Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

An empirical pipeline for personalized diagnosis of Lafora disease mutations.

Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients.

Incomplete cavernous sinus syndrome as the initial manifestation of a previously undetected metastatic prostate adenocarcinoma.

BACKGROUND: Cavernous sinus syndrome presents as unilateral ophthalmoplegia associated with sympathetic denervation, pain, paresthesias, and V1 and V2 distribution numbness. The etiology may be vascular, inflammatory, infectious, and, less commonly, neoplastic (metastatic). METHODS: We report a patient with incomplete cavernous sinus syndrome as the initial manifestation of previously undetected metastatic prostate adenocarcinoma. RESULTS: A 59-year-old man presented with a 2-month history of left hemicranial headaches with ptosis and binocular diplopia. Clinical evaluation found left third, fourth, and sixth cranial nerve palsy with mydriasis and ptosis. An MRI showed an enhancing lesion at the clivus with infiltration of left cavernous sinus. A trans-sphenoidal biopsy was performed, leading to diagnosis of metastatic prostate adenocarcinoma. The patient underwent treatment and achieved clinical improvement. CONCLUSIONS: In middle-aged men, it is important to include metastatic prostate adenocarcinoma in the differential diagnosis of cavernous sinus syndrome, even in the absence of primary tumor diagnosis.