Drug Repurposing for Rare Diseases

Currently, there are about 7000 identified rare diseases, together affecting 10% of the population. However, fewer than 6% of all rare diseases have an approved treatment option, highlighting their tremendous unmet needs in drug development. The process of repurposing drugs for new indications, compared with the development of novel orphan drugs, is a time-saving and cost-efficient method resulting in higher success rates, which can therefore drastically reduce the risk of drug development for rare diseases. Although drug repurposing is not novel, new strategies have been developed in recent years to do it in a systematic and rational way. Here, we review applied methodologies, recent accomplished progress, and the challenges associated in drug repurposing for rare diseases

Three-dimensional facial morphology in Cantu syndrome

Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP-sensitive potassium (KATP) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken. However, an overwhelming number of CS patients receive misdiagnoses based on an evaluation of coarse facial features. By analyzing three-dimensional images of CS faces, we quantified facial dysmorphology in a cohort of both male and female CS patients with confirmed ABCC9 variants. Morphometric analysis of different regions of the face revealed gender-specific significant differences in face shape. Moreover, we show that 3D facial photographs can distinguish between CS and other genetic disorders with specific facial dysmorphologies that have been mistaken for CS-associated anomalies in the past, hence assisting in an earlier clinical and molecular diagnosis. This optimizes genetic counseling and reduces stress for patients and parents by avoiding unnecessary misdiagnosis

Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes:from clinical manifestations towards personalized treatment options

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.</p

Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes:from clinical manifestations towards personalized treatment options

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.</p

Behavioral and cognitive functioning in individuals with Cantu syndrome

Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (KATP ) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults

Treatment with liraglutide or naltrexone-bupropion in patients with genetic obesity:a real-world study

Background: Rare genetic obesity commonly features early-onset obesity, hyperphagia, and therapy-resistance to lifestyle interventions. Pharmacotherapy is often required to treat hyperphagia and induce weight loss. We describe clinical outcomes of glucagon-like peptide-1 analogue liraglutide or naltrexone-bupropion treatment in adults with molecularly confirmed genetic obesity (MCGO) or highly suspected for genetic obesity without definite diagnosis (HSGO). Methods: We conducted a real-world cohort study at the Obesity Center CGG at Erasmus University Center, Rotterdam, Netherlands, between March 19, 2019, and August 14, 2023. All patients with MCGO and HSGO who were treated with either liraglutide or naltrexone-bupropion were included. Liraglutide 3 mg and naltrexone-bupropion were administered according to the manufacturer's protocol. Treatment evaluation occurred short-term, after 12 weeks on maximum or highest-tolerated dose, preceded by the 4–5 week dose escalation phase. Differences in anthropometrics, body composition, metabolic markers, self-reported appetite, eating behaviour, and quality of life (QoL) were evaluated. Findings: Ninety-eight adults were included in the analysis: 23 patients with MCGO and 75 patients with HSGO, with median BMI of 42.0 kg/m2 (IQR 38.7–48.2) and 43.7 kg/m2 (IQR 38.0–48.7), respectively. After liraglutide treatment, median weight at evaluation significantly decreased compared to baseline in both groups: −4.7% (IQR −6.0 to −1.5) in patients with MCGO and −5.2% (IQR −8.1 to −3.5) in patients with HSGO. Additionally, improvements were observed in appetite, fat mass, fasting glucose, and HbA1c in both patients with MCGO and with HSGO. Patients with HSGO also reported significant improvements in several domains of QoL and eating behaviour. In patients with MCGO and HSGO treated with naltrexone-bupropion, mean weight at evaluation significantly differed from baseline: −5.2% ± 5.8 in patients with MCGO and −4.4% ± 4.7 in patients with HSGO. Appetite, fat mass, and waist circumference significantly decreased in both groups. Obesity-related comorbidities improved in significant proportions of patients treated with liraglutide or naltrexone-bupropion. Interpretation: In conclusion, our short-term findings show potential of liraglutide and naltrexone-bupropion as treatment options for adults with (a clinical phenotype of) genetic obesity. Funding: MB, EvdA, and EvR are supported by the, a non-profit foundation supporting academic obesity research.</p

