Inspired by a colleague’s patient
Iodice A, Pisani F. Status dystonicus: management and prevention in children at high risk. Acta Biomed. 2019 Sep 6;90(3):207-212.
Status dystonicus (SD) is a movement disorder emergency associated with significant morbidity and life-threatening events that requires immediate and effective treatment. Nevertheless, SD is currently an under-recognized and undertreated condition, partly due to the lack of a standard definition and because it can be the acute complicated course of both primary and secondary dystonias. In subjects with SD, due to the delay of identification and lacking prevention of trigger and precipitant factors, intensive care management is consistently required.
We performed a critical review of this topic, outlining clinical features and linked genetic disorders to recognize subject at higher risk of SD, describing precipitant and trigger factors and proposing potential pharmacological treatment strategies in order to prevent hospitalization.
Genetic predisposition included: primary dystonias particularly in the case of TOR1A mutation; epileptic encephalopathy such as ARX and GNAO1 genetic variants and neurodegenerative disorders as PANK2. Early recognition of SD should be oriented by the following sign and symptoms: fever, tachycardia, respiratory change, hypertension, sweating and autonomic instability, elevated serum CK. Pain, fever and dehydration are main trigger factors that have to be prevented or quickly controlled. Achieving sleep could be the first therapeutic option in those with high risk of developing SD. Recently, enteral or transdermal clonidine as safety and efficacy therapeutic alternative was proposed.
Recognizing high risk children for Status dystonicus from the onset of subtle signs and avoiding trigger factors could drive towards better management avoiding intensive treatments.
Malaquias MJ, Fineza I, Loureiro L, Cardoso L, Alonso I, Magalhães M. GNAO1 mutation presenting as dyskinetic cerebral palsy. Neurol Sci. 2019 Oct;40(10):2213-2216.
From the paper:
We report a new case of a GNAO1 mutation, in an 18-year-old girl with global development delay, hypotonia, and HMD, from an early age with a long period of stabilization, mimicking a full-term dyskinetic cerebral palsy.
The phenotypic spectrum associated with mutations in GNAO1 has revealed a genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and HMD. A biochemical analysis of 15 different GNAO1 mutant alleles, conducted by Feng et al., established that gain-of-function (GOF) and normal-function (NF) mutations for inhibition of cAMP are associated with the phenotype of movement disorder, while the loss-of-function (LOF) mutations are related to epileptic encephalopathy phenotype. To our knowledge, seven other cases of GNAO1 mutation (c.625C>T) with normal function have been previously reported, all with movement disorder phenotype.
Patients with GNAO1 mutations can present with a severe, progressive HMD with prolonged life-threatening exacerbations which are refractory to medication. However, our patient presented with a more indolent course, completely free from epileptic seizures, which was reported in very few other cases. Among patients with movement disorder, tetrabenazine appears to be the most effective drug and GPi-DBS, the most effective treatment. Nevertheless, our patient experienced some benefit with dopaminergic therapy (gait, chorea, and tremor). A positive response to dopaminergic drugs was not common in previously published cases. The identification of GNAO1 mutation as the cause made us consider early GPi-DBS as a valid treatment option for this patient.
Our case highlights the genotype-phenotype correlation which is important for early diagnosis, the variable long-term outcome of the disease, and that the dopamine replacement therapy is a valid therapeutic option in advanced stages of this condition, possibly because of a secondary dopaminergic deficiency in the late disease course.
Gerald B, Ramsey K, Belnap N, Szelinger S, Siniard AL, Balak C, Russell M, Richholt R, De Both M, Claasen AM, Schrauwen I, Huentelman MJ, Craig DW, Rangasamy S, Narayanan V. Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results. Semin Pediatr Neurol. 2018 Jul;26:28-32.
Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.
Okumura A, Maruyama K, Shibata M, Kurahashi H, Ishii A, Numoto S, Hirose S, Kawai T, Iso M, Kataoka S, Okuno Y, Muramatsu H, Kojima S. A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features. Brain Dev. 2018 Nov;40(10):926-930.
We report on a 4-year-old girl with a de novo GNAO1 mutation who had neurological findings, including decreased spontaneous movements, hypotonia, and dystonic features. She was referred to our hospital because of delayed psychomotor development. She showed hypotonia and decreased spontaneous movements. Voluntary movements of the limbs were more frequent in the lower extremities than in the upper extremities. Occasional dyskinetic features, such as awkward hand/foot posturing and grimacing, were seen during the voluntary movements. Serum metabolic screening, head magnetic resonance imaging, and electroencephalography were unremarkable. Whole-exome sequencing revealed a de novo mutation in the patient's GNAO1 gene, c.709 G > A (p.E237K). We calculated the free-energy change using the FoldX Suite to evaluate the impact of the E237K mutation. The FoldX calculations showed an increased free-energy change in the active state of the GNAO1 protein, indicating that the E237K mutation destabilizes the active state complexes. No seizures, chorea, tremor, or myoclonia, which are frequently reported in patients with GNAO1 mutations, were observed as of the last follow up. Our patient will improve the understanding of early neurological features in patients with GNAO1 mutations.
Feng H, Khalil S, Neubig RR, Sidiropoulos C. A mechanistic review on GNAO1-associated movement disorder. Neurobiol Dis. 2018 Aug;116:131-141.
Mutations in the GNAO1 gene cause a complex constellation of neurological disorders including epilepsy, developmental delay, and movement disorders. GNAO1 encodes Gαo, the α subunit of Go, a member of the Gi/o family of heterotrimeric G protein signal transducers. Go is the most abundant membrane protein in the mammalian central nervous system and plays major roles in synaptic neurotransmission and neurodevelopment. GNAO1 mutations were first reported in early infantile epileptic encephalopathy 17 (EIEE17) but are also associated with a more common syndrome termed neurodevelopmental disorder with involuntary movements (NEDIM). Here we review a mechanistic model in which loss-of-function (LOF) GNAO1 alleles cause epilepsy and gain-of-function (GOF) alleles are primarily associated with movement disorders. We also develop a signaling framework related to cyclic AMP (cAMP), synaptic vesicle release, and neural development and discuss gene mutations perturbing those mechanisms in a range of genetic movement disorders. Finally, we analyze clinical reports of patients carrying GNAO1 mutations with respect to their symptom onset and discuss pharmacological/surgical treatments in the context of our mechanistic model.