Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes.

BackgroundNonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder...

Hypothalamic dysfunction may underlie endocrine abnormalities in Prader-Willi syndrome (PWS), a genetic disorder that features GH deficiency, obesity, and infertility. One of the genes typically inactivated in PWS, MAGEL2, is highly expressed in the hypothalamus. Mice deficient for Magel2 are obese with increased fat mass and decreased lean mass and have blunted circadian rhythm. Here, we demonstrate that Magel2-null mice have abnormalities of hypothalamic endocrine axes that recapitulate phenotypes in PWS. Magel2-null mice had elevated basal corticosterone levels, and although male Magel2-null mice had an intact corticosterone response to restraint and to insulin-induced hypoglycemia, female Magel2-null mice failed to respond to hypoglycemia with increased corticosterone. After insulin-induced hypoglycemia, Magel2-null mice of both sexes became more profoundly hypoglycemic, and female mice were slower to recover euglycemia, suggesting an impaired hypothalamic counterregulatory response. GH insufficiency can produce abnormal body composition, such as that seen in PWS and in Magel2-null mice. Male Magel2-null mice had Igf-I levels similar to control littermates. Female Magel2-null mice had low Igf-I levels and reduced GH release in response to stimulation with ghrelin. Female Magel2-null mice did respond to GHRH, suggesting that their GH deficiency has a hypothalamic rather than pituitary origin. Female Magel2-null mice also had higher serum adiponectin than expected, considering their increased fat mass, and thyroid (T(4)) levels were low. Together, these findings strongly suggest that loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS.

An Obese Female with Prader-Willi Syndrome and Daytime Sleepiness

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by neonatal hypotonia, developmental delay/intellectual disability, and characteristic feeding behaviors with failure to thrive during infancy; followed by hyperphagia and excessive weight gain later in childhood. Individuals with PWS also manifest complex behavioral phenotypes. Approximately 25% meet criteria for autism spectrum disorder (ASD). PWS is caused by the absence of paternally expressed, maternally silenced genes at chromosome 15q11-q13. MAGEL2 is one of five protein-coding genes in the PWS-critical domain. Truncating point mutations of the paternal allele of MAGEL2 cause Schaaf-Yang syndrome, which has significant phenotypic overlap with PWS, but is also clinically distinct; based on the presence of joint contractures, and a particularly high prevalence of autism spectrum disorder (up to 75% of affected individuals). The clinical and molecular overlap between PWS and Schaaf-Yang syndrome, but also their distinguishing features provide insight into the pathogenetic mechanisms underlying both disorders.

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.

Schaaf-Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader-Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss-of-function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation.

Prader-Willi syndrome: advances in genetics, pathophysiology and treatment

Reduced pituitary volume with relative T1 shortening correlates with behavior in Prader-Willi syndrome

Prader-Willi syndrome is caused by the loss of paternal gene expression on 15q11.2-q13.2, and one of the mechanisms resulting in Prader-Willi syndrome phenotype is maternal uniparental disomy of chromosome 15. Various mechanisms including trisomy rescue, monosomy rescue, and post fertilization errors can lead to uniparental disomy, and its mechanism can be inferred from the pattern of uniparental hetero and isodisomy. Detection of a mosaic cell line provides a unique opportunity to understand the mechanism of uniparental disomy; however, mosaic uniparental disomy is a rare finding in patients with Prader-Willi syndrome. We report on two infants with Prader-Willi syndrome caused by mosaic maternal uniparental disomy 15. Patient 1 has mosaic uniparental isodisomy of the entire chromosome 15, and Patient 2 has mosaic uniparental mixed iso/heterodisomy 15. Genome-wide single-nucleotide polymorphism array was able to demonstrate the presence of chromosomally normal cell line in the Patient 1 and trisomic cell line in Patient 2, and provide the evidence that post-fertilization error and trisomy rescue as a mechanism of uniparental disomy in each case, respectively. Given its ability of detecting small percent mosaicism as well as its capability of identifying the loss of heterozygosity of chromosomal regions, genome-wide single-nucleotide polymorphism array should be utilized as an adjunct to the standard methylation analysis in the evaluation of Prader-Willi syndrome.

P135 – 2956: Prader-Willi syndrome, not so rare among the floppy infants

P140 – 3036: Prader Willi syndrome – Different clinical pictures at different ages

Children with Prader-Willi Syndrome (PWS) can present with social deficits and repetitive behaviors that are also encountered in autism spectrum disorder (ASD). This study aimed at ascertaining possible differences in psychopathology between PWS and ASD, with particular attention to obsessional thinking, repetitive behaviors, and impulsivity. Seventy-one children, aged 4-15 years: 24 with PWS, 23 with ASD, and 24 community controls, were assessed on two standardized parent-reported questionnaires: the child behavior check list (CBCL) and the autism spectrum quotient (AQ). Group differences were tested with one-way ANOVA. ASD had higher CBCL internalizing symptom scores (67.50±9.09) than PWS (56.62±9.02, Cohen's d=1.20). On specific CBCL items, PWS had more obsessionality than ASD, which, in turn, showed more impulsivity than PWS. ASD had higher AQ scores than PWS, with small to medium effect sizes (d's ranging from 0.22 to 0.53). The PWS phenotype was characterized by intense obsessionality, more marked than in ASD. ASD had greater psychopathology than PWS, especially of the internalizing type. Although limited by the small sample size, this study identified obsessionality as a common feature in PSW. Considering the negative impact on daily functioning, this symptom deserves clinical attention for specific treatment approaches.

