Abstract
Neurometabolic disorders are often inherited and complex disorders that result from abnormalities of enzymes important for development and function of the nervous system. Recently, biallelic mutations in NAXE (APOA1BP) were found in patients with an infantile, lethal, neurometabolic disease. Here, exome sequencing was performed in two affected sisters and their healthy parents. The best candidate, NAXE, was tested for replication in exome sequencing data from 4351 patients with neurodevelopmental disorders. Quantitative RT-PCR, western blot and form factor analysis were performed to assess NAXE expression, protein levels and to analyze mitochondrial morphology in fibroblasts. Vitamin B3 was administered to one patient. Compound heterozygous missense (c.757G>A: p.Gly253Ser) and splicing (c.665-1G>A) variants in NAXE were identified in both affected sisters. In contrast to the previously reported patients with biallelic NAXE variants, our patients showed a milder phenotype with disease onset in early adulthood with psychosis, cognitive impairment, seizures, cerebellar ataxia and spasticity. The symptoms fluctuated. Additional screening of NAXE identified three novel homozygous missense variants (p.Lys245Gln, p.Asp218Asn, p.Ile214Val) in three patients with overlapping phenotype (fluctuating disease course, respiratory insufficiency, movement disorder). Lastly, patients with the c.665-1G>A splicing variant showed a significant reduction of NAXE expression compared to control fibroblasts and undetectable NAXE protein levels compared to control fibroblasts. Based on the metabolic pathway, vitamin B3 and coenzyme Q treatment was introduced in one patient in addition to antiepileptic treatment. This combination and avoidance of triggers was associated with continuous motor and cognitive improvement. The NAXE variants identified in this study suggest a loss-of-function mechanism leading to an insufficient NAD(P)HX repair system. Importantly, symptoms of patients with NAXE variants may improve with vitamin B3/coenzyme Q administration.
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Acknowledgements
This research was supported by the Foundation of the University Medical Center Schleswig Holstein “Gutes Tun!” (A.M.). Funding has been obtained from the Hermann and Lilly Schilling Foundation, the Alexander von Humboldt Foundation, Canadian Institutes of Health Research, and the Joachim Herz Stiftung.
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Joanne Trinh, Sophie Imhoff and Marija Dulovic-Mahlow are joint first authors and equally contributed. Katja Lohmann and Norbert Brüggemann are shared last authors and equally contributed.
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415_2019_9640_MOESM2_ESM.mp4
The clinical picture was initially characterized by severe generalized spasticity, epileptic seizures and intermittent fever of unknown source as shown on two pictures from October 2015 when the patient underwent 72-hour EEG. In the second part of the video (recorded in February 2018), the tracheostomy was removed and the patient was able to eat in addition to PEG infusions. Attention, memory and other cognitive functions were improved and the patient was able to speak, to follow instructions and to have conversations. The video shows perioral dyskinesias, dystonic laterocollis, jerky head movements probably related to dystonia, and generalized spasticity impairing fine finger movements. She had divergent strabism, bilateral adductor paresis, vertical gaze-evoked nystagmus when looking upward and horizontal gaze-evoked nystagmus. There was also a positive relative afferent pupil defect of the right eye and reduced visual acuity (right 0.1, left 0.2) (not shown) (MP4 3205 kb)
The video demonstrates patient II.4 at the age of 21 years with reduced concentration and memory problems, impairment of executive function including an abnormal Luria test, finger myoclonus when holding out the arms in front of her, dysmetric and ataxic finger-to-finger tests, positive rebound phenomenon, wide-based ataxic gait and inability to perform the tandem gait independently (MOV 16491 kb)
Over the disease course, patient II.4 developed psychotic symptoms including anxiety, persecutory delusions and bizarre behaviour. She additionally presented with mild gait ataxia (MOV 21358 kb)
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Trinh, J., Imhoff, S., Dulovic-Mahlow, M. et al. Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment. J Neurol 267, 770–782 (2020). https://doi.org/10.1007/s00415-019-09640-2
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DOI: https://doi.org/10.1007/s00415-019-09640-2