Clinical features, MR brain scan findings and suggested investigations in (non-mitochondrial) inherited metabolic disorders associated with epilepsy
| Disorder | Gene | Main clinical features (excluding seizures, intellectual disability/cognitive decline) | Main brain imaging findings | Initial investigations | Treatment |
| Disorders of energy metabolism | |||||
| Guanidinoacetate methyltransferase deficiency | GAMT | Behavioural problems, speech delay | Absent or reduced creatine peak on cranial MR spectroscopy | Plasma and urine creatine metabolites. | Creatine; dietary |
| GLUT1 deficiency syndrome | SLC2A1 | Movement disorders | Hypometabolism on PET studies | Lumbar puncture (CSF/blood glucose ratio and lactate) | Ketogenic diet |
| Biotin-responsive basal ganglia disease | SLC19A3 | 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 crises | Typically no specific biochemical abnormalities—high index of clinical and radiological suspicion needed | Biotin and thiamine |
| Biotinidase deficiency | BTD | Spastic paraparesis, ataxia, optic neuropathy, hearing loss, eczema, alopecia | Variable – may include periventricular white matter changes, cerebral atrophy and spinal cord involvement | Urine organic acid profile. Serum biotinidase enzyme activity | Biotin |
| Disorders of intoxication | |||||
| Urea cycle defects | OTC, 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 | |||||
| CTX | CYP27A1 | Neuropsychiatric: pyramidal and cerebellar signs. Axonal polyneuropathy. Tendon xanthomas. Ask about previous cataracts and diarrhoea | Symmetrical high signal lesions in globus pallidus and deep cerebellar white matter. Low signal lesions in dentate nuclei on T2-weighted MRI | Serum cholestanols. Urine bile alcohols | Chenodeoxycholic acid |
| Niemann–Pick C disease | NPC1, NPC2 | Psychiatric features. Ataxia and movement disorders. Vertical supranuclear gaze palsy. Cataplexy | May be normal. Cerebellar atrophy. Periventricular white matter abnormalities | Plasma oxysterols. Filipin staining in fibroblasts. | N-butyl-deoxynojirimycin (miglustat) |
| Lafora disease | EPM2A, NHLRC1 | Visual hallucinations. Dysarthria. Ataxia. Spasticity | May be normal | Skin biopsy (Lafora bodies). | Supportive |
| Disorders of folate metabolism / transport | |||||
| MTHFR deficiency | MTHFR | Thrombosis. Psychiatric features. Pyramidal signs. NOTE: anaemia is not a typical feature | May be normal. White matter abnormalities | Plasma amino acid profile. MTHFR enzyme activity. | Betaine and folic acid |
| Folate transporter deficiency | FOLR1 | Polyneuropathy | White matter abnormalities. Hypomyelination | Serum folate. CSF 5-MTHF. | Folinic acid |
| Others | |||||
| Serine deficiency | PHGDH | Polyneuropathy. Ataxia. Ask about cataracts | White matter abnormalities | Plasma and SCF amino acid profile. | Serine |
| Pyridoxine-dependent epilepsy | ALDH7A1 | Typically refractory neonatal onset seizures | Thinning of the corpus callosum. Mega cisterna magna | Plasma/urine alpha-aminoadipic semialdehyde. Plasma/CSF pipecolic acid | Pyridoxine |
| Pyridoxal phosphate responsive seizures | PNPO | Typically refractory neonatal onset seizures | May be normal | CSF amino acid profile. CSF pyridoxal 5’-phosphate level. CSF neurotransmitters. Urine organic acids. | Pyridoxal phosphate |
| Intracellular disorders of cobalamin metabolism | cblA, cblB, cblC, cblD, cblE, cblF, cblG | Megaloblastic anaemia. Thrombosis. Psychiatric features. Optic atrophy. Spinal cord disease | White matter abnormalities. Dorsal and lateral column T2-hyperintensity | Plasma 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.