Mutations in the mitochondrial cysteinyl-tRNA synthase gene,CARS2,lead to a severe epileptic encephalopathy and complex movement disorder

Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

Download Full-text

Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder

Journal of Child Neurology ◽

10.1177/0883073816666474 ◽

2016 ◽

Vol 31 (14) ◽

pp. 1598-1601 ◽

Cited By ~ 22

Author(s):

Leonie A. Menke ◽

Marc Engelen ◽

Mariel Alders ◽

Vincent J. J. Odekerken ◽

Frank Baas ◽

...

Keyword(s):

Movement Disorder ◽

Missense Mutation ◽

Developmental Delay ◽

Recurrence Risk ◽

Epileptic Encephalopathy ◽

Missense Mutations ◽

Phenotype Correlation ◽

Affected Child ◽

Sibling Pairs ◽

Hyperkinetic Movement Disorder

In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents.

Download Full-text

P.378A complex movement disorder associated with myasthenic features: a novel phenotype caused by a homozygous NGLY1 mutation

Neuromuscular Disorders ◽

10.1016/j.nmd.2019.06.540 ◽

2019 ◽

Vol 29 ◽

pp. S191-S192

Author(s):

D. Jacquier ◽

J. Good ◽

B. Laubscher ◽

D. Mercati ◽

E. Roulet-Perez ◽

...

Keyword(s):

Movement Disorder ◽

Complex Movement

Download Full-text

GLUT1 deficiency syndrome as a cause of encephalopathy that includes cognitive disability, treatment-resistant infantile epilepsy and a complex movement disorder

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2011.11.009 ◽

2012 ◽

Vol 55 (5) ◽

pp. 332-334 ◽

Cited By ~ 5

Author(s):

John M. Graham

Keyword(s):

Movement Disorder ◽

Deficiency Syndrome ◽

Cognitive Disability ◽

Treatment Resistant ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

Infantile Epilepsy ◽

Complex Movement

Download Full-text

A 17-Year-Old Female with Systemic Lupus Presents with Complex Movement Disorder: Possible Relationship with Antiribosomal P Antibodies

Case Reports in Neurological Medicine ◽

10.1155/2013/590729 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Muhammed Emin Özcan ◽

Meriç Adil Altınöz ◽

Hasan Hüseyin Karadeli ◽

Talip Asil ◽

Abdulkadir Koçer

Keyword(s):

Movement Disorder ◽

Antiphospholipid Antibodies ◽

Sudden Onset ◽

Systemic Lupus ◽

Rare Presentation ◽

Glycoprotein I ◽

Neuronal Stimulation ◽

Caucasian Female ◽

Complex Movement

Complex movement disorder is a relatively rare presentation of neurolupus. Antiphospholipid antibodies are associated with movement disorders likely via aberrant neuronal stimulation. Antiribosomal P antibodies have been previously associated with neuropsychiatric disorders but their correlation with movement disorder was not previously established. Our case report involves a 17-year-old Caucasian female patient positive for only antiribosomal P antibody and lupus anticoagulant who presented with a sudden onset of complex movement disorder. After complete cessation of physical signs with olanzapine, anticardiolipin and anti-β2 glycoprotein I antibodies became positive which indicates a likely discordance between movement disorder and antiphospholipid antibodies. This also indicates a potential causal role of antiribosomal P antibodies in inducing movement disorder.

Download Full-text