Natural history of adults with KBG syndrome: A physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Cannabidiol treatment of severe refractory epilepsy in children and young adults.

INTRODUCTION: Since 2016, the Paediatric Department of the Filadelfia Epilepsy Hospital, Denmark, has been treating patients with cannabidiol for severe refractory epilepsy. This study describes treatment results, evaluates the effect of clobazam co-medication and compares findings in Dravet and Lennox-Gastaut patients with results in patients with other epilepsies. METHODS: This was a retrospective cohort study including 78 patients treated with off-label cannabidiol in 2016-2019. Diagnoses, previous and concomitant treatment, and presence of motor seizures were assessed. Effect on seizures was evaluated by seizure frequency registration or perceived effect in patients without seizure frequency registration. RESULTS: In 51 patients with seizure frequency registration, 31.4% had ≥ 50% seizure reduction at three months, 31.1% at six months, 28.1% at 12 months and 20.0% at 24 months. At the same periods, some degree of seizure reduction was: 68.6%, 57.8%, 46.9% and 20.0%, respectively. Seizure reduction was higher with clobazam co-medication. In Dravet and Lennox-Gastaut patients, 70.0% had ≥ 50% seizure reduction at three months compared with 22.0% in patients with other epilepsies, where some degree of seizure reduction at three months were 80.0% and 65.9%, respectively. CONCLUSIONS: Cannabidiol is a treatment option in children and young adults with severe refractory epilepsy other than Dravet and Lennox-Gastaut syndromes, but close evaluation of its effects is important to taper off treatment in case a treatment effect is lacking. Clobazam co-medication increases seizure reduction. FUNDING: none. TRIAL REGISTRATION: not relevant.

Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1.

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Mosaicism for c.431_454dup in ARX causes a mild Partington syndrome phenotype.

A common in frame duplication in ARX (c.431_454dup24) was found in a five year-old boy who presented with mild Partington syndrome. The duplication was detected by PCR amplification followed by fragment length analysis and was located in exon 2 spanning the two polyalanine tracts commonly seen to expand. Detection of the duplication by DNA sequencing was difficult due to preferential sequencing of the normal allele, demonstrating the superiority of fragment length analysis in mosaic cases. The clinical symptoms were mild to moderate developmental delay with only the hand dystonia to suggest Partington syndrome. This patient is the first male reported to be mosaic for the duplication, and his clinical features are subtle. This study shows that in males with a phenotype of mild Partington syndrome and in heterozygous females fragment length analysis should be preferred over DNA sequencing.