Table 4

Clinical features, MR brain scan findings and suggested investigations in (non-mitochondrial) inherited metabolic disorders associated with epilepsy

DisorderGeneMain clinical features (excluding seizures, intellectual disability/cognitive decline)Main brain imaging findingsInitial investigationsTreatment
Disorders of energy metabolism
 Guanidinoacetate methyltransferase deficiencyGAMT Behavioural problems, speech delayAbsent or reduced creatine peak on cranial MR spectroscopyPlasma and urine creatine metabolites.Creatine; dietary
 GLUT1 deficiency syndromeSLC2A1 Movement disordersHypometabolism on PET studiesLumbar puncture (CSF/blood glucose ratio and lactate)Ketogenic diet
 Biotin-responsive basal ganglia diseaseSLC19A3 Recurrent encephalopathy, dystonia, pyramidal tract signs, external ophthalmoplegia (often following fever or other metabolic stress)Bilateral and symmetric increased T2 signal intensity in the caudate nucleus, putamen, thalamus, infratentorial and supratentorial brain cortex and brain stem. Vasogenic oedema during acute crisesTypically no specific biochemical abnormalities—high index of clinical and radiological suspicion neededBiotin and thiamine
 Biotinidase deficiencyBTD Spastic paraparesis, ataxia, optic neuropathy, hearing loss, eczema, alopeciaVariable – may include periventricular white matter changes, cerebral atrophy and spinal cord involvementUrine organic acid profile. Serum biotinidase enzyme activityBiotin
Disorders of intoxication
 Urea cycle defectsOTC, ASS, ASL, ARG1, CPS1, NAGS, SLC25A15 Encephalopathy (hyperammonaemia). Protein aversion, headaches, recurrent vomiting. Spastic paraparesis (ARG1 only)May be normal. Cerebral oedema. White matter abnormalities (FLAIR)Plasma ammonia. Plasma amino acid profile. Urine organic acid profile (orotic acid)Dietary. Nitrogen scavengers, for example, sodium benzoate and sodium phenylbutyrate
Disorders of lipid metabolism / storage
 CTXCYP27A1 Neuropsychiatric: pyramidal and cerebellar signs. Axonal polyneuropathy. Tendon xanthomas. Ask about previous cataracts and diarrhoeaSymmetrical high signal lesions in globus pallidus and deep cerebellar white matter. Low signal lesions in dentate nuclei on T2-weighted MRISerum cholestanols. Urine bile alcoholsChenodeoxycholic acid
 Niemann–Pick C diseaseNPC1, NPC2 Psychiatric features. Ataxia and movement disorders. Vertical supranuclear gaze palsy. CataplexyMay be normal. Cerebellar atrophy. Periventricular white matter abnormalitiesPlasma oxysterols. Filipin staining in fibroblasts.N-butyl-deoxynojirimycin (miglustat)
 Lafora diseaseEPM2A, NHLRC1 Visual hallucinations. Dysarthria. Ataxia. SpasticityMay be normalSkin biopsy (Lafora bodies).Supportive
Disorders of folate metabolism / transport
 MTHFR deficiencyMTHFR Thrombosis. Psychiatric features. Pyramidal signs. NOTE: anaemia is not a typical featureMay be normal. White matter abnormalitiesPlasma amino acid profile. MTHFR enzyme activity.Betaine and folic acid
 Folate transporter deficiencyFOLR1 PolyneuropathyWhite matter abnormalities. HypomyelinationSerum folate. CSF 5-MTHF.Folinic acid
Others
 Serine deficiencyPHGDH Polyneuropathy. Ataxia. Ask about cataractsWhite matter abnormalitiesPlasma and SCF amino acid profile.Serine
 Pyridoxine-dependent epilepsyALDH7A1 Typically refractory neonatal onset seizuresThinning of the corpus callosum. Mega cisterna magnaPlasma/urine alpha-aminoadipic semialdehyde. Plasma/CSF pipecolic acidPyridoxine
 Pyridoxal phosphate responsive seizuresPNPO Typically refractory neonatal onset seizuresMay be normalCSF amino acid profile. CSF pyridoxal 5’-phosphate level. CSF neurotransmitters. Urine organic acids.Pyridoxal phosphate
 Intracellular disorders of cobalamin metabolismcblA, cblB, cblC, cblD, cblE, cblF, cblG Megaloblastic anaemia. Thrombosis. Psychiatric features. Optic atrophy. Spinal cord diseaseWhite matter abnormalities. Dorsal and lateral column T2-hyperintensityPlasma amino acid profile, including homocysteine. Plasma methylmalonic acid. Urine organic acid profile.Hydroxocobalamin intramuscularly (betaine, folic acid)
  • CTX, Cerebrotendinous xanthomatosis; GAMT, guanidinoacetate methyltransferase; GLUT1, glucose transporter protein type 1; MTHFR, methylenetetrahydrofolate reductase.