Differential Diagnosis
Phenotypic and EEG features associated with KCNT1 pathogenic variants are not sufficient to diagnose KCNT1-related epilepsy. All genes known to be associated with early-infantile epileptic encephalopathy (30 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis of KCNT1-related epilepsy including other genes less commonly associated with epilepsy of infancy with migrating focal seizures (SCN1A, SCN2A, SLC12A5, SLC25A22, TBC1D24, PLCB1) and autosomal dominant nocturnal frontal lobe epilepsy (CHRNA4, CHRNB2, DEPDC5, CRH). Note: At seizure onset, it is most important to distinguish KCNT1-related epilepsy from potentially treatable causes of early infantile-onset epileptic encephalopathy, such as neurometabolic disorders, CNS infection, structural brain lesions, and other syndromes . Table 2. Treatable Disorders Associated with Early Infantile-Onset Epileptic Encephalopathy
Conditions | Gene(s) | MOI | Clinical Findings | Treatment |
|---|
ALDH7A1 | AR | plasma urine alpha-aminoadipic semialdehyde; plasma CSF pipecolic acid | Seizures/encephalopathy responsive to pyridoxine Pyridoxamine 5'-phosphate oxidase deficiency (OMIM 610090) | — |
PNPO | AR | Lactic acidemia; Hypoglycemia | Seizures/encephalopathy responsive to pyridoxal 5-prime phosphate Biotinidase deficiency | — |
BTD | AR | Deficient biotinidase enzyme activity in serum or plasma; Ketolactic acidosis, organic aciduria, hyperammonemia; Skin rash, alopecia, recurrent viral or fungal infections | Lifelong biotin supplementation Glucose transporter 1 deficiency syndrome | — |
SLC2A1 | ADAR | CSF glucose concentration; Absence seizures beginning age 3 | Ketogenic diet Creatine deficiency syndromes | GAMT GATM |
SLC6A8 | ARXL | Cerebral creatine deficiency on brain MR spectroscopy; Suggestive ratio of guanidinoacetate, creatine, /or creatinine in plasma urine | Creatine monohydrate supplementation Holocarboxylase synthetase deficiency (OMIM 253270) | — |
HLCS | AR | Ketolactic acidosis, organic aciduria, hyperammonemia; Skin rash, alopecia | Responsive to biotin Serine biosynthesis disorders | PHGDH PSAT1 |
PSPH | AR | Congenital or acquired microcephaly, congenital cataracts | L-serine glycine supplementation can reduce seizures, improve psychomotor symptoms, prevent progression depending on subtype | — |
Other | Infection of the CNS | NA | — | — |
MRI, blood culture /or lumbar puncture suggestive of infection | Antibiotic, antiviral, or antifungal therapy Structural brain lesions | NA | (Multi)focal lesions on brain MRI | Tuberous sclerosis complex |
Source: GeneReviews — "KCNT1-Related Epilepsy"
