Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.
Objective Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. Methods Glucose metabolism and pancreas development were investigated in the Smn2B/− intermediate SMA mouse model and type I SMA patients. Results Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Interpretation Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis.
The dysregulation of apoptosis occurs in many cutaneous disease states. Several apoptosis inhibitors have been shown elevated in neoplasms and in some inflammatory conditions, but their relation to proliferative and apoptotic states has not been defined. We examined the expression of the apoptosis inhibitor survivin in a panel of keratinocytic neoplasms and hyperproliferative skin lesions using both immunohistochemistry and a newly developed in situ hybridization technique. Proliferation and apoptotic indices were also assessed by immunohistochemical staining for proliferating cell nuclear antigen and TUNEL, respectively. We found the highest rate of proliferation in verrucae and psoriasis followed by actinic keratosis, squamous and basal cell carcinoma, lichen simplex chronicus, and seborrheic keratosis; all were significantly (P < 0.05) higher than normal skin. Apoptotic rate was increased in squamous (P = 0.05) and basal cell carcinoma (P = 0.03), but not significantly different from normal skin in the other lesions tested. Survivin expression was seen in most neoplasms and hyperproliferative lesions, but not normal skin. Survivin expression was often restricted to the upper third of the epidermis in psoriasis and lichen simplex chronicus, whereas all the other lesions stained diffusely. Survivin expression appears to be a consistent feature of keratinocytic neoplasms and hyperproliferative lesions and may contribute to the formation of epidermal hyperplasia seen in all of these disease states. KeywordsApoptosis; Keratinocyte; Proliferating cell nuclear antigen; TUNEL; Survivin Maintenance of homeostasis in the skin requires a delicate balance among proliferation, differentiation, and apoptosis. Disruption of the regulatory mechanisms governing these normal processes likely occurs in neoplastic and hyperproliferative disease states. The expression of various inhibitors of apoptosis, primarily of the Bcl-2 family, has been examined in multiple epidermal tumors and inflammatory conditions. For example, the apoptosis inhibitors bcl-2 and bcl-X L are expressed in melanoma 1-4 and nonmelanoma skin cancer. 5-9 In basal and squamous cell carcinoma (SCC), bcl-2 expression was detectable in the malignant keratinocytes but not in adjacent nonmalignant cells. 6 Weak bcl-2 expression was consistently found in keratinocytes comprising lesions of contact dermatitis, psoriasis, and seborrheic keratosis. 6 Dummer et al 10 examined bcl-2 expression in both benign and malignant cutaneous T-cell infiltrates and found significantly higher bcl-2 expression in the Address correspondence to Huntsman Cancer Institute, Suite 5243, 2000, Circle of Hope, Salt Lake City, Utah, 84112 (e-mail: doug.grossman@hci.utah.edu). Keratinocyte proliferation has been assessed in a number of benign and malignant skin conditions by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) or Ki-67. Increased proliferation compared with normal skin was shown in psoriasis, 12,13 ichthyosis, 12 chronic dermatitis, 12,13 and verr...
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