Multiple Sulfatase Deficiency (MSD) Simple Guide + Podcast

Everything to know about MSD, from the experts.

Podcast

Author and Contributing Experts to this Guide include:

Rachel Wyatt Genetic Counselor LinkedIn
Lars Schlotawa Pediatrician and Child Neurologist LinkedIn
Mauricio De Castro Physician and Scientist, Associate Director for the Air Force Medical Genetics Center
Amber Olsen Executive Director and Founder of the United MSD Foundation LinkedIn

Disclaimer: One of the sources cited in this article is Dr. Mauricio De Castro, Associate Director for the Air Force Medical Genetics Center in Biloxi, Mississippi. He is also an internist and clinical geneticist, and an assistant professor of medicine at the University of Mississippi. Dr. De Castro’s statements are his own and are not reflective of the Air Force or the United States government.

What is Multiple Sulfatase Deficiency?

Multiple sulfatase deficiency (MSD) is an extremely rare genetic condition that affects multiple body systems. The signs and symptoms can vary widely across individuals.

MSD has three subtypes that are based on when an individual begins to show symptoms, how quickly those symptoms progress, and symptom severity. They are neonatal, infantile, and juvenile 1.

The signs and symptoms of MSD will vary by individual. Some of the more common symptoms include: regression, or loss of skills starting around age two and six 2, heart disease, loss of hearing, neurological differences, and airway compromise. MSD is a progressive disorder, meaning that as time goes on, the symptoms will get worse.

Continuous care and monitoring will be essential for these children as they age.

Other names for multiple sulfatase deficiency include:

  • MSD
  • Austin syndrome
  • juvenile sulfatidosis, Austin type
  • mucosulfatidosis

In order to understand what is occurring on a cellular basis that causes MSD, we have to think back to highschool biology. In our cells, there are organelles that carry out different functions. One organelle, called the lysosome, works to break down waste material in the cell and get rid of it.

It is able to break down waste, because it is filled with enzymes which you can think of as little scissors. In MSD, both copies of our SUMF1 gene are not working properly.

This means that its protein, formylglycine-generating enzyme (FGE) is also not working. When FGE is not working, then it is unable to turn on the sulfatase enzymes.

Without those enzymes, a specific waste called glycosaminoglycans begin to build up in the cells and get stored in tissues. The more of the waste that is stored, the worse the symptoms get 3.

Most individuals with MSD do not live past their 13th birthday 4. Once symptoms begin to appear, patients with MSD will continue to worsen. However, how long it takes for a disease to progress will vary across patients.

As mentioned above, MSD has three subtypes:

Neonatal MSD

This is the most severe form of MSD. The first signs of neonatal MSD can actually be seen while the baby is still in utero. The child might be measuring small for their gestational age and when they are born will likely experience difficulty breathing 5.

The progression of the disease is rapid and death usually occurs before age 2 6. Children with the neonatal form of MSD often experience “coarse” facial features, meaning that certain features of their face are more pronounced.

Infantile MSD

Most individuals with MSD, will fall into this subtype. At birth these children tend to not have any striking features. Sometime in the first three years of life, these children will begin to experience signs and symptoms including a decline in their sensory and motor skills.

This form is also further divided by mild and severe types:

Attenuated infantile MSD

Individuals with this subtype of MSD will progress more slowly than the severe infantile form. Patients will likely be small for their age and experience difficulty feeding. Like other individuals with MSD, this subtype will experience a loss of neurologic ability resulting in developmental delay and cognitive ability around age 3-36 months 7.

Some children may be able to move and communicate on a limited basis from age 3-9 years.

Severe infantile MSD

Individuals with severe infantile MSD will have symptoms appear at an earlier age (around 1 year) and progress at a faster rate than attenuated. Additionally, more body systems will be affected 8. Individuals with this subtype will likely have skeletal changes and differences in facial features 9.

Juvenile MSD

The rarest form of MSD is Juvenile. Individuals with this subtype have signs and symptoms that appear later than the other forms (typically around 3 to 7 years). Individuals with this condition likely have some sulfatase enzymes still working, making their presentation milder than others, but more difficult to diagnose 10.

While they could still experience neurological decline, it is to a lesser degree. They might also experience some of the other features such as flaky skin, and some facial features 11 12

“Regardless of the subtype, there are three main areas of the body that tend to be affected by MSD. Those are the brain, skin, and skeleton,” said Rachel Wyatt, a genetic counselor and recent graduate of the University of Alabama at Birmingham's Genetic Counseling Master's Program.

“Commonalities include the deterioration of the white matter in the brain or developmental delays and seizures. With the skin, we see differences such as ichthyosis or a scaly skin, coarse facial features, or even hypertrichosis, which is just an excessive hair growth. Skeletal differences include things such as scoliosis or joint stiffness.

“However, there are many other features that are also associated with MSD such as poor growth, ear and respiratory infections, heart problems such as thickening of the heart muscle, and enlarged organs,” she added.

The Relationship Between Lysosomes and MSD

In broad terms, multiple sulfatase deficiency is a multisystem lysosomal storage disorder.

To understand the root causes of MSD, it’s important to understand the role of lysosomes in the body.

The body’s cells each contain several structures called organelles that carry out important functions. A lysosome is one of these organelles. Its main function is to act as a trash compactor of sorts that uses enzymes to break down the cell’s waste.

But when those enzymes don’t work, cells fill with waste and that causes a variety of medical complications. These conditions are collectively known as lysosomal storage disorders.

“By virtue of being alive, we generate a lot of byproducts, substances that the body can't readily get rid of. As a result, we've developed lysosomes that essentially target these things that are hard to breakdown or that the body needs to get rid of, and then they just essentially eat them, engulf them and then dissolve the byproducts.

“This creates simpler substances that the body can get rid of. But when lysosomes don’t work properly, the body cannot get rid of one of these substances,” explained Dr. Mauricio De Castro, the Associate Director for the Air Force Medical Genetics Center in Biloxi, Mississippi.

Dr. De Castro is also an internist and clinical geneticist, and an assistant professor of medicine at the University of Mississippi.

When that happens, and your body can’t ‘take out the trash,’ waste starts to pile up, creating a backlog and a mountain of undisposed waste.

“With a lysosomal storage disorder, if the body doesn't get rid of the substances, they accumulate. The problem becomes that once they accumulate, they have nowhere to go but to tissues. And so, these substances start depositing and piling up in different tissues.

“There are dozens of storage disorders, but the lysosomal ones, they all have in common this deposition of substances in tissues, which give us the different symptoms that we see,” added Dr. De Castro.

In most storage disorders, only one of the body’s enzymes is affected. That means one of the substances that the body uses to breakdown these byproducts of metabolism are usually missing. This is one enzyme that goes into the lysosome and targets a specific substance.

But MSD is not like other lysosomal storage disorders.

Dr. De Castro further explained, “With multiple sulfatase deficiency, however, the problem is not on a lysosomal enzyme per se, but on a common part of the pathway for all lysosomal enzymes, for all sulfatases in particular.

“There are about 15, 16, 17 different sulfatases in the body. We know of 9 of them that are associated with human disease. All the sulfatases have as their last step an activation, a common thread, a common activator called the formylglycine-activating enzyme (FGE).

“With multiple sulfatase deficiency, the mutation is actually in that final part of the pathway. All the sulfatases converge on this very last step that depends on this formylglycine-activating enzyme. But when the enzyme doesn't work, the sulfatases can't complete activation.”

Because MSD is actually a deficiency of all the different sulfatases. Including those that are associated with disease, this creates a combination of several different conditions. And that is why some patients are so severely affected.

It is a disease-causing variation (mutation) in the SUMF1 gene that prevents the sulfatase enzymes from being able to do their job within the body.

“Typically, FGE helps modify sulfatases and allow them to break down complex sugars and fat that contain chemical groups called sulfates. When you're not able to break down these molecules, they build up within the cell and gradually accumulate, preventing proper function within the cell and leading to the features that we do see with MSD,” added Wyatt.

“It's believed the more FGE function that you have, the less severe the manifestations of MSD are due to some of that residual activity.”

What Causes Multiple Sulfatase Deficiency?

MSD is an inherited condition passed on through in an autosomal recessive pattern. This means both copies of SUMF1 are not functioning properly.

Parents of an affected individual, both carry one copy of the non-functional gene, but they don’t show signs and symptoms of MSD because their other copy is working correctly. This makes them a carrier of the condition.

When two carrier parents have a child there is a 25% chance that child will be affected with MSD, a 50% chance that their child will be a carrier, and a 25% chance that the child will not be a carrier or affected.

Specifically, harmful changes in the SUMF1 (sulfatase-modifying factor-1) gene cause MSD. This gene allows cells to make the formylglycine-generating enzyme (FGE) that is responsible for activating sultafases in a cell, which aid in breaking down substances that contain chemical groups known as sulfates. These substances include a variety of sugars, fats, and hormones.

