RARE DISEASE
Fetal alcohol syndrome
Fetal alcohol syndrome
Fetal alcohol syndrome
Synonyms: ARBD, ARND, Alcohol-related birth defects, Alcohol-related neurodevelopmental disorder, FAS, FASD, Fetal alcohol spectrum disorders
Synonyms: ARBD, ARND, Alcohol-related birth defects, Alcohol-related neurodevelopmental disorder, FAS, FASD, Fetal alcohol spectrum disorders
Synonyms: ARBD, ARND, Alcohol-related birth defects, Alcohol-related neurodevelopmental disorder, FAS, FASD, Fetal alcohol spectrum disorders
Drug discovery
0
drugs
With orphan designations
Overview
Fetal alcohol syndrome (FAS) is the most severe fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure. It is characterized by distinct facial dysmorphology (e.g., smooth philtrum, thin vermilion border), growth retardation, and neurodevelopmental impairments including cognitive deficits, behavioral challenges, and lifelong functional limitations [1][6][16]. While preventable, FAS has no cure, necessitating early multidisciplinary interventions to optimize outcomes [1][3].
Therapies
Multidisciplinary care: Developmental screenings, neurobehavioral assessments, and specialist referrals (neurology, mental health, occupational therapy) [1][3].
Pharmacotherapy: Stimulants (e.g., methylphenidate) for ADHD symptoms; mood stabilizers for comorbid conditions [3][8].
Behavioral/educational interventions: Parent training, social skills programs, and individualized education plans to address cognitive and adaptive deficits [8][18].
Categories: rare developmental anomalies during embryogenesis, rare disorders due to toxic effects, rare otorhinolaryngological diseases, rare surgical maxillo-facial diseases, rare teratologic disorders
Research Papers
1,491 drug discovery papers about Fetal alcohol syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,491 drug discovery papers about Fetal alcohol syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | Maternal gut and vaginal microbiota, alcohol use during pregnancy, and infant fetal alcohol spectrum disorder diagnosis in a South African cohort
Abstract Background The detrimental impact of alcohol consumption on the gut microbiome is well-established. However, less is known about how alcohol exposure during pregnancy affects the maternal gut and vaginal microbiota, or how these microbial changes relate to subsequent infant diagnosis of fetal alcohol spectrum disorder (FASD). We therefore investigated associations between self-reported alcohol use during pregnancy, infant FASD diagnosis, and maternal gut and vaginal microbiota. Methods Fecal samples (n = 207) and vaginal swabs (n = 28) from pregnant participants recruited through antenatal clinics in the Western Cape Province of South Africa were profiled by 16S rRNA V1-V2 amplicon sequencing. Maternal alcohol use was assessed using Alcohol Use Disorder Identification Test (AUDIT) scores, and FASD was diagnosed in infants using revised Institute of Medicine criteria. Microbial diversity, taxonomic profiles and PICRUSt2 -predicted functional pathways were analyzed using vegan , phyloseq and MaAsLin3 . Results Maternal AUDIT scores were negatively associated with maternal gut microbiota richness, Shannon, and Inverse Simpson diversity ( p < 0.05). Observed richness was also reduced in participants whose infants were diagnosed with FASD ( p = 0.046). Gut microbiota community structure was not significantly associated with alcohol use or infant FASD diagnosis. However, taxonomic and functional analysis suggested gram-positive taxa depletion with alcohol use and FASD diagnosis, and impaired one-carbon metabolism among participants with infants diagnosed with FASD. Vaginal microbiota diversity and composition were not associated with alcohol use or infant FASD diagnostic group. Conclusions This is the first human study to investigate the maternal gut and vaginal microbiota in relation to alcohol use during pregnancy and infant FASD outcomes. Our findings suggest that alcohol use is associated with disruption of the maternal gut microbiota, with potential implications for FASD development in exposed infants. Further investigation of alcohol-associated maternal microbial disturbances may inform microbiota-targeted strategies to improve maternal and infant health linked to alcohol use.
