Inspired by a colleague's patient's diagnosis
Algahtani H, Ibrahim B, Shirah B, Aldarmahi A, Abdullah A. More Than a Decade of Misdiagnosis of Alternating Hemiplegia of Childhood with Catastrophic Outcome. Case Rep Med. 2017;2017:5769837. doi: 10.1155/2017/5769837. Epub 2017 Aug 16.
Alternating hemiplegia of childhood (AHC) is a distinct clinical disorder characterized by recurrent episodes of hemiplegia, abnormal ocular movement, and progressive developmental delay. It is an extremely rare genetic disorder related to ATP1A3 gene mutations. In this paper, we present a case of AHC in which the diagnosis was missed for many years until severe hypoxic brain insult occurred from prolonged status epilepticus. Not only we are presenting an interesting clinical entity and radiological images, but also we are shedding the light on a rare genetic disease with catastrophic sequelae. The challenges in diagnosis and treatment lead to a poor outcome as seen in our case. Although early recognition and accurate diagnosis and treatment of the disease may not change the outcome, counseling of the family may change their expectation and reduce their frustration. Referral to a center with expertise in genetic disorders and access to genetic laboratories is of paramount importance in the diagnosis of this disease. Due to the rarity of this disease in Saudi Arabia, a genotype-phenotype correlation is not feasible.
Nakamura Y, Hattori A, Nakashima M, Ieda D, Hori I, Negishi Y, Ando N, Matsumoto N, Saitoh S. A de novo p.Arg756Cys mutation in ATP1A3 causes a distinct phenotype with prolonged weakness and encephalopathy triggered by fever. Brain Dev. 2017 Oct 21. pii: S0387-7604(17)30264-4.
Patients with a mutation at Arg756 in ATP1A3 have been known to exhibit a distinct phenotype, characterized by prolonged weakness and encephalopathy, triggered by febrile illness. With only eight reports published to date, more evidence is required to correlate clinical features with a mutation at Arg756. Here we report an additional case with an Arg756Cys mutation in ATP1A3. A four-year-old boy showed mild developmental delay with recurrent paroxysmal episodes of weakness and encephalopathy from nine months of age. Motor deficits, which included bilateral hypotonia, ataxia, dysmetria, limb incoordination, dysarthria, choreoathetosis, and dystonia, were observed from one year and three months. Whole-exome sequencing detected a heterozygous de novo variant at c.2266C>T (p.Arg756Cys) in ATP1A3. The episodic course and clinical features of this case were consistent with previously reported cases with mutations at Arg756. Furthermore, his phenotype of marked ataxia was more similar to that of an Arg756Cys patient with relapsing encephalopathy and cerebellar ataxia syndrome, than to those with Arg756His and Arg756Leu mutations. This report therefore provides evidence of genotype-phenotype correlations in ATP1A3-related disorders as well as in patients with mutations at Arg756 in ATP1A3.
Hainque E, Caillet S, Leroy S, Flamand-Roze C, Adanyeguh I, Charbonnier-Beaupel F, Retail M, Le Toullec B, Atencio M, Rivaud-Péchoux S, Brochard V, Habarou F, Ottolenghi C, Cormier F, Méneret A, Ruiz M, Doulazmi M, Roubergue A, Corvol JC, Vidailhet M, Mochel F, Roze E. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood. Orphanet J Rare Dis. 2017 Oct 2;12(1):160.
Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.
We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.
In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.
Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.
Carecchio M, Mencacci NE. Emerging Monogenic Complex Hyperkinetic Disorders. Curr Neurol Neurosci Rep. 2017 Oct 30;17(12):97.
PURPOSE OF REVIEW:
Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.
Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,. Thanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.