Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.

Randomized clinical trial of low dose suramin intravenous infusions for treatment of autism spectrum disorder.

BACKGROUND: There is a critical need for effective treatment of the core symptoms of autism spectrum disorder (ASD). The purinergic antagonist suramin may improve core symptoms through restoration of normal mitochondrial function and reduction of neuro-inflammation via its known antagonism of P2X and P2Y receptors. Nonclinical studies in fragile X knockout mice and the maternal immune activation model support these hypotheses. METHODS: We conducted a 14 week, randomized, double-blind, placebo-controlled proof -of-concept study (N = 52) to test the efficacy and safety of suramin intravenous infusions in boys aged 4-15 years with moderate to severe ASD. The study had 3 treatment arms: 10 mg/kg suramin, 20 mg/kg suramin, and placebo given at baseline, week 4, and week 8. The Aberrant Behavior Checklist of Core Symptoms (ABC-Core) (subscales 2, 3, and 5) was the primary endpoint and the Clinical Global Impressions-Improvement (CGI-I) was a secondary endpoint. RESULTS: Forty-four subjects completed the study. The 10 mg/kg suramin group showed a greater, but statistically non-significant, numeric improvement (- 12.5 ± 3.18 [mean ± SE]) vs. placebo (- 8.9 ± 2.86) in ABC-Core at Week 14. The 20 mg/kg suramin group did not show improvement over placebo. In exploratory analyses, the 10 mg/kg arm showed greater ABC Core differences from placebo in younger subjects and among those with less severe symptoms. In CGI-I, the 10 mg/kg arm showed a statistically significant improvement from baseline (2.8 ± 0.30 [mean ± SE]) compared to placebo (1.7 ± 0.27) (p = 0.016). The 20 mg/kg arm had a 2.0 ± 0.28 improvement in CGI-I, which was not statistically significant compared to placebo (p = 0.65). CONCLUSION: Suramin was generally safe and well tolerated over 14 weeks; most adverse events were mild to moderate in severity. Trial Registration Registered with the South African Health Authority, registration number DOH-27-0419-6116. CLINICALTRIALS: Gov registration ID is NCT06058962, last update posted 2023-09-28.

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Aging in Fragile X Premutation Carriers.

It is now recognized that FMR1 premutation carriers (PC) are at risk to develop a range of neurological, psychiatric, and immune-mediated disorders during adulthood. There are conflicting findings regarding the incidence of hypertension, hypothyroidism, diabetes, and cancer in these patients that warrant further study. A retrospective controlled study was performed in a convenience sample of 248 controls (130 men, 118 women) and 397 FMR1 PC with and without fragile X-associated tremor ataxia syndrome (FXTAS) (176 men, 221 women); all participants were at least 45 years old (men: mean 62.4, SD 9.5; women: mean 62.8, SD 9.9; p = 0.63). Memory and cognitive assessments (Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III)) and molecular testing (CGG repeats and FMR1-mRNA levels) were performed. Additional data included body mass index (BMI), cholesterol levels, blood pressure, hemoglobin A1c (HbA1c) levels, and medical history. A higher percentage of PC subjects self-reported having a diagnosis of hypertension (50.0 vs. 35.0 %, p = 0.006) and thyroid problems (20.4 vs. 10.0 %, p = 0.012) than control subjects. When comparing controls versus PC with FXTAS, the association was higher for diabetes (p = 0.043); however, the effect was not significant after adjusting for demographic predictors. Blood pressure, blood glucose levels, HbA1c, and BMI values were not significantly different between the two groups. The PC with FXTAS group performed consistently lower in neuropsychological testing compared with the PC without FXTAS group, but the differences were very small for all but the WAIS full-scale IQ. Based on these findings, it appears that the risk for hypertension, thyroid problems, and diabetes may be more frequent in PC with FXTAS, which will require verification in future studies.

Executive Dysfunction in Female FMR1 Premutation Carriers.

There is now growing evidence of cognitive weakness in female premutation carriers (between 55 and 199 CGG repeats) of the fragile X mental retardation gene, including impairments associated with executive function. While an age-related decline in assessments of executive function has been found for male premutation carriers, few studies have explored whether female carriers show a similar trajectory with age. A total of 20 female premutation carriers and 21 age- and IQ-matched healthy controls completed a battery of tasks assessing executive function tasks, including the behavioural dyscontrol scale (BDS), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), Haylings sentence completion test and the digit span task (forward and backward). Performance was compared between premutation carriers and healthy controls, and the association between task performance and age was also ascertained. Compared to controls, female premutation carriers had significant impairment on the BDS, SDMT, PASAT, and Haylings sentence completion task, all of which rely on quick, or timed, responses. Further analyses revealed no significant association between age and task performance for either premutation carriers or controls. This study demonstrates that a cohort of female premutation carriers have deficits on a range of tasks of executive function that require the rapid temporal resolution of responses. We propose that the understanding of the phenotype of premutation carriers will be advanced through use of such measures.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations.