Introduction: Schaaf-Yang syndrome (SYS) is a rare autosomal dominant disorder, first identified in 2013, resulting from mutations in the paternal allele of the MAGEL2 gene. Schaaf-Yang syndrome exhibits clinical features similar to those of Prader-Willi syndrome (PWS), including hypotonia, joint contractures, developmental delay, and intellectual disability. However, SYS is also characterized by unique manifestations, such as recurrent hyperthermia, feeding difficulties, respiratory distress, and seizures. This case report describes the first SYS case identified in Iran. Case Presentation: A one-year-old female, born to consanguineous parents, presented with recurrent episodes of hyperthermia, respiratory distress, and seizures since the neonatal period. Despite initial empirical treatment with broad-spectrum antibiotics for suspected infections, her symptoms persisted. Physical examination revealed hypotonia, camptodactyly, and hand contractures. Genetic testing confirmed SYS with a MAGEL2 gene mutation (c.1923dupC, p.V643Gfs*70) and probable pathogenic variants in ASPM and KIF7. The hyperthermia was attributed to hypothalamic dysfunction, a hallmark of SYS, rather than an infectious cause. The patient remains under follow-up without specific pharmacological intervention. Conclusions: This case emphasizes the importance of considering SYS in patients presenting with unexplained fever, seizures, and neurodevelopmental delays. Early genetic testing is crucial for diagnosing SYS and differentiating it from conditions such as PWS or infection-related disorders. Timely diagnosis can improve management strategies and help reduce the risk of lasting neurological impairments associated with this genetic disorder.

Disclosure: R. Sritharan: None. J. Lodge: None. S. Tadros: None. L. Menzies: None. E.F. Gevers: None. PWS is a complex neurodevelopmental disorder characterised by neonatal hypotonia,failure to thrive, hypothalamic and endocrine dysfunction, behavioural and learning difficulties and hyperphagia. It is caused by absence of expression of paternally imprinted genes on chromosome 15q11-q13. PWS is confirmed by genetic methylation analysis of this region. Most patients with PWS are referred for genetic investigations in the first months of life due to severe hypotonia and/or failure to thrive. However, it is known that some patients are still only diagnosed in adulthood, with resulting missed opportunities for prompt early treatments for PWS, such as growth hormone therapy. Little information is available on age of diagnosis of PWS, and whether opportunities to request genetic investigation are missed in childhood. We therefore aimed to study age at diagnosis of PWS in the UK. To do so, we assessed data as reported to the UK patient association PWSA-UK from 1968-2023, and additionally audited PWS genetic testing by the North Thames Genomics Laboratory Hub from 2019-22. Of 1145 people registered at PWSA as having PWS, 945 had an age of diagnosis recorded. Of these, 254 (28%) were diagnosed over 1 year of age. From March 2021 to Sept 2023, 13 were diagnosed over 1 year of age with a mean age at diagnosis of 9.27 yr (95% CI 4.15 to 14.4) and with 8 patients below 5 years of age. We assessed PWS diagnoses made in blocks of 4 years from 1968, and the number of PWS diagnoses in people over age 1 year in those time blocks. The number of diagnoses in people over 1 year of age appeared to decrease since 1996 to 7 but from 2015 this has been fluctuating. North Thames Genomics Laboratory Hub provides testing for around 10 million people in and around London. Over a 3-year period between 2019-2022, there were 59 requests for PWS testing. 28 of these were positive (a 47% diagnostic yield). 20/28 (71%) of patients were diagnosed under 1 month of age, 7% were diagnosed at 1-24 months of age, 3.5% at 2-5 yrs and 18% at >5 yrs of age (one at age 9, two at age 18, one at age 29 and one at 33 yrs of age). Most tests were performed in children under1 month of age (91% yield), followed by those over 5 yrs of age (30% yield). For 10 individuals, microarray was requested, however methylation studies would have been more appropriate. All patients diagnosed over 5 years of age had hypotonia and were described as hyperphagic and having intellectual disability, and 75% were obese. Patients diagnosed after age 8were described as having neonatal hypotonia and may have been eligible for genetic testing soon after birth. These data suggest that a considerable percentage of patients are diagnosed with PWS after the first year of life in the UK. Further root analysis, interventions, and education is required to reduce age at diagnosis in patients with PWS to allow for optimal management starting in the first few months of life. Presentation: 6/1/2024