New insights into therapeutic options for Pompe disease

Richard, Emmanuel; Douillard-Guilloux, Gaëlle; Caillaud, Catherine

doi:10.1002/iub.529

Cited by 18 publications

(13 citation statements)

References 70 publications

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“…Only functional studies indicate how mutations impair protein ability, providing data that could be clinically relevant. This is true for genes encoding metabolic enzymes critically important for human pathologies [24–27] and, even more, for transcription factors, like FOXC2 , that are responsible for regulating the expression of a broad range of genes both during development and in adult tissues [12, 17, 28]. …”

Section: Discussionmentioning

confidence: 99%

FOXC2disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function

Tavian

Missaglia

Maltese³

et al. 2016

Oncotarget

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Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema.

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Section: Discussionmentioning

confidence: 99%

FOXC2disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function

Tavian

Missaglia

Maltese³

et al. 2016

Oncotarget

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“…Beyond an initial improvement, most patients continue to decline, albeit at a slower rate than untreated patients, and remain below population norms [ 29 ]. Due to the time required to administer infusions, ERT by itself is considered burdensome to patients and caregivers [ 57 ]; whether this affects patient adherence and satisfaction would also provide more context to the understanding of the overall burden of Pompe disease.…”

Section: Discussionmentioning

confidence: 99%

The humanistic burden of Pompe disease: are there still unmet needs? A systematic review

et al. 2017

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BackgroundHumanistic burden considers the impact of an illness on a patient’s health-related quality of life (HRQoL), activities of daily living (ADL), caregiver health, and caregiver QoL. Humanistic burden also considers treatment satisfaction and adherence to treatment regimens. Pompe disease is an autosomal recessive, progressive, multisystemic neuromuscular disease. Approval of enzyme-replacement therapy (ERT) markedly improved prognosis for patients, but considerable morbidity and a substantial humanistic burden remain. This article characterizes the humanistic burden of Pompe disease through a systematic literature review.MethodsA systematic search of MEDLINE® and Embase® with back-referencing and supplementary literature searches was performed to retrieve data from interventional and non-interventional studies on the humanistic burden of Pompe disease. Publications were screened according to predefined criteria, extracted, and assessed for quality. Extracted data were narratively synthesized.ResultsNo publications on the humanistic burden of infantile-onset Pompe disease (IOPD) were identified. As such, of 17 publications included here, all are in patients with late-onset Pompe disease (LOPD). Thirteen publications were initiated after approval of ERT, two were initiated before, and two overlapped the approval of ERT. The review shows that LOPD patients have a significantly lower HRQoL than the general population, even if treated with ERT. On transitioning to ERT, treatment was associated with improvement in the physical component score of the SF-36 and fatigue, although the SF-36 mental component score remained stable. Physical HRQoL remained below population norms after 4 years of ERT. Significantly more ERT-treated patients reported pain than controls, and bodily pain worsened in later years following ERT initiation. Treatment-naïve LOPD patients had significantly poorer ADL functioning compared with the general population, although ERT stabilized deteriorating functioning impairment. ERT studies showed caregivers provide 17.7 h/week informal care on average. Fifty percent, 40% and <20% of caregivers reported mental health, physical health, and financial/relational problems, respectively. In ERT-naïve patients, wheelchair use and home ventilatory support was associated with lower physical HRQoL and ADL functioning. In ERT-treated patients, key factors predicting worse HRQoL and ADL functioning were higher respiratory distress, poorer sleep quality, greater pain, and more fatigue.ConclusionsPompe disease has a substantial humanistic burden, with strong inter-relationships among and between humanistic burden parameters and clinical progression.

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“…Other specific treatments 52,53 are being developed, including gene therapy, 54 autologous hematopoietic cell transplantation in association with lentivirus, 55 chaperone use, 56 secondgeneration recombinant ERT, and substrate reduction therapy, but their clinical benefits have not been demonstrated yet. 52,54 New phenotype in patients with classical infantile-onset Pompe disease receiving enzyme replacement therapy ERT with AAG resulted in a new phenotype. 35 It is not a shift from the classical phenotype to the late-onset phenotype but one with specific clinical characteristics.…”

Section: New Treatmentsmentioning

confidence: 99%