Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria and arreflexia. A variety of measures are currently used to quantify disease progression, including the Friedreich Ataxia Rating Scale, examiner-rated functional disability scales, self-reported activities of daily living and performance measures such as the timed 25-foot walk, 9-hole pegboard test, PATA speech test, and low-contrast letter acuity vision charts. The present study examines the rate of disease progression over one and two years in a cohort of 236 Friedreich ataxia patients using these scales and performance measure composites. The Friedreich Ataxia Rating Scale and performance-measure composites captured disease progression, with a greater sensitivity to change over two years than over one year. The measures differed in their sensitivity to change and in possible bias. These results help to establish norms for progression in FRDA that can be useful in measuring the long-term success of therapeutic agents and defining sample-size calculations for double-blind clinical trials.

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Glycoprotein H (gH) is conserved among all herpesviruses and is essential for virus entry and cell fusion along with gL, gB, and, in most alphaherpesviruses, gD. Within the gH/gL heterodimer, it is thought that gH accounts for the fusion function and gL acts as a chaperone for the folding and transport of gH. Here, we found that the N terminus of gH2 contains important elements involved in both its folding and its transport. Our conclusions are based on the phenotypes of a series of gH deletion mutants in which the signal sequence (residues 1 to 18) was retained and N-terminal residues were removed up to the number indicated. The first mutant, gH2⌬29 (deletion of residues 19 to 28), like wild-type (WT) gH, required gL for both transport and function. To our surprise, two other mutants (gH2⌬64 and gH2⌬72) were transported to the cell surface independent of gL but were nonfunctional, even when complexed with gL. Importantly, a fourth mutant (gH2⌬48) was transported independent of gL but was functional only when complexed with gL. Using a panel of monoclonal antibodies against gH2, we found that when gH2⌬48 was expressed alone, its antigenic structure differed from that of gH2⌬48/gL or gH2-WT/gL. Mutation of gH2 residue R39, Y41, W42, or D44 allowed gL-independent transport of gH. Our results also show that gL is not merely required for gH transport but is also necessary for the folding and function of the complex. Since gH2⌬64/gL and gH2⌬72/gL were nonfunctional, we hypothesized that residues critical for gH/gL function lie within this deleted region. Additional mutagenesis identified L66 and L72 as important for function. Together, our results highlight several key gH residues: R39, Y41, W42, and D44 for gH transport and L66 and L72 for gH/gL structure and function.Glycoprotein H (gH) is conserved among all herpesviruses and is essential for virus entry. The herpes simplex virus (HSV) gH/gL heterodimer represents the functional form of these proteins (22,35,39). This heterodimer is an essential component of the core fusion machinery that also includes gB (41). Four glycoproteins (gB, gD, gH, and gL) as well as a gD receptor are required for entry into most alphaherpesviruses, including HSV (42). The current hypothesis is that the gDreceptor complex is required to stabilize the virus-cell interaction and also acts as a trigger for fusion that requires gB and/or gH/gL. The crystal structures of gD (5, 26) and gB (21) have been solved. The structure of gB closely resembles those of other known fusion proteins, most notably the vesicular stomatitis virus G protein (38), leaving open the question of the precise role of gH/gL.In HSV, the formation of the gH/gL complex is necessary for protein localization both in the virion envelope and on the cell surface (22,35,39). When gH is expressed in the absence of gL, it remains in the endoplasmic reticulum (ER) (22,25). When gL, which lacks a transmembrane domain, is expressed in the absence of gH, it is secreted from cells (8,22,35). It is hypothesized that gL harbors a chap...