2026-08-05 | Mental Health Disorders, Suicide Attempts, Substance Use, and Substance Use Disorders in Adults with Fetal Alcohol Spectrum Disorders: A Gender-Separated Study
Abstract Fetal alcohol spectrum disorders (FASD) are a group of neurodevelopmental disorders caused by alcohol exposure during pregnancy. FASD is associated with various neurocognitive disorders over the entire lifespan. Comorbid mental health disorders seem to be highly prevalent. Suicide attempts and substance use as well as substance use disorders are also associated with FASD in adults. However, previous studies report small or very selective samples. Little is known about gender differences in larger samples of adults with FASD. Structured clinical interviews based on DSM-5 diagnostic criteria were administered for the diagnosis of mental health disorders, suicidality, and substance use including substance-related disorders. Data was analyzed separately for men and women to identify gender differences. The sample consisted of 238 adults (51.3% female, 48.7% male, 0% non-binary) who live with FASD, 31% of male and 41% of female participants fulfilled criteria for at least one comorbid mental health disorder, primarily anxiety (men = 13.8%, women = 13.1%), major depression (men = 7.8, women = 9.8%), and PTSD (men = 0.9%, women = 4.1). At least one suicide attempt was reported by 32.8% of women and 17.2% of men. Suicide attempts were significantly more prevalent among women. The 30-day prevalence for alcohol was 49.1% for men and 36.1% for women. Alcohol use disorders were present in 2.6% of men and 0.8% of women. The 12-month prevalence for cannabis use was 30.2% for men and 17.2% for women. Cannabis use disorders were present in 1.7% of men and 0.8% of women. This study identified overall high rates of mental health disorders, suicide attempts, substance use, and substance use disorders in women and men with FASD. The results highlight the need for specialized treatment not only targeting FASD-specific symptoms but also addressing the comorbid conditions.
2026-07-30 | Folic acid prevention of neural tube defects requires retinoic acid produced by ALDH1L1.
Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neural tube defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescuable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by retinoids. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, thereby increasing RA biosynthesis. Knockdown of ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling results in overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as an unexpected enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention.
2026-07-16 | Myelin Alteration in Neurodevelopmental Disorders: Integrating Clinical and Preclinical Evidence.
Myelination is a fundamental neurobiological process that enables rapid and efficient neural signal transmission, playing a key role in shaping brain connectivity and function-particularly during early development. Given the high energetic cost and tight developmental timing of myelination, disruptions in myelin formation or maintenance can increase vulnerability to genetic and environmental factors during critical periods. As such, impaired myelination and oligodendrocyte dysfunction may contribute to the pathogenesis of various neurodevelopmental disorders (NDDs). This review synthesizes current knowledge on the role of myelin-related changes in the pathophysiology of NDDs-including Autism Spectrum Disorder (ASD), Attention-Deficit/ Hyperactivity Disorder (ADHD), Fetal Alcohol Spectrum Disorders (FASD), intellectual developmental disorders, and communication, motor, and specific learning disorders-integrating findings from both animal models and human research. Taken together, the evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention.
2026-07-15 | The NKCC1 Antagonist Bumetanide, Administered After Prenatal Alcohol Exposure, Mitigates Ethanol-Induced Aberrance in Tangential Migration of GABAergic Interneurons in Mouse Medial Prefrontal Cortex.
Prenatal ethanol (alcohol) exposure (PreEE) results in abnormal tangential migration of medial ganglionic eminence (MGE)-derived GABAergic interneurons (GINs) in the embryonic mouse medial prefrontal cortex (mPFC); later in life, this is associated with impaired behavioral flexibility commonly seen in fetal alcohol spectrum disorders (FASD). The PreEE-induced abnormal tangential migration involves, in part, ethanol potentiating GABAA receptor-mediated depolarization, the latter due to elevated intracellular chloride sustained primarily by the Na-K-Cl cotransporter NKCC1 in embryonic GINs. We previously reported that coincident administration of the NKCC1 antagonist bumetanide with PreEE prevents the PreEE-induced aberrant migration of GINs in the mPFC. However, such simultaneous dispensing rarely occurs in real life. In this light, the present study assessed whether bumetanide administered after PreEE mitigates the PreEE-induced aberrant tangential migration. NKCC1-like immunofluorescence was assessed following immunohistochemical processing of 30-μm cryosections derived from embryonic day (E)14.5 wild-type mouse brains. Nkx2.1Cre-Ai14 mice were used to genetically label MGE-derived GINs. Pregnant dams were fed 5% ethanol (w/w) from E13.5 to E16.5, followed by bumetanide treatment (320 mg/kg liquid diet) from E17.5 until postnatal day (P) 0 (birth). Forty-micron cryosections from brains of progeny were collected at P0, and the density as well as spatial distribution of tdTomato-fluorescent (Nkx2.1+) GINs in the mPFC quantified. Within the timeframe of PreEE, the NKCC1 protein is expressed ubiquitously in the embryonic mouse brain, including the dorsomedial telencephalon, the precursor to mPFC. PreEE increased the overall density of Nkx2.1+ GINs and accelerated their dorsal-to-ventral dispersion across the developing mPFC. Post-PreEE treatment with the NKCC1 antagonist bumetanide diminished these effects, reducing dorsal accumulation while preserving the baseline population of GINs. These results indicate that blocking the NKCC1 chloride importer bumetanide can mitigate PreEE-induced interneuronopathy when administered after PreEE, implicating NKCC1 as a potential pharmacological target for post-PreEE therapeutic intervention of FASD.
