RARE DISEASE
Smith-Magenis syndrome
Smith-Magenis syndrome
Smith-Magenis syndrome
Synonyms: 17p11.2 microdeletion syndrome
Synonyms: 17p11.2 microdeletion syndrome
Synonyms: 17p11.2 microdeletion syndrome
Drug discovery
6
drugs
With orphan designations
Overview
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a heterozygous 17p11.2 deletion (90%) or RAI1 mutation (10%), characterized by intellectual disability, sleep-wake inversion (due to disrupted circadian melatonin secretion), distinctive craniofacial features, and behavioral challenges (self-injury, hyperactivity). Common comorbidities include speech delays, scoliosis, recurrent infections, and obesity [1][2][5][13][17]. Management focuses on melatonin regulation, behavioral interventions, and multidisciplinary support [3][8][12].
Burden
High caregiver strain due to chronic sleep disruption, behavioral crises, and frequent medical needs (e.g., infections, surgeries) [9][13][19].
Lifelong disability with 70–96% requiring speech/OT support; 25–45% have congenital heart/renal defects [5][15][17].
Increased hospitalization risks from self-injury, respiratory infections, and seizure comorbidities [9][15][19].
Therapies
Sleep: Nighttime melatonin supplementation + morning β1-blockers (e.g., acebutolol) to counteract inverted circadian rhythms [3][13].
Behavioral: Structured routines, communication therapy, and low-dose antipsychotics (e.g., risperidone) for aggression/self-injury [8][12][18].
Multidisciplinary care: Genetic, ENT, ophthalmologic, and developmental evaluations; scoliosis/obesity monitoring [1][6][17].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases
Research Papers
102 drug discovery papers about Smith-Magenis syndrome, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
102 drug discovery papers about Smith-Magenis syndrome, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-22 | Weight Loss Following Liraglutide Therapy in a Patient With Smith-Magenis Syndrome: A Case Report
This case reviews the use of a Glucagon-Like Peptide-1 Receptor Agonist (GLP1RA) in a young man presenting with excessive hunger and rapid weight gain compounded by an underlying rare form of genetic obesity, Smith-Magenis syndrome. The patient had, prior to presentation, seen an accelerated and persistent weight gain over the last five years despite attempts at portion control and behavior modification. Due to concerns of worsening metabolic disease, including prediabetes, dyslipidemia, and fatty liver disease, we started the patient on daily liraglutide and gradually titrated to the maximum dose over five months. He was able to tolerate the medication without severe gastrointestinal side effects, and alongside lifestyle and behavioral modifications, the patient lost 22.2 kg (49 lbs) over the course of 11 months. To our knowledge, there is only one other published case report documenting the use of GLP1RA therapy in a patient with Smith-Magenis syndrome.
2026-06-22 | RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression.
Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. Retinoic Acid Induced 1 ( RAI1 ) gene encodes a nucleosome-binding protein haploinsufficient in Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates developmental gene expression progression, including the precocious induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.
2026-06-05 | Tirzepatide for weight and behavior management in a patient with Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.
2026-05-18 | Melatonin Levels in 89 Individuals With Smith Magenis Syndrome.
In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.
2026-01-01 | Immunodeficiency in a case diagnosed with Smith-Magenissyndrome
Smith-Magenis syndrome is a complex genetic disorder caused by deletion or mutation of the retinoic acid-induced 1 gene located primarily on chromosome 17p11.2. This syndrome is characterized by a series of physical, developmental, and behavioral abnormalities, including immune deficiencies presenting as recurrent infections. We report a 4-year-old male patient who presented to the pediatric immunology-allergy clinic with the complaint of frequent illnesses with the diagnosis of Smith-Magenis syndrome. As a result of the clinical and laboratory examinations, the patient was diagnosed with IgG subclass deficiency and was started on intravenous immunoglobulin replacement therapy. Recurrent infections associated with antibody deficiencies represent a very rare critical aspect of the syndrome that requires further investigation in the clinical setting. The complexity of Smith-Magenis syndrome necessitates an integrated healthcare strategy to provide holistic management of this multifaceted condition and highlights the need for ongoing research into its genetic, immunological, and neurodevelopmental dimensions. This rare case report sheds light on further research and provides a better understanding of the clinical presentation of the syndrome.
2026-06-22 | Weight Loss Following Liraglutide Therapy in a Patient With Smith-Magenis Syndrome: A Case Report
This case reviews the use of a Glucagon-Like Peptide-1 Receptor Agonist (GLP1RA) in a young man presenting with excessive hunger and rapid weight gain compounded by an underlying rare form of genetic obesity, Smith-Magenis syndrome. The patient had, prior to presentation, seen an accelerated and persistent weight gain over the last five years despite attempts at portion control and behavior modification. Due to concerns of worsening metabolic disease, including prediabetes, dyslipidemia, and fatty liver disease, we started the patient on daily liraglutide and gradually titrated to the maximum dose over five months. He was able to tolerate the medication without severe gastrointestinal side effects, and alongside lifestyle and behavioral modifications, the patient lost 22.2 kg (49 lbs) over the course of 11 months. To our knowledge, there is only one other published case report documenting the use of GLP1RA therapy in a patient with Smith-Magenis syndrome.
2026-06-22 | RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression.
Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. Retinoic Acid Induced 1 ( RAI1 ) gene encodes a nucleosome-binding protein haploinsufficient in Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates developmental gene expression progression, including the precocious induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.
2026-06-05 | Tirzepatide for weight and behavior management in a patient with Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.
2026-05-18 | Melatonin Levels in 89 Individuals With Smith Magenis Syndrome.
In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.
2026-01-01 | Immunodeficiency in a case diagnosed with Smith-Magenissyndrome
Smith-Magenis syndrome is a complex genetic disorder caused by deletion or mutation of the retinoic acid-induced 1 gene located primarily on chromosome 17p11.2. This syndrome is characterized by a series of physical, developmental, and behavioral abnormalities, including immune deficiencies presenting as recurrent infections. We report a 4-year-old male patient who presented to the pediatric immunology-allergy clinic with the complaint of frequent illnesses with the diagnosis of Smith-Magenis syndrome. As a result of the clinical and laboratory examinations, the patient was diagnosed with IgG subclass deficiency and was started on intravenous immunoglobulin replacement therapy. Recurrent infections associated with antibody deficiencies represent a very rare critical aspect of the syndrome that requires further investigation in the clinical setting. The complexity of Smith-Magenis syndrome necessitates an integrated healthcare strategy to provide holistic management of this multifaceted condition and highlights the need for ongoing research into its genetic, immunological, and neurodevelopmental dimensions. This rare case report sheds light on further research and provides a better understanding of the clinical presentation of the syndrome.
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Drug Discovery Landscape
6 orphan drug designations for Smith-Magenis syndrome, including 2 approved therapies.
6 orphan drug designations for Smith-Magenis syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Tasimelteon | small molecules | EMA | 2023-10-13 | — | Vanda Pharmaceuticals Netherlands B.V. |
melatonin | small molecules | FDA | 2016-11-03 | — | WORPHMED Srl |
Acebutolol hydrochloride | small molecules | EMA | 2016-10-14 | — | Worphmed Srl |
Melatonin | small molecules | EMA | 2016-10-14 | — | Worphmed Srl |
tasimelteon [Hetlioz LQ] | small molecules | FDA | 2010-04-30 | 2020-12-01 | Vanda Pharmaceuticals, Inc. |
tasimelteon [Hetlioz] | small molecules | FDA | 2010-04-30 | 2020-12-01 | Vanda Pharmaceuticals, Inc. |
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