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Generalized dystonia in a patient with a novel mutation in the GLUD1 gene

Hyperinsulinism-hyperammonemia syndrome (HHS; MIM 606762) is a form of congenital hyperinsulinism caused by mutations in the glutamate dehydrogenase 1 gene (GLUD1). This gene encodes glutamate dehydrogenase (GDH), which catalyzes the oxidation of glutamate to ammonia. Mutations in GLUD1 cause GDH hyperactivity by lowering the enzyme’s sensitivity to guanosine-50-triphosphate (GTP), an allosteric inhibitor of GDH, resulting in persistent hyperammonemia and hyperinsulinism. Although GLUD1-related HHS is frequently associated with epilepsy and mental retardation, generalized dystonia has only been reported in 1 case. Here, we confirm this association and describe a fulminant clinical progression of dystonia to dystonic storm, as well as significant improvement with bilateral globus pallidus internus deep brain stimulation (GPi-DBS). The female patient grew normally until 6 months of age, when she had an episode of generalized tonic–clonic seizures that responded poorly to antiepileptic drugs. Laboratory tests at age 33 months revealed hypoglycemia and hyperinsulinemia followed by persistent hyperammonemia. She also had moderate mental retardation, although her EEG and brain MRI appeared normal. A diagnosis of HHS was made, and we began treatment with diazoxide, which controlled her blood glucose levels and stopped the seizures. At age 11, she developed stereotyped repetitive neck rotation and upper arm contraction. The dystonic movements spread to whole areas of the body within a few months and were refractory to pharmacotherapy that included trihexyphenidyl, risperidone, clonazepam, baclofen, and L-3,4-dihydroxyphenylalanine. The patient eventually developed a life-threatening dystonic storm at age 16, and bilateral GPi-DBS was performed. GPi-DBS had a striking impact on her symptoms; her preoperative Burke-Fahn-Marsden Dystonia Rating Scale score of 112 decreased to 11.5 after GPi-DBS (Video). This improvement was essentially stable on examination 1 year after surgery. The genetic study was approved by the ethics committee, and participants provided written informed consent. We analyzed GLUD1 gene exons by PCR sequencing and confirmed the presence of a heterozygous sequence variation in exon 7: c.943C>T (Fig. 1A). Basal GDH activity was 35 nmol/min/mg of protein (control, 29), and allosteric inhibition by GTP (IC50) was 1819 nM (control, 135). These results are consistent with HHS caused by GLUD1 gene mutations. The patient underwent magnetic resonance spectroscopy (H-MRS) at age 14 (Fig. 1B–D), according to a previously reported method. Coding exons of the TOR1A and THAP1 genes did not contain mutations. Bahi-Buisson et al previously described generalized dystonia with prominent cranial-cervical features in a patient affected with the major GTP-binding site mutation. The mutation in the presented case lies in the same region. Further parallels include the age of dystonia onset, repeated hypoglycemic seizures, and moderate learning disability. Although epilepsy is reported frequently with the major mutation in the GTP-binding site, clonazepam may have masked the patient’s EEG aberrations. This case further supports that mutations in the GLUD1 gene could be a potential cause of dystonia and also suggests that GLUD1-related dystonia occurs through unique GLUD1 gene mutation– induced disruption of metabolic pathways. GLUD1 mutations can induce GDH overactivity that chronically depletes glutamate, which serves as the precursor of GABA. Loss of GABAergic inhibition is critical in dystonia development. Indeed, an MRS study showed that this patient had reduced levels of GABA and glutamate in the basal ganglia. Moreover, our patient showed decreased GABA levels in CSF and plasma (96 pmol/mL [normal controls, 239 6 76] and 74 pmol/mL [normal controls, 120–210], respectively). These data suggest that HHS-associated dystonia may be caused by altered GABAergic neurotransmission from GDH overactivity following direct mutation of the major GTP-binding site.