Behavioral and Psychiatric Disorders in Syndromic Autism.

Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families.

The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations.

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene-protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed.

Gender Diverse Autistic Young Adults: A Mental Health Perspective.

Gender diverse autistic young adults often face mental health challenges which can increase the challenge of obtaining gender-affirming care. Social and communication differences associated with autism compounds the already complex process of navigating a path toward gender affirmation for individuals with these intersecting identities. In this case series of four gender diverse autistic adults, we demonstrate that success in management of their mental health crises was achieved through enlisting family and social support, obtaining effective mental health treatment, and accessing gender-affirming healthcare. These cases selected from two neuropsychiatric outpatient tertiary referral clinics demonstrate that effective mental health treatment supports ultimate success for these individuals in their journeys toward living as the gender with which they identify. We conclude that healthcare practices and treatment recommendations which incorporate internationally recognized standards of care guidelines for gender diverse individuals improve patient outcomes.

Interoception in Practice: The Gut-Brain Connection.

Tony is a five and a half-year-old boy who has been a patient in your primary care practice since he was adopted at birth. He has been treated by a child and adolescent psychiatrist for behavioral concerns starting at age 3 years and has been diagnosed with autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD) combined type, anxiety disorder, and insomnia. He presents today with complaints of repeated emesis and refusal to eat or drink over the past 2 weeks and is now dehydrated. Tony was born at 30 weeks' gestational age by vaginal delivery with a birth weight of 4lbs 15oz and was described as minimally responsive at birth. There was known prenatal exposure to tobacco and methamphetamine and inadequate prenatal care. The maternal history is notable for a reported diagnosis of bipolar affective disorder, prostitution, and being unhoused at the time of delivery. Tony received antibiotics after delivery for presumed newborn infections. As an infant, he had kidney reflux, low serum ferritin, insomnia, and failure to thrive. Regarding developmental milestones, Tony was sitting up at 7 months, walking at 14 months, talking at 18 months, and speaking in full sentences by 24 months. When he presented to the psychiatric service at age 3 years, behavioral problems included irritability with destructive rages, excessive fears, separation anxiety, hyperactivity, and impulsivity with a lack of awareness of danger to the extent that he required a safety harness when in public and security locks in the home because of repeated elopements. Tony also had at the time of his initial presentation significant defiance, extreme tantrums, violent aggressive outbursts, cognitive rigidity, repetitive behaviors, resistance to change, frequent nondirected vocalizations, and self-injurious behaviors including slapping himself on the head and biting of his hands and feet. Review of systems includes complaints of frequent abdominal and neck pain, persistent insomnia, night terrors, restrictive eating habits with poor weight gain, and reduced sensitivity to pain. Treatment history included gabapentin and subsequently divalproex for seizure-like episodes (despite negative EEG) described as frequent staring spells with repetitive biting of his lips. Psychotropic medications were risperidone for irritability associated with autism and clonidine extended release for ADHD. He also took melatonin for sleep. During his well-child check at the age of 5 years, Tony is making good progress from a developmental standpoint, has age-appropriate expressive and receptive language skills, is fluent in both English and Spanish, is able to recite the alphabet, counts to 20, has learned to swim, and is demonstrating interest in planets and astrology. He is reported to have a secure attachment to his adoptive parents and is described as emotionally sensitive, caring, kind, considerate, and empathetic. He has good eye contact and can read facial expressions. He is affectionate and protective of his infant sibling, his biological sister, who is also adopted by his parents and now living in the home. Tony made an excellent adjustment to the start of kindergarten and up until this point was responding positively to his psychotropic medication regimen. But then at age five and a half, Tony experienced sudden and unexplained behavioral worsening, which was followed by the onset of recurrent vomiting and refusal to eat or drink. Comprehensive medical workup including upper endoscopy and biopsy resulted in a diagnosis of eosinophilic esophagitis (EoE). What would be your next step?

Exploring Three Core Psychological Elements When Treating Adolescents on the Autism Spectrum: Self-Awareness, Gender Identity, and Sexuality.

For those growing up on the autism spectrum, adolescence is associated with unique challenges. This narrative review explores three core psychological elements for clinicians to consider when treating adolescents on the autism spectrum: self-awareness, gender identity, and sexuality. Developmental tasks of adolescence include adaptation to a maturing mind and body, increased expectations for independence, and the ability to establish satisfying interpersonal relationships. What are welcome opportunities for non-autistic peers can become nearly insurmountable hurdles for autistic teens, which, in turn, could lead to crisis, particularly if skills needed for success in managing these tasks have not yet been acquired.