2026-08-06 | Maternal gut and vaginal microbiota, alcohol use during pregnancy, and infant fetal alcohol spectrum disorder diagnosis in a South African cohort
Abstract Background The detrimental impact of alcohol consumption on the gut microbiome is well-established. However, less is known about how alcohol exposure during pregnancy affects the maternal gut and vaginal microbiota, or how these microbial changes relate to subsequent infant diagnosis of fetal alcohol spectrum disorder (FASD). We therefore investigated associations between self-reported alcohol use during pregnancy, infant FASD diagnosis, and maternal gut and vaginal microbiota. Methods Fecal samples (n = 207) and vaginal swabs (n = 28) from pregnant participants recruited through antenatal clinics in the Western Cape Province of South Africa were profiled by 16S rRNA V1-V2 amplicon sequencing. Maternal alcohol use was assessed using Alcohol Use Disorder Identification Test (AUDIT) scores, and FASD was diagnosed in infants using revised Institute of Medicine criteria. Microbial diversity, taxonomic profiles and PICRUSt2 -predicted functional pathways were analyzed using vegan , phyloseq and MaAsLin3 . Results Maternal AUDIT scores were negatively associated with maternal gut microbiota richness, Shannon, and Inverse Simpson diversity ( p < 0.05). Observed richness was also reduced in participants whose infants were diagnosed with FASD ( p = 0.046). Gut microbiota community structure was not significantly associated with alcohol use or infant FASD diagnosis. However, taxonomic and functional analysis suggested gram-positive taxa depletion with alcohol use and FASD diagnosis, and impaired one-carbon metabolism among participants with infants diagnosed with FASD. Vaginal microbiota diversity and composition were not associated with alcohol use or infant FASD diagnostic group. Conclusions This is the first human study to investigate the maternal gut and vaginal microbiota in relation to alcohol use during pregnancy and infant FASD outcomes. Our findings suggest that alcohol use is associated with disruption of the maternal gut microbiota, with potential implications for FASD development in exposed infants. Further investigation of alcohol-associated maternal microbial disturbances may inform microbiota-targeted strategies to improve maternal and infant health linked to alcohol use.
2026-08-05 | Mental Health Disorders, Suicide Attempts, Substance Use, and Substance Use Disorders in Adults with Fetal Alcohol Spectrum Disorders: A Gender-Separated Study
Abstract Fetal alcohol spectrum disorders (FASD) are a group of neurodevelopmental disorders caused by alcohol exposure during pregnancy. FASD is associated with various neurocognitive disorders over the entire lifespan. Comorbid mental health disorders seem to be highly prevalent. Suicide attempts and substance use as well as substance use disorders are also associated with FASD in adults. However, previous studies report small or very selective samples. Little is known about gender differences in larger samples of adults with FASD. Structured clinical interviews based on DSM-5 diagnostic criteria were administered for the diagnosis of mental health disorders, suicidality, and substance use including substance-related disorders. Data was analyzed separately for men and women to identify gender differences. The sample consisted of 238 adults (51.3% female, 48.7% male, 0% non-binary) who live with FASD, 31% of male and 41% of female participants fulfilled criteria for at least one comorbid mental health disorder, primarily anxiety (men = 13.8%, women = 13.1%), major depression (men = 7.8, women = 9.8%), and PTSD (men = 0.9%, women = 4.1). At least one suicide attempt was reported by 32.8% of women and 17.2% of men. Suicide attempts were significantly more prevalent among women. The 30-day prevalence for alcohol was 49.1% for men and 36.1% for women. Alcohol use disorders were present in 2.6% of men and 0.8% of women. The 12-month prevalence for cannabis use was 30.2% for men and 17.2% for women. Cannabis use disorders were present in 1.7% of men and 0.8% of women. This study identified overall high rates of mental health disorders, suicide attempts, substance use, and substance use disorders in women and men with FASD. The results highlight the need for specialized treatment not only targeting FASD-specific symptoms but also addressing the comorbid conditions.
