Wolman disease (WD) is a rare inherited condition caused by lysosomal acid lipase (LAL) deficiency first described in Iranian-Jewish (IJ) children. Newborns with WD are healthy and active, but soon the infant develops symptoms of severe malnutrition in the first few months of life, and often dies before the age of 1 year. Harmful amounts of lipids accumulate in the spleen, liver, bone marrow, intestine, adrenal glands, and lymph nodes. Although worldwide incidence is estimated at 1/350,000 newborns, WD occurs at higher than expected frequency in the IJ community of the Los Angeles area. As a validation study, we analyzed 162 DNA specimens of IJ origin by automated sequencing. For LIPA p.G87V (ggc>gtc, alternative numbering p.G66V), a heterozygous frequency of 5/162 (3.086%) was discovered. Thus, we estimate that as high as 1 in 4200 newborns of IJ couples may be at risk. Additional studies are required to confirm and further validate the higher frequencies seen in our sample pool, and to determine if people of IJ and even possibly Middle Eastern descent are at a higher risk for WD.

Background: Metastatic pancreatic cancer (MPC) is associated with an extremely high mortality. Current NCCN guidelines recommend systemic therapy, as it is superior to best supportive care. Undertreatment of MPC continues to be an issue. Recent treatment and survival data of MPC in Veterans' Affairs' (VA) hospitals have not been published. The relationship between MPC treatment and survival and the American College of Surgeons' (ACS) Committee on Cancer (CoC) accreditation in VA hospitals has not been studied. Methods: Nationwide data from the National Veterans Affairs Cancer Cube Registry was analyzed. In total, 6,775 patients were diagnosed with MPC between 2000 and 2014. CoC accreditation of each VA hospital was obtained using the ACS website. Results: MPC constitutes 52.31% of all pancreatic cancer diagnosed (6,775/12,951 cases). The near totality was men (97.44%). The above 70 years age group and the 60-70 years age group were the most common ages at diagnosis with 39.39% and 38.02% respectively. The proportion of early-onset pancreatic cancer (EOPC) was 2.84%. When compared to all stages of pancreatic cancer, stage IV pancreatic cancer had a lower proportion of cancer originating from the head of the pancreas (39.33% versus 50.63%) and more originating from the tail (17.99% versus 13.39%). Tumors originating from head of the pancreas are more likely to cause biliary symptoms and thus are more likely to be caught at an earlier stage. Overall, treatment rate in the VA at the national level with first-line chemotherapy was 37.61%. The rate of treatment over the years has increased in a linear fashion from 33.01% in 2000 to 41.95% in 2014. This has corresponded with an increase of 1-5 years survival of 9.29% in 2000 to 22.99% in 2014 and 5-10 years survival from 0.96% in 2000 to 6.00% in 2012. Treatment rates in CoC-accredited and non-CoC accredited VA hospitals were similar (38.94% and 38.12%, respectively). Survival rates in CoC-accredited and non-COC accredited VAs were similar with a 1-5 years survival rate of 8.89% and 8.57%, respectively. Conclusions: Treatment and survival of MPC have risen significantly in the past decade at VA hospitals.CoC accreditation is not associated with a change in treatment or survival rates.

Autosomal recessive hereditary inclusion body myopathy (HIBM or IBM2) is a progressive adult onset muscle wasting disorder characterized by sparing of the quadriceps. IBM2 is also known as distal myopathy with rimmed vacuoles or nonaka myopathy. IBM2 is associated with mutations in the UDP-GlcNAc 2-Epimerase/ManNAc Kinase gene (GNE). GNE is the rate-limiting enzyme of N-Acetylneuraminate (Neu5Ac, Sialic acid) biosynthesis. The GNE coding region of 64 symptomatic patients were sequenced. Twenty-eight patients were found to bear GNE mutations. Ten novel mutations were identified among nine patients, including four nonsense (p.R8X, p.W204X, p.Q436X, and p.S615X) and five missense (p.R71W, p.I142T, p.I298T, p.L556S, and p.E2G) variations spanning both the epimerase and kinase domains of GNE. Additionally, a synonymous variation (p.Y591Y, codon tac > tat) was seen in a patient bearing compound heterozygous nonsynonymous mutations (p.S615X and p.Y675H). Six of the nine are Caucasian, one patient is Taiwanese, one patient is Asian Indian, and one patient is of European descent. These findings further expand the clinical and genetic spectrum of IBM2.

Hereditary inclusion body myopathy (HIBM) is a young-adult onset autosomal recessive disorder caused by a hypomorphic rate limiting enzyme of sialic acid biosynthesis. The enzyme is UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, and is encoded by the GNE gene. HIBM causes slowly progressive muscle weakness and atrophy. Patients are typically diagnosed at 20-30 years of age, and most patients are incapacitated and wheelchair-confined by 30-50 years of age. Some sialic acid containing glycoproteins, including neural cell adhesion molecule (NCAM), are hyposialylated in HIBM muscle biopsy samples. We developed a method to allow detection of serum NCAM sialylation using Western blot, and tested serum samples from several patients and a HIBM mouse model. Preliminary results showed a clear difference in polysialylated and hyposialylated forms of NCAM extracted from serum, and showed NCAM is hyposialylated in HIBM serum samples. This initial finding may prove useful in reducing the need for serial muscle biopsies in HIBM treatment trials. Additional studies are underway to further validate this finding and to evaluate the specificity, reliability, and robustness of this potential serum biomarker for HIBM.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.