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity.

Electroencephalogram (EEG) for children with autism spectrum disorder: evidential considerations for routine screening.

Routine electroencephalograms (EEG) are not recommended as a screen for epileptic discharges (EDs) in current practice guidelines for children with autism spectrum disorder (ASD). However, a review of the research from the last three decades suggests that this practice should be reevaluated. The significant comorbidity between epilepsy and ASD, its shared biological pathways, risk for developmental regression, and cognitive challenges demand increased clinical investigation requiring a proactive approach. This review highlights and explains the need for screening EEGs for children with ASD. EEG would assist in differentiating EDs from core features of ASD and could be included in a comprehensive assessment. EEG also meets the demand for evidence-based precision medicine and focused care for the individual, especially when overlapping processes of development are present.

Deletion of TOP3B Is Associated with Cognitive Impairment and Facial Dysmorphism.

Deletions of different regions of chromosome 22q11 have been extensively characterized in the literature, with a recent review outlining common deletions with a standardized system proposed for classification and nomenclature. The genotype-phenotype relationships have not been sufficiently elucidated for these deletions, and it remains unclear which specific genes play the dominant roles in producing associated clinical features. Several deletions involve entirely distinct regions of chromosome 22q11 but do not overlap, suggesting that a number of different genes contribute to the clinical features. Studies of patients with small deletions involving only 1 or 2 genes may provide more convincing evidence for the impact of individual genes on the observed phenotype. In this case report, we present a 12-year-old female with autism, cognitive impairment, dysmorphic features, and behavioral concerns and a 268-kb deletion of chromosome 22q11.22 including TOP3B, the only recognized disease-causing gene in the deletion. The mechanism of pathogenesis contributing significantly to our patient's clinical findings may relate to interaction between TOP3B and fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates translation and is altered in fragile X syndrome, a condition involving developmental delay, learning disability, and autism. All these features are recognized in our patient.

"Is It Her Hormones?": Psychiatric Diagnoses and Polycystic Ovarian Syndrome.

CASE: Beth, whom you have cared for in your primary care practice since she was born, is a 15-year-old adolescent girl with no prior psychiatric history who developed significant symptoms of clinical depression, associated with self-injurious behavior (cutting on wrists, arms, and thighs). She denied any known precipitant for her depression.She is a ninth grade honors student in the gifted program at a local high school and is described as a talented musician, playing multiple musical instruments as well as soccer and basketball. She has good family support, was sociable, and had several close friends. She denied any history of trauma and denied ever using recreational drugs or other mood-altering substances.At this visit, she reported feeling "sad and anxious." Family history was significant for maternal depression, which persisted through her teens and twenties. Her older sister had been diagnosed with Social Anxiety Disorder. Beth reported anhedonia, fatigue and irritable mood, lack of motivation, impaired concentration, and anxiety related to failing grades.You decide to begin medication because of the severity of her symptoms, and 1 week after starting fluoxetine 10 mg, she reportedly overdosed on an unknown quantity of acetaminophen. Within a few days of switching to escitalopram (due to persistent gastrointestinal complaints while taking fluoxetine), she developed homicidal ideation. She reported feeling grandiose, empowered, invincible, elated, and "crazy," although she never demonstrated or endorsed psychotic symptoms. She became fixated upon the idea that she could kill someone and "get away with it." At the time she tried to suffocate a peer with her hands, she was described as having "a glazed over look in her eyes." Moods were now described as alternating between depressed and elated, with mood shifts occurring every few days. These symptoms did not improve after the antidepressant medication was discontinued.Subsequently, patient was admitted for acute psychiatric care, at which time she was described as depressed, but with an "expansive and irritable" mood, and with obsessive suicidal ideation. She had developed a plan to hang herself in the home. She started to believe that her mother was trying to give her "poison." She reported panic attacks and said that she wanted to be in the hospital where she could feel "safe." She claimed to have an "entity inside of her body who was a bully" and who was "taking over her body" and stated that he put her hand over her peer's mouth, as she watched.Psychological testing included the Minnesota Multiphasic Personality Inventory-Adolescent, showed significant paranoia, bizarre mentation, and poor reality testing. Along with interview and observation, it was determined that patient met criteria for the DSM-IV-TR clinical diagnosis of Other Specified Bipolar Disorder, with psychotic features.Aripiprazole was initiated at a dosage of 2 mg; however, moods were still described as fluctuating between extremes every few hours. It was discontinued after reaching 5 mg due to affective blunting. Risperidone 0.5 mg twice daily helped patient to feel and act "more like herself"; however, she continued to report significant depression. The addition of lamotrigine 25 mg daily, in addition to individual Dialectical Behavior Therapy, finally led to improvement of mood and a gradual return of her normal baseline, with reportedly stable emotional, social, and academic functioning.The patient's mother remained convinced that this adolescent's mood instability was caused by underlying hormonal problems so you refer her to endocrinology. Beth developed puberty at age 8, with menses occurring on average of twice yearly. She was found to have elevated free testosterone level of 8.6 (reference range, 1.2-7.5). She was of normal weight (body mass index = 21.85 kg/m) and did not manifest acne, male pattern hair thinning, or hirsutism. Thyroid functions, 17-OH progesterone, follicle-stimulating hormone/luteinizing hormone, and estradiol were within normal limits. Prolactin elevation (46.3) was assumed to be due to Risperidone. Patient refused ovarian ultrasound.After starting oral contraceptives to establish monthly menses, patient's emotional and behavioral symptoms continue to remain stable. After Beth decided on her own to discontinue psychotropic medications, she continued for 17 months following her initial visit to remain free of neuropsychiatric symptoms.Now that her symptoms seem resolved; you wonder what the medical diagnosis for Beth was? You wonder if "hormones" may have caused or contributed to her psychiatric presentation.

