Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders.

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)-valine(406)-proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype-phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient.

Multiple sulfatase deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD). Mutations in the SUMF1 gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi-organ failure. MSD was caused by a homozygous SUMF1 stop mutation (c.191C>A, p.Ser64Ter). FGE protein and sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two sulfatases, and molecular confirmation.

Soluble CD90 as a potential marker of pulmonary involvement in systemic sclerosis.

OBJECTIVE: Vascular injury and endothelial cell (EC) activation are pathogenic hallmarks of systemic sclerosis (SSc; scleroderma). Human CD90 is highly expressed on activated ECs and can be shed from the cell surface. This study was conducted to examine whether soluble CD90 (sCD90) is elevated in the sera of patients with SSc and linked to pulmonary involvement and in particular, pulmonary arterial hypertension (PAH). METHODS: sCD90 serum concentrations were assessed in 76 patients with SSc and related to clinical data, lung function, 6-minute walk distance, echocardiography, bronchoalveolar lavage fluid, and laboratory parameters. Thirty-one healthy volunteers and 29 patients with idiopathic retroperitoneal fibrosis (IRF) served as controls. RESULTS: sCD90 serum concentrations were elevated in patients with SSc compared to healthy volunteers (P = 0.001) and patients with IRF (P = 0.01). SSc patients with pulmonary fibrosis (P = 0.006) and patients with PAH (P < 0.001) had increased sCD90 serum concentrations compared to patients without the respective pulmonary manifestation of SSc. sCD90 levels correlated with diffusing capacity for carbon monoxide (n = 65; r = -0.348, P = 0.005) and systolic pulmonary artery pressure (n = 53; r = 0.469, P < 0.001). Receiver operating characteristic curve testing determined an optimal cutoff value of ≥626 ng/ml with a sensitivity of 68% and a specificity of 83% for PAH (area under the curve 0.773, 95% confidence interval 0.648-0.898; P < 0.001). CONCLUSION: sCD90 concentrations were increased in the sera of SSc patients, particularly in patients with vascular involvement of the lungs. These data suggest that sCD90 should be further evaluated as a marker for diagnosis of PAH in SSc.

Elevated serum osteopontin levels in idiopathic retroperitoneal fibrosis.

OBJECTIVES: To investigate the role of serum osteopontin concentrations for monitoring idiopathic retroperitoneal fibrosis. METHODS: In 22 patients with idiopathic retroperitoneal fibrosis serum concentrations of osteopontin were measured by an enzyme-linked immunosorbant assay and related to retrospectively gathered clinical data, contrast enhanced magnetic resonance imaging studies, and laboratory parameters. Patients with secondary causes, an inflammatory abdominal aortic aneurysm, and immunoglobulin G4-associated idiopathic retroperitoneal fibrosis were excluded. Twenty-two healthy volunteers served as controls. RESULTS: Serum osteopontin concentrations of patients with idiopathic retroperitoneal fibrosis were elevated compared to healthy controls (p=0.017) and correlated with the transverse diameter of the periaortic cuff as determined by imaging studies (ρ=0.549; p=0.008). Patients presenting with a diameter greater than 10mm had higher osteopontin concentrations than patients with smaller diameters (p=0.004). Increased inflammatory activity as determined by the presence of contrast enhancement in imaging studies (p<0.001) and the presence of typical symptoms (p=0.013) were associated with higher osteopontin concentrations. CONCLUSIONS: Serum osteopontin concentrations were elevated in patients with idiopathic retroperitoneal fibrosis. Increased concentrations correlated with the presence of clinical symptoms and extended disease or activity parameters on magnetic resonance imaging.