasms syndrome. Atypical absences, atonic and generalized tonic-clonic seizures are common later in childhood.

FOLINIC ACID RESPONSIVE SEIZURES

This metabolic disorder is an allelic condition to pyridoxine dependent epilepsy with similar biochemical markers. Individuals may have a partial pyridoxine response, then may require co-therapy with folinic acid. Research is underway into the mechanism for folinic acid response. In CSF studies of biogenic amines, an unknown peak (peak X) is seen.

GLUCOSE TRANSPORTER 1 DEFICIENCY SYNDROME (GLUT1DS)

The predominant seizure type in this metabolic disorder is absence seizures; myoclonic seizures and focal seizures are also seen. Around 10% of patients with early onset absence seizures and 5% of patients with epilepsy with myoclonic atonic seizures have GLUT1 deficiency syndrome. A strong clue is the presence of paroxysmal exercise-induced dyskinesia in family members (or in the affected individual), which may be worse in the morning or after a period of fasting and relieved by carbohydrate. The ketogenic diet is the treatment of choice for GLUT1 deficiency syndrome and may result in seizure control and potentially improve cognitive outcome. Diagnosis may be suspected if a reduced CSF-blood glucose ratio (< 0.46) is found. The diagnosis can be confirmed by looking for reduced glucose transport across the erythrocyte membrane (which carries the same glucose transporter), and by pathogenic variant analysis of the solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) gene.

MITOCHONDRIAL DISORDERS

Epilepsy (with prominent myoclonic seizures) is a common feature of a number of mitochondrial disorders including:

• Polymerase gamma (POLG)-related disorders - intractable seizures with status epilepticus and epilepsia partialis continua occur, with developmental regression and liver dysfunction. Caused by pathogenic variants in POLG.
• MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) frequently leads to seizures, especially during acute stroke-like episodes where focal seizures arise in the involved cortical areas. Epilepsia partialis continua may occur.
• MERRF (myoclonic epilepsy with ragged red fibres) presents in the second decade or later, as a progressive myoclonus epilepsy with typical EEG findings of giant somatosensory potentials and photosensitivity. Clinically, patients show prominent myoclonic seizures as well as other seizure types.

PEROXISOMAL DISORDERS

Peroxisomal disorders are an uncommon cause of epilepsy, usually presenting with seizures in early life, in a neonate or infant with severe neurological impairment. Malformations of cortical development may co-occur in specific peroxisomal disorders, including Zellweger syndrome and neonatal adrenoleucodystrophy. Focal seizures, generalized seizures and epileptic spasms may occur. Diagnosis is through identification of abnormal levels of very long chain fatty acids.

Pyridoxine-Dependent (ALDH7A1)-DEE and Pyridox(am)ine 5’-Phosphate Oxidase (PNPO) Deficiency

In pyridoxine-dependent DEE, there is a defect in α-aminoadipic semialdehyde (AASA) dehydrogenase, with accumulation of products that inactivate pyridoxal-5-phosphate (PLP). Biochemical markers include increased AASA (specific) and pipecolic acid (non specific) in urine, plasma and CSF (even on treatment). The diagnosis is supported by finding a pathogenic variant in the antiquitin gene (ALDH7A1, chromosome 5q31).

In pyridox(am)ine 5’-phosphate oxidase (PNPO) deficiency, biochemical markers may be unhelpful with only subtle findings. Pyridoxine supplementation is ineffective, the patients require PLP to ameliorate the neurological condition.

For both pyridoxine-dependent-DEE and PNPO Deficiency, the severity of the accompanying epilepsy can vary from severe early onset epilepsies (with suppression-burst patterns) to intractable focal seizures. Myoclonic seizures and unusual rotatory or bobbing eye movements with head nodding are distinctive seizure features. Any child with onset of intractable seizures under the age of 2 years warrants a trial of pyridoxine and PLP, for a minimum of one month. Neonates may be mistakenly thought to have hypoxic ischemic encephalopathy, as they may be in poor condition at birth, have lactic acidosis and a history of fetal distress in labour. Preterm delivery is common.