10 April 2020
RECENT ARTICLES ABOUT AHC PUBLISHED BY THE DUKE GROUP
The group of the AHC Clinic at the Duke University Medical Center, directed by Professor Mohamad Mikati, has recently published four sequential articles about Alternating Hemiplegia of Childhood.
These are their comments and recommendations about each of these articles.
- In the article by Ghusayni et al. (Ghusayni R, Richardson JP, Uchitel J, Abdelnour E, McLean M, Prange L, Abrahamsen T, Song A, Petrella JR, Mikati MA. Magnetic resonance imaging volumetric analysis in patients with Alternating hemiplegia of childhood: A pilot study. Eur J Paediatr Neurol. 2020 Feb 13:S1090-3798(20)30032-5.) they used the technique of Quantitative MRI to determine the volume of different brain regions of AHC patients as compared to normal controls. First they determined that the use of this technique whether automated using the special program called FreeSurfer or done by manual segmentation of different brain regions was highly reproducible with high correlation between automated and manual segmentation and between two consecutive manual segmentations. Then they found that there was a negative correlation between cerebellar volume and age of 14 patients studied suggesting that cerebellar volume may decrease with age in AHC patients. Given that this is a cross sectional study (each patient’s MRI was evaluated once) there is a need to perform prospective studies in which serial MRIs are done on the same patient to definitively determine volume changes with time.
This study showed that the techniques used can be used perform such studies in AHC patients. Depending on the results of such studies the above technique could potentially be useful as an outcome measure, biomarker, to follow progress of AHC patients during long-term therapeutic trials. link
- In the article of Tran et al. (Tran L, Richards J, McDonald M, McConkie-Rosell A, Stong N, Jasien J, Shashi V, Mikati MA. Epileptic encephalopathy with features of rapid-onset dystonia Parkinsonism and alternating hemiplegia of childhood: a novel combination phenotype associated with ATP1A3 mutation. Epileptic Disord. 2020 Feb 1;22(1):103-109.) a four-year, nine-month-old boy is reported who presented with the following manifestations.
1) Frequent and recurrent episodes of focal and generalized tonic seizures and of convulsive status epilepticus since the age of four months of age with concurrent developmental delay that started with the onset of the seizures.
2) Recurrent attacks of unilateral and bilateral hemiplegia between the ages of 7 months and 2.5 years.
3) Regression at the age of 21 months, after a febrile illness with status epilepticus, with development of continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms.
The etiology was determined to be a novel and de novo p.V589F ATP1A3 mutation.
This article showed that this ATP1A3 mutation caused a combination phenotype that features of each of epileptic encephalopathy, alternating hemiplegia of childhood, and rapid-onset dystonia Parkinsonism. Thus, physicians and caretakers taking care of patients with epileptic encephalopathy should be on the lookout for symptoms of AHC and regression with dystonia as combination phenotypes can occur. link
- In the article of Uchitel et al. (Uchitel J, Abdelnour E, Boggs A, Prange L, Pratt M, Bonner M, Jasien J, Dawson G, Abrahamsen T, Mikati MA. Social impairments in alternating hemiplegia of childhood. Dev Med Child Neurol. 2020 Feb 7.) they studied 34 AHC patients of social responsiveness an autism. They found that 27 of the 34 AHC patients had impaired social responsiveness as indicated by a high Social Responsiveness Scale, Second Edition (SRS-2) scores as compared to the scores of normally developing individuals. In these AHC patients, all categories of social responsiveness were impaired. These included social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior. The presence of epilepsy increased the chance of impaired social responsiveness. Of these 27 patients at the time of the completion of the study, 9 had been referred for formal evaluations of autism and all those nine had been diagnosed to have autism spectrum disorder.
This study highlighted the importance of screening AHC patients, as early as possible, for autism spectrum disorder symptoms and of referring them for formal evaluation for autism as this will allow them be appropriately managed and will allow them to have more resources for their management. link
- In the editorial written by Fernandes and Mikati (Fernandes C, Mikati MA. The expanding spectrum of ATP1A3 related disease. Eur J Paediatr Neurol. 2019 May;23(3):345-346.) the authors review expanding spectrum of ATP1A3 related disorders and provide a table that shows the distinct and overlapping symptoms of these diseases. These include in Alternating Hemiplegia of Childhood (AHC), Rapid Onset Dystonia-Parkinsonism (RDP), Relapsing encephalopathy with cerebellar ataxia (RECA), Childhood schizophrenia, autism, epileptic encephalopathy, Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), and childhood rapid onset ataxia (CROA). The symptoms associated with these syndromes are presented in a succinct table for quick reference and comparison. There are, in addition, many reported patients with intermediate and combination phenotypes.
The editorial then argues that based on the above observations, the presence of multiple symptoms associated with ATP1A3 mutations even if the patients do not fit a specific syndrome should raise the suspicion of ATP1A3 related disease. In the absence of any other clear etiology, this should lead to gene sequencing of such patient to rule out an ATP1A3 mutation. link