Neurodevelopmental Disorder With Involuntary Movements

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with involuntary movements (NEDIM) is caused by heterozygous mutation in the GNAO1 gene (139311) on chromosome 16q13.

Heterozygous mutation in the GNAO1 gene can also cause early infantile epileptic encephalopathy-17 (EIEE17; 615473).

Description

NEDIM is a neurodevelopmental and neurodegenerative disorder characterized by delayed psychomotor development and infantile or childhood onset of hyperkinetic involuntary movements, including chorea and athetosis. The abnormal movements can be severe, sometimes resulting in inability to sit, walk, speak, or eat. Hyperkinetic movements can be exacerbated by specific triggers, such as stress, illness, or high temperature. Some patients have brain abnormalities, such as cerebral atrophy or thin corpus callosum, and some patients may develop seizures (summary by Ananth et al., 2016 and Danti et al., 2017).

Clinical Features

Kulkarni et al. (2016) reported 2 brothers, born of unrelated parents, with a severe and progressive neurodevelopmental disorder characterized by markedly abnormal involuntary movements. One presented at 18 months of age with hypotonia, motor delay, and increased serum creatine kinase. He developed repeated exacerbations of choreoathetoid movements that were refractory to medication and became debilitating, necessitating multiple hospitalizations and placement of a feeding tube. His brother presented with similar features around 2 years of age. EEG in both boys showed diffuse slowing, but no epileptiform activity, and both had normal brain imaging. Surgical placement of deep brain stimulation electrodes significantly reduced the abnormal movements in both patients. In comparison to the EIEE17 phenotype, Kulkarni et al. (2016) noted that these boys did not have seizures, but did have a similar movement disorder as some patients with EIEE17, thus expanding the neurologic phenotype associated with GNAO1 mutations.

Saitsu et al. (2016) reported 2 unrelated teenaged girls with NEDIM. They presented in infancy with global developmental delay and hypotonia, and developed severe involuntary movements in early childhood, including dystonia, athetosis, and chorea. One patient developed status dystonicus that was refractory to treatment. Her condition progressed, and she became bedridden with a tracheostomy and enterostomy. Her brain imaging was normal. The other patient also had a progressive movement disorder, often exacerbated by febrile illness. She developed complex partial seizures at 10 years of age. Brain imaging in this patient showed progressive cerebral and cerebellar atrophy, brainstem atrophy, and thin corpus callosum. The patients were severely disabled, with little or no eye contact or head control and inability to sit, walk, or talk.

Ananth et al. (2016) reported 6 patients, including a pair of dizygotic twins, with global developmental delay and hypotonia since infancy, but without seizures. Five patients developed severe abnormal involuntary movements, such as chorea and ballismus, by age 4 years, and the sixth by age 14 years. The patients developed quadriplegia: 2 patients never achieved motor skills and only 1 had limited ambulation with a walker at age 15 years. None of the patients had expressive speech, most had limited purposeful movements, and most required a feeding tube. Four patients had multiple admissions to the intensive care unit for their chorea, which was sometimes triggered by excitement or stress, and 2 patients died of complications during hospitalization. The least affected patient presented in infancy with hypotonia, developmental delay, and mild dyskinesia. In childhood, he was able to stand, ambulate with a walker, and participate in school, but still required assistance with all activities of daily living. He developed chorea at age 14 years, after which he showed severe motor regression and loss of many functions. Brain imaging in these patients was normal in infancy and early childhood, but some patients developed progressive abnormalities, mainly global atrophy and abnormal signals in the globus pallidus. During exacerbations, some patients showed prominent autonomic features, such as tachycardia, hyperthermia, hypertension, or diaphoresis. Ananth et al. (2016) noted that the severe exacerbations of the movement disorder can be refractory to treatment and be life-threatening, but that aggressive treatment with anesthetic drips may prevent secondary complications. Some patients had some response of the baseline chorea to tetrabenazine. None of the patients had seizures, indicating that GNAO1 mutations can cause severe neurologic signs and encephalopathy in the absence of epilepsy.