Low Dose Loxapine: Neuromotor Side Effects and Tolerability in Autism Spectrum Disorders.

OBJECTIVE: New and repurposed drugs are urgently needed to treat individuals with autism spectrum disorders (ASD). Loxapine (LOX) in low doses of 5-15 mg/day resembles an atypical antipsychotic (Stahl 2002 ). Our recent open pilot study of LOX found significant behavioral improvements and overall weight neutrality in 16 adolescents and adults with ASD. The present study examined an outpatient sample for LOX neuromotor tolerability. METHODS: Consecutive outpatients with Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) ASD diagnoses receiving LOX were examined for tardive dyskinesia (TD) and extrapyramidal side effects (EPS) using the Dyskinesia Identification System: Condensed User Scale (DISCUS), and for akathisia using the Barnes Akathisia Rating Scale. Data were also then retrospectively extracted from clinic charts regarding age, gender, diagnoses, LOX doses, treatment duration, concomitant medications, and LOX dosage reductions. RESULTS: Thirty-four subjects (25 male, 9 female) participated. Mean age was 23.4 years at LOX initiation (range 8-52). Thirteen subjects (38.2%) received loxapine for ≥5 years. Mean LOX dose was 8.9 mg/day (range 5-30 mg) and mean duration was 4.2 years (range 0.8-13). Fourteen subjects (41.2%) received concomitant atypical antipsychotics. Benztropine was prescribed in 5 of 34 subjects (14.7%). Three subjects manifested tics at baseline, but lower final DISCUS scores. Subject 26, with Prader-Willi syndrome, manifested TD. Apart from LOX 5 mg daily he received paroxetine 40 mg daily, which reduces LOX metabolism significantly. Akathisia objective scores were positive in 6 subjects (17.6%): Subject 2 scored 3 (pacing was present also at baseline); subjects 6, 7, and 11 each scored 1; and subjects 18 and 23 each scored 2. Six of 9 subjects (66.7%) with expressive language were positive for subjective akathisia. CONCLUSIONS: Low dose LOX was well tolerated, with lower than expected TD rates. This confirms clinical resemblance to an atypical antipsychotic. Individuals with neuromuscular problems including Prader-Willi Syndrome receiving LOX require close monitoring. Further study of LOX in ASD is warranted.

Partial Deletion of Chromosome 1p31.1 Including only the Neuronal Growth Regulator 1 Gene in Two Siblings.

We present two siblings with a partial deletion of chromosome 1p31.1 involving only the neuronal growth regulator 1 (NEGR1) gene. The siblings had a history of neuropsychiatric and behavioral problems, learning difficulties, hypotonia, mild aortic root dilatation, hypermobility, and scoliosis. This is the first clinical report of a microdeletion of chromosome 1p31.1 involving only the NEGR1 gene.