Chorea, psychosis, acanthocytosis, and prolonged survival associated with ELAC2 mutations

Case description

An Assyrian 69-year-old woman born in Turkey was evaluated at our center for a slowly progressive Huntingtonian disorder. Family history was negative. The patient came to Sweden at age 33; she never went to school and learned only a few Swedish words, and could perform simple transactions. She had type 2 diabetes mellitus, bilateral sensorineural hearing loss requiring aids since age 58, and a follicular thyroid tumor, and is a silent carrier of α-thalassemia (table e-1; doi.org/10.5061/dryad.j6s420k).

At age 52 years, the patient developed short memory impairment and increasing difficulties managing activities of daily living. Four years later, she reported olfactory hallucinations and became obsessed with cleaning and doing laundry to remove the perceived foul smells. Perioral movements were documented during an emergency room visit at age 56 for psychiatric issues, and were noted by her family to have been present for many years, predating treatment with aripiprazole. The olfactory hallucinations became so severe that she tried to commit suicide by setting her apartment on fire at age 58. This resulted in admission to a psychiatric unit for a year and treatment with aripiprazole. At age 61, worsened gait, balance, and involuntary movements were evident. For the last 3 years, she has required a walker and reports numbness in her calves. She has lost weight, but there is no evidence of feeding dystonia or dysphagia. Recently, she has become fecally incontinent.

On examination, the patient had chorea in the feet and perioral area, dystonic posturing in the hands and reduced arm movements, a waddling gait, bradykinesia, apraxia, and atrophy of the hand muscles (video 1). A simplified psychometric evaluation demonstrated significant deficits in several domains (table e-2). EEG performed twice was normal; neurophysiologic studies revealed a sensorimotor demyelinating polyneuropathy and myopathy. Muscle biopsy revealed both cytochrome oxidase (COX)–negative and ragged-red fibers. Brain MRI demonstrated atrophy in the left perirolandic frontal and temporal cortex, while FDG-PET showed reduced bilateral hypometabolism in these regions and in the insular cortex, more pronounced on the left side (figures e-1 and e-2; doi.org/10.5061/dryad.j6s420k). An incidental aneurysm in the anterior communicating artery was found and treated conservatively; there was no evidence of brain calcifications on CT scans. Huntington disease (HD) and other HD phenocopies were ruled out (appendix; doi.org/10.5061/dryad.j6s420k). Acanthocytes were found on wet blood smears (figure e-3; doi.org/10.5061/dryad.j6s420k). Whole exome sequencing revealed compound heterozygous variants c.394G>A (p.Gly132Arg) and c.1040C>T (p.Ser347Phe) in the ELAC2 gene (figure e-4; doi.org/10.5061/dryad.j6s420k). ECG was normal but repeated echocardiography demonstrated stable mild ventricular septum hypertrophy without evidence of pump failure. Although we did not find any evidence of respiratory chain defect in the muscle biopsy, the patient's fibroblasts revealed accumulation of unprocessed mitochondrial transcripts but normal steady-state levels of mitochondrial mRNAs and tRNAs (figure 1, A and B). These fibroblasts showed severe growth impairment when using galactose as energy source (figure 1C). Treatment with coenzyme Q10 has been started and regular echocardiography is planned.

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Figure Northern blot analysis of total RNA extractions from primary fibroblasts

(A) Steady-state levels of mitochondrial mRNAs. 18S rRNA was used as loading control. Controls: C1 and C2, patient: ELAC2mut. (B) Steady-state levels of mitochondrial tRNA-tryptophane (mt-tW) and the nuclear-encoded tRNA-cysteine (cyto-tC) from control (C1, C2) and patient fibroblasts, grown for 14 days on galactose-containing medium. *Unprocessed mitochondrial transcript, arrow = tRNA. (C) Growth curves of control and patient fibroblasts grown on galactose. Experiments were performed in triplicates. Error bars indicate standard error.

Publication history

Previously published at bioRxiv doi: 10.1101/244848. Received by Neurology: Neuroimmunology & Neuroinflammation February 8, 2018. Accepted in final form July 19, 2018.