Severe Dystonic Movement Disorder and Developmental Encephalopathy Due to Hexokinase 1 Mutation

Background: Hexokinase 1 (HK1) is a brain-specific kinase that catalyzes the first, rate-limiting step in glycolysis. HK1 is mostly bound to the outer mitochondrial membrane and has additional roles in cell survival and antiapoptotic signaling. Autosomal-dominant variants in HK1 have been reported in a few patients with a neurodevelopmental phenotype and visual abnormalities.

Clinical Course: The proband was born at term by secondary cesarean delivery due to birth arrest to healthy, unrelated parents. Pregnancy was uneventful. At the age of 3 hours, he presented with respiratory distress, hypoglycemia and lactic acidosis. Clinical examination showed encephalopathy, hyperexcitability, muscular hypertonia and absent gag reflex. Cerebrospinal fluid (CSF) analysis revealed increased lactate, severely decreased glucose (CSF/serum ratio 0.3, ref. 0.65) and neurotransmitter abnormalities. MRI/MRS demonstrated cortical and thalamic atrophy, absent septum pellucidum, and increased lactate. Trio-exome sequencing identified a de novo, heterozygous missense variant in the HK1 gene. Ketogenic diet was started on day 6 due to hypoglycorrhachia. Neurotransmitter and CSF glucose, but not CSF/serum glucose ratio and lactate, normalized 4 months after initiation of treatment. cMRI showed stable findings. However, the patient developed a generalized dystonic movement disorder, epileptic spasms, sleep disruption and abnormal breathing pattern with desaturations. Symptomatic treatment with sedatives, analgesics, antidystonic, and antiepileptic medication included gabapentin, clonidine, chloral hydrate, diazepam, morphine, and vigabatrin.

Conclusion: We describe a patient presenting with progressive developmental encephalopathy and severe dystonic movement disorder due to a de novo, heterozygous HK1 mutation and thus expand the phenotypic spectrum of this rare neurometabolic disorder.

Publication History

Article published online:
28 October 2021