was similar in patients from NA (2.5 [2.0] years) and from ROW (1.9 [1.6] years), but diagnosis was delayed by 1.3 (1.8) years in NA compared with 2.1 (2.7) years in ROW. The most frequently observed mutations were missense (49% in NA and 43% in ROW). Similar symptoms were present in patients from NA and ROW: typical facial features (82% in NA); hepatosplenomegaly (78%); joint stiffness (74%); otitis (67%); hernia (66%); and enlarged tongue (61%). The median number of surgeries was 3 (min/ max, 0–13) for NA and 2 (0–17) for ROW. The most frequent surgeries in NA were ear tubes (63% of patients from NA), adenoidectomy (55%), hernioplasty (43%), and tonsillectomy (42%). Conclusion: Information on patients with Hunter syndrome from NA in HOS sug- gests similar patient demography and symptoms to patients from ROW. The delay in diagnosis is greater in ROW compared to NA. The burden of illness in Hunter patients is severe with significant multiple impairment of organs and systems and frequent need for surgical interventions. doi:10.1016/j.ymgme.2008.11.095 95. Podocyte injury and GL-3 accumulation are progressive in Fabry disease Behzad Najafian a , Marie-Claire Gubler b , Chester Whitley a , Michael Mauer a , a University of Minnesota, Minneapolis, MN, USA, b Hopital Necker-Enfants Malades Introduction: Fabry disease is predominantly known through its vascular lesions. However, natural history of its renal complications is poorly understood. We studied glomerular lesions in biopsies from Fabry patients using quantitation of structural parameters by unbiased stereology. Methods: Renal biopsies from 8 (M/F = 6/2) Fabry patients [4–35 (median 15) years old] were studied by electron microscopy. Fractional volumes of GL-3 inclusions per podocytes [Vv (Inc/PC)], mesangial [Vv (Inc/Mes)] and endothelial cells [Vv (Inc/ Endo)], foot process width (FPW) and %endothelial fenestration were estimated. Six normal living kidney donors were used as controls. Results: Three patients had detectable proteinuria (max. 0.75 g/day). FPW was greater (p = 0.009) in Fabry patients (5,761,130 nm) than controls (406,134 nm) with no overlap between the groups. FPW increased progressively with age (r = 0.87, p = 0.005). Similarly, there was a trend for progressive increase of Vv(Inc/PC) with age (r = 0.67, p = 0.07). This trend when excluding a 13 years old female with minimal Fabry lesions, was statistically significance (r = 0.75, p = 0.05). The three oldest pa- tients (15, 19 and 35 years old) had the greatest, but almost identical Vv(Inc/PC) val- ues (0.46, 0.47 and 0.46). There was no relationship between Vv(Inc/PC) and Vv(Inc/ Mes) or Vv(Inc/Endo). However, Vv(Inc/Mes) and Vv(Inc/Endo) were significantly cor- related (r = 0.90; p = 0.003). There was no relationship between age and Vv(Inc/Mes) or Vv(Inc/Endo). Also, glomerular endothelial fenestration was significantly reduced in Fabry patients (4119%) compared to controls (5316%). Conclusion: Our preliminary data suggest that podocyte injury occurs early in Fabry disease and is progressive with age. Podocyte GL-3 accumulation is simi- larly progressive with age, but may reach to a plateau at older ages. Reduced endothelial fenestration, first described here, could be a manifestation of endothe- lial injury in Fabry disease. Careful quantitation of Fabry lesions is required for the proper development of structural/functional relationships and end points for clinical trials. doi:10.1016/j.ymgme.2008.11.096 96. Canavan disease treatment using glyceryltriacetate Aryan Namboodiri a , C. Madhavarao a , P. Arun a , S. Mog a , N. Grunberg a , W. Gahl b , Y. Anikster c , J. Moffett a , a Uniformed Services University, Bethesda, MD, USA, b National Institutes of Health, c Safra Children Hospital, Sheba Medical Center Canavan disease (CD) is a neurodegenerative genetic disorder caused by defects in aspartoacylase (ASPA). ASPA catalyzes the deacetylation of N-acetylaspartate (NAA), an abundant nervous system-specific amino acid derivative. Our central hypothesis is that CD pathology results primarily from inadequate myelin lipid syn- thesis caused by a deficiency in the supply of NAA-derived acetate. Previously, we examined acetate levels and myelin-associated lipid synthesis in the murine model of CD (ASPA/), and found that brain acetate levels were decreased almost 80%, and certain myelin associated lipids were reduced by approximately 1/3. Subsequently we found that oral administration of glyceryltriacetate (GTA) can increase acetate lev- els in the brain over 15-fold within 1 h of administration, indicating that GTA could be used to prevent the severe acetate deficiency in CD. We tested