When FGE is not present or not working correctly, sulfatases go unactivated and are unable to break down a type of waste called glycosaminoglycans (GAGs). Instead the GAGs build up in the cells, causing them to die.

Cells that die in particular tissues, such as the brain, skeleton, and skin, cause many of the signs and symptoms of MSD.

Signs and Symptoms of Multiple Sulfatase Deficiency

Symptoms of MSD will vary from person to person, just as the amount of working sulfatase enzymes will vary. Typically, symptoms will develop in infancy through early childhood.

Because MSD plays a role in the functioning of 17 different sulfatases, there is overlap with the signs and symptoms of other lysosomal storage disorders with only one affected sulfatase. Some individuals with MSD have features similar to a class of lysosomal storage disorders called, mucopolysaccharidoses (e.g., developmental regression, organomegaly, skeletal deformities) while other individuals present primarily with neurologic regression (associated with leukodystrophy) 13.

“All of the lysosomal storage disorders have things that distinguish them. But they all have similar features. What I mean by that is that they all have some degree of central nervous system involvement, some degree of neurologic deterioration, some degree of development delay, of cognitive issues, that they can be from mild to very severe,” said Dr. De Castro.

“There are laboratory findings that may point in the direction of MSD. So when we do the urine testing or enzyme levels, lysosomal enzyme levels, and blood and leukocytes, you would get a clue that it's MSD and not one of the individual sulfatases.

“This is because you should see a generalized disturbance in glycosaminoglycans or sulfatides, whereas for the individual enzyme ones, you typically see one or two enzymes out of normal range. With multiple sulfatase deficiency, you would see all of them or almost all of them,” added Dr. De Castro.

In addition, similarities across all subtypes include progressive neurologic deterioration, heart disease, hearing loss, and airway compromise.

Specific symptoms include 14 15 16

Neurologic

  • Developmental delay and progressive neurologic deterioration (including spasticity)
  • Difficulty with balance and coordination,
  • Some features which overlap with features of Autism
  • Epilepsy
  • Small head or a large head, Enlarged structures in the brain due to fluid buildup

Musculoskeletal

  • Short stature
  • Irregular ribs (associated with dysostosis multiplex)
  • Curvature of the spine
  • Differences in the vertebra structure and stability (risk of spinal cord compression)
  • short bones in the hand
  • Joint stiffness and contractures
  • Broad thumbs and toes
  • Hip dislocation or dysplasia (abnormal growth)
  • Extreme weakness due to neurodegeneration and demyelination
  • Osteopenia (weakened bones)

Craniofacial

  • Coarse facial features
  • Eye complications: Corneal clouding,Retinopathy, retinitis pigmentosa, Strabismus (abnormal eye alignment), Optic nerve abnormalities, Cataracts, Glaucoma
  • Ears complications: Hearing disorders, recurrent ear infections
  • Mouth/oral/Jaw: Difficulty feeding, an overgrowth of the gum tissue, abnormal teeth enamel, airway obstruction, abnormal tracheal structure, small jaw

Cardiovascular

  • At risk for: Atrial septal defects (ASD), aortic insufficiency, Secondary valve disease, cardiac hypertrophy, Coronary artery disease, irregular heart beat, high blood pressure

Skin

  • Might experience dry and scaly skin, and/or excessive hair growth

Gastrointestinal

  • Liver and spleen enlargement
  • Swallowing dysfunction may lead to excessive drooling and feeding difficulties.
  • Issues with gallbladder
  • Gastroesophageal reflux disease (GERD)
  • Urinary retention, Urinary infections, Neurogenic bladder

Respiratory

  • Risk of progressive upper airway obstruction, sleep apnea, and risk for aspiration pneumonia

These signs and symptoms can point to MSD, but additional verification through lab testing is necessary before a definitive diagnosis can be made.

“The problem with multiple sulfatase deficiency is that sometimes it's hard to make the diagnosis because it looks like so many other conditions.

“I don't think that anybody would be able to make a diagnosis of multiple sulfatase deficiency just by looking at a patient. There isn't really, as we say, a pathognomonic finding for this because there is pretty significant overlap with a number of disorders, not just lysosomal storage disorders but other storage disorders and other genetic conditions,” said Dr. De Castro.

Prevalence and Risk Factors for Multiple Sulfatase Deficiency

MSD is considered an ultra-rare disease with an estimated prevalence of 1 in 1 million to 1.4 million individuals 17.

There have been approximately 100 cases reported to date, but this number may not be accurate or it could be underestimated due to a lack of reporting to registries or an under-diagnosis of the condition, especially in areas where advanced genetic testing is not common 18 19

“We're currently underway of calculating the frequency via so-called allele frequency, which means that we look for mutations in the genes of all people. But we haven't come up with a number yet, so that's still underway,” explained Dr. Lars Schlotawa, a German pediatrician, neurologist and research scientist who was on the original team that identified the causative gene SUMF1. He has been working with the MSD community since 2004.

“It’s a gut feeling of how rare it is. For example, in Germany, I can say we've got no more than four living kids at the moment. With all the parents and patients I got in touch with over the past years, I would say it's about 50 to 100 worldwide.

“But I think it's entirely underestimated because, of course, we can only get in touch with the ones who have the internet, have the phone, or access to whatever new media and new technologies. There will be a lot of more patients elsewhere in the world,” he added.

Men and women are equally affected and no ethnic predisposition has been identified.

The primary risk factor is genetic. In families where one child has already been diagnosed with MSD, there’s a 25% chance that a sibling could be affected by this condition.

That’s because if one child has MSD, it indicates that both parents likely have one copy of a nonfunctioning SUMF1 gene.

Diagnosis of Multiple Sulfatase Deficiency

MSD can be suspected in a person who displays many of the clinical features associated with the condition. The diagnosis can be further confirmed if a child has low levels of at least two sulfatases and elevated sulfatide levels.

Testing glycosaminoglycan levels can also be an indicator, although these levels can be normal in some people who have MSD.

“When there's clinical suspicion of MSD, first of all, you should do a urine test for the excretion of sulfatides as well as glycosaminoglycans. But we also know kids that don't secrete either type of storage material, and so you could also miss it by this.

The other thing you could do is that you look for enzyme activities in blood cells, leukocytes, or also skin cells if you want to get a skin biopsy done. You would look for sulfatase activities.

There are various tests for them that you can measure pretty easily,” said Dr. Schlotawa.

“However, don't stop after measuring only one sulfatase because there are single sulfatase deficiencies. You would miss MSD if you don't check a second one or, better, a third one,” he added.

Molecular genetic testing for harmful changes of the SUMF1 gene is a primary way to determine if a person has MSD.

“Through molecular testing, we’re looking at the SUMF1 gene and essentially reading it to find any sort of spelling errors or differences that would prevent it from working properly. About 99% of patients with MSD are found to have two of these changes within the SUMF1 genes,” said Wyatt.

Unfortunately, with an ultra-rare disease like MSD, there can be delays in getting the right diagnosis.

“The bad thing about it is that usually with all of these rare diseases, there's a heavy delay in getting the right diagnosis. In some cases, we know everything from children diagnosed early on because there was an experienced person taking care of the child, or it was born in a center, in a metabolic center, a genetic center, or the parents just by chance met the right physician very early on. But in any other case, when it wasn't like this, there was a delay of the diagnosis,” said Dr. Schlotawa.

Treatment and Care Options for Multiple Sulfatase Deficiency

Unfortunately, there is currently not a cure for MSD. But there are approaches to treating individual symptoms.

“Due to the variability of how MSD can present in each individual, there's likely going to be their own unique management particular to the signs and symptoms by looking at different body systems that are affected within that individual. For example, if someone's having seizures, then it would be important to get a consultation with a neurologist and look into antiepileptic medication to help alleviate seizures and prevent them,” said Wyatt.

One of the ways the condition is managed is through genetic counseling. For people considering a family, genetic counseling can provide valuable information about the implications of all genetic disorders, including MSD, to help people make informed medical decisions prior to pregnancy.

After the specific changes in SUMF1 have been identified, prenatal testing is available for families looking to have another child.

Treatment of someone diagnosed with MSD requires a multisystem approach.

Depending on the needs of the patient, a team of caregivers may include specialists in neurology, metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry, among others. A paper was recently published that provided detailed clinical management.

Families can access this paper, print it out, and bring it with them to appointments 20.

“It's a long list of every organ that could be affected and while you should treat all these symptoms, the most important thing to look at is that it’s a palliative treatment right from the beginning. You should be on top of what parents want, what they could cope with, and how quality of life for everyone, the patient as well as the family, could look like in a reasonable way,” said Dr. Schlotawa.

The good news is that progress continues towards a cure.

