Genetic approaches to understanding the causes of stuttering

Stuttering is a common but poorly understood speech disorder. Evidence accumulated over the past several decades has indicated that genetic factors are involved, and genetic linkage studies have begun to identify specific chromosomal loci at which causative genes are likely to reside. A detailed investigation of one such region on chromosome 12 has identified mutations in the GNPTAB gene that are associated with stuttering in large families and in the general population. Subsequent studies identified mutations in the functionally related GNPTG and NAGPA genes. Mutations in these genes disrupt the lysosomal targeting pathway that generates the Mannose 6-phosphate signal, which directs a diverse group of enzymes to their target location in the lysosome of the cell. While mutations in these three genes can be identified in less than 10% of cases of familial stuttering, this knowledge allows a variety of new studies that can help identify the neuropathology that underlies this disorder

Imaging and imagination: understanding the endo-lysosomal system

Lysosomes are specialized compartments for the degradation of endocytosed and intracellular material and essential regulators of cellular homeostasis. The importance of lysosomes is illustrated by the rapidly growing number of human disorders related to a defect in lysosomal functioning. Here, we review current insights in the mechanisms of lysosome biogenesis and protein sorting within the endo-lysosomal system. We present increasing evidence for the existence of parallel pathways for the delivery of newly synthesized lysosomal proteins directly from the trans-Golgi network (TGN) to the endo-lysosomal system. These pathways are either dependent or independent of mannose 6-phosphate receptors and likely involve multiple exits for lysosomal proteins from the TGN. In addition, we discuss the different endosomal intermediates and subdomains that are involved in sorting of endocytosed cargo. Throughout our review, we highlight some examples in the literature showing how imaging, especially electron microscopy, has made major contributions to our understanding of the endo-lysosomal system today

N-acetylglucosamine-1-phosphate transferase, alpha/beta and gamma subunits; N-acetylglucosamine-1- (GNPTAB, GNPTG)

GlcNAc-1-phosphotransferase catalyzes the transfer of a GlcNAc-1-phosphate residue from UDP-GlcNAc to C6 positions of selected mannoses in highmannose- type oligosaccharides of the hydrolases (Goldberg and Kornfeld 1981; Natowicz et al. 1982; Varki and Kornfeld 1983). At a biological level this reaction is followed by the removal of the terminal GlcNAc by an N-acetylglucosamine-1-phosphodiester α-N-acetyl-glucosaminidase, usually referred to as “uncovering enzyme” (UCE; see Chap. 78; Article ID: 332135). Sequential action of these two enzymes results in the formation of the mannose-6-phosphate (Man-6-P) marker, a specific tag acquired by lysosomal hydrolases that ensures recognition by M6P receptors and delivery to the endosomal/lysosomal system (Braulke and Bonifacino 2009)

Carpal tunnel syndrome in the elderly: nerve conduction parameters Síndrome do túnel do carpo em idosos: parâmetros de condução nervosa

OBJECTIVE: To establish nerve conduction parameters for carpal tunnel syndrome (CTS) electrodiagnosis in the elderly. METHOD: Thirty healthy subjects (65-86 years), 9 male and 21 female, were studied. Routine median and ulnar sensory and motor nerve conduction studies, median mixed palmar latency, comparative latency techniques median to ulnar (sensory, mixed and motor lumbrical-interossei), median to radial (sensory), and combined sensory index (CSI) were performed in both hands. RESULTS: The upper limits of normality (97.5%) were: median sensory distal latency 3.80 ms (14 cm); median motor distal latency 4.30 ms (8 cm); median palmar latency 2.45 ms (8 cm); lumbrical-interossei latency difference 0.60 ms (8 cm); comparative median to radial 0.95 ms (10 cm); comparative median to ulnar 0.95 ms (14 cm); comparative palmar median to ulnar 0.50 ms (8 cm); and CSI 2.20 ms. Sensory and mixed latencies were measured at peak. CONCLUSION: Our results establish new nerve conduction parameters for mild CTS electrodiagnosis in the elderly and will be helpful to reduce the number of false positive cases in this age.<br>OBJETIVO: Estabelecer parâmetros de condução nervosa para o eletrodiagnóstico da síndrome do túnel do carpo (STC) em idosos. MÉTODO: Foram estudadas 30 pessoas idosas (65-86 anos) saudáveis. Foi realizado estudo de condução nervosa sensitiva e motora rotineira dos nervos mediano e ulnar, latência palmar mista do mediano, técnicas de comparação de latências mediano-ulnar (sensitivo, misto e motor lumbrical-interósseo) e mediano-radial (sensitivo) e índice sensitivo combinado (ISC) em ambas as mãos. RESULTADOS: Os limites superiores de normalidade, 97,5% foram: latência distal sensitiva do mediano 3,80 ms (14 cm); latência distal motora do mediano 4,30 ms (8 cm), latência palmar do mediano 2,45 ms (8 cm), diferença de latência lumbrical-interósseo 0,60 ms (8 cm), comparação mediano-radial 0,95 ms (10 cm), comparação mediano-ulnar 0,95 ms (14 cm), comparação mediano-ulnar palmar 0,50 ms (8 cm) e ISC 2,20 ms. As latências sensitivas e mistas foram medidas no pico. CONCLUSÃO: Nossos resultados estabelecem novos valores de condução nervosa para o eletrodiagnóstico da STC leve em idosos