The cleavage and polyadenylation specific factor 1 (CPSF1) gene encodes a subunit of the cleavage and polyadenylation specificity factor (CPSF), a multi-protein complex essential for mRNA 3' end processing. The role of CPSF1 in retinal function and eye development has been demonstrated using zebrafish models and heterozygous variants in CPSF1 have been reported in early-onset high myopia (MIM: 618827). Here, we present a patient with bilateral congenital cataracts and intellectual disability with a novel homozygous missense variant (c.3817G>C; p.Asp1273His) in CPSF1. This amino acid change is predicted to change the protein structure with likely damaging effect. Proteomic results in white blood cells revealed increased CPSF1 protein abundance and dysregulated proteins in pathways linked to cellular signalling processes, protein degradation, and exosome biology. To our knowledge, this is the first report of recessive CPSF1-related disease in humans presenting as a case with congenital cataracts, intellectual disability, and hyperphagia.

Muscle-Eye-Brain disease (MEB) is a dystroglycanopathy that belongs to the congenital muscular dystrophies. Central nervous system manifestations include congenital brain abnormalities, neurodevelopmental delay, and epilepsy, making it a rare but important cause of developmental and epileptic encephalopathy. This systematic review aims to explore all current literature data regarding clinical and electroencephalographic features of MEB cases with epilepsy. We conducted a literature review of previously published cases of patients with MEB and epilepsy in the PubMed and Scopus databases in the English language, focusing on seizure semiology and electroencephalographic features. We included 52 studies with 80 patients. The clinical spectrum of patients with MEB is broad, including hypotonia at birth, ocular symptoms, delay of motor milestones, and intellectual disability. Serum creatine kinase levels are significantly elevated (median value 1600 IU/L). POMGnT1 mutation is, by far, the most common mutation in MEB patients, reported in 38.8% of cases, followed by GMPPB (10%), FKTN, POMT2, or DPM2 mutations (less than 10%, respectively). Epilepsy is a common feature, with onset usually in the first 6 months of life. Absences are the most common seizure type (58.8% of patients), followed by generalized tonic-clonic (33.8%) and focal seizures (21.3%). Patients present with drug-resistant epilepsy in approximately one fourth of cases (21.3%). Electroencephalogram (EEG) shows focal or multifocal discharges in approximately half of the cases, with a predominance over frontal or temporal regions. Slow and disorganized EEG background activity is commonly observed in 92.9% of cases. Epilepsy is a common feature in MEB patients; its age of onset is usually in the first months of life, and it is often drug-resistant. It can manifest with all seizure types, with absences being the most common type. EEG shows focal or multifocal discharges with a slow and disorganized EEG background. The POMGnT1 mutation is the most common in MEB patients with epilepsy. A clear understanding of the electroclinical patterns in MEB patients can contribute to improved diagnostic precision and management.

X-linked adrenal hypoplasia congenita (AHC) is a rare, life-threatening disorder caused by pathogenic variants in NR0B1 (DAX1), leading to adrenal insufficiency and hypogonadotropic hypogonadism. AHC is often associated with Xp21 contiguous gene deletion syndrome, which involves the deletion of multiple genes, including NR0B1, GK, DMD, and IL1RAPL1, resulting in a spectrum of phenotypic manifestations, such as glycerol kinase deficiency (GKD), Duchenne muscular dystrophy (DMD), and neurodevelopmental disorders. We report two cases of AHC with neurodevelopmental delays due to contiguous Xp21 deletions involving NR0B1 and IL1RAPL1, each diagnosed through distinct clinical pathways. Case 1 involved a neonate with adrenal insufficiency, persistent hyperCKemia, and excessive urinary glycerol excretion, leading to a diagnosis of Xp21 deletion syndrome with DMD and GKD. The patient's sister, an asymptomatic carrier, exhibited elevated CK levels and mild developmental delays. Array comparative genomic hybridization identified a novel complex structural variation, including duplication-deletion-duplication rearrangement, which may have modified clinical manifestations. Case 2 involved a 10-year-old boy with AHC and developmental delay that was initially considered a consequence of adrenal crises. Genetic analysis confirmed an Xp21 deletion, including IL1RAPL1, implicating it in his intellectual disability. A literature review reveals that Xp21 deletions involving IL1RAPL1 are strongly associated with neurodevelopmental delays, suggesting a distinct phenotype within Xp21 deletion syndromes. Early genetic diagnosis via chromosomal microarray analysis facilitates precise delineation of deletion regions, aiding in clinical management, genetic counseling, and early intervention strategies. Further studies are needed to elucidate genotype-phenotype correlations in Xp21 deletion syndromes and optimize individualized medical care.