“We're at a really, really exciting time in terms of MSD because so many things are going on. There are new animal models being created. There are trials with gene therapy, even clinical trials on the horizon. We’re looking for drugs that could be repurposed for treatment of MSD. It's still at a very early stage, and definitely too early to say we found something that is really working because it's never been tested in patients so far,” added Dr. Schlotawa.

The hopeful tone for a cure was echoed by Dr. De Castro as well.

“There are some other research avenues that the United MSD Foundation is pursuing with small molecules and drug screens and things like that that may yield some form of treatment that may be helpful for patients with MSD, but I sincerely believe the hope really to cure this will be gene therapy.

“Now there are some forms of enzyme replacement therapy. They are looking at gene therapy for some of the other disorders. Some replacement therapies have been hit and miss for some of these other disorders. It helps with some of the symptoms, and some of the symptoms not so much. I think that pursuing gene therapy and going directly to the mistake, so to speak, and fix it is what eventually will help patients with MSD.”

Prognosis of Multiple Sulfatase Deficiency

On average individuals with MSD live until their 13th birthday 21. However, this is the average, meaning that there are children that do not live as long and some that will live longer.

Prognosis can be better estimated when the subtype of MSD is taken into consideration.

Part of the problem with talking about length of survival is that it does not always consider quality of life. Due to multiple systemic problems, a person with MSD will face several chronic and life-threatening challenges, greatly reducing their quality of life.

“With complex care, you can let someone with MSD live a long life. But definitely I think quality of life is impaired at any point in MSD. As long as the disease just started and there's not the full spectrum of symptoms, I think you have a really good quality of life. After the point where you run through neurodegeneration, which can be quite fast at any point in life, you lose a lot of skills, and this definitely affects your quality of life,” said Dr. Schlotawa.

What to do Next: Living with Multiple Sulfatase Deficiency

Because this is such a rare condition, it’s highly recommended to take advantage of the support and advocacy resources that are available to individuals with MSD.

Some of these include the United MSD Foundation and MSD Action Foundation, which both offer educational resources and opportunity to connect with other individuals who have experienced MSD whether directly as a patient or family members.

“Learning more about the individuals that have MSD can help educate us as providers and really allows for a better understanding of the condition as a whole,” said Wyatt.

“There are so many initiatives going on. You can join them via Facebook. I think all these parents call each other very frequently. They talk to each other. There's a lot of knowledge in this community that could easily be exchanged and people are happy to give advice because they all run through the same problems and they're all facing the same problems, not only medically but also psychologically, with their fears and their hopes. Whoever is diagnosed with MSD should reach out to this community,” added Dr. Schlotawa.

“Because multiple sulfatase deficiency involves 17 different sulfatases, by fixing MSD, we will learn so much about all these other sulfatase deficiencies. We will learn so much about treating other lysosomal storage disorders,” said Dr. De Castro.

At a minimum, annual visits to various specialists should take place, including neurologists, ophthalmologists, otolaryngologic and musculoskeletal specialists, gastrointestinal/ nutrition providers, respiratory doctors, and renal metabolic specialists.

Those with MSD need to be monitored closely at all times for any changes, since signs and symptoms can appear and progress quickly.

For More Information on MSD

United MSD Foundation 7600 Lakeridge Drive Ocean Springs, MS 39564 USA Email: aolsen@unitedmsdfoundation.org Website: http://www.unitedmsdfoundation.org/

MSD Action Foundation 35 Grattan Lodge, Balgriffin,, Dublin 13 Ireland Email: info@msdactionfoundation.org Website: https://www.savingdylan.com/

Genetic and Rare Diseases (GARD) Information Center PO Box 8126 Gaithersburg, MD 20898-8126 Phone: (301) 251-4925 Toll-free: (888) 205-2311 Website: http://rarediseases.info.nih.gov/GARD/

Referenced Sources

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  3. Hopwood J, Ballabio A. Multiple sulfatase deficiency and the nature of the sulfatase family. In In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York: McGraw-Hill. 2001:3725–32.
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  9. Schlotawa L, Ennemann EC, Radhakrishnan K, Schmidt B, Chakrapani A, Christen HJ, Moser H, Steinmann B, Dierks T, Gärtner J. *SUMF1* mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet. 2011;19:253–61.
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  16. Multiple Sulfatase Deficiency
  17. Hopwood J, Ballabio A. Multiple sulfatase deficiency and the nature of the sulfatase family. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York: McGraw-Hill. 2001:3725–32.
  18. Ahrens-Nicklas R, Schlotawa L, Ballabio A, Brunetti-Pierri N, De Castro M, Dierks T, Eichler F, Ficicioglu C, Finglas A, Gaertner J, Kirmse B, Klepper J, Lee M, Olsen A, Parenti G, Vossough A, Vanderver A, Adang LA. Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement. Mol Genet Metab. 2018;123:337–46.
  19. Hopwood J, Ballabio A. Multiple sulfatase deficiency and the nature of the sulfatase family. In In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York: McGraw-Hill. 2001:3725–32.
  20. Ahrens-Nicklas R, Schlotawa L, Ballabio A, Brunetti-Pierri N, De Castro M, Dierks T, Eichler F, Ficicioglu C, Finglas A, Gaertner J, Kirmse B, Klepper J, Lee M, Olsen A, Parenti G, Vossough A, Vanderver A, Adang LA. Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement. Mol Genet Metab. 2018;123:337–46.
  21. Schlotawa L, Preiskorn J, Ahrens-Nicklas R, et al. A systematic review and meta-analysis of published cases reveals the natural disease history in Multiple Sulfatase Deficiency [published online ahead of print, 2020 Jul 4]. J Inherit Metab Dis. 2020;10.1002/jimd.12282. doi:10.1002/jimd.12282

