Research Spotlight

Posted May 15th 2016

A founder mutation in vps11 causes an autosomal recessive leukoencephalopathy linked to autophagic defects.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Zhang, J., V. Lachance, A. Schaffner, X. Li, A. Fedick, L. E. Kaye, J. Liao, J. Rosenfeld, N. Yachelevich, M. L. Chu, W. G. Mitchell, R. G. Boles, E. Moran, M. Tokita, E. Gorman, K. Bagley, W. Zhang, F. Xia, M. Leduc, Y. Yang, C. Eng, L. J. Wong, R. Schiffmann, G. A. Diaz, R. Kornreich, R. Thummel, M. Wasserstein, Z. Yue and L. Edelmann (2016). “A founder mutation in vps11 causes an autosomal recessive leukoencephalopathy linked to autophagic defects.” PLoS Genet 12(4): e1005848.

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Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.


Posted May 15th 2016

Long-term follow-up and sudden unexpected death in gaucher disease type 3 in egypt.

Raphael Schiffmann M.D.

Raphael Schiffmann, M.D.

Abdelwahab, M., D. Blankenship and R. Schiffmann (2016). “Long-term follow-up and sudden unexpected death in gaucher disease type 3 in egypt.” Neurol Genet 2(2): e55.

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OBJECTIVE: To describe the long-term follow-up and distinct phenotype of a large cohort of patients with Gaucher disease type 3 on enzyme replacement therapy (ERT) in Egypt. METHODS: A prospective cohort study of 78 patients on ERT who were followed for up to 9 years with yearly evaluations that included EEG and cognitive testing. RESULTS: Of the patients, 73% were homozygous for the L444P GBA1 mutation; all but 7 were neurologically symptomatic. Supranuclear gaze palsy with variable but stable cognitive function was present in 91% of patients. Convergent strabismus and bulbar dysfunction were noted in 22% and 37%, respectively. Features of oppositional defiant disorder were present in 54% of patients. Twenty-three patients (30%) developed seizures while on ERT for 1-9 years. Of those, 12 patients (15%) died suddenly and unexpectedly at a mean age of 6.7 +/- 5.0 years (range 1.5-18). Sudden death was usually associated with a seizure disorder or a terminal seizure, but 7 of 12 patients had a preceding normal EEG. An additional 11% had background slowing or epileptogenic activity on EEG without clinical seizures. There were 3 familial cases of sudden unexpected death. CONCLUSIONS: Despite having the most common GBA1 genotype known to be associated with neuronopathic Gaucher disease, patients with Gaucher disease type 3 in Egypt have a phenotype and a clinical outcome on ERT that are very different from those observed in other populations. Identifying putative modifying genes of this ethnic group is likely to lead to better therapy for neuronopathic Gaucher disease generally.


Posted May 15th 2016

Pustular psoriasis eruption with dabrafenib, a braf inhibitor.

Alan M. Menter M.D.

Alan M. Menter M.D.

Fawaz, B., L. Dickson and A. Menter (2016). “Pustular psoriasis eruption with dabrafenib, a braf inhibitor.” J Dermatolog Treat Apr 14 [Epub ahead of print]

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Targeted BRAF inhibition with vemurafenib and dabrafenib has dramatically improved the survival rate in metastatic melanoma. These agents are now being tested for their efficacy against other tumors with BRAF mutations, including lung adenocarcinoma. While cutaneous adverse events are prevalent with BRAF inhibition, our patient, to our knowledge, is the first to develop a psoriatic eruption with BRAF inhibitors. We postulate that the elevation of tumor necrosis factor-alpha (TNF-alpha) and the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway due to BRAF inhibition may be responsible for the eruption. More studies are needed to further elucidate the immunopathogenic mechanisms behind this adverse event. The response to MEK inhibitors and/or increased TNF-alpha inhibition may help support or debunk our hypothesis.


Posted May 15th 2016

A review of biologic therapies targeting il-23 and il-17 for use in moderate-to-severe plaque psoriasis.

Alan M. Menter M.D.

Alan M. Menter M.D.

Campa, M., B. Mansouri, R. Warren and A. Menter (2016). “A review of biologic therapies targeting il-23 and il-17 for use in moderate-to-severe plaque psoriasis.” Dermatology and therapy 6(1): 1-12.

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The development of several highly effective biologic drugs in the past decade has revolutionized the treatment of moderate-to-severe plaque psoriasis. With increased understanding of the immunopathogenesis of psoriasis, the emphasis has turned toward more specific targets for psoriasis drugs. Although the complex immunological pathway of psoriasis is not yet completely understood, current models emphasize the significant importance of interleukin (IL)-23 and IL-17. Several biologic drugs targeting these cytokines are now in various stages of drug development. Drugs targeting IL-23 include BI-655066, briakinumab, guselkumab, tildrakizumab, and ustekinumab. Drugs targeting IL-17 include brodalumab, ixekizumab, and secukinumab. While many of these have shown safety and good efficacy in clinical trials of moderate-to-severe plaque psoriasis, long-term safety is still to be established.


Posted May 15th 2016

Patient-relevant needs and treatment goals in nail psoriasis.

Alan M. Menter M.D.

Alan M. Menter M.D.

Blome, C., A. Costanzo, E. Dauden, C. Ferrandiz, G. Girolomoni, R. Gniadecki, L. Iversen, A. Menter, K. Michaelis-Wittern, A. Morita, H. Nakagawa, K. Reich and M. Augustin (2016). “Patient-relevant needs and treatment goals in nail psoriasis.” Qual Life Res 25(5): 1179-1188.

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PURPOSE: Patient-centered health care implies that medical decisions are made jointly by physician and patient, based on patient needs. Aims were to (a) identify treatment goals for a new questionnaire on patient needs and benefits in nail psoriasis treatment; (b) analyze the importance of treatment goals in patients with nail psoriasis in general and in defined subgroups; and (c) determine the association between overall treatment goal importance and quality of life. METHODS: The study comprised the following steps: qualitative survey on needs and burdens in 120 patients; development of items by an interdisciplinary expert group; item testing in 55 patients in four countries; revision of the questionnaire and assessment in 203 patients in six countries (Germany, Denmark, Italy, Spain, USA, Japan). The percentage of patients rating the goals as ‘quite/very important’ was compared between various patient subgroups. RESULTS: Based on 692 free-text statements, 26 items were developed which were reduced to 24 items after pilot testing. Each of these treatment goals applied to the majority of patients in the multi-center study. Goal importance increased with severity of nail psoriasis, but not with age or disease duration. Manual dexterity and social interaction were of particular importance. Goal importance and quality of life were associated, but not redundant (r = 0.612, p < 0.001). CONCLUSIONS: Patients with nail psoriasis have manifold and specific treatment goals. Goal importance is a construct different from disease-specific quality of life and should be assessed separately. The new questionnaire can support goal setting in clinical practice.