Genetic Obesity Disorders:Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population

Objective: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. Study design: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated. Results: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P &lt; .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity.Conclusions: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.</p

Clinical phenotypes of adults with monogenic and syndromic genetic obesity

Objective: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. Methods: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. Results: A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patients with CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1–6) years in patients with MO, 9 (IQR: 4–13) years in patients with SO, and 21 (IQR: 13–33) years in patients with CO (p &lt; 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p &lt; 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p &lt; 0.001). Conclusions: We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.</p

Dementia in Rare Genetic Neurodevelopmental Disorders:A Systematic Literature Review

BACKGROUND AND OBJECTIVES: Knowledge of young-onset Alzheimer disease in adults with Down syndrome has greatly improved clinical care. However, little is known about dementia in rare genetic neurodevelopmental disorders (RGNDs). In this review, a comprehensive overview is provided of reports on dementia and cognitive/adaptive trajectories in adults with RGNDs. METHODS: A systematic literature review was conducted in Embase, Medline ALL, and PsycINFO on December 6, 2022. The protocol was registered in PROSPERO (CRD42021223041). Search terms for dementia, cognitive and adaptive functioning, and RGNDs were combined using generic terms and the Orphanet database. Study characteristics and descriptive data on genetic diagnosis, clinical and neuropathologic features, comorbidities, and diagnostic methods were extracted using a modified version of the Cochrane Data Extraction Template. RESULTS: The literature search yielded 40 publications (17 cohorts, 23 case studies) describing dementia and/or cognitive or adaptive trajectories in adults with 14 different RGNDs. Dementia was reported in 49 individuals (5 cohorts, 20 cases) with a mean age at onset of 44.4 years. Diagnostics were not disclosed for half of the reported individuals (n = 25/49, 51.0%). A total of 44 different psychodiagnostic instruments were used. MRI was the most reported additional investigation (n = 12/49, 24.5%). Comorbid disorders most frequently associated with cognitive/adaptive decline were epilepsy, psychotic disorders, and movement disorders. DISCUSSION: Currently available literature shows limited information on aging in RGNDs, with relatively many reports of young-onset dementia. Longitudinal data may provide insights into converging neurodevelopmental degenerative pathways. We provide recommendations to optimize dementia screening, diagnosis, and research.</p

Dementia in Rare Genetic Neurodevelopmental Disorders:A Systematic Literature Review

BACKGROUND AND OBJECTIVES: Knowledge of young-onset Alzheimer disease in adults with Down syndrome has greatly improved clinical care. However, little is known about dementia in rare genetic neurodevelopmental disorders (RGNDs). In this review, a comprehensive overview is provided of reports on dementia and cognitive/adaptive trajectories in adults with RGNDs. METHODS: A systematic literature review was conducted in Embase, Medline ALL, and PsycINFO on December 6, 2022. The protocol was registered in PROSPERO (CRD42021223041). Search terms for dementia, cognitive and adaptive functioning, and RGNDs were combined using generic terms and the Orphanet database. Study characteristics and descriptive data on genetic diagnosis, clinical and neuropathologic features, comorbidities, and diagnostic methods were extracted using a modified version of the Cochrane Data Extraction Template. RESULTS: The literature search yielded 40 publications (17 cohorts, 23 case studies) describing dementia and/or cognitive or adaptive trajectories in adults with 14 different RGNDs. Dementia was reported in 49 individuals (5 cohorts, 20 cases) with a mean age at onset of 44.4 years. Diagnostics were not disclosed for half of the reported individuals (n = 25/49, 51.0%). A total of 44 different psychodiagnostic instruments were used. MRI was the most reported additional investigation (n = 12/49, 24.5%). Comorbid disorders most frequently associated with cognitive/adaptive decline were epilepsy, psychotic disorders, and movement disorders. DISCUSSION: Currently available literature shows limited information on aging in RGNDs, with relatively many reports of young-onset dementia. Longitudinal data may provide insights into converging neurodevelopmental degenerative pathways. We provide recommendations to optimize dementia screening, diagnosis, and research.</p