Transcript

Brenna: You're listening to The Rare Disease Connection, a production of Aspect Health and raredisease.com. Our cells contain a number of structures called organelles that carry out important functions. You'll likely remember hearing that the mitochondria are the powerhouse of the cell. Brenna: But what about the lysosome? The lysosome is an equally important organelle that oftentimes is forgotten about unless it's not working as it should. The lysosome can be thought of as a trash compactor filled with enzymes that work hard to breakdown the cell's waste. But when those enzymes are not functioning, our cells fill with waste and it causes a variety of complications. This leads to classic conditions called lysosomal storage disorders. Brenna: Today we're going to focus on multiple sulfatase deficiency, a lysosomal storage disorder with 17 affected enzymes. For families facing a new diagnosis, you likely have more questions than answers. That's why we're here. Rare Disease Connection and our additional resources on raredisease.com and your DNA.com bring together people whose expertise can explain what you're facing, from diagnosis to prognosis to treatment options, all the way to questions like who do I talk to and where are the people who've been through this before? You'll find those answers here. Brenna: From doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, they're all within your reach. We're here to connect you. This is Rare Disease Connection. Brenna: Hey, everyone. This is Brenna, co-host of Rare Disease Connection and Director of Patient Education at your DNA.com. Today I'm going to bring you conversations with four experts in multiple sulfatase deficiency. Brenna: Before we get started, you should know that this podcast is just the beginning. We have taken the information from this podcast and added additional resources, explanations, links, and references for you in a downloadable guide. You can get your free copy by going to raredisease.com/msd. That's raredisease.com/msd. So let's get started. Brenna: Our first guest today is Rachel Wyatt, a genetic counselor in San Antonio, Texas. Thank you for joining us today, Rachel. Why don't you start out by introducing us to you? Rachel Wyatt: Well, my name is Rachel Wyatt. I'm a recent graduate from the University of Alabama at Birmingham's Genetic Counseling Master's Program. While I was there, I was fortunate enough to have the opportunity to rotate in the newborn screening and metabolic clinic at the Children's Mercy Hospital in Kansas City, Missouri. While I was there, I was able to counsel many different families, as well as be exposed to just a wide variety of metabolic conditions from birth all the way up until adulthood. Brenna: That sounds fantastic. So on this episode, as you know, we're going to be focusing on multiple sulfatase deficiency. So why don't we use your genetics expert and start there, and explain a little bit about what's actually occurring on a genetic level that causes multiple sulfatase deficiency? Rachel Wyatt: Yeah. So multiple sulfatase deficiency, or MSD for short, is a lysosomal storage disorder caused by any sort of disease-causing variation in gene called SUMF1. So the lysosomes are responsible for just breaking down and recycling materials within our cells such as fats and sugars. A lysosomal storage disorder just means that one of these enzymes that helps breaks down these molecules isn't working as we would expect it to. Rachel Wyatt: In the case of MSD, this enzyme that isn't working is called formylglycine-generating enzyme or FTE. It's impaired due to a disease-causing variation in the SUMF1 gene, which prevents it from being able to do its job within the body. Typically, we would expect the FTE to help modify sulfatases and allow them to breakdown complex sugars and fat that contain chemical groups called sulfates. When you're not able to breakdown these molecules, they build up within the cell and gradually accumulate, preventing proper function within the cell and leading to the features that we do see with MSD. Rachel Wyatt: So another way to think about this is picturing a paper shredder within your office and use this to breakdown on paper and make it into smaller pieces. So if you aren't able to shred these pieces of paper, then you're going to see a buildup of all these old documents and pieces of paper that you don't currently need to do your job. However, if they start building up, then you're unable to gather the correct documents and the ones that you actually want to use to be able to properly do your job. Rachel Wyatt: So in the case of MSD, you can think of this paper shredder as the sulfatases. They breakdown sulfates into smaller more manageable pieces for the body to use properly. FTE can be thought of as the battery or a plug. So it's not breaking down these molecules itself, however, it's necessary for the sulfatases to work properly. It's believed the more FTE function that you have, the less severe the manifestations of MSD are due to some of that residual activity. Brenna: That makes sense. So thinking about the inheritance of this, is this a condition that's inherited through different generations? Rachel Wyatt: Yes. So this is a hereditary condition, which means that it can be passed on within a family. It's inherited in what's called an autosomal recessive manner, which just means that both copies of your SUMF1 gene need to have some sort of variant or change that prevents them from working. Rachel Wyatt: We have two copies of every gene: one from our mom and one from our dad. So in this case, we would expect that both parents have one copy that was changed in some manner. However, we wouldn't expect them to have any of the features of this condition since they do also have one typical copy that's able to properly work. Brenna: So thinking about risk for families who might already have a child with multiple sulfatase deficiency, what would be the likelihood for them to have other children with this condition? Rachel Wyatt: Yeah, that's an excellent question. So you typically would say that there's a 25% chance that they could have another child who is affected with this condition, and that's because if they have one child who has MSD, then we can say that both parents likely have one of these SUMF1 copies that's been altered. Brenna: So moving into the diagnosis of multiple sulfatase deficiency, what sort of tests would someone have to undergo to actually receive a diagnosis? Rachel Wyatt: So there are two main ways of diagnosing someone with MSD. One is through molecular testing, and that's looking at that SUMF1 gene that I mentioned and trying to see ... Essentially reading it and finding any sort of spelling errors or differences that would prevent it from working properly. About 99% of patients with MSD are found to have two of these changes within the SUMF1 genes. Rachel Wyatt: There's also another way, which is through biochemical testing. Rather than looking at the DNA itself, we look at specific substances in the body that we would expect to be at lower or higher levels based on not being able to properly breakdown these sulfates. So in the case of MSD, that means having at least two sulfatases that aren't properly working or at lower levels than we would expect. Brenna: So thinking about that testing and how someone gets a diagnosis, from my understanding, there's different subtypes to multiple sulfatase deficiency. Can you explain for us a little bit those different subtypes and what they might mean for patients? Rachel Wyatt: So you're correct. MSD has three main subtypes, and those are neonatal and then infantile, as well as juvenile. These types are really based upon age of onset, the rate of progression of the disease, as well as the overall severity. Neonatal is the most severe form. It's presenting as early as the prenatal period with a very fast progression in features that sadly often ends in death within the first two years of life. Rachel Wyatt: The second subtype, infantile MSD, is the most common that we see. It typically presents within the first three years of life. It has either a slower clinical course or attenuated form with cognitive disabilities identified around two years old or a more severe manifestation where the majority of the child's developmental milestones are lost by the age of five. The last or third subtype is juvenile MSD. This is the rarest subtype with even later onset of symptoms and generally a milder presentation. Rachel Wyatt: However, regardless of the subtype, there are three main areas of the body that tend to be affected by MSD, which are the brain, skin, and skeleton. So some commonalities include the deterioration of the white matter in the brain or developmental delays and seizures. As far as the skin goes, we see differences such as ichthyosis or a scaly skin, coarse facial features, or even hypertrichosis, which is just an excessive hair growth. Rachel Wyatt: Then skeletal differences include things such as scoliosis or joint stiffness. However, there are many other features that are also associated with MSD such as poor growth, ear and respiratory infections, heart problems such as thickening of the heart muscle, and enlarged organs. Brenna: So thinking about all of those different systems that can be affected, when someone actually receives the diagnosis, what assessment and monitoring do they need? Rachel Wyatt: Unfortunately, there's not currently a cure for this condition. However, individual symptoms can be looked at or better managed. So due to the variability of how MSD can present in each individual, there's likely going to be their own unique management particular to the signs and symptoms. So, as you mentioned, looking at each of the different body systems that are affected within that individual. So, for example, if someone's having seizures, then it'd be important to get a consultation with a neurologist and look into antiepileptic medication to help alleviate seizures and prevent them. Brenna: So thank you again, Rachel, for spending time with us today. I think you're really able to breakdown multiple sulfatase deficiency for us. In closing, what would be your best advice for a family whose child has just been diagnosed? Rachel Wyatt: I think since this is such a rare condition that I would highly recommend just taking advantage of the support and advocacy resources that are available to individuals with MSD. So the examples are the United MSD Foundation and MSD Action Foundation, which both offer educational resources and opportunity to connect with other individuals who have experienced MSD whether directly as a patient or family members. They have other services as well. Rachel Wyatt: I also think it's very valuable to participate in the patient registry, just because this is such a rare condition that learning more about the individuals that have been MSD can help educate us even as providers and really allows for a better understanding of the condition as a whole. Brenna: Thanks, Rachel, for all of your insight into MSD. Receiving a diagnosis with an underlying genetic component could be confusing and even scary at times. Genetic counselors play an invaluable role in the story of anyone diagnosed with a rare disease. If you or a family member have questions, I would recommend looking at nsgc.com to find a genetic counselor near you. Brenna: Our next guest is Dr. Lars Schlotawa. Dr. Schlotawa has been working with the MSD community since 2004 and was on the original team that identified the causative gene SUMF1. He is also a pediatrician and a neurologist in Germany and a board member on the United MSD Foundation. Thank you for joining us today. So why don't you just start out telling us a little bit about yourself? Lars Schlotawa: Yeah, my name is Lars Schlotawa. I'm from Goettingen, Germany where I work as a consultant in pediatrics. I'm a trained medic and got my MD degree