Kufor-Rakeb syndrome-associated psychosis: a novel loss-of-function ATP13A2 variant and response to antipsychotic therapy.

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

Adults with paternal UPD14 causing Kagami-Ogata syndrome: Case report and review of the literature.

Kagami-Ogata syndrome (KOS) is a clinically recognizable syndrome in the neonatal period. It is characterized by specific skeletal anomalies and facial dysmorphisms. It is typically caused by paternal uniparental disomy of chromosome 14, while epimutations and microdeletions are less commonly reported causes. In the pediatric setting, KOS is a well delineated syndrome. However, there is a dearth of literature describing the natural history of the condition in adults. Herein, we describe a 35-year-old man, the first adult with KOS reported due to paternal uniparental disomy 14, and review reports of KOS in other affected adults. This highlights the variability in neurocognitive phenotypes, the presence of connective tissue abnormalities, and the uncertainties around long-term cancer risk.