MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia.

Frataxin is an evolutionarily conserved mitochondrial protein responsible for iron homeostasis and metabolism. A deficiency of frataxin (encoded by FXN) leads to Friedreich's ataxia (FRDA), a progressive disorder that affects both the central and peripheral nervous systems, most commonly via a pathogenic GAA trinucleotide expansion. In contrast, pathogenic variants in ALG1 in humans cause a form of congenital disorder of glycosylation. Here, we present a 15-year-old boy with a clinical presentation that raised concern for complex hereditary spastic paraplegia (HSP), with motor features including progressive spastic paraparesis, cervical dystonia, cerebellar dysfunction, and diminished lower extremity reflexes. The proband was initially found to have a novel compound heterozygous variant in ALG1 on exome sequencing, along with N-glycan profiling revealing evidence of defective mannosylation and Western blot analysis demonstrating an 84% reduction in ALG1 expression. Although several of his clinical features could be explained by the ALG1 variant specifically or considered as part of the presentation of CDGs in general, there were additional phenotypes that suggested an alternative, or additional, genetic diagnosis. Subsequently, he was found to have biallelic pathogenic GAA repeat expansions in FXN on genome sequencing, leading to a diagnosis of FRDA. Given that FRDA explained all his clinical features, the ALG1 variant may have been a hypomorphic form and/or a biochemical phenotype. Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.

Categorization of a Universal Coding System to Distinguish Use of Durable Medical Equipment and Supplies in Pediatric Patients.

Importance: Although durable medical equipment and supplies (DMES) are commonly used to optimize the health and function in pediatric patients, little is known about the prevalence of use and spending on DMES. Objective: To categorize the Healthcare Common Procedure Coding System (HCPCS) for distinguishing DMES types, and to measure the prevalence and related spending of DMES in pediatric patients using Medicaid. Design, Setting, and Participants: This study is a cross-sectional analysis of the 2018 Merative Medicaid Database and included 4 569 473 pediatric patients aged 0 to 21 years enrolled in Medicaid in 12 US states from January 1 to December 31, 2018. Data were analyzed from February 2019 to April 2023. Exposure: DMES exposure was identified with the Centers for Medicare & Medicaid Services HCPCS codes. Three pediatricians categorized HCPCS DMES codes submitted by vendors for reimbursement of dispensed DMES into DMES types and end-organ systems; 15 expert reviewers refined the categorization (2576 DMES codes, 164 DMES types, 14 organ systems). Main Outcomes and Measures: The main outcome was DMES prevalence & Medicaid spending. The χ2 test was used to compare DMES prevalence and Wilcoxon rank sum tests were used to compare per-member-per-year (PMPY) spending by complex chronic conditions (CCC). Results: Of the 4 569 473 patients in the study cohort, 49.3% were female and 56.1% were aged 5 to 15 years. Patients used 133 of 164 (81.1%) DMES types. The DMES prevalence was 17.1% (95% CI, 17.0%-17.2%) ranging from 10.1% (95% CI, 10.0%-10.2%) in patients with no chronic condition to 60.9% (95% CI, 60.8%-61.0%) for patients with 2 or more CCCs. The PMPY DMES spending was $593, ranging from $349 for no chronic condition to $4253 for 2 or more CCCs. Lens (7.9%), vision frames (6.2%), and orthotics for orthopedic injury (0.8%) were the most common DME in patients with no chronic condition. Enteral tube / feeding supplies (19.8%), diapers (19.2%), lower extremity orthotics (12.3%), wheelchair (9.6%), oxygen (9.0%), and urinary catheter equipment (4.2%) were among the most common DMES in children with 2 or more CCCs. Conclusions and Relevance: In this cross-sectional study, HCPCS distinguished a variety of DME types and use across pediatric populations. Further investigation should assess the utility of the HCPCS DMES categorization with efforts to optimize the quality and safety of DMES use.

[The role of neuropsychiatry in the care of children and adults with cerebral palsy].

Neuropsychiatric symptoms are commonly reported in cerebral palsy. These symptoms interact in complex ways with the core motoric features of cerebral palsy, and require specialised care. We argue for increased awareness of these symptoms by clinicians, and the need for greater integration of neuropsychiatric specialists into the core teams involved in multidisciplinary care for individuals with cerebral palsy and their families.

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

OBJECTIVES: Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP. METHODS: We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline. RESULTS: We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES. INTERPRETATION: WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.