therapies for down syndrome regression disorder

Conditions: Down Syndrome; Regression

Summary: individuals with down syndrome (ds) have an increased risk of numerous co-occurring conditions, including the neuropsychiatric condition known as down syndrome regression disorder (dsrd). a dsrd diagnosis often includes a sub-acute onset of catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression and is most commonly observed in adolescents and young adults. the study evaluates the safety and efficacy of three currently prescribed therapies: lorazepam, intravenous immunoglobulin (ivig) and tofacitinib.

recent published case reports and clinical experience of the investigators indicate down syndrome regression disorder (dsrd) may be successfully treated with immune-modulating therapies, in addition to current pharmacologic options. this study is a multidimensional clinical trial designed to advance the understanding of the etiology of dsrd and to evaluate the safety and efficacy of three distinct therapeutic approaches to treating dsrd: (1) the benzodiazepine lorazepam (ativan™) (2) intravenous immunoglobulin (ivig, gammagard™) or (3) the jak inhibitor tofacitinib (xeljanz™). participants will be randomized into one of the three treatment arms above for the 12-week study period, with a subset of participants undergoing an initial 12-week observational period. specific aims: 1. to define the relative safety profile of lorazepam, ivig, and tofacitinib in dsrd. 2. to compare the efficacy of lorazepam, ivig, and tofacitinib in dsrd. 3. to investigate potential mechanisms underlying dsrd and its response to therapies.

Eligibility criteria:
inclusion criteria: * individuals with ds between the ages of 8 and 30 years, inclusive. ds is broadly defined to include complete trisomy 21, robertsonian translocation trisomy 21, partial trisomy 21 (segmental duplication), and mosaic trisomy 21. * diagnosis of possible or probable dsrd per 2022 consensus guidelines. * must agree to random treatment assignment. * must agree to complete a washout of any medications intended to treat symptoms of dsrd or that may interfere with study interventions. * must be able to present with a study partner or legal guardian at all study visits. exclusion criteria: general * weight less than 40 kg. * pregnant or breast feeding. * past or current tobacco smoking. * poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements. * known allergies, hypersensitivity, or intolerance to lorazepam, ivig, or tofacitinib. * participants may be excluded for other unforeseen reasons or confounding reasons for dsrd symptoms at the study doctor's discretion. co-occurring conditions * any co-occurring genetic disorder. * active symptomatic cardiac disease. * clinically significant chronic or active viral infection, including but not limited to hiv, hepatitis, cmv, ebv, hsv or untreated tuberculosis. * untreated chronic or active bacterial infection. * untreated hypothyroidism or hyperthyroidism. * history of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster. * history of malignancy (solid tumor or leukemia). * moyamoya syndrome or stroke (active or prior). * baseline abnormal renal function indicative of moderate or severe renal disease by egfr \<=45. * history of acute narrow-angle glaucoma. * history of venous or arterial thrombosis. * iga deficiency with antibodies against iga. * pathogenic neuronal autoantibody positivity against established causes of autoimmune encephalopathy in csf. * any subject with a history of anaphylaxis or a severe systemic response to blood or plasma-derived products. medications or interventions * any vaccination planned during the study or within the last 6 weeks. * use of electroconvulsive therapy, lorazepam, or a jak inhibitor within the last 4 weeks. * use of ivig within the last 8 weeks. * use of immunosuppressant drugs (e.g., prednisone, mycophenolate mofetil, azathioprine) within the last 8 weeks. * use of rituximab within the past 6 months, unless b cell levels have recovered and are above 50 cells/ul. * use of other immunosuppressant biologics (e.g., adalimumab, etanercept) within the past 6 months. * use of strong cp3a4 inhibitors or inducers (e.g., ketoconazole, rifampin) within the last 4 weeks. * use of moderate cp3a4 inhibitors with a strong cyp2c19 inhibitor (e.g., fluconazole) within the last 4 weeks. * use of moderate cyp2c9 inhibitors (e.g., valproic acid) within the last 4 weeks. * use of strong cyp1a2 inducers (e.g., phenobarbital) or moderate cyp1a2 inhibitors (e.g., fluvoxamine) within the last 4 weeks. * use of certain mood stabilizers or anticonvulsants (e.g., clonazepam, lithium, oxcarbazepine) within the last 4 weeks. * any prior use of methotrexate, cyclophosphamide, or other chemotherapeutics. * any prior solid organ transplant. * any prior neurosurgical intervention. * any subject who has received blood or plasma products ≤ 30 days prior to first baseline visit.

Keywords: catatonia autoimmune disorder sleep loss of skills autoimmune encephalopathy