Menke et al. (2016) reported 2 unrelated boys with NEDIM. Hypotonia and delayed motor development was apparent in the first year of life. Neither was able to sit unsupported, and both had onset of involuntary movements, interpreted as mobile dystonia with myoclonic jerks, around 1.5 to 3 years of age. Verbal abilities were delayed or absent. EEG and brain imaging showed no abnormalities.

Danti et al. (2017) reported 6 unrelated patients with NEDIM confirmed by genetic analysis. The patients had a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, dystonia, and self-injurious behavior to a milder phenotype with moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. The onset of abnormal hyperkinetic movements ranged from 4 months to 9 years of age (median 2 years). Three patients had hypotonia in infancy. The severity of the movement disorder varied, with the most severely affected patient developing continuous generalized choreoathetosis and facial dyskinesia that progressed to status dystonicus requiring intensive care with sedation, ventilation, tracheostomy, and gastrostomy. This patient had increased serum creatine kinase and renal failure, leading to multisystemic deterioration and death at age 4 years. Among the patients, hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention. Five patients had well-controlled epilepsy; a seventh reported patient had a more severe phenotype consistent with EIEE17. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients.

Clinical Management

Kulkarni et al. (2016) found that surgical placement of deep brain stimulation electrodes significantly reduced the abnormal movements in 2 brothers with NEDIM.

Sakamoto et al. (2017) reported follow-up of a 19-year-old woman with NEDIM associated with a GNAO1 mutation (R209C; 139311.0007); the patient had previously been reported by Saitsu et al. (2016). She had progressive severe chorea that had been resistant to antiepileptics. Treatment with topiramate resulted in a significant improvement in the frequency and severity of chorea. The authors suggested that the efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated calcium channels.

Danti et al. (2017) noted that most of their 7 patients with severe abnormal involuntary movements were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2 of 7 patients. Emergency deep brain stimulation was life saving in 1 patient.

Molecular Genetics

In 2 brothers with NEDIM, Kulkarni et al. (2016) identified a de novo heterozygous missense mutation in the GNAO1 gene (R209H; 139311.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in one of them. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. Using exome sequencing, Menke et al. (2016) identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed.

In 2 unrelated patients with NEDIM, Saitsu et al. (2016) identified 2 different de novo heterozygous missense mutations in the GNAO1 gene (R209C, 139311.0006 and E246K, 139311.0007). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would result in adverse effects.

In 6 patients, including 2 sibs, with NEDIM, Ananth et al. (2016) identified de novo heterozygous missense mutations in the GNAO1 gene: E246K was found in 4 patients, R209H was found in 1 patient, and R209G (139311.0008) was found in 1 patient. The mutations were found by whole-exome sequencing; functional studies of the variants and studies of patient cells were not performed. None of the patients had seizures, suggesting that these mutations may be specific to the movement disorder.

In 6 patients with NEDIM, Danti et al. (2017) identified de novo heterozygous mutations in the GNAO1 gene (see, e.g., R209C, 139311.0006 and E246G, 139311.0009). Functional studies of the variants and studies of patient cells were not performed.

Genotype/Phenotype Correlations

In 2 unrelated boys with NEDIM, Menke et al. (2016) identified de novo heterozygous missense mutations affecting codon 209 in the GNAO1 gene (R209H, 139311.0010 and R209L). In a review of 26 published patients with GNAO1 mutations, Menke et al. (2016) found that those with mutations affecting codon 209 (e.g., R209C, R209H, R209G) or 246 (E246K; 139311.0008) had developmental delay with a hyperkinetic movement disorder but without seizures. These mutations were recurrent de novo mutations, probably related to both being part of CpG dinucleotides, which are vulnerable to spontaneous deamination. In contrast, patients with mutations affecting other residues had the more severe phenotype of infantile-onset epileptic encephalopathy (EIEE17). Menke et al. (2016) noted that affected sib pairs with the same de novo mutation had been reported, and they estimated a recurrence risk of 5 to 15% after 1 affected child with GNAO1 mutations.