a little while ago. But in between, I also do basic research. I spent some time in the UK, in Cambridge, and was working there on autophagy and lysosomal disorders. So I'm doing both things being a physician as well as a researcher. Yeah, this is what I am. Brenna: Sounds great. So speaking from your experience as a physician and as a researcher, when you hear multiple sulfatase deficiency, what initially comes to mind for you? Lars Schlotawa: Well, this is a good question, and I thought about it. Basically, I'm working on multiple sulfatase deficiency for decades now because I joined the lab where the gene underlying the disease was discovered in 2004. I joined the group by that time. And so, I got involved into this very early. So this is my personal experience with multiple sulfatase deficiency because I never left it since then. Lars Schlotawa: If you think about the disease and when I think about the patients, I would say it's a rare disease, just pop into my mind, as well as it's a terrible disease because we've got nothing we can do so far for it. Yeah, I think about my patients that I know, especially their decline. So it touches everything. But I also think about a lot of hope and initiatives and the thriving time for MSD, because so many things are going on in terms of looking for a therapy and in search for a therapy. This is what I think about when I hear multiple sulfatase deficiencies. Brenna: So you mentioned that it's a rare disease. Just how rare is multiple sulfatase deficiency and is it more common in certain populations or gender or areas of the world? Lars Schlotawa: Well, actually we still ... When I talk to we, it's me and my colleagues working on sulfatase deficiency. We can actually not name it. There's been one piece of work that's been done in the '90s. There they calculated the frequency of MSD in Australia. They said it is one newborn in 1.4 million newborns, which is really rare. We're currently underway of calculating the frequency via so-called allele frequency, which means that we look for mutations in the genes of all people. But we haven't come up with a number yet, so that's still underway. Lars Schlotawa: Then there's the, well, let's say, gut feeling of how rare it is. It's just like for Germany, I can say we've got no more than four living kids at the moment. With all the parents and patients I got into touch over the past years, I would say it's about 50 to 100 worldwide. But I think it's entirely unestimated because, of course, we can only get in touch with the ones having internet, having the phone call, access to whatever new media and new technologies. There will be a lot of more patients elsewhere in the world. Lars Schlotawa: Coming back to your question, there are no real hotspots for MSD, probably except the fact that as it is an inherited disease and a few areas in the world where you have marriages within close community, you will have a higher frequency of affected children. But there's no real hotspot of this apart from such areas. Brenna: So taking just a moment to take a step back and think of this condition as a whole, what signs and symptoms would someone with multiple sulfatase deficiency expect to experience? Lars Schlotawa: This is a difficult question to answer because it's a broad spectrum of different symptoms. I would say that let's name it the classical phenotype of MSD, and the classical appearance would rather be development delay, so when a child is not reaching milestones at a time and they're not able to speak at the right age, they're not able to walk at the right age. So something like this is definitely in the classical MSD patient, as well as probably what we call coarse facies, which means the face looks a bit broad. There are some things too that if there's an experienced person, he or she might recognize that this is an underlying disease going on. Lars Schlotawa: Then there's also skin infection in MSD. There's ichthyosis, which means there's a dry and scaly skin. This is also pretty obvious for MSD. But describing MSD makes it a little bit difficult because it involves a lot of different symptoms as well as different diseases because of the unique pathophysiology of the disease. And so, there's way more. Lars Schlotawa: You can also have a neurodegenerative disease in MSD, so you lose skills. You can also ... Whatever [inaudible 00:17:51] in autism type spectrum, as well as there are also children who are born with a lot of symptoms of MSD and suffer a lot from this and die very early on. Everything like this is MSD, but I would say if you want to recognize this, think about MSD as soon as you see something like childhood dementia, a dry, scaly ichthyotic skin, as well as some signs of the so-called mucopolysaccharidosis, this all makes up MSD. Brenna: So thinking about the fact that it's a very rare condition and that it has such a broad spectrum of possibilities in terms of their phenotype or the signs and symptoms, what might make a physician suspicious? Is it difficult for these kids to get a diagnosis? Lars Schlotawa: Well, if you stick to the clinical signs that are just mentioned in my last answer, I think, to me, it looks pretty obvious that you would recognize MSD. But, of course, if they're not all symptoms already there at the moment when the physician sees the child for the very first time, you might miss the diagnosis. Lars Schlotawa: The other thing how it could be missed is if you do a biochemistry setup and don't think about everything there, then you will also likely miss it. But I think with new technologies getting into all kind of work, like when you use genetics more often than we did before and you're not relying on your senses to make a diagnosis, I think we'll pick it up even earlier. Brenna: So how old are these kids normally when they receive this diagnosis? Is there an average age where it gets picked up? Lars Schlotawa: Well, the bad thing about it is that usually all of these rare diseases, there's a heavy delay in getting the right diagnosis. And so, we know everything from children diagnosed early on because there was an experienced person taking care of the child, or it was born in a center, in a metabolic center, a genetic center, or the parents just by chance met the right physician very early on. But in any other case, when it wasn't like this, there was a delay of the diagnosis. Lars Schlotawa: Recently, I was talking to a family, and it took them eight years until the right diagnosis. And so, this was heavily delayed. So actually it could be at any age, but usually I would say before kids go to school. Meanwhile, you will be able to find the right diagnose. Brenna: So I know you've talked about biochemical markers as well as genetic variants. How does someone actually receive the diagnosis? What sort of testing do they have to go through? Lars Schlotawa: So when there's clinical suspicion of MSD, what you should check is, first of all, you should do a urine test for the excretion of sulfatides as well as glycosaminoglycans or GAGs in short. This is one thing. But we also know kids that don't secrete either type of storage material, and so you could also miss it by this. Lars Schlotawa: The other thing you could do is that you look for so-called enzyme activities in blood cells, leukocytes, or also skin cells if you want to get a skin biopsy done. You would look for sulfatase activities. There are various of them that you can measure pretty easily. Lars Schlotawa: This is also one of the important things. Don't stop after measuring only one sulfatase because there are single sulfatase deficiencies. You would miss MSD if you don't check a second one or, better, a third one. Lars Schlotawa: Then in genetic testing, I think it will become a gold standard in the future also for diagnostics, but as soon as you have a clinical suspicion, some biomarkers tested, so urine or blood, you should confirm it genetically by sequencing the underlying gene, the SUMF1 gene, to look for mutations. Lars Schlotawa: Even if there's no mutation on the SUMF1 gene, you should go a little bit further and look for large deletions because this could sometimes also be a cause for MSD. When the whole SUMF1 gene is missing, we call that a large deletion. Brenna: So now that our patient that we're talking about has a diagnosis. Let's think about what management might look like. What is the current landscape for care or management for these patients? Lars Schlotawa: As it affects the whole body, it's a difficult care for the patients and it involves a lot of people who should be, ideally, specialists from their respective organ system and also experience in neurodegenerative diseases, childhood diseases, as well as metabolic diseases. But this is the ideal world. Lars Schlotawa: As long as you take care of everything, what could go wrong there, and it's a long list of every organ that could be affected, but you should definitely take care of all of these different symptoms. I would say basically the most ... Well, from my point of view, the most important things to look at is that you should not forget that there's also ... It's a palliative treatment right from the beginning. You should be on top of what parents want, what they could cope with, and how quality of life for everyone, the patient as well as the family, could look like in a reasonable way. Brenna: So what is the life expectancy for someone with multiple sulfatase deficiency and what's the quality of life? Lars Schlotawa: This is also a very good question. So we got recent data around this because we collected a lot of patient records, as well as doing a readout from published cases on MSD. 50% survival rate in MSD, but this is from the literature and does not reflect the quality of life. It's something between 13 and 16 years of age. Lars Schlotawa: We know of patients who lived longer, up to their 40s. We also know a lot of patients who died within the very first year of life. So this is the spectrum. I would say that the old patients definitely had a reduced quality of life because, of course, you can do everything for a child as you want. With complex care, you can let them live very, very long. But definitely I think quality of life is impaired at any point in MSD. Lars Schlotawa: And so, as long as the disease just started and there's not the full spectrum of symptoms, I think you have a really good quality of life. After the point where you run through neurodegeneration, which is quite fast at any point in life, in children, you lose a lot of skills, and this definitely affects your quality of life. Lars Schlotawa: But we never quantify quality of life. There are a lot of good things, how you could assess it, and will definitely do this in the future, or even as a readout, to see that we can do better with probably a treatment or at least a better care for the patients. This is definitely something that should be done for MSD very, very soon. Brenna: So it sounds like right now there might not be a cure for MSD, but is there any treatments or managements coming down the pipeline that we can expect? Lars Schlotawa: Oh, we're working on it, and I'm happy to be involved, due to the initiative of parents and patient organizations worldwide. As I said before, we're at a really, really exciting time in terms of MSD because so many things are going on. Lars Schlotawa: So there are new animal models being created. There are trials with gene therapy, even clinical trials on the horizon. We look for drugs that could be repurposed for treatment of MSD. Of course, it's still at a very early stage, and definitely too early to say we found something that is really working because it's never been tested in patients so far. Lars Schlotawa: But for me, knowing MSD for a while, there was nothing we can tell to parents except, well, it is like it is and we can do nothing for your child. Enjoy it as long as possible. We do everything to maintain