TBC1D24-related disorders include a wide phenotypic ranging from mild to lethal seizure disorders, non-syndromic deafness, and composite syndromes such as DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). The TBC1D24 gene has a role in cerebral cortex development and in presynaptic neurotransmission. Here, we present a familial case of a lethal early-onset epileptic encephalopathy, associated with two novel compound heterozygous missense variants on the TBC1D24 gene, which were detected by exome sequencing. The detailed clinical data of the three siblings is summarized in order to support the variability of the phenotype, severity, and progression of this disorder among these family members. Functional studies demonstrated that the identified novel missense mutations result in a loss of expression of the protein, suggesting a correlation between residual expression, and the disease severity. This indicates that protein expression analysis is important for interpreting genetic results when novel variants are found, as well as for complementing clinical assessment by predicting the functional impact. Further analysis is necessary to delineate the clinical presentation of individuals with TBC1D24 pathogenic variants, as well as to develop markers for diagnosis, prognosis, and potential targeted treatments. © 2016 Wiley Periodicals, Inc.

Inborn error metabolic screening in individuals with nonsyndromic autism spectrum disorders.

AIM: To perform metabolic testing on 406 patients (age range 3-22y [mean 6.71, SD 4.15], 343 males and 63 females) with nonsyndromic autism spectrum disorders (ASD) to assess the diagnostic yield. In addition, we reviewed our hospital's clinical database of 8500 patients who had undergone metabolic testing to be identified for inborn errors of metabolism (IEM), and described the characteristics of those with IEM and nonsyndromic ASD. METHOD: Neuropsychological evaluation included the Social Communication Questionnaire and Child Behavior Checklist. For metabolic testing/screening, urine samples were analyzed for the diagnosis of cerebral creatine deficiency syndromes, purine and pyrimidine disorders, amino acid metabolism defects, mucopolysaccharidoses, and organic acidurias. RESULTS: The 406 recruited participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria of ASD. No biochemical evidence of a metabolic disorder was detected in any of the 406 patients studied. Concerning the retrospective evaluation from the 8500 who had metabolic testing, 464 individuals had a diagnosis of an IEM (394 without the diagnosis of ASD and 70 with ASD diagnosis). Only one individual with IEM had a diagnosis of nonsyndromic ASD at the time of the metabolic study; the metabolic testing had revealed diagnosis of urea-cycle disorder. INTERPRETATION: Metabolic testing should be considered in the work-up of individuals with syndromic ASD, but metabolic testing is not cost-effective for individuals with nonsyndromic ASD.

Methadone use in a male with the FMRI premutation and FXTAS.

The fragile X-associated tremor ataxia syndrome (FXTAS) is caused by the premutation in FMR1 gene. Recent reports of environmental toxins appear to worsen the progression of FXTAS. Here we present a case of male adult with FXTAS and a long history of methadone use. The patient shows a faster progression in both symptoms of disease and MRI changes compared to what is typically seen in FXTAS. There has been no research regarding the role of narcotics in onset, progression, and severity of FXTAS symptoms. However, research has shown that narcotics can have a negative impact on several neurodegenerative diseases, and we hypothesize that in this particular case, methadone may have contributed to a faster progression of FXTAS as well as exacerbating white matter disease through RNA toxicity seen in premutation carriers.

The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

"The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion.

A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form.

Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation.

De Novo variants in the KMT2A (MLL) gene causing atypical Wiedemann-Steiner syndrome in two unrelated individuals identified by clinical exome sequencing.

BACKGROUND: Wiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation. CASE PRESENTATION: For patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3-4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively. CONCLUSIONS: Based on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.

Association between macroorchidism and intelligence in FMR1 premutation carriers.

Characteristics of fragile X syndrome include macroorchidism and intellectual disability, which are associated with decreased FMRP levels. FMRP is highly expressed in many tissues, but primarily in the brain and testis. The relationship between these two characteristics has not previously been studied in the premutation or carrier state. To examine this among premutation carriers and a possible association with IQ, we evaluated macroorchidism status among 213 males including 142 premutation carriers and 71 controls. The prevalence of macroorchidism among premutation carriers was 32.4% (46 out of 142), and 5.6% among controls (4 out of 71, P < 0.0001). Among premutation carriers, the age-adjusted odds ratio (OR) of macroorchidism was significantly increased with increasing FMR1 mRNA (OR 1.84, 95% confidence interval [CI] 1.04-3.25; P = 0.035). With respect to the association between macroorchidism and IQ, after adjustment for number of CGG repeats and age, premutation carriers with macroorchidism had lower verbal IQ (104.67 ± 15.86, P = 0.0152) and full scale IQ (102.98 ± 15.78, P = 0.0227) than premutation carriers without macroorchidism (verbal IQ 112.38 ± 14.14, full scale IQ 110.24 ± 14.21). Similar associations were observed for both verbal IQ (P = 0.034) and full scale IQ (P = 0.039) after being adjusted for age and FMR1 mRNA. These preliminary data support a correlation between macroorchidism and lower verbal and full scale IQ in a relevant proportion of premutation carrier males. Whether this is due to higher levels of FMR1 mRNA or to lower FMRP levels it remains to be established.

