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SDS & Science Snapshots (2024-03-23)

In this issue: Three different case reports about various aspects of SDS, and the affected SDS patients' unique experiences.

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email or message us on Facebook! This is all for you!

The last few weeks have brought us three different case reports published in the biomedical literature, each highlighting a different aspect of the disease.

A case report of a young patient with SDS whose diagnosis was nearly missed

This case report shares the story of a young patient with SDS whose diagnosis was nearly missed due to inconsistent genetic test results and liver issues not always recognized as typical for SDS.

Initially, the patient was thought to have a rare, genetic liver disease or mitochondrial disease. The authors describe in great detail their findings regarding the liver of the patient, such as electron microscopy imaging of the inside structure of liver cells, including mitochondria. Note, that the ribosomes in the mitochondria (a.k.a. mitoribosomes) are structurally different and responsible for translating genetic information encoded in mitochondrial DNA. These ribosomes are NOT involved in SDS, but can cause mitochondrial diseases if there is a defect. Mitochondria are organelles responsible for converting energy from food into ATP, the chemical energy our cells need to live and thrive. Check out our blog post on ribosomes and mitochondria, here. The authors report:

"Ultrastructural analysis of SDS-related hepatic pathology has not been previously reported. In our patient, EM on liver biopsy specimens was notable for numerous small mitochondria that were densely packed within the cytoplasm, reminiscent of “oncocytic transformation” usually seen with the primary mitochondrial condition, mitochondrial DNA depletion syndrome."

As we all know, SDS is a rare genetic syndrome characterized by multiorgan dysfunction with typical presenting features that include exocrine pancreatic, hematologic, and skeletal abnormalities. It is now also established that the liver is often affected. However, the long-term implications are not known, and there is no treatment available for the frequently reported highly elevated liver enzymes (transaminases) in young children. We know from the SDS patient community that many patients undergo liver biopsy before being diagnosed with SDS, with no clinically actionable outcomes. For most patients, the liver enzyme levels go back down into (or close to) normal levels within the first 5 years of life. The authors report:

"SDS-related liver disease has an overall good prognosis, as the elevates transaminases, hepatosteatosis, and fibrosis tend to normalize around 5 years of age. Adult patients with SDS usually have no evidence of clinical liver disease, with few rare exceptions."

We believe that this assumption warrants further investigation, as there is very little data available about adult SDS patients' overall health. Despite the high prevalence of highly elevated liver enzymes in early childhood, very little is known about the condition. There is a high need for research in this area.

The genetic workup of the child has not been straightforward, either. Whole exome sequencing (WES) initially missed the diagnosis. The authors looked into why. They think that it is either because not all the relevant symptoms were listed in the WES test request, and therefore the SDS genes may not have received the proper attention at the data interpretation step by the testing company, or perhaps there was a problem with the test analytics due to the SBDS pseudogene SBDSP1. Check out our blog post on pseudogenes to learn more. The authors report:

"Interestingly, the SBDS gene variants that were ultimately identified on the patients WGS were within genetic regions that could have been identified on WES, with one variant within exon 2 (c.183_184delTAinsCT), and the other a 5′ donor splice-site mutation between exons 2 and 3 (c.258 + 2T > C). This is significant because c.183_184delTAinsCT and c.258 + 2T > C are two of the most common pathogenic variants in SBDS."

The full article is available here:

A success story of treating an SDS patient with AML in China

One of the biggest concerns we face as SDS patients and caregivers is the risk of developing leukemia, specifically acute myeloid leukemia, or AML for short. The risk is estimated to be around 30% by age 30, which keeps on going up after that. AML develops when the blood-forming stem cells in the bone marrow accumulate new mutations (also known as somatic mutations) that allow them to grow out of control. We have covered the mechanism of this in an educational video, here.

To make matters worse, AML in SDS patients often contains p53 mutations, which makes its treatment even harder than it already is. Combined with the increased sensitivity to chemotherapy that would be needed to get rid of AML, there are very few success stories of a positive outcome.

The medical and scientific community is hard at work trying to find better treatment options for AML, for both the general population and for SDS patients, as highlighted at many scientific conferences, including the AA-MDS Symposium which our team attended just last week. More about that soon.

Today, we want to highlight a brand new case report from Beijing, China, in which the authors report success in treating one SDS patient who developed AML. The approach was to treat the AML first to reduce the number of AML cells, in order to increase the likelihood of success for hematopoietic stem cell transplant. This is not a new approach, and many groups are looking for a good combination of chemotherapeutic drugs that can work for SDS. It seems that for this particular patient, they found something that worked. The authors report:

"At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case."

At the time of this article, the patient has been 6 months post-transplant and well. We wish the 15 year-old-patient continued health and recovery.

We have reached out to the authors to learn more and will update this blog post if new information becomes available.

Ma C, Lang H, Chen Y, Yang L, Wang C, Han L, Chen X, Ma W.Anticancer Drugs. 2024 Mar 15. doi: 10.1097/CAD.0000000000001594. Online ahead of print.PMID: 38502829

A case of a severe, zoonic infection of a 17-year-old patient with SDS

In this recent case report, the authors share the case of a 17-year-old patient who was diagnosed with SDS as a child and treated with GCSF and PERT but lost to follow-up for several years. She came to the emergency room very ill with an acute infection, which developed into sepsis. The primary infection was identified as rat-bite fever (RBF), an important bacterial zoonosis primarily caused by Streptobacillus moniliformis in North America, but the pathogenesis is understudied.

"She reported exposure to pet rats, dogs, cats, chickens, guinea pigs, sugar gliders, and a snake."

From the information available to us about the article, it is unclear whether the patient made a full recovery or not. We have reached out to the authors to request more information and will update this blog post as we learn more.

If you or your child has SDS, please discuss with your healthcare team whether pets are safe for your household, and/or what special precautions should be taken around them. Frequent recommendations from the SDS community include being extra careful around cat litter and avoiding handing cat litter to SDS patients and any people who may be immune-compromised (such as pregnant people) to reduce the risks of toxoplasmosis.

Warning: there are disturbing images included in the original article. Viewer discretion is advised.

Mayhew J, Luttrell H, Barros K, Blazin L, Nichols C, Avashia-Khemka N, Lavik JP, Relich RF, Skinner D, Zhou J, Saraf A, Khaitan A.Pediatr Blood Cancer. 2024 May;71(5):e30918. doi: 10.1002/pbc.30918. Epub 2024 Feb 23.PMID: 38391125 No abstract available.


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