Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies.

Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals.

Pain management challenges in a patient with mucopolysaccharidosis IVA.

It is important to consider all potential pain management modalities including alternative treatment on managing complex pain presentations. Acupuncture is a treatment modality that may result in reduction of pain in patients with significant medical comorbidities due to MPS IVA.

Intellectual disability: A potentially treatable condition.

The application of genomics has greatly increased the diagnosis of specific monogenic causes of intellectual disability and improved our understanding of the neuronal processes that result in cognitive impairment. Meanwhile, families are building rare disease communities and seeking disease-specific treatments to change the trajectory of health and developmental outcomes for their children. To date, treatments for intellectual disability have focussed on metabolic disorders, where early treatment has improved cognition and neurodevelopmental outcomes.

The Mendelian disorders of chromatin machinery: Harnessing metabolic pathways and therapies for treatment.

The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions.

Gathering the Stakeholder's Perspective: Experiences and Opportunities in Rare Genetic Disease Research.

Background: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders' (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation.

Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis.

Objectives: Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria ( variants) and infantile sialic acid storage disease/Salla disease ( variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders.

The experience of one pediatric geneticist with telemedicine-based clinical diagnosis.

Telemedicine has long been considered as an attractive alternative methodology in clinical genetics to improve patient access and convenience. Given the importance of the dysmorphology physical examination and anthropometric measurement in clinical genetics, many have wondered if lost information would hamper diagnosis. We previously addressed this question by analyzing thousands of diagnostic encounters in a single practice involving multiple practitioners and found no evidence for a difference in new molecular diagnosis rates.

Novel chorioretinal findings in two siblings with mucopolysaccharidosis type VI.

Purpose: To describe and compare the systemic and ocular findings in two siblings with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), one treated with recombinant galsulfase, and one who was untreated.

Method: One female patient aged 33 years (case 1) who had received galsulfase enzyme replacement therapy for 11 years, and her younger male sibling by 3 years (case 2), who had declined systemic treatment, underwent clinical ophthalmic examination and retinal ocular coherence tomography. The female sibling underwent electrophysiology testing of visual function.

Distinct diagnostic trajectories in NBAS-associated acute liver failure highlights the need for timely functional studies.

Variants of uncertain significance (VUS) are commonly found following genomic sequencing, particularly in ethnically diverse populations that are underrepresented in large population databases. Functional characterization of VUS may assist in variant reclassification, however these studies are not readily available and often rely on research funding and good will. We present four individuals from three families at different stages of their diagnostic trajectory with recurrent acute liver failure (RALF) and biallelic variants, confirmed by either trio analysis or cDNA studies.

Consolidation of the clinical and genetic definition of a related neurodevelopmental syndrome.

Background: A neurodevelopmental syndrome was recently reported in four patients with heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.

Methods: We newly identified 17 patients with variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature.

Early-onset vitamin B-dependent epilepsy due to pathogenic variants in a premature infant: A case report and review of the literature.

Vitamin B-dependent epilepsies are a heterogeneous group of disorders characterized by decreased availability of the active cofactor pyridoxal-5'-phosphate (PLP). While pathogenic variants in or genes account for most cases of these disorders, biallelic pathogenic variants in have been shown to cause a form of early onset vitamin B-dependent epilepsy (EPVB6D). PLPBP is thought to play a role in the homeostatic regulation of vitamin B, by supplying PLP to apoenzymes while limiting side-reaction toxicity related to excess unbound PLP.

Galactose treatment of a PGM1 patient presenting with restrictive cardiomyopathy.

We report a patient diagnosed with PGM1-CDG at 11 years of age after two biallelic likely pathogenic variants in were found on research genomic sequencing. To our knowledge, he is the first patient with PGM1-CDG to be reported with a restrictive cardiomyopathy. Other clinical manifestations included cleft palate, asymptomatic elevated transaminases, intellectual disability and myopathy resulting in exercise intolerance.

Acute liver dysfunction with delayed peak of serum aminotransferase levels as a presentation of ornithine transcarbamylase deficiency in females.

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease.

Smith-Lemli-Opitz syndrome: clinical and biochemical correlates.

Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis.

Methods: We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features.

Advances in genomic testing.

Background: Advances in genomic technology and our understanding of Mendelian disease-causing genes have led to an increased use of genomic testing in clinical practice.

Objective: The aim of this paper is to outline recent advances in genetic and genomic testing and the implications for clinical practice.

Discussion: Next-generation genomic sequencing is improving the diagnostic yield for patients with suspected genetic disease.