Heterozygous deletion in exon 6 of STEX gene causing ataxia with oculomotor apraxia type 2 (AOA-2) with ovarian failure

Ataxia with oculomotor apraxia type 2 (AOA2), recently renamed as ATX-SETX, is an autosomal recessive, progressive neurodegenerative disorder belonging to inherited cerebellar ataxias. The pathogenic variants of the SETX gene have been implicated in ATX-SETX. We report the case of a 21-year-old woman presenting with ataxia, oculomotor apraxia and dystonia. She had elevated serum α-fetoprotein (AFP), follicle stimulating hormone (FSH) and luteinising hormone (LH) levels and moderate cerebellar atrophy. On further evaluation, she was found to have premature ovarian failure as well. Multiplex ligation-dependent probe amplification detected a heterozygous deletion in exon 6 of the SETX gene. A combination of cerebellar ataxia, oculomotor apraxia with elevated AFP and cerebellar atrophy are highly suggestive of ATX-SETX. In rare instances, it may be associated with premature ovarian failure with elevated FSH and LH levels, necessitating hormonal survey and fertility evaluation in all patients with ATX-SETX.

Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2

Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased transcription stress near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. In the absence of Senataxin, we found that Cockayne Syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and recombination protein RAD52 to target and resolve transcription bubbles containing R-loops, leading to error prone repair and genomic instability. These results show that transcription stress is an important contributor to SETX mutation-associated chromosome fragility and AOA2.

Corticobasal syndrome with Balint syndrome: a clue for Alzheimer disease pathology

Context: Balint syndrome (BS), first described in 1909, has three core features: optic ataxia, oculomotor apraxia and simultanagnosia, and has been described after various conditions amongst vascular, infectious, demyelinating and degenerative diseases1 . It has already been reported concomitant with corticobasal syndrome (CBS)2 . Case report: 59 year-old male without history of previous diseases presented with behavior changes in the last two years. He had a previous diagnosis of “stroke” because frequent falls to the left side and difficulty in using his left hand for simple daily activities. After that, he gradually evolved with visual problems (bumped into objects inside his house), fear of walking or sitting, and required constant assistance for basic activities of daily living. On physical examination he presented with clear visuospatial dysfunction, characterized by simultanagnosia, oculomotor apraxia and optic ataxia. Bilateral asymmetric upper limb apraxia (worse on left side), dystonic posturing and stimulus-sensitive myoclonus in the left arm were also present. No signs of parkinsonism or language/speech disturbances were identified. Brain MRI showed severe asymmetric biparietal lobe atrophy (right more than left). DISCUSSION: The pathologic findings underlying CBS are variable, including Corticobasal Degeneration, Progressive Supranuclear Palsy, Frontotemporal Lobar Degeneration and Alzheimer Disease (AD). The association of BS and CBS favors the possibility of AD pathologic findings3 . Imaging methods like FDG-PET have recently been shown to be capable of distinguishing AD-related CBS from those associated with other pathologies4 . FDG-PET is not widely available in our country; than the presence of BS in CBS patients may individualize their treatment.

Largest Cohort Study of Gaucher Disease Type 3 from a Single Center in Egypt Spanning Two Decades

Background and objectives:Gaucher disease (GD) is renowned for genotype/phenotype studies and therapeutic innovation. However, the vast majority of the literature is focused on Type 1 GD related to the founder mutation, p.Asn409Ser in GBA gene although p.Leu483Pro GBA mutation associated GD may be far more prevalent across the world. In Egypt GD represents as high as 14.7% of all reported lysosomal disorders with the neuronopathic forms. Therefore, a large single center cohort study of a highly consanguineous GD population has the potential to inform genotype/phenotype, natural history studies and illuminate unmet needs. Methods:At University of Cairo's Pediatric Hematology Clinic since 1998, we have managed a total of 156 patients with GD with longitudinal data captured under an approved IRB protocol. In the present study, we focused analysis on 85 patients in whom we had long-term outcome after 20 years of enzyme replacement therapy (ERT). GBA gene analysis was performed by whole exome sequencing of DNA isolated from dry blood spots. Data on the clinical phenotype indicators at baseline and during ERT were collected including liver and spleen volumes, growth parameters, bone status, neurological assessment and eye movement. SPSS (Statistical Package for the Social Sciences) version 24 was used to compile data, assess significance and survival by Kaplan Meier analysis. Overall survival (OS) is defined as date of diagnosis till date of death, patients alive or lost during follow up was considered censored till the last date of follow up. Results:The median age at diagnosis was 1 year (IQR: 0.08-15 years) with majority (64.7%) diagnosed in first 2 years of life (range 0.5-2 yrs). The patient population was highly consanguineous and 51% of the patients reported positive family history of GD. The most prevalent genotype (75% of patients) was p.Leu483Pro homozygous. Homozygosity for p.Asp448His was present in 11% of patients. Other GBA mutations included: p.Leu483Pro homozygous in 3 patients, one heteroallelic with p.Leu483Pro; pArg87Trp homozygous in 2 patients; p.Arg398Gln homozygous in one patient). Hematological features of patients at diagnosis revealed anemia in 76% and thrombocytopenia in 22%. Massive splenomegaly (˃15 Multiples of Normal by ultrasonography) was present in 49%, 4 patients were splenectomised, hepatomegaly (˃2.5 MN) in 11%, liver cirrhosis with hepatopulmonary syndrome in one patient. Skeletal findings included multiple fractures in 3 patients and kyphosis in 3 patients. The most common neurological findings were oculomotor apraxia, squint and bulbar symptoms (48%, 30.6% and 29.4% respectively). Bone marrow examination showed Gaucher cell infiltration in 76% of the patients. Patients received Imiglucerase (Cerezyme) dose individualized by baseline disease severity. Debilitating and potentially life-threatening visceral and hematologic disease was reversed with ERT (table 1). One splenectomized patient with massive hepatomegaly and hepatopulmonary syndrome showed complete reversal on high dose ERT. Preliminary observer reported outcomes (by clinician and parent) with respect to neurological findings including oculomotor apraxia appeared to show mild improvement. Follow-up of 10 patients in whom ERT was initiated early had striking overall outcomes progressing through school and university. At 20 years, the overall survival was 71%; 20 patients died from disease complications mostly pulmonary and progressive neurological disease. Comparison of the OS in relation to gender, age at diagnosis, severity of hematological and visceral parameters showed that none of the studied variables affects OS (p˃0.05) (fig. 1). Conclusion:This study represents the largest and most extensive single-center cohort of GD3 patients with predominant p.Leu483Pro homozygous GBA genotype, without presence of a complex allele. Patients had uniformly very early-onset disease before age 2 years with devastating hematological and visceral disease which was effectively reversed by ERT. During 20 year-follow up of the cohort, there was striking reversal of hematovisceral disease and about a third of the patients succumbed to complications of GD3. OS was not correlated with severity of baseline disease underscoring the potential role of modifier genes. Disclosures No relevant conflicts of interest to declare.

Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2

Ataxia with oculomotor apraxia type 2 (AOA2) is a slowly progressive, autosomal recessive disease characterized by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy. The genetic basis of AOA2 is biallelic mutation of the SETX gene, resulting in reduced or absent senataxin, a DNA/RNA repair protein essential for genomic stability.In this report, we describe a case of AOA2 with two clear pathogenic SETX mutations, one of which is novel. We then discuss two further likely in cis SETX sequence changes, previously reported in the literature as pathogenic, and present the case that they are likely benign polymorphisms.

Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.