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Cognitive impairment in multiple sclerosis (MS) can adversely impact participation in employment, activities of daily living, and wider society. It affects 40–70% of people living with MS (pwMS). There are few effective treatments for cognitive impairment in people with MS. Neuromodulation with intermittent theta-burst stimulation (iTBS) has potential for treating cognitive impairment in pwMS. This single-centre mixed-methods feasibility randomised controlled trial (NCT04931953) will assess feasibility, acceptability, and tolerability of procedures used for applying iTBS for improving cognitive performance in pwMS. Participants will be randomised into three intervention groups with varying lengths of iTBS treatment (from 1 to 4 weeks) and a sham-control group. Quantitative data will be collected at three time points (baseline, end of intervention, and 8-week follow-up). End of the intervention semi-structured interviews will explore the views and experiences of the participants receiving the intervention, analysed using framework analysis. Quantitative and qualitative data will be synthesised to explore the impact of the iTBS intervention. Ethical approval has been received from the Health Research Authority (21/LO/0506) and recruitment started in June 2022. The results will inform the design of an RCT of the efficacy of iTBS as a therapeutic intervention for cognitive impairment in pwMS.

Background/Objectives: Ataxia telangiectasia (A‐T) is an inherited multisystem disorder with increased sensitivity to ionising radiation and elevated cancer risk. Although other cancer predisposition syndromes have established cancer screening protocols, evidence‐based guidelines for cancer screening in A‐T are lacking. This study sought to assess feasibility of a cancer screening protocol based on whole‐body MRI (WB‐MRI) in children and young people with A‐T. Design/Methods: Children and young people with A‐T were invited to undergo a one‐off non‐sedated 3‐Tesla WB‐MRI. Completion rate of WB‐MRI was recorded and diagnostic image quality assessed by two experienced radiologists, with pre‐specified success thresholds for scan completion of >50% participants and image quality between acceptable to excellent in 65% participants. Positive imaging findings were classified according to the ONCO‐RADS system. Post‐participation interviews were performed with recruited families to assess the experience of participating and feelings about waiting for, and communication of, the findings of the scan. Results: Forty‐six children and young people with A‐T were identified, of which 36 were eligible to participate, 18 were recruited and 16 underwent WB‐MRI. Nineteen parents participated in interviews. Fifteen participants (83%) completed the full WB‐MRI scan protocol. The pre‐specified image quality criterion was achieved with diagnostic images obtained in at least 93% of each MRI sequence. Non‐malignant scan findings were present in 4 (25%) participants. Six themes were identified from the interviews: (1) anxiety is a familiar feeling, (2) the process of MRI scanning is challenging for some children and families, (3) preparation is essential to reduce stress, (4) WB‐MRI provides the reassurance about the physical health that families need, (5) WB‐MRI experience turned out to be a positive experience and (6) WB‐MRI allows families to be proactive. Conclusion: This study shows that WB‐MRI for cancer screening is feasible and well‐accepted by children and young people with A‐T and their families. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Cognitive impairment in multiple sclerosis (MS) can adversely impact participation in employment, activities of daily living, and wider society. It affects 40–70% of people living with MS (pwMS). There are few effective treatments for cognitive impairment in people with MS. Neuromodulation with intermittent theta-burst stimulation (iTBS) has potential for treating cognitive impairment in pwMS. This single-centre mixed-methods feasibility randomised controlled trial (NCT04931953) will assess feasibility, acceptability, and tolerability of procedures used for applying iTBS for improving cognitive performance in pwMS. Participants will be randomised into three intervention groups with varying lengths of iTBS treatment (from 1 to 4 weeks) and a sham-control group. Quantitative data will be collected at three time points (baseline, end of intervention, and 8-week follow-up). End of the intervention semi-structured interviews will explore the views and experiences of the participants receiving the intervention, analysed using framework analysis. Quantitative and qualitative data will be synthesised to explore the impact of the iTBS intervention. Ethical approval has been received from the Health Research Authority (21/LO/0506) and recruitment started in June 2022. The results will inform the design of an RCT of the efficacy of iTBS as a therapeutic intervention for cognitive impairment in pwMS. [ABSTRACT FROM AUTHOR]

OBJECTIVE. Our goal was to describe the neurologic and clinical features of affected males from families with X-linked patterns of severe mental retardation, hypotonia, recurrent respiratory infection, and microduplication of Xq28 that consistently includes the MECP2 (methyl-CpG binding protein 2) gene. STUDY DESIGN. To identify duplications, multiplex ligation-dependent probe amplification of the MECP2 gene was performed on male probands from families with X-linked mental retardation. The males either had linkage to Xq28 or had a phenotype consistent with previous reports involving Xq28 functional disomy. After detection of a duplication of MECP2, additional family members were tested to confirm the MECP2 duplication segregated with the affected phenotype, and X-inactivation studies were performed on carrier females. RESULTS. Six families with multiple affected males having MECP2 duplications were identified by multiplex ligation-dependent probe amplification, and the carrier mothers were subsequently shown to have highly skewed X inactivation. In 5 of 6 families, the microduplication extended proximally to include the L1 cell adhesion molecule gene. The primary clinical features associated with this microduplication are infantile hypotonia, recurrent respiratory infection, severe mental retardation, absence of speech development, seizures, and spasticity. CONCLUSIONS. Although many of the phenotypic features of our patients are rather nonspecific in cohorts of individuals with syndromic and nonsyndromic mental retardation, the proneness to infection is quite striking because the patients had normal growth and were not physically debilitated. Although the etiology of the infections is not understood, we recommend considering MECP2 dosage studies and a genetics referral in individuals with severe developmental delay and neurologic findings, especially when a history of recurrent respiratory ailments has been documented. KEY WORDS. mental retardation, hypotonia, recurrent infection, MECP2, duplication., PEDIATRICS 2006;118:e1687-e1695. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0395 Michael J. Friez, PhD, Julie R. Jones, PhD, Katie Clarkson, MD, Herbert Lubs, MD, Dianne Abuelo, MD, Jo-Ann Blaymore Bier, MD, Shashidhar Pai, MD, Richard Simensen, [...]