Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Novel DCC variants in congenital mirror movements and evaluation of disease-associated missense variants.

Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases. We re-evaluated the 15 known disease-associated DCC missense variants by determining minor allele frequency (MAF) and pathogenicity using four in silico tools combining previous pathogenicity scores and the ACMG/AMP standards and guidelines and classified them in three groups. Group I contains three DCC missense variants that are rather unlikely to be associated with a higher risk to CMM and/or ACC. The five variants in group II may represent susceptibility factors to altered midline crossing in the central nervous system. Group III includes seven variants absent in publically available databases and representing possible pathogenic alleles, with four predicted to have a severe impact on protein function. Based on this data and the variable expressivity and incomplete penetrance present in heterozygous carriers of a DCC variant, classification and clinical interpretation of missense variants is challenging in the absence of evidence of pathogenicity originated from functional studies. Evaluation of missense variants by MAF and a weighted combination of several computational algorithms is recommended.

A novel ATP1A3 mutation with unique clinical presentation.

Mutations in the ATP1A3 gene are associated with rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) as well as RDP/AHC intermediate presentations. Phenotypic diversity is being recognized. In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP. A novel heterozygous ATP1A3 missense mutation c.2600G>A (p.Gly867Asp, G867D) was detected in a 15-year-old girl. Her clinical phenotype is partially consistent with an intermediate presentation between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism and comprises additional yet unreported features. With onset at 4½ years of age recurrent paroxysmal flaccid hemiplegia alternating in laterality was triggered by watching television or playing computer games. Occlusion of both eyes reliably stopped the plegic attacks with the patient remaining awake. Our observation further widens the phenotypic spectrum associated with ATP1A3 mutations.

The expanding clinical and genetic spectrum of ATP1A3-related disorders.

OBJECTIVE: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. METHODS: We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. RESULTS: Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. CONCLUSION: AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.

Children's Depression Screener (ChilD-S): development and validation of a depression screening instrument for children in pediatric care.

The aim of the present study was to develop and validate the Children's Depression Screener (ChilD-S) for use in pediatric care. In two pediatric samples, children aged 9-12 (N(I) = 200; N(II) = 246) completed an explorative item pool (subsample I) and a revised item pool (subsample II). Diagnostic accuracy of each of the 22 items from the revised pool was evaluated in order to select the best items for the brief instrument ChilD-S. Areas under the curve (AUCs) of the revised item pool and the ChilD-S were compared. A diagnostic interview, the Kinder-DIPS, served as gold standard. For the purpose of screening for depressive disorders in children, the eight-item ChilD-S (AUC = 0.97) performed just as well as the revised 22-item pool (AUC = 0.94). For the ChilD-S the optimal cut-off point of ≥11 yielded a sensitivity of 0.91 and a specificity of 0.89. The ChilD-S shows high potential for depression screening of children in pediatric care.