MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats.

Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

Elevated GFAP induces astrocyte dysfunction in caudal brain regions: A potential mechanism for hindbrain involved symptoms in type II Alexander disease.

Alexander Disease (AxD) is a "gliopathy" caused by toxic, dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene. Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by 4 years of age and suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, approximately half of all AxD patients diagnosed have onset >4 years and brainstem/spinal cord involvement. Type II AxD patients experience ataxia, palatal myoclonus, dysphagia, and dysphonia. No study has examined a mechanistic link between the GFAP mutations and caudal symptoms present in type II AxD patients. We demonstrate that two key astrocytic functions, the ability to regulate extracellular glutamate and to take up K(+) via K+ channels, are compromised in hindbrain regions and spinal cord in AxD mice. Spinal cord astrocytes in AxD transgenic mice are depolarized relative to WT littermates, and have a three-fold reduction in Ba(2+) -sensitive Kir4.1 mediated currents and six-fold reduction in glutamate uptake currents. The loss of these two functions is due to significant decreases in Kir4.1 (>70%) and GLT-1 (>60%) protein expression. mRNA expression for KCNJ10 and SLC1A2, the genes that code for Kir4.1 and GLT-1, are significantly reduced by postnatal Day 7. Protein and mRNA reductions for Kir4.1 and GLT-1 are exacerbated in AxD models that demonstrate earlier accumulation of GFAP and increased Rosenthal fiber formation. These findings provide a mechanistic link between the GFAP mutations/overexpression and the symptoms in those affected with Type II AxD.

Improving Access and Guideline Adherence in Pulmonary Care in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating, progressive neuromuscular disease that results in cardiopulmonary failure and death. In 2018, the DMD Care Considerations guidelines were updated to improve the multidisciplinary approach to care and promote early respiratory management. We sought to evaluate the impact of a multidisciplinary clinic on access to pulmonary care and adherence to respiratory care guidelines. METHODS: Utilizing retrospective data, we assessed for pulmonary care between 2016-2019 and congruence with guidelines from March 2018-February 2019. Using a standardized visit protocol, subjects were monitored for adherence to pulmonary function testing (PFT) and polysomnography (PSG) recommendations. RESULTS: Of the 84 subjects with DMD, only 51.2% had prior pulmonary involvement, and approximately one-third were seen in the year prior to clinic onset. Only 23% of subjects with a pulmonary referral completed this visit. After clinic initiation, the average age of a subject's first pulmonary contact decreased from 11.8 y to 7.9 y (P < .001), and 45% of the 77 unique clinic subjects had no previous pulmonary encounter. Adherence to PFT guidelines increased in both ambulatory (8.7% to 86.1%) and non-ambulatory subjects (25.9% to 90.1%). Approximately 79% of subjects seen in clinic either completed or had an order for PSG in the last 12 months. CONCLUSIONS: Development of a multispecialty clinic expanded access to pulmonary care and evaluation in subjects with DMD. Continued care in this clinic will allow a better understanding of barriers to access and the opportunity to monitor long-term pulmonary health.