Zellweger UK: A glimmer of hope

© Zellweger UK

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions.

Peroxisomes are membrane-bound organelles found in nearly all eukaryotic cells. They contain over 70 distinct enzymes required for normal lipid metabolism and are responsible for many other biochemical processes essential for normal development of health.1 Zellweger Spectrum Disorders (ZSDs) belong to the group of Peroxisome Biogenesis Disorders (PBDs).2,3 They represent inherited autosomal recessive disorders caused by mutations in about 13 PEX genes which encode proteins (so called peroxins) essential for the biogenesis of peroxisomes.2

Mutations are largely found in PEX1, less commonly in PEX6 and occasionally in PEX10, PEX12 and PEX26. These peroxins are important components of the peroxisomal import machinery bringing metabolic enzymes into the peroxisome. When peroxisomal enzymes are not imported into the organelle, they cannot function or are degraded. This has major consequences for most of the metabolic pathways located in peroxisomes.

A loss of peroxisomal functions is generally accompanied by the accumulation of substrates which can only be processed in peroxisomes and may be toxic (e.g. very-long chain fatty acids (VLCFAs), phytanic acid, a branched-chain fatty acid from dairy products, or bile acid precursors), and a shortage of peroxisomal products (e.g. myelin sheath lipids). Peroxisomes are required for normal brain development and function and the formation of myelin, which insulates neuronal cells.

Getting to know ‘PBD-ZSD’

PBD-ZSD is characterised by the impaired function of peroxisomes. Defective peroxisome biogenesis, assembly, protein import and subsequent loss of metabolic functions leave affected children with a plethora of health conditions such as moderate to profound sensorineural hearing loss, retinal degeneration, global disabilities, seizures, osteopenia, liver dysfunction, adrenal insufficiency, renal stones, respiratory compromise and leukodystrophy.2,3 As functional peroxisomes are important during development, patients suffering from PBD-ZSD already show symptoms from birth.

It is estimated that around one child in every 50,000 born will be affected with PBD-ZSD, however, as new-born screening for ZSD rolls out in more US states, we may well see this number increase. As diagnostics improve, we are also discovering that the Zellweger spectrum is wider than first thought. We are now seeing a few patients at the mildest end of the spectrum living into their thirties and even beyond without experiencing a great deal in the way of symptoms until their later years. However, it is less common for children on the spectrum to reach adulthood and there are still far too many on the very severe end of the spectrum born severely symptomatic and unlikely to see their first birthday. There is currently no cure and there are no effective treatments specific to ZSD.

The consequences of a complex metabolic condition

The physical and mental challenges that come with a complex metabolic condition like this are huge; the world can be a terrifying place for a child with such profound visual and hearing loss that touch is their only access to understanding the world around them. Many children, especially as the condition progresses, experience extreme pain due to dislocation, renal stones or poor bone health, and they can suffer multiple seizures daily as well as many hospitalisations for repeated pneumonias. Yet, with the support of their families they so often show incredible resilience and strength of character; smiling even on the worst of days and showing extraordinary determination even after suffering terrible progression of the disease.

For families, the sheer volume of care for a medically complex child can be overwhelming, and the degenerative nature of the condition adds a huge emotional and financial strain. Something as simple as a toy that a child on the Zellweger spectrum can see, interact with and understand, or a seat that is supportive enough for a child to sit without strain or discomfort, can be hundreds or even thousands of pounds. Living with a rare condition is also extremely isolating for families, especially given how rare and widespread the disease is.

The role of Zellweger UK

We are a small, entirely parent run charity set up to raise awareness and support research into Zellweger Spectrum Disorder and closely related peroxisome disorders. We are currently supporting 64 families impacted by this little-known condition across the UK and Ireland. We offer resources and information on peroxisomal disorders and connect families via private online forums; often a lifeline, especially for newly diagnosed families in those overwhelming and frightening days and weeks after diagnosis, as they try to begin to come to terms with their child’s prognosis.

Our annual family conferences bring families together in person and face to face with a glimmer of hope: some of the few specialists and research teams across and outside of the UK and who are working to better understand the condition from a molecular, diagnostic and therapeutic viewpoint; some of the people around the world that care deeply about peroxisome biology and peroxisomal disorders. As the charity grows our conferences grow too and this year, we were proud to have researchers from the UK, the Netherlands and the US, and we even welcomed our first attending family from the Netherlands.

Our support does not stop when a child dies; we are here to support grieving families and we can offer personalised memory jewellery and a shoulder to lean on. For bereaved families, our conferences are that rare place where your child is remembered, spoken about openly and so missed; a place where our children are the driving force behind the conference and the charity.

We also provide small family grants for anything that can help impact an affected child’s life in a positive and meaningful way. We were recently humbled to see a child benefit developmentally from a small grant to purchase a Tomato Soft-Touch Sitter seat. He needed a minimally supportive chair for daily sessions to help him work and strengthen his trunk, but to get this government funded, his family would need to return his fully supportive chair. This was not an option for a little boy who could only tolerate up to ten minutes in the tomato seat without tiring and this would have left him with no appropriate seating for the large part of his day. By providing a family grant, we were able to purchase the Tomato seat for him. This seating system was so successful that he not only gained enough trunk control to progress to an even less supportive chair, but he was able to gain enough strength to sit in and use a regular toddler swing at the park; something nobody dared hope he would ever be able to do.

The future

As the charity gains momentum, we are increasing our outreach. We have established links to academic and medical institutions and are excited about our visits and the opportunity to talk to researchers and students. We have also recently joined the Global Partners’ Programme with the GFPD (Global Foundation for Peroxisomal Disorders), the global charity for PBD-ZSD and closely related peroxisomal disorders. Our aim is to donate more funds to medical and scientific research through their programme and via our own initiatives. We were very pleased to be able to offer a first small grant for support of a PhD student working on peroxisomes and their impact on health and disease.

There are challenges that come hand in hand with running a small rare disease charity: most people have never heard of the peroxisome and fewer people have heard of Zellweger spectrum disorders. We are run entirely by parents either grieving the death of their own child or still caring for medically complex children. Those of us who have lost our children to this disease work knowing that any potential medical breakthrough is already too late for our own child, and those of us with children still battling this condition work knowing that the chance of any intervention being discovered in time for their child is very small.

Nonetheless, our children inspire us to push forward, to raise more awareness, reach out further to metabolic clinics so that we can engage and support more families, and crucially to increase our funds so that we can offer larger grants towards research, in the name of our own affected children.

 

Registered Charity Number 1166389

 

References

 

1          Islinger M, Schrader M. 2011. Quick Guide Peroxisomes. Curr Biol 21:R800-R801

2          Waterham HR, Ferdinandusse S and Wanders RJ. 2016. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta 1863:922-33

3          Braverman NE, Raymond G.V and Rizzo W.B, et al. 2016. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab 117:313-21.

 

Zellweger UK

Kerry Hughes (Treasurer)

Natasha Anderson-Hunt (Chair)

+44 (0)1460 68405

Admin@zellweger.org.uk

Please note, this article will appear in issue 33 of Scitech Europa Quarterly, which is available in December 2019.

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