RESUMEN

BACKGROUND: In cases of ethylene glycol (EG) toxicity requiring hemodialysis (HD), fomepizole is dosed every four hours. HD efficiently clears EG and its toxic metabolites, and it's unclear if multiple doses (MD) of fomepizole improve patient outcomes or whether a single dose (SD) prior to initiation of HD is sufficient. METHODS: We reviewed cases of EG toxicity at a toxicology referral center from 2008 to 2018. Patients treated with HD with EG levels greater than 20 mg/dL were included. Duration of dialysis, creatinine at discharge, hospital length of stay (LOS), and complications were analyzed. We compared patients who received a single dose of fomepizole prior to HD to those who received continued dosing during and after HD. RESULTS: Twenty-five patient encounters were identified (MD: 20; SD: 5). Initial bicarbonate (11 [SD] vs. 9 mg/dL [MD]) and pH (7.1 vs. 7.1) were similar between the groups; however, there was a trend toward a greater proportion of patients with renal dysfunction in the MD group: 11 (55%) vs. 1 (20%). HD was initiated a median interval of 5.2 h [SD] vs. 5.7 h [MD] after a dose of fomepizole. There was one death in the MD group and none in the SD group. Median creatinine on the day of discharge was 0.7 mg/dL (IQR: 0.57-3.8) in the SD group and 2.0 mg/dL (0.90-7.0) in the MD group. LOS was similar (5.8 days [95% CI 3.6-8.0] vs. 7.6 days [5.3-9.9]) (p = .61). CONCLUSION: Patients with moderately severe EG toxicity (acidosis and no initial renal dysfunction) treated with a single dose of fomepizole prior to HD had similar outcomes to those receiving continued dosing of fomepizole during or after HD. This raises the possibility that a single dose of fomepizole may be sufficient if HD is initiated quickly.

Asunto(s)

Glicol de Etileno/toxicidad , Fomepizol/administración & dosificación , Diálisis Renal/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the survival motor neuron (SMN) protein. SMN mediates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs. Here, we investigated SMN requirement for the biogenesis and function of U7--an snRNP specialized in the 3'-end formation of replication-dependent histone mRNAs that normally are not polyadenylated. We show that SMN deficiency impairs U7 snRNP assembly and decreases U7 levels in mammalian cells. The SMN-dependent U7 reduction affects endonucleolytic cleavage of histone mRNAs leading to abnormal accumulation of 3'-extended and polyadenylated transcripts followed by downstream changes in histone gene expression. Importantly, SMN deficiency induces defects of histone mRNA 3'-end formation in both SMA mice and human patients. These findings demonstrate that SMN is essential for U7 biogenesis and histone mRNA processing in vivo and identify an additional RNA pathway disrupted in SMA.

Asunto(s)

Regiones no Traducidas 3' , Histonas/metabolismo , Atrofia Muscular Espinal/metabolismo , ARN Mensajero/metabolismo , Ribonucleoproteína Nuclear Pequeña U7/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Histonas/genética , Humanos , Ratones , Atrofia Muscular Espinal/genética , Células 3T3 NIH , ARN Mensajero/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy.

Asunto(s)

Endorribonucleasas/antagonistas & inhibidores , Neuronas Motoras/efectos de los fármacos , Atrofia Muscular Espinal/fisiopatología , Quinazolinas/farmacología , Ribonucleoproteínas Nucleares Pequeñas/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Transgénicos , Neuronas Motoras/fisiología , Músculos/efectos de los fármacos , Músculos/metabolismo , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/fisiología , Quinazolinas/administración & dosificación , Quinazolinas/farmacocinética , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Transmisión Sináptica

RESUMEN

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by mutations in the survival of motor neuron 1 (SMN1) gene and deficient expression of the ubiquitously expressed SMN protein. Pathologically, SMA is characterized by motor neuron loss and severe muscle atrophy. During muscle atrophy, the E3 ligase atrogenes, atrogin-1 and muscle ring finger 1 (MuRF1), mediate muscle protein breakdown through the ubiquitin proteasome system. Atrogene expression can be induced by various upstream regulators. During acute denervation, they are activated by myogenin, which is in turn regulated by histone deacetylases 4 and 5. Here we show that atrogenes are induced in SMA model mice and in SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. This activation during both acute denervation and SMA disease progression is suppressed by treatment with a histone deacetylase inhibitor; however, this treatment has no effect when atrogene induction occurs independently of myogenin. These results indicate that myogenin-dependent atrogene induction is amenable to pharmacological intervention with histone deacetylase inhibitors and help to explain the beneficial effects of these agents on SMA and other denervating diseases.

Asunto(s)

Proteínas Musculares/genética , Atrofia Muscular Espinal/genética , Miogenina/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Animales , Células HEK293 , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Ratones , Ratones Endogámicos , Proteínas Musculares/metabolismo , Atrofia Muscular Espinal/enzimología , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo

RESUMEN

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

Asunto(s)

Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Proteínas del Complejo SMN/metabolismo , Sinapsis/patología , Animales , Western Blotting , ADN/genética , Fenómenos Electrofisiológicos , Genotipo , Inmunohistoquímica , Ratones , Microscopía Electrónica , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/inervación , Músculo Esquelético/patología , Atrofia Muscular Espinal/genética , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Técnicas de Placa-Clamp , Fenotipo , Reacción en Cadena de la Polimerasa , Proteínas del Complejo SMN/biosíntesis , Proteínas del Complejo SMN/genética , Proteína 1 para la Supervivencia de la Neurona Motora , Proteína 2 para la Supervivencia de la Neurona Motora

RESUMEN

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes degeneration of α-motor neurons. Frequently, muscle weakness is very severe causing affected infants to die before reaching two years of age, but mild forms of the disease can be characterized by relatively static muscle weakness for many years. SMA is caused by recessive mutations of the SMN1 gene, but all patients retain at least one copy of SMN2, a similar gene capable of producing low levels of full-length SMN protein. No treatments currently exist for SMA patients, but the identification of therapeutic targets and the development of suitable animal models for preclinical testing have resulted in increased drug development efforts in the past ten years. Here, we review the current status of many of these programs, including those designed to activate SMN2 gene expression, modulate splicing of SMN2 preRNAs, stabilize SMN protein, replace SMN1, provide neuroprotective support, and transplant neural cells.

Asunto(s)

Atrofia Muscular Espinal/metabolismo , Animales , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo

RESUMEN

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.

Asunto(s)

Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/metabolismo , Regulación hacia Arriba , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Actividad Motora , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Proteínas del Complejo SMN/genética , Proteínas del Complejo SMN/metabolismo