Myotonic dystrophy type 1 (DM1) is the most common adult muscular dystrophy, with variable pediatric presentations. Data on quality of life (QoL) and fatigue in children are limited. This study evaluated clinical features, QoL, and fatigue in pediatric DM1. We conducted a cross-sectional study of 24 children with genetically confirmed DM1 followed at a tertiary pediatric neuromuscular clinic between January 2020 and January 2024. Clinical data were retrospectively reviewed, and patients were categorized into congenital, childhood-onset, or juvenile-onset subtypes. QoL and fatigue were assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales, Neuromuscular Module, and Multidimensional Fatigue Module, with both parent-proxy and self-reports obtained during routine visits. The cohort (median age 14 years, IQR:8.5-15.75) comprised congenital (n = 4), childhood-onset (n = 11), and juvenile-onset (n = 9) cases. The most common presenting symptoms were hand stiffness(75 %), weakness(54 %), and learning difficulties(50 %). Intellectual disability or learning difficulties were present in 79 %. Multisystem involvement included cardiac (25 %), respiratory (17 %), gastrointestinal (42 %), and ophthalmologic (42 %) complications. Parent-proxy reports revealed reduced QoL across all subgroups (median total scores 43.5-62.0 vs. ≥80 in healthy children). Fatigue was prominent, with sleep/rest fatigue most impaired, particularly in juvenile-onset patients (median 20.8 vs. 79.2 in childhood-onset, p = 0.007). Children with DM1 exhibit significant multisystem morbidity and marked impairments in QoL and fatigue. Cognitive and behavioral difficulties are prevalent, supporting the need for routine neuropsychological assessment and educational support. Multidisciplinary care should incorporate systematic QoL and fatigue evaluation, with targeted interventions such as sleep management to optimize long-term outcomes.

Limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that generally result in weakness and loss of limb-girdle muscles, leading to severe disability and early mortality due to cardiac and respiratory complications. Heterogeneity across and within individual LGMD subtypes in addition to variability in progression rates presents significant challenges to traditional drug development approaches for these diseases. In an effort to discuss these challenges, as well as opportunities in support of advancing drug development for LGMD, on February 8, 2024, The Speak Foundation assembled a multistakeholder group consisting of academic medical experts, patients and caregivers, patient advocacy organizations, senior leaders from the US Food and Drug Administration, and commercial drug developers. This review will provide an overview of the broad range of topics discussed at the workshop, including LGMD pathophysiology, natural history studies, clinical outcomes, patient-focused drug development, surrogate end points, the Accelerated Approval pathway, and future directions for LGMD drug development. Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and brain malformations including, classically, cobblestone lissencephaly with cerebral and cerebellar dysplasia. There is a spectrum of severity and mild, typical, and severe phenotypes are recognized. Disease onset typically occurs in early infancy with poor suck/swallow, weak cry, and floppiness. Serum creatine kinase (CK) levels are usually in the thousands (10-60 times higher than normal). Motor development peaks at around age five to six years and thereafter regresses as muscle atrophy progresses. In the typical case, sitting without support or sliding along the floor on the buttocks may be the peak motor function. Deep tendon reflexes are diminished or absent after early infancy. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later-onset features include a myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death. The diagnosis of FCMD is established in a proband with biallelic pathogenic variants in FKTN identified by molecular genetic testing. Treatment of manifestations: Physical therapy and stretching exercises, treatment of orthopedic complications; mobility assistance devices such as long leg braces and wheelchairs; use of noninvasive respiratory aids or tracheostomy; prompt treatment of respiratory tract infections; anti-seizure medications; medical and/or surgical treatment for gastroesophageal reflux; gastrostomy tube placement when indicated to assure adequate caloric intake; cardiomyopathy treatment per cardiologist. Surveillance: Monitor gastrointestinal function and for signs/symptoms of gastroesophageal reflux; for orthopedic complications including foot deformities and scoliosis; for myocardial involvement by chest radiography, EKG, and echocardiography in individuals older than age ten years; and respiratory function in individuals with advanced disease. FCMD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FKTN pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FKTN pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.