Autosomal Recessive Limb-Girdle Muscular Dystrophy-3: A Case Report of a Patient with Autism Spectrum Disorder.

Limb-girdle muscular dystrophies are a group of genetic disorders classically manifesting with progressive proximal muscle weakness. Affected individuals present with atrophy and weakness of the muscles of the shoulders and hips, and in some cases, intellectual disability or developmental delay has also been reported. Limb-girdle muscular dystrophy-3 is a recessive disorder caused by biallelic variants in the SGCA gene. Similarly, symptoms include proximal muscle weakness, elevated CPK, calf muscle pseudohypertrophy, and mobility issues. Cardiac symptoms and respiratory insufficiency are also common symptoms. This case report details a 3-year-old male with muscular weakness, elevated CK, and a neurodevelopmental disorder in whom a homozygous missense variant in c.229C>T (p.Arg77Cys) associated with limb-girdle muscular dystrophy-3 was found. This report shows the association between SGCA c.229C>T and neurodevelopmental disorders as observed in other muscular dystrophies.

Gait Abnormalities in Children with Phelan-McDermid Syndrome.

Background: Phelan-McDermid syndrome is a genetic disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 and is characterized by autism spectrum disorder, intellectual disability, speech and language abnormalities, hypotonia, and mild dysmorphic features. Early literature in Phelan-McDermid syndrome did not include gait abnormalities as part of the syndrome although recent prospective studies report that the prevalence of gait abnormalities ranges from 55% to 94%. We compared gait abnormalities in individuals with Phelan-McDermid syndrome, idiopathic autism spectrum disorder, and typically developing controls, and explored associations between gait abnormalities, autism spectrum disorder, and intellectual functioning. Method: The study cohort consists of 67 participants between the ages of 3 and 18 years, divided into 3 groups: Phelan-McDermid syndrome (n = 46), idiopathic autism spectrum disorder (n = 11), and typically developing controls (n = 10). Gait was recorded using a video camera and scored across 26 gait features using a "Gait Clinical Observations scale" designed specifically for this study. Results: Gait abnormalities were significantly higher in the Phelan-McDermid syndrome group as compared to idiopathic autism spectrum disorder or typically developing controls. The number of gait abnormalities across groups was also significantly correlated with Intellectual Quotient/Developmental Quotient (IQ/DQ). In analysis of covariance including IQ/DQ, the effect of group was not significant, but the effect of IQ/DQ was significant. Conclusions: Overall differences in gait abnormalities were determined by the degree of intellectual disability, which was significantly higher in Phelan-McDermid syndrome.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Case Reports of Aortic Aneurism in Fragile X Syndrome.

Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests connective tissue dysplasia. In addition to mitral valve prolapse, aortic dilatation has been identified within individuals with FXS. Abnormal elastin fiber networks have been found in the skin, valves, and aorta in individual cases. Aortic dilatation has been described in other connective tissue disorders, particularly Marfan syndrome. However, while aortic aneurysms are characteristic of Marfan syndrome, no similar cases have been reported in FXS patients to date. This case report details the presentation of two patients with FXS and aortic aneurysm. Our two cases highlight the risks of aortic pathology in FXS, and the need for monitoring in asymptomatic patients with significant aortic dilatation.

Exploring Parents' Concerns Regarding Long-Term Support and Living Arrangements for Their Children with Fragile X Syndrome.

Given limited data regarding future planning specific to Fragile X Syndrome (FXS) individuals and the growing population of individuals within this community, this study sought to explore the concerns and challenges caregivers of individuals affected by FXS encounter when considering long-term support plans. This involved identifying the reasons individuals with FXS continue to reside with family and the reservations caregivers have regarding future supports and living arrangements. We administered an anonymous online survey consisting of 34 questions assessing eligibility, living arrangements/supports, and future concerns. We found that most individuals with FXS were affected with moderate Intellectual and Developmental Disabilities (IDD) and co-occurring behavioral conditions but had overall good health. The majority of individuals with FXS currently resided with family due to parental desire, their own desire, and the inability to live independently. For one-third of caregivers, the plan for future living arrangements is to continue residing with family members long-term. A large proportion of caregivers had not considered alternative arrangements or were unsure. More than 70% of caregivers of individuals with FXS are concerned about multiple aspects of the individual's future. Caregivers of younger individuals are the most concerned, but also believe they have time before they need to plan or are unable to currently assess the future need for support.