quality of life, but there's nothing we can actually cure in your kid. And this is a horrible thing to say for a doctor. Lars Schlotawa: So I'm really, really hopeful that there's something coming down the line very soon. I'm pretty excited about this and to see what's really going on. There will be drawbacks definitely and not everything will work out right. But, of course, if there's something ... At least when there's one therapy left, it will be better than none. Brenna: Exactly. You have to try. You have to start somewhere. In my closing statement, and again thank you so much for joining us today, but can you provide us with what you think might be your best advice for someone who has a child or a loved one who's been diagnosed? Lars Schlotawa: Yeah. Probably yes. So one thing definitely, and this is what I tell my patients and parents every time, is like although it looks like there's no cure so far and there's still nothing we can do for the kids, they stay the parents' kids and they are like they are. They could be laughed and they will be laughed. There will be so many things that will be funny and the parents will experience from their children, although it's a terrible disease. And so, they should not forget about the fun that kids could have despite any disease. Lars Schlotawa: The other thing that is really ... What I now tell everyone is go out and join the MSD community because there are so many lovely parents out there who are taking care of their children worldwide, although it's not around the corner and probably you'll never or only rarely meet them physically. Lars Schlotawa: There are so many initiatives going on. You can join them via Facebook. I think all these parents, they call each other very frequently. They talk to each other. There's a lot of knowledge in this community that could easily be exchanged and people are happy to give advice because they all run through the same problems and they're all facing the same problems, not only medically but also psychologically, and with their fears and their hopes and everything. And so, this is also a very good thing to do. Whoever is diagnosed with MSD should reach out to this community and look for some help there. Brenna: Thank you, Dr. Schlotawa, for spending time with us today. When a condition is as rare as multiple sulfatase deficiency, it is important that you connect with a physician familiar with the condition. Make sure you ask your family doctor to connect you to experts. Brenna: Our next guess is Dr. Mauricio De Castro, the Associate Director for the Air Force Medical Genetics Center in Biloxi, Mississippi. His center not only provides genetic testing for the military, but also for families in the surrounding areas. Dr. De Castro would like let you know that his ideas and statements are his own and are not reflective of the Air Force or the United States government. Welcome, Dr. De Castro. So why don't you just start off telling us a little bit about yourself? Mauricio De Castro: Great. So my name is Mauricio De Castro. I am an internist and clinical geneticist. I am the Director of the Air Force Medical Genetics Center, which is the reference laboratory for the Department of Defense. I am also an assistant professor of medicine at the University of Mississippi and participate in some nonprofits such as the Multiple Sulfatase Deficiency Foundation. Mauricio De Castro: My training, I did internal medicine first, which I found very interesting, but then was drawn to the uniqueness of genetic patients and the ability to do both the lab work and the clinical medicine. And so, both of those things appealed very much to me, and so I went into the clinical genetics source and then did a fellowship in something we'll call clinical molecular, which essentially allowed me to be able to run a genetics lab. And now here we are. Brenna: Genetics has a way of bringing people in. So thinking about- Mauricio De Castro: Yes, [crosstalk 00:30:14]. Brenna: Yeah. Thinking about your experience as a lab director as well as a clinical geneticist, when someone says multiple sulfatase deficiency, what immediately comes to mind for you? Mauricio De Castro: So I will tell you that in contrast with a lot of different conditions, when I first hear it, I might think about some book or some paper that I read somewhere or something striking about the condition. When somebody says multiple sulfatase deficiency, I think about a person in particular, and the first patient that I ever saw, which is Willow. Mauricio De Castro: So Willow is one of a handful of patients diagnosed in the US with multiple sulfatase deficiency, the first person that I saw with the condition. The reason why I think of a person for this particular condition is because the great work Willow's mother, Amber, has done with this. I guess we can talk a little bit more about that a little bit later, but Amber is such a fantastic human being in some of the things that she's done. It left such an impression on me that the first thing that I think of when somebody says multiple sulfatase deficiency are Willow and Amber. Brenna: Well, then I think we're very lucky that we're going to get to hear from Amber on this podcast a little bit later. So backing up, MSD or multiple sulfatase deficiency has been defined as a lysosomal storage disorder. But what does that mean and what's actually occurring in the cells? Mauricio De Castro: Right. So lysosomal storage disorders essentially are a group of conditions that have this one thread in common. The thread in common is that there's a problem with the way that lysosomes work. So I guess we should start by talking about what the lysosome means and then, by extension, what a storage disorder is. Mauricio De Castro: The lysosomes are organelles. There are parts of the cell that their job is to essentially give rid of trash. That's the way that I ... It's the analogy that I use usually when I talk to the lay people about this, is lysosomes get rid of the trash in the cell. Mauricio De Castro: So by virtue of being alive, we generate a lot of byproducts, substances that the body can't readily get rid of. And so, we've developed these organelles called lysosomes that essentially target these things that are hard to breakdown or that the body needs to get rid of, and then they just eat it up essentially. They engulf them and then dissolve it. They dissolve the lysosome into more simple substances that the body can get rid of. So a lysosomal storage disorder is a condition that happens when the body cannot get rid of one of these substances. Mauricio De Castro: And so, what happens if it can't get rid of it is that it builds up. It's essentially the same. Going back to the trash analogy, if the garbage company, the trash company doesn't come by and pick up your trash and they just leave it by the side of your house, pretty soon you're going to have a pretty dirty street full of trash, and garbage and stuff's going to be piling up and there's going to be mountains of trash. Mauricio De Castro: It's similar in lysosomal storage disorder. If the body doesn't get rid of the substances, they accumulate. The problem becomes that once they accumulate, they have nowhere to go but to tissues. And so, these substances start depositing, start piling up in different tissues. And so, there are several different, dozens really, storage disorders, but the lysosomal ones, they all have in common this deposition of substances in tissues, which give us the different symptoms that we see. Brenna: So with multiple sulfatase deficiency, what is that trash and why is it built up? Mauricio De Castro: So multiple sulfatase deficiency is a very interesting condition for a number of reasons. The problem with multiple sulfatase deficiency is, unlike any other lysosomal storage disorders ... So for the lysosomal storage disorders, usually what happens is that one of the enzymes, so one of the substances that the body uses to breakdown these byproducts of metabolism or what have you, the problem with lysosomal storage disorders is that these patients are usually missing one enzyme, one enzyme that goes into the lysosome and targets a specific substance. Mauricio De Castro: With multiple sulfatase deficiency, however, the problem is not on a lysosomal enzyme per se, but on a common part of the pathway for all lysosomal enzymes, for all sulfatases in particular. So we're going a little bit more into that. Mauricio De Castro: So there are about 15, 16, 17 different sulfatases in the body. We know of nine of them that are associated with human disease. All the sulfatases have as their last step an activation, a common thread, a common activator called the formylglycine-activating enzyme. Mauricio De Castro: What happens is that with multiple sulfatase deficiency, the mutations or the changes, the change is actually in that final part of the pathway. And so, all the sulfatases converge, so to speak, on this very last step that's depending on this formylglycine-activating enzyme. And so, when the enzyme doesn't work, the sulfatases can't complete for activation. Mauricio De Castro: So with multiple sulfatase deficiency, it's actually a deficiency of nine different sulfatases. Actually, all sulfatases, but nine of them that we know are associated with disease. And so, it's a combination of several different conditions. That's why it's so interesting and that's why some of these patients are so severely affected. Brenna: So thinking about the symptoms, with these other enzymes being associated with other lysosomal storage disorders, is there overlap in some of the signs, symptoms, or features with other sulfatase-affected conditions? Mauricio De Castro: Yeah. Yeah, yeah. That's a great question, Brenna. So I will tell you that ... Yes, so there is significant overlap with some of the other conditions. Actually, that's the problem with multiple sulfatase deficiency is that sometimes it's hard to make the diagnosis because it looks like so many other conditions. Mauricio De Castro: And so, all of the lysosomal storage disorders, they all have their thing that distinguish them. But they all have similar features. What I mean by that is that they all have some degree of CNS involvement, of central nervous system involvement, so some degree of neurologic deterioration, some degree of development delay, of cognitive issues, that they can be from mild to very severe. Mauricio De Castro: Of course, facial features, which is when the substances deposit in the bones in the face and the tongue. So patients can have things like a thickened tongue or a thickened supraorbital ridges, which is where your eyebrows are, and overall thickening of the facial features. They can have problems with other brain malformations in addition to having a little mental delay, so things like hydrocephalus and things like that. Mauricio De Castro: And so, yeah, by all means, there is significant overlap. When you look at the clinical manifestations of multiple sulfatase deficiency, you find really that's a combination of all of those nine different sulfatases with varying degrees. And so, obviously no patient is the same. It's not the patient, but a variety of features. Mauricio De Castro: And so, it's interesting to see that some patients will develop a more severe course with more severe neurological involvement. Some of them will be a little bit milder. We get these subtypes. Really when the multiple sulfatase deficiency is very severe, the patient could die at a very young age, and some patients that actually do not get diagnosed until late infancy and, in some cases, maybe even adolescence. And so, but we do see a pretty significant overlap with these other sulfatase, individual sulfatase. Brenna: So thinking about the flip side of that questions, outside of the molecular differences that we've talked about, is there a sign or a symptom or a physical feature that you can see that makes MSD different