Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of <i>ATP8A2</i>

Abstract

Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.

A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability ofATP8A2-related disorders caused by missense changes

“…Compared to other cases in the literature, our patients exhibited many features shared by most other patients including developmental delay, intellectual disability, and dysarthria (Narishige et al, 2022). However, they presented with a milder clinical manifestation comparable to two families reported by Guissart et al harboring missense variants in the N domain near the p.Leu538Pro variant.…”

“…ATP8A2 mutations have been identified as the underlying cause of CAMRQ4 syndrome which is characterized by encephalopathy, intellectual disability, severe hypotonia, psychomotor delay, chorea, and optic atrophy (Alsahli et al, 2018; Cacciagli et al, 2010; Damásio et al, 2021; Guissart et al, 2020; Martín-Hernández et al, 2016; McMillan et al, 2018; Narishige et al, 2022; Onat et al, 2013). Additionally, individuals with ATP8A2 mutations may exhibit other neurological manifestations such as tremors, seizures, and/or abnormal brain imaging, especially cerebellar atrophy (Guissart et al, 2020).…”

Lipid transport by Candida albicans Dnf2 is required for hyphal growth and virulence

“…Mutations in P4-ATPase genes are associated with a number of diseases and the fungal genes are becoming linked to pathogenesis. Human P4-ATPase mutations are linked to neurological disease (ATP8A2, ATP9A, ATP8B2, ATP10B, ATP11A), metabolic and cardiovascular disease (ATP10A, ATP10D), cholestasis and hearing loss (ATP8B1), systemic sclerosis (ATP8B4), severe Covid-19 (ATP11A), cancer progression (ATP11B) and hemolytic anemia (ATP11C) (22,23,(32)(33)(34)(35)(36)(37)(24)(25)(26)(27)(28)(29)(30)(31). The P4-ATPase Apt1-Cdc50 from Cryptococcus neoformans transports a variety of substrates, including GlcCer, and is essential in polysaccharide secretion, stress tolerance, fungal survival inside macrophages, and virulence (38)(39)(40)(41).…”

Clinical Characteristics Suggestive of a Genetic Cause in Cerebral Palsy: A Systematic Review

“…After initial screening, 134 articles were included for data extraction and analysis based on full-text review. [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146]…”