Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.

Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome, however no monogenic XPO1-related disorder has been described to date.

Lymphatic Obstruction and Edema in Neonate due to Left Subclavian Central Venous Catheter.

There are several causes of generalized edema in sick neonates. We describe two newborns that developed progressive and treatment-resistant generalized edema. We suggest this is due to impaired lymphatic flow from the thoracic duct as a result of a central venous catheter in the left subclavian vein.

LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics.

LIM kinase 1 (LIMK1) plays a pivotal role in dynamic actin remodeling through phosphorylation of cofilin, thereby regulating exocytosis. We report two individuals harboring variants with dissimilar phenotypes: one exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. We suspected that the divergent phenotypic features arose from opposing effects on LIMK1 activity.

Rethinking Newborn Screening: A Case of GALM Deficiency.

Galactosemia is a group of hereditary disorders of galactose metabolism. A new type of galactosemia was discovered, caused by a deficiency in galactose mutarotase (GALM), which catalyzes the epimerization between beta- and alpha-D-galactose. All GALM-deficient patients reported in the literature (n = 44) had abnormal newborn screening (NBS) results or did not receive NBS (n = 2).

A rare triplication of 16p11.2: Unravelling the genomic complexity and review of the literature.

16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.

Reply to Bouva et al. Comment on "Dijkstra et al. A False-Negative Newborn Screen for Tyrosinemia Type 1-Need for Re-Evaluation of Newborn Screening with Succinylacetone. 2023, , 66".

We thank the authors for their comments [...

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons.

Molecular and Phenotypic Characterization of the -Related Disorder.

Background And Objectives: Heterozygous variants in RAR-related orphan receptor B () have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with pathogenic variants and to provide arguments in favor of the pathogenicity of variants.

A False-Negative Newborn Screen for Tyrosinemia Type 1-Need for Re-Evaluation of Newborn Screening with Succinylacetone.

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen.

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening.

The Wilson and Jungner (W&J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of for IMDs to decide on eligibility for NBS.

Macrocephaly and developmental delay caused by missense variants in RAB5C.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C.

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the Gene.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in .

Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency.

The sodium-dependent multivitamin transporter that facilitates the uptake of the water-soluble vitamins biotin, pantothenic acid, and the vitamin-like substance lipoate is coded by the gene. Variants in this gene cause a relatively novel treatable metabolic disorder. Here we describe the second case.

Increased dynamin expression precedes proteinuria in glomerular disease.

Dynamin plays an essential role in maintaining the structure and function of the glomerular filtration barrier. Specifically, dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, and knocking down dynamin expression causes proteinuria. Moreover, promoting dynamin oligomerization with Bis-T-23 restores podocyte function and reduces proteinuria in several animal models of chronic kidney disease.

[Fever with a rash caused by chronic meningococcemia].

Background: Fever with a rash is a common clinical presentation, which can be caused by various medical conditions.

Case Description: A 14-year old boy presented at the outpatient clinic with a two-week history of fever, myalgia and purpuric skin lesions. Blood cultures showed an infection with Neisseria meningitidis.

[A neonate with peculiarly arranged skin abnormalities].

A tropical doctor reviewed a female Malawian neonate with a vesicular rash and linear hyperpigmentation that followed the lines of Blaschko. This distribution is typical for incontinentia pigmenti, a congenital X-linked dermatosis, which usually resolves spontaneously in adolescence.

Pellagra: a non-communicable disease of poverty.

Pellagra is a disease of poverty that is treatable but easily overlooked. The disease is caused by a deficiency of niacin and is clinically characterized by the triad of dermatitis, diarrhoea and dementia. We describe two cases of pellagra in a Malawian district hospital and discuss the pathogenesis, clinical manifestations and treatment of the disease.

C4d staining in renal allograft biopsies with early acute rejection and subsequent clinical outcome.

Background And Objectives: Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during acute rejection is regarded as an inferior prognostic sign. This case-control study investigated the prognostic role of mere C4d staining for graft outcome during an ARE in a well defined cohort of similarly ARE-treated patients.