than these single sulfatase conditions? Mauricio De Castro: So there are laboratory findings that may point in the direction of MSD. So when we do the urine testing or enzyme levels, lysosomal enzyme levels, and blood and leukocytes, you would get a clue that it's MSD and not one of the individual sulfatases, because you should see a generalized disturbance in glycosaminoglycans or sulfatides or whatever, whereas for the individual enzyme ones, you typically see one or two enzymes out of normal range. With multiple sulfatase deficiency, you would see all of them or almost all of them. Mauricio De Castro: But outside of the laboratory findings, no, not really. I don't think that anybody would be able to make a diagnosis of multiple sulfatase deficiency just by looking at a patient. There isn't really, as we say, a pathognomonic finding for this because there is pretty significant overlap with a number of disorders, not just lysosomal storage disorders but other storage disorders and other genetic conditions. So, no, not really. Brenna: I think that just makes this condition all that much more interesting. Mauricio De Castro: I would agree. Brenna: So switching gears a little bit, now that researchers understand the cause for MSD and they're beginning to look at treatment options, I know that there are a lot of patient organization-led funding trying to research different types of cures for MSD. Can you tell us a little bit about any research projects that you might have heard of? Mauricio De Castro: Yeah, totally. So I have mentioned in the beginning I do sit in the board of directors for the Multiple Sulfatase Deficiency Foundation. So this is something that Amber got started, Willow's mother. She's been the driving force behind much of the research, not just here in the US but really around the world. Mauricio De Castro: So Amber, you'll talk to her and she'll tell you the story, but when she first heard the doctor's diagnosis, she went knocking on doors. Literally got on a plane, went to Europe, knocked on the door of the labs of people that have been doing research in sulfatases and lysosomal storage disorders. And so, much of the research has been [inaudible 00:41:03] by the MSD foundation. Mauricio De Castro: I know that the foundation is pursuing several different research avenues with the most promising being gene therapy. So I know that they're working with different companies and things. Again, I'll let Amber go into more detail on this. But it looks like there is some data to suggest, and the right now the data comes from mice, I believe, to suggest that gene therapy may be an effective treatment for this. Mauricio De Castro: There are some other research avenues that the foundation is pursuing with small molecules and drug screens and things like that that may yield some form of treatment that may be helpful for patients with MSD, but I sincerely believe the hope really to cure this will be gene therapy. Mauricio De Castro: Now there are some forms of enzyme replacement therapy. They are looking at gene therapy for some of the other disorders. Some replacement therapy have been hit and miss for some of these other disorders. It helps with some of the symptoms, some of the symptoms not so much, some of the symptoms it can help. And so, I think that pursuing gene therapy and going directly to the mistake, so to speak, and fix it is what eventually will help patients with MSD. Brenna: I think gene therapy is on the minds of a lot of rare diseases. It's not always a great fit for all of them, but I think with multiple sulfatase deficiency having this domino effect, if you're able to mitigate the step essentially at the beginning, then you could have a great impact on a lot of the sulfatases. Mauricio De Castro: Absolutely, and early diagnosis will be paramount to that. We don't know what gene therapy's going to do for somebody that has extensive disease or how much of that you'll be able to reverse, those are difficult questions to answer right now, but if we can make a diagnosis early enough, and this is important because a lot of patients go undiagnosed for a long time because it's such a rare diagnosis, but if we can make the diagnosis early, that gene therapy, or any other therapy really that they come up with that comes out of research, has a much better chance of not just delaying the disease but also maybe even preventing some of the features from developing. Brenna: Along that same line, and I'm not sure if you know the answer for this, but a number of inborn errors of metabolism, on the newborn screening, do you think MSD might one day be on the newborn screening? Mauricio De Castro: So that's a difficult question. I don't know how familiar you are with the process to get something in the newborn screen, but it is a lengthy process. It can vary from state to state because although there is a minimum standard that states have to meet, each state has different conditions that they add. So, for example, if you're born in New York, you're screened for things than if you're born in Mississippi or Louisiana. Mauricio De Castro: And so, the process to get something on there is ... It is fraught with some obstacles. So the question physicians and researchers and patient advocate organizations have to answer are, well, is there a good test to detect ... With blood sensitivity? Are we going to pick up people with this condition when they're born? Is there enough of the substance going around in blood? Is it a good test? Is it easy to perform? Can the state's public health [inaudible 00:44:28]? Those sorts of questions. Mauricio De Castro: But the other questions are, well, is there a treatment for it? There's this thought that if there's a condition for which there isn't an effective treatment for, is it worthwhile putting on the newborn screen? Mauricio De Castro: And so, I'm not a metabolic geneticist. This is not my area of expertise, but I can tell you that years ago, I don't know, four or five years ago, there was a conversation going on in the field about whether or not to add Krabbe disease. So Krabbe disease is a terrible neurodegenerative disorder in which patients develop this rapidly progressive neurodegeneration and usually will die between six and 36 months of age. Mauricio De Castro: And so, there was this conversation going around of, well, should we add this condition to the newborn screen? If we add it, what good is it going to do for the parents to know? Because there's absolutely nothing that we can offer the parents in terms of treatment. Mauricio De Castro: And so, those are difficult question to answer. So in the case of MSD, as of right now, would we be able to offer parents anything other than information? Not really. If gene therapy becomes a reality, however, I think that there's a very good case to be made, an excellent case to be made. We're adding it and you'll be able to pick it up and you'll be able to fix it right away. But as I mentioned, there's some other ethical questions surrounding it. Well, if you do detect it, what would you do with it? Mauricio De Castro: A point could be made, well, parents will probably want to know that information. You can plan for things. You can try experimental therapy. There's a variety of things that we could argue that the parents can do. But as I mentioned, it's a problem that involves multiple parties. It's not straightforward. Brenna: No, of course. I know I threw that one at you, so I appreciate you taking the time to explain some of the intricacies of that process. In my final question, I want to know what you would like people to know about MSD. If they had to leave this podcast knowing one thing, what would you hope their takeaway message would be? Mauricio De Castro: All right. Here's my takeaway message. MSD is an exceedingly rare disorder. There's maybe 100 cases, we suspect more if you counted mild cases that we're not diagnosing. But around the world, it's between 100 and 300 cases. Mauricio De Castro: Because it's such a rare disorder and they're a small group of people. It's very hard for the community to get the traction and attention that they need for pharmaceutical companies and other big organizations to hear their pleas really because they're a small community. And so, even though it's a small community, the people in the community have so much heart that it's very difficult to see them put it in all this effort and get very little return. Mauricio De Castro: So what I would like people to know is that even though they're a small community, there are very real people, families affected with this devastating neurological disorder for which we have no cure. A cure is within reach with enough funding. The team has done so much so far, but with a little bit more funding, I know that they can cross threshold. They can go all the way to the gene therapy. There's a very real probability that we may be able to help not just the children with it now, but the children that will be born with it. Mauricio De Castro: To do that, I would say, well, people will say, well, it's 100 kids, it's 200 kids. Should we really invest all this money in all these things? People say these things, and it doesn't come from a place of hate. I think it comes from a place of being practical with all the ... We have genetic disorders and conditions. Having a group of 100 and 200 people may not sound impressive. Mauricio De Castro: But the thing that I would say to that is, well, because multiple sulfatase deficiency involves 17 different sulfatases, what I say when I hear that sort of argument is, well, by fixing MSD, we will learn so much about all these other sulfatase deficiencies. We will learn so much about treating other lysosomal storage disorders. When you pull all those people, you're not talking about thousands and thousands of patients worldwide. Mauricio De Castro: And so, by helping the MSD group reach their goal of finding gene therapy, you're not only helping the MSD kids, families, and parents. You're helping every single child and family and parent out there that has a child with a lysosomal storage disorder or a storage disorder, really just rare genetic disorders. And so, that's my takeaway point right there, Brenna. Brenna: Thank you, Dr. De Castro. It is clear that there are a number of research projects in motion for multiple sulfatase deficiency. With rare conditions like MSD, it is truly the passion and drive of the families that accomplish breakthroughs in treatments. Brenna: This brings us to our last guest Amber Olsen, a mother of a child with multiple sulfatase deficiency and the founder of the United MSD Foundation. Welcome, Amber. So why don't you start out just telling us a little bit about yourself? Amber Olsen: Okay. Amber Olsen. I live in Ocean Springs, Mississippi, which is right on the Gulf. I'm married to a military guy, retired military navy. We have three girls: 17, 13, and six. I'm from Montana. I got my bachelor's in business from the University of Montana. I own a staffing company, Nextaff Gulf Coast. Brenna: Wonderful. And so, when you hear multiple sulfatase deficiency, what immediately comes to mind for you? Amber Olsen: I mean I think of my daughter Willow when you say it. But from the science sense, I know it's a very complex genetic condition with multiple enzyme deficiencies. Very interesting scientifically, but devastating to children that have it. Brenna: So why don't we start off with you telling us a little bit about Willow? Introduce us to her. Amber Olsen: Sure. So Willow is my six-year-old. She was born fine. We didn't know anything was going on. Regular pregnancy, full term. Whenever we would go to the pediatrician and do the milestone test, she would be a little behind, but it was never super concerning. The doctor's like, "She'll catch up," and I'm like, "Well, my older children were putting the Cheerio in the bottle." He's like, "Well, she'll do it," and she would