The patient is a 17-year-old male born at term following a pregnancy complicated by maternal alcohol and substance abuse. Development was delayed: he walked at age 18 months, requiring braces for support, and his first words were at age 4 years. Medical history includes strabismus status post surgery at age 1 year, hypothyroidism, asthma, gastroesophageal reflux disease, kidney dysfunction, ischemic stroke, and epilepsy well controlled on valproic acid. The patient had an episode of dystonia associated with anti-psychotic treatment (haloperidol, aripiprazole) for bipolar disorder and aggression at age 9. Limited medical record documentation exists regarding the history of ischemic stroke. Magnetic resonance imaging (MRI) of the brain at ages 9 and 12 were normal. Family history is positive for bipolar disorder in his mother. Paternal family history is unknown. The patient has three healthy maternal half-siblings; ancestry is Caucasian.
He first presented to our institution at age 15 years 6 months for management of his seizures. The patient had a wide-based gait, balance impairment, and dysarthria. He demonstrated developmental skills at the 3- to 5-year level. At 2 months after his initial evaluation, he had the abrupt onset of severe choreo-athetotic movements affecting his face, arms, and trunk (see Supplemental Video). These movements dramatically affected his gait and resulted in use of a wheelchair. His speech, behavior, and short-term memory worsened as well. There was no acute preceding event or change of medication (benztropine 1 mg twice daily, valproic acid 500 mg twice daily, dextroamphetamine 5 mg once daily, diphenhydramine 50 mg every 6 h as needed, levothyroxine 31.25 mcg once daily, fluoxetine 20 mg once daily). Shortly thereafter, the patient was admitted twice to a psychiatric hospital because of anger issues and aggression, but did not require change of medication. He had another seizure after his 16th birthday and a third brain MRI was normal. Over the next several months, his condition worsened due to the involuntary movements and he was no longer able to feed or bathe himself. Gastrostomy (G) tube feeding was required for caloric support. His hyperkinetic movements failed to respond to benztropine 1 mg BID and valproic acid 500 mg BID.
Evaluation in a Pediatric Movement Disorders clinic at age 16 years and 4 months showed continuous choreo-athetotic movements of his face, trunk, and extremities. A trial with tetrabenazine (TBZ) 12.5 mg BID was initiated, which markedly improved his involuntary movements within 2 weeks. At his most recent follow-up visit (age 17 years), he was able to walk, feed himself, and use the bathroom independently. He continued to have antecollis and difficulties with gait, balance, and dysarthria, but was close to his baseline presentation.
Additional neurodiagnostic testing included a normal (fourth) brain MRI, single-nucleotide polymorphism (SNP) chromosomal array, Fragile X DNA testing, and mitochondrial DNA sequencing and deletion/duplication testing. A fasting lumbar puncture revealed a slightly low cerebrospinal fluid (CSF) glucose of 48 mg/dL (normal range 50-75); however, plasma-to-CSF glucose ratio (0.56) was not suggestive of GLUT1 deficiency. CSF lactate, pyridoxal phosphate, neurotransmitter metabolites, tetrahydrobiopterin, neopterin, 5-methyltetrahydrofolate, and succinyladenosine were all normal. CSF amino acids did not identify any abnormalities consistent with a metabolic disorder. Plasma amino acids showed elevated alanine and glycine, but were normal on repeat testing. Lactate, pyruvate, and urine organic acids were normal. In light of extensive negative work-up, whole exome sequencing was performed using the methods previously described.
Results identified a heterozygous missense variant, c.737T>C (p.L246P) in the EEF1A2 gene (NM_001958.3). Targeted testing of the patient's maternal grandmother was negative; biological parental samples were not available to confirm a de novo occurrence in the patient.