the acetate deficiency hypothesis by studying the effectiveness and tolerability of GTA using the tremor rat model of CD. Tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 to 14, and at 5.8 g/kg from day 15 to 23 and thereafter, in food (7.5%) and water (5%). Performance of the treated tremor rats improved sig- nificantly in rotarod balancing as well as in locomotion tests after about 8 weeks of treatment. Further, no toxicity was detectable, and no histopathological lesions were noted in any organ examined. doi:10.1016/j.ymgme.2008.11.097 97. Autophagy dysfunction in Alzheimer s disease and other late-age onset neu- rodegenerative diseases Ralph Nixon, Orangeburg, NY, United States, Nathan Kline Institute, New York University School of Medicine Primary lysosomal dysfunction in congenital lysosomal storage disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of recognized inherited adult-onset neurodegenerative diseases that are caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic path- ways has grown considerably. I will briefly discuss examples of neurodegenerative diseases across the lifespan characterized by prominent autophagic-lysosomal dys- function, which may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. I will highlight Alzheimer’s disease (AD) as a disease within this group and discuss how the genes and other risk factors promoting this disease contribute to progressive lysosomal system dysfunction and neuronal cell death. Our recent studies indicate that neuronal macroautophagy is constitutively active and that clearance of autophagic substrates is exceptionally efficient in healthy neurons. Impaired autophagosome clearance rather than autophagy induction most likely accounts for the extensive autophagic-lysosomal pathology observed in spo- radic AD. This research was supported by the National Institute on Aging. doi:10.1016/j.ymgme.2008.11.098 98. Small molecule therapies for neurologic manifestations of LSD in humans Marc Patterson, Mayo Clinic, Rochester, MN, United States The treatment of LSDs was revolutionized by the introduction of enzyme replace- ment therapy (ERT) in the last decade of the 20th century. ERT has proven effective in reversing or ameliorating most of the non-neurologic manifestations of these dis- eases, but in general has not influenced the progression of neurologic disease. Small molecule therapies are under development to fill this therapeutic hiatus. Chaperone (or enzyme enhancement) therapy is currently under investigation for Pompe, Fabry and Gaucher disease; substrate reduction therapy is approved for Gau- cher disease and is under investigation in Niemann-Pick disease, type C. Preclinical studies have indicated potential for molecules targeting downstream effectors of neu- rologic injury, including inflammation, apoptosis, calcium maldistribution and mistrafficking of macromolecules. Chaperone therapy is aimed at substantially correcting the primary deficiency, and in subjects with appropriate mutations, has the potential to reverse the pheno- type. In contrast, the other interventions are directed at mechanisms downstream of the primary mutation, and in theory (and practice) have more modest effects. Com- bination therapies with small molecules targeting multiple pathways have shown additive or synergistic effects in animal models. Translation of these promising findings to clinical studies is challenging for sev- eral reasons. In many LSDs, the pool of likely participants is small, and enrolling a suf- ficient number of subjects to adequately power a traditional randomized controlled trial may not be feasible. Even if subjects are available, acceptable study endpoints may not be defined; in many LSDs there are no well established markers of neurologic progression. Innovative solutions including small clinical trials, N of 1 studies and metabolomic’ approaches to identification of biomarkers are promising responses to this conundrum. The rise of personalized medicine highlights these problems in the broader population and the challenges they pose for both regulatory authorities and investigators. doi:10.1016/j.ymgme.2008.11.099 99. Long-term clinical trial with miglustat in Niemann-Pick disease type C Marc Patterson a , Darlenn Vecchio b , Elizabeth Jacklin c , Ed Wraith c , a Mayo Clinic, Rochester, USA, Rochester, MN, United States, b Columbia University, New York, USA, c Royal Manchester Children s Hospital, UK Introduction: Niemann-Pick disease type C (NP-C) is an invariably progressive neurological disorder. The clinical trial, OGT 918-007, indicated that miglustat slowed Abstracts / Molecular Genetics and Metabolism 96 (2009) S12–S47 S33