Hemiplegic migraine presents as recurrent episodes of migraine with associated unilateral weakness. Patients can present with more severe paroxysmal episodes of encephalopathy. Treatment varies widely and it is not standardized. Despite the growing understanding of genetic causes of hemiplegic migraine, pathogenic variants in SLC4A4 are the only described etiology with recessive inheritance. Better understanding of the various genetic causes and associated symptoms of hemiplegic migraine would allow more personalized treatments leading to a reduction in morbidity. This case describes a 34-year-old patient with episodes of hemiplegic migraine and paroxysmal encephalopathy who was found to have homozygous SLC4A4 pathogenic variants. It describes his initial renal and ocular dysfunction in childhood followed by hemiplegic migraine in adolescence and episodes of encephalopathy in adulthood. In his most recent presentation, the patient improved after initiation of high-volume bicarbonate repletion and steroids. SLC4A4 pathogenic variants are associated with a multiorgan syndrome in which neurologic symptoms typically develop in adolescence or young adulthood. Common symptoms include hemiplegic migraine and paroxysmal attacks of acute encephalopathy. In this case, there was improvement with initiation of steroids despite no evidence of cerebral edema. Furthermore, rapid correction of pH and volume status additionally contributed to clinical improvement. Recognizing the diverse set of genetic causes of hemiplegic migraine and the evolution of symptoms over time can lead to improved diagnosis and identification of appropriate treatment strategies.