eventually do it. So she caught up. She was just a little delayed. Amber Olsen: She started crawling and started walking, running, but she's never said any words. And so, when she turned 18 months, I was like, "She should be saying some words," and he's like, "Yeah." He said she had major ear infections. I said, "Is it the ear infections?" and he said, "Maybe. Maybe she's got hearing issues from the ear infections." Amber Olsen: And so, we took her adenoids out at two, which was the youngest we could do it. Then I went back two weeks later and I was like, "There's something else wrong. There's something going on." So he's like, "Yeah, let's go ahead and go down the route to try to figure out what it is." Amber Olsen: So we went to an endocrinologist because she was small stature, and he said hormones are fine, everything's fine. Then we went to Dr. Marcus Lee, who's a neurologist. So this was when she was like two and three months. He said she looks okay, but he's like, "Let's do ... " Amber Olsen: One of the things that he honed in on was when she would step up to the bed, the medical bed, or whatever it's called, she would lose balance. He's like, "Has she always done that?" and I'm like, "No. She was walking and running, but she seems to have more balance issues," which he was like, "Oh." I mean knowing now, he's thinking regression. Amber Olsen: So he did a microarray and it came back that she was a carrier of multiple sulfatase deficiency. Then he did the gene test, the SUMF1 gene test, to confirm. So it was like about, I think, four weeks' worth of testing and then he comes back with a story about multiple sulfatase deficiency. Brenna: And so, what was that like when you first heard the diagnosis? What was going through your mind and through your husband's mind? Amber Olsen: Yeah. So he called me at work. He had told she was a carrier and he's like, "Let's hope that she doesn't have it." And so, we're hopeful she doesn't have that. Amber Olsen: So I Googled it in between the test of the carrier and the test of the confirmation, and it's like 20 kids in the world, it's fatal, body's completely going to breakdown, kids have skin, eye, organ, major cognitive issues. I mean it's like I couldn't have dreamed up a worse nightmare disease. And it takes time. It's not instant. It's over time. Most kids don't live until 10 years of age. Amber Olsen: So we're just hopeful that she doesn't have it. Then when he called me at work and confirmed she has it, it's just like this surreal kind of, "What?" You don't even know what to do with that information. So then you grab on to the next step. So I'm like, "Okay. We'll go to St. Jude and she'll get some kind of something, or we'll go to Mexico and she'll get some kind of medicine. We'll hang on to that," like that's the next thing. Amber Olsen: So we go to Jackson, to Children's in Jackson, which is our closest children's hospital. Dr. Kirmse, who is a metabolic geneticist and has actually seen an MSD patient, which is crazy, he sat down with us. The drive was like three hours, and so Tom and I were driving up there and we're like, "Okay, this is what he's going to tell us." Amber Olsen: And so, we get up there and he's like, "There's nothing. There's nothing you can do. What I'm going to talk to you about is palliative care. We're going to take care of her, help make her comfortable while she slowly declines. All the medicines and the treatments and stuff like that as she slowly fades away." It was just super devastating. So we turned that. Amber Olsen: From there, I'd already Googled and I found a dad in Ireland, Alan Finglas, who had a foundation. He started the first foundation in the world on MSD, the MSD Action Foundation the year before when his son was diagnosed on. So we Skyped with him and he said we need time and money. And so, that was my first introduction into the world where parents pushed science. Brenna: And so, from this terrible devastating news, you clung to advocacy and action and you formed your own foundation. Is that correct? Amber Olsen: Right. So we went from there. Well, after we talked to Alan ... I did talk to Kirmse about it. I was like, "Look, there's this dad in Ireland. Is this harebrained? Is this the way it's done?" He's like, "This is the way it's done. That's how cystic fibrosis has treatments. That's how stuff happens with parents pushing." So I'm like, "Okay." Amber Olsen: So we flew to Europe in July. So she was diagnosed in May, May 9th, of '16. We flew to Europe July of '16, Tom and I did. I've never been to Europe. So we flew to Cambridge in the UK. There's was a doctor's conference, lysosomal storage disease conference, a little one on the Cambridge University. Amber Olsen: So Alan and his wife Michelle were there, Tom and I. Then I had Googled a couple other doctors that were ... Lars, Dr. Lars Schlotawa, invited him. Then there was doctors at this conference, one of them being Andrea Ballabio, who is the founder of the gene, the SUMF1 gene. He discovered that in 2002. He had done a gene therapy in a mouse in 2008 that was successful. Amber Olsen: So Alan's like, "We just need to get with him." Then he knew another guy that was running the conference, and we had three other doctors there and then Lars and we just sat. So we arrived at this doctor's conference that we're not invited to. It's not for patients or parents or advocacy organizations even. So the guy had arranged for us to meet these doctors at lunch time. Amber Olsen: So we're sitting out there waiting. We got there an hour early and then we're sitting out there waiting. Then a couple of them come. They're eating lunch. I mean we just flew all this way into a country I've never been to talking about this disease. Amber Olsen: I remember Dr. Tim Cox, he's a British doctor, and he said, "First of all," he said, "I know you guys ... I'm so sorry. This is devastating news and everything. I'm so sorry about your children." He's like, "But I want you to understand what you're doing will not help your children." He said, "It's going to take years. I just want to be frank with you and honest with you." And so, I looked at Tom and I started to cry. Tom looked at me and he's like, "Well, somebody's got to do it. Somebody's got to step up." And so, that's how it all started. We came back, started a foundation, started fundraising, and started pushing research. Brenna: So with your foundation, the United Multiple Sulfatase Deficiency Foundation, what's been the most challenging either information or in the projects that you're championing and what's been the most rewarding for you? Amber Olsen: So the most challenging thing to me is that it's not so much science, it's money, and that it was hard for me in the beginning and I really didn't believe it. I thought that maybe it was scientifically just to get a cure, to save these kids. It's just not there yet. Amber Olsen: As we got further into it, it's like ... I remember when Dr. Steven Gray said, "If you had $3 million, you could have a treatment in 18 months." And so, that to me ... It still hits me. I mean right now, if we have $5 million, we could manufacture the [inaudible 00:58:45] sector and move forward. It's that money is sitting between these children living or dying. Amber Olsen: Then the other one was the [inaudible 00:58:55]. So when we first started, there was nothing out there. When kids were diagnosed, it's terrible, but you have no support system. It's a double-edged sword. But now families can call us and come to us and say, "What do we do? Where do we go?" We figured out ... Like Dr. Schlotawa is our German doctor, European specialist. Then Dr. Rebecca Ahrens. Now she spent the last two years on MSD, so she knows more than probably anybody in the US. And so, we created these spots where patients can go and kind of the pathway, I guess, for them and created some hope. Brenna: Absolutely. I think from a condition that's so rare, to be able to have connected so many families is an amazing accomplishment, because, like you said and like you've experienced with your diagnosis story, you need someone to talk to who's going to understand what's going on. Amber Olsen: Right. Brenna: So it's clear for you guys that you need funding and you need money. So are there any upcoming events or ways to give that we could put out there? Amber Olsen: Yeah. So we have a couple events locally here on the coast that, of course, are up in the air now. But we'd love for people to do birthday fundraisers on Facebook. It's super easy. It's very ... Not so much of an impact to the person who's setting up the fundraiser, but getting your friends to give $10. We have a Cheers From Over Here campaign going where we have a virtual birthday party instead of ... If they can't buy you a beer, they can buy you a beer online for $10 and contribute to the fundraiser. It's just easy. Amber Olsen: Facebook prompts you anyway to do a birthday fundraiser. So you just scroll down and pick Cure MSD, which is our name on Facebook. Then you just set for the total on everything and a deadline. Once we see it out there, we can also help you make it work really well. Brenna: Well, hopefully after this, we'll get some more birthdays rolling in. Amber Olsen: Right. We'll say we'll take any kind of online donation. We'll take a check. If you know of a corporation that does matching, we'd love to work with them, any grant opportunities from private foundations. I mean we've gotten money from Bloomberg Philanthropies. I mean we'll take it from wherever we can get it. Brenna: That's great. So in closing, as, first and foremost, a mother of a child with this condition and then also as a champion, what's your best advice for someone who has a loved one who's just been diagnosed with multiple sulfatase deficiency? Amber Olsen: So I mean if people reach out to me now because they found me online, the first thing I tell people is to connect with the specialist. So a grad student told me this when we first started, because I had no idea how to even look at a scientific paper. But she's like the authors on the article are a good way to start. So if you look ... Was it the beginning or the end? Who's the major author? Brenna: The main author tends to be the last one on those papers. Amber Olsen: So if you go to the last author, like Google your disease and then find scientific papers, go to the last author and email them. It's usually pretty easy to find those emails for the scientist, and just start talking to them, because they love to talk about the disease. I mean they've spent their life working on it. And so, they would be so excited to meet a patient. Then just start organizing yourself into a Facebook group and trying to bring patients together and then go from there. Amber Olsen: I mean it's pretty amazing what you can do with a few people. These doctors are so willing to help. Then I do that with the clinicians, too. It's like you want to find those specialists. People are like, "You email a doctor?" and I'm like, "Yeah. They're a person. They'll answer you eventually. Or if they don't, just email them back again." Brenna: Amber, thank you for sharing your story with us today. If you're interested in getting involved with the United MSD Foundation, you can go to their website at curemsd.com to learn more. Brenna: I want to thank all of you for joining us today as we explored multiple sulfatase deficiency. We had the chance to hear from four amazing experts. But it's only just the beginning. We have taken all of today's information and included it in a free downloadable guide. You can get your free copy by going to raredisease.com/msd. We would love to connect with you. Brenna: If you need to talk to someone, we're standing by. Go to raredisease.com/help. We are waiting for you. Rare Disease Connection is a production of Aspect Health and raredisease.com. Thanks for joining us.

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