2026-07-30 | Folic acid prevention of neural tube defects requires retinoic acid produced by ALDH1L1.
Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neural tube defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescuable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by retinoids. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, thereby increasing RA biosynthesis. Knockdown of ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling results in overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as an unexpected enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention.
2026-07-16 | Myelin Alteration in Neurodevelopmental Disorders: Integrating Clinical and Preclinical Evidence.
Myelination is a fundamental neurobiological process that enables rapid and efficient neural signal transmission, playing a key role in shaping brain connectivity and function-particularly during early development. Given the high energetic cost and tight developmental timing of myelination, disruptions in myelin formation or maintenance can increase vulnerability to genetic and environmental factors during critical periods. As such, impaired myelination and oligodendrocyte dysfunction may contribute to the pathogenesis of various neurodevelopmental disorders (NDDs). This review synthesizes current knowledge on the role of myelin-related changes in the pathophysiology of NDDs-including Autism Spectrum Disorder (ASD), Attention-Deficit/ Hyperactivity Disorder (ADHD), Fetal Alcohol Spectrum Disorders (FASD), intellectual developmental disorders, and communication, motor, and specific learning disorders-integrating findings from both animal models and human research. Taken together, the evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention.
2026-07-15 | The NKCC1 Antagonist Bumetanide, Administered After Prenatal Alcohol Exposure, Mitigates Ethanol-Induced Aberrance in Tangential Migration of GABAergic Interneurons in Mouse Medial Prefrontal Cortex.
Prenatal ethanol (alcohol) exposure (PreEE) results in abnormal tangential migration of medial ganglionic eminence (MGE)-derived GABAergic interneurons (GINs) in the embryonic mouse medial prefrontal cortex (mPFC); later in life, this is associated with impaired behavioral flexibility commonly seen in fetal alcohol spectrum disorders (FASD). The PreEE-induced abnormal tangential migration involves, in part, ethanol potentiating GABAA receptor-mediated depolarization, the latter due to elevated intracellular chloride sustained primarily by the Na-K-Cl cotransporter NKCC1 in embryonic GINs. We previously reported that coincident administration of the NKCC1 antagonist bumetanide with PreEE prevents the PreEE-induced aberrant migration of GINs in the mPFC. However, such simultaneous dispensing rarely occurs in real life. In this light, the present study assessed whether bumetanide administered after PreEE mitigates the PreEE-induced aberrant tangential migration. NKCC1-like immunofluorescence was assessed following immunohistochemical processing of 30-μm cryosections derived from embryonic day (E)14.5 wild-type mouse brains. Nkx2.1Cre-Ai14 mice were used to genetically label MGE-derived GINs. Pregnant dams were fed 5% ethanol (w/w) from E13.5 to E16.5, followed by bumetanide treatment (320 mg/kg liquid diet) from E17.5 until postnatal day (P) 0 (birth). Forty-micron cryosections from brains of progeny were collected at P0, and the density as well as spatial distribution of tdTomato-fluorescent (Nkx2.1+) GINs in the mPFC quantified. Within the timeframe of PreEE, the NKCC1 protein is expressed ubiquitously in the embryonic mouse brain, including the dorsomedial telencephalon, the precursor to mPFC. PreEE increased the overall density of Nkx2.1+ GINs and accelerated their dorsal-to-ventral dispersion across the developing mPFC. Post-PreEE treatment with the NKCC1 antagonist bumetanide diminished these effects, reducing dorsal accumulation while preserving the baseline population of GINs. These results indicate that blocking the NKCC1 chloride importer bumetanide can mitigate PreEE-induced interneuronopathy when administered after PreEE, implicating NKCC1 as a potential pharmacological target for post-PreEE therapeutic intervention of FASD.
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