Explore the vast range of titles available.

Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2. To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result. An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management. Ontario's pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.

Kym Boycott, Mark O'Driscoll and colleagues report identification of mutations in STAMBP , a gene encoding the deubiquitinating isopeptidase STAMBP, in individuals with microcephaly–capillary malformation syndrome. Microcephaly–capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP , a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor–mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.

Abstract Purpose Newborn screening for 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) has a high false-positive rate. A second-tier steroid profile using liquid chromatography mass spectrometry can improve specificity. Multiple screening algorithms were evaluated to optimize the performance of screening for salt-wasting CAH (SW-CAH). Methods Principal components analysis guided potential combinations of steroid biomarkers for evaluation in a study population of 1710 immunoassay-positive samples proceeding to the second-tier steroid profile in the Newborn Screening Ontario program between August 2020 and April 2023. A Monte Carlo simulation was used to evaluate the performance of algorithms and cutoffs. Results Optimal performance for the identification of SW-CAH used a 3-component second-tier algorithm: detectable 21-deoxycortisol (≥ 2.1 nmol/L); 17-hydroxyprogesterone + 21-deoxycortisol ≥ 40 nmol/L; and ratio of (17-hydroxyprogesterone + 21-deoxycortisol)/cortisol ≥ 0.3. All 8 cases of SW-CAH were accurately identified with a positive predictive value of 70% and 100% sensitivity for SW-CAH, whereas 1 known case of simple virilizing (SV) CAH screened negative. When applied to 26 historical cases, the algorithm identified all 13 cases of SW-CAH and all 6 SV-CAH cases, whereas other forms of CAH were filtered out because of low 21-deoxycortisol. Conclusion Using 21-deoxycortisol for second-tier screening and applying a 3-component algorithm can improve performance of newborn screening for SW-CAH, reducing burden on patients and the health care system. Although cases of SV-CAH may be identified, the thresholds were set to identify life-threatening SW-CAH with a high positive predictive value and 100% sensitivity.

Mutations in ABCC9 have been implicated in the development of Cantu syndrome, Brugada syndrome and isolated dilated cardiomyopathy (DCM). ABCC9 codes for the SUR2A subunit of the cardiac K(ATP) channel. Missense mutations are implicated in the development of Cantu as gain of function effects, but a null mutation has been reported in the literature as causing isolated DCM. We report a large family with an ABCC9 mutation. The female proband presented at age 63 with severe bradycardia requiring a pacemaker, and was diagnosed at age 67 with DCM. A heterozygous null mutation in ABCC9, c.169C >T (p. Gln57X) in exon 2 was discovered and was reported in 2009 as presumed pathogenic. Her obligate carrier brother had severe DCM in his mid 50’s requiring cardiac transplantation. Her obligate carrier sister is reported to have a pacemaker in her 60’s with no DCM. In the subsequent generation, a male with the mutation at age 46 had a normal LV size and function, with a reported mild concentric LVH. Four other mutation carriers (ages 32, 40, 42 and 59) have no echocardiographic evidence of DCM. Although non-penetrance and variable expressivity could explain the large number of unaffected mutation carriers in the family, it remains unclear if this ABCC9 mutation is responsible for the DCM in this family. Despite mutations in this gene being reported in 2004 as causing DCM, there are few subsequent reports of affected families, and no reports of familial segregation. This family illustrates the difficulty in interpreting molecular results when literature is limited and published before more stringent criteria for pathogenicity were established. The importance of careful family follow up of purported genetic mutations cannot be overstated. A critical literature review and correlating familial genotype and phenotype information should be performed when interpreting molecular genetic test results.

Dépistage de l’amyotrophie spinale chez le nouveau-né : recommandations sur le dépistage et le suivi de la maladie en Ontario.