Pediatrics

Armstrong, E. S., J. Reynolds, S. Carroll, C. Sturdivant and M. S. Suterwala (2019). “Comparing videofluoroscopy and endoscopy to assess swallowing in bottle-fed young infants in the neonatal intensive care unit.” J Perinatol Jul 22. [Epub ahead of print].

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OBJECTIVE: To determine the diagnostic accuracy of videofluoroscopy (VFSS) and endoscopy (FEES) in detecting laryngeal penetration and tracheal aspiration in bottle-fed young infants in the NICU. STUDY DESIGN: VFSS and FEES findings of 22 infants were compared to each other and to a composite reference standard in this prospective study. Sensitivity, specificity, positive and negative predictive values were calculated for each assessment. RESULT: Agreement between VFSS and FEES was high (92%) for aspiration and moderate (56%) for penetration, with FEES detecting more instances of penetration. Compared to the composite reference standard, FEES had greater sensitivity and a higher negative predictive value for penetration than VFSS. Because of the low prevalence of aspiration, diagnostic accuracy could not be determined for aspiration for either assessment. CONCLUSION: FEES appears to be more accurate in detecting penetration in this population, and both assessments are valuable tools in a comprehensive feeding and swallowing evaluation.

Mochel, F., C. Delorme, V. Czernecki, J. Froger, F. Cormier, E. Ellie, N. Fegueux, S. Lehericy, S. Lumbroso, R. Schiffmann, P. Aubourg, E. Roze, P. Labauge and S. Nguyen (2019). “Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.” J Neurol Neurosurg Psychiatry Jun 18. [Epub ahead of print].

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a severe neurodegenerative disease leading to death usually within a few years after symptoms onset. Patients present with cognitive decline, behavioural changes and pyramidal signs in the context of patchy white matter lesions. ALSP is a primary microgliopathy caused by haploinsufficiency of the colony-stimulating factor 1 receptor (CSF1R). CSF1R is critical for the development, maintenance and activation of microglia. We hypothesised that haematopoietic stem cell transplantation (HSCT) can be relevant in ALSP by correcting CSF1R loss-of-function in microglia. We provide the first prospective report of a patient with ALSP with a 30-month follow-up after a successful HSCT. We present in parallel the clinical outcome of a consecutive patient with similar age, sex and disease course who did not undergo HSCT . . . We present the positive long-term outcome of HSCT in a patient with CSF1R-related ALSP. This patient presented with a rapidly progressive disease evolution before HSCT, as usually observed in ALSP. Her dreadful neurological decline stopped from 6 months post-transplant and DWI lesions kept regressing 30 months post-transplant. A consecutive patient with similar age, sex and disease course who did not undergo HSCT suffered a dramatic worsening of her disease. A patient with ALSP, misdiagnosed as metachromatic leukodystrophy and transplanted for that reason, seems to have remained stable but no further detail is available. Instead, we provide the first detailed prospective report of HSCT in CSF1R-related ALSP. Further observations are encouraged to confirm the ability of HSCT to halt disease progression in ALSP. (Excerpts from text, p. 1, 2; no abstract available.)

Tian, W., Z. Ye, S. Wang, M. A. Schulz, J. Van Coillie, L. Sun, Y. H. Chen, Y. Narimatsu, L. Hansen, C. Kristensen, U. Mandel, E. P. Bennett, S. Jabbarzadeh-Tabrizi, R. Schiffmann, J. S. Shen, S. Y. Vakhrushev, H. Clausen and Z. Yang (2019). “The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells.” Nat Commun 10(1): 1785.

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Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of alpha-galactosidase A in a Fabry disease mouse model, and find that an alpha2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

Saint-Val, L., T. Courtin, P. Charles, C. Verny, M. Catala, R. Schiffmann, O. Boespflug-Tanguy and F. Mochel (2019). “GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination.” AJNR Am J Neuroradiol Apr 25. [Epub ahead of print].

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Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.

Choquet, K., D. Forget, E. Meloche, M. J. Dicaire, G. Bernard, A. Vanderver, R. Schiffmann, M. R. Fabian, M. Teichmann, B. Coulombe, B. Brais and C. L. Kleinman (2019). “Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200.” J Biol Chem 294(18): 7445-7459.

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RNA polymerase III (Pol III) is an essential enzyme responsible for the synthesis of several small noncoding RNAs, a number of which are involved in mRNA translation. Recessive mutations in POLR3A, encoding the largest subunit of Pol III, cause POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), characterized by deficient central nervous system myelination. Identification of the downstream effectors of pathogenic POLR3A mutations has so far been elusive. Here, we used CRISPR-Cas9 to introduce the POLR3A mutation c.2554A–>G (p.M852V) into human cell lines and assessed its impact on Pol III biogenesis, nuclear import, DNA occupancy, transcription, and protein levels. Transcriptomic profiling uncovered a subset of transcripts vulnerable to Pol III hypofunction, including a global reduction in tRNA levels. The brain cytoplasmic BC200 RNA (BCYRN1), involved in translation regulation, was consistently affected in all our cellular models, including patient-derived fibroblasts. Genomic BC200 deletion in an oligodendroglial cell line led to major transcriptomic and proteomic changes, having a larger impact than those of POLR3A mutations. Upon differentiation, mRNA levels of the MBP gene, encoding myelin basic protein, were significantly decreased in POLR3A-mutant cells. Our findings provide the first evidence for impaired Pol III transcription in cellular models of POLR3-HLD and identify several candidate effectors, including BC200 RNA, having a potential role in oligodendrocyte biology and involvement in the disease.