OTHER-RARE-DISEASE-TOPICS

RARE-DISEASE

How To Diagnose LSDs?

Learn more about early diagnosis of lysosomal storage disorders: Fabry disease, Pompe Disease, Gaucher disease, Acid Sphingomyelinase Deficiency (ASMD, also known as Niemann-Pick Type A/B), mucopolysaccharidoses (MPSs).

When shall we think of a rare disease from Neurological perspective

Many LSDs are associated with the emergence of neurological manifestations, Dr. Dina Saleh will today speak to us about the suspicion of a rare disease from neurologist perspective.&nbsp;

What is the role of Artificial Intelligence in accelerating patient's diagnosis?

Summary of the Presentation:&nbsp;
It is impossible for a physician to memorize information about thousands of rare diseases. Modern computers can easily "memorize" huge quantities of digital information. &nbsp;If the computer can also extract and use this information in a meaningful way, this has a high potential for improving diagnosis and treatment.
Short Biography of the speaker:
Prof. Fatma Al Jasmi (UAE)- Chairman
Chair of Genetics and Genomics department, Professor at College of Medicine and Health Science, UAE University.
Metabolic Consultant at Tawam hospital, Al Ain, UAE.
Founding member of UAE Rare Disease Society.

What are the new diagnostics modalities used to expedite Rare Disease patients identification?

Summary of the Presentation:&nbsp;
In this video, Prof. Zuhair Al Hassnan speaks about the new diagnostic approaches in the rare diseases field

Short Biography of the speaker:
Prof. Zuhair Al Hasnan (KSA)
Consultant genetics at the King Faisal Specialist Hospital &amp; Research Centre (KFSH&amp;RC), Riyadh.
Professor at the College of Medicine, Alfaisal University, Riyadh.
Scientist at the Department of Genetics, KFSH&amp;RC, Riyadh.

What are Lysosomal Storage disorders?

Summary of the Presentation:&nbsp;
In this video, Dr. Nawal Makhseed speaks about the lysosomal storage diseases (LSDs) and gives a brief about those genetic diseases from her Clinical experience.

Short Biography of the speaker:
Dr. Nawal Makhseed (Kuwait)
Pediatric Metabolic Consultant Jahra hospital, Kuwait.
Heads research projects on microcephaly, peroxisomal disorders and congenital disorders of glycosylations.

The role and importance of Patients Associations and Scientific societies ; UAE experience

<h2>Summary of the Presentation:</h2>
Dr. Fatma Bastaki speaks about the achievements and vision of the UAE rare diseases society.

Short Biography of the speaker:
Dr. Fatma Bastaki (UAE)
Consultant Pediatrician, Clinical Geneticist and Metabolist at Latifa Hospital, Dubai, UAE.
Founding and board member of UAE Rare Disease Society.

The role and importance of Patients Associations and Scientific societies ; Oman Experience

Summary of the Presentation:
In this video, Dr. Nadia speaks about the status of the Omani rare disease society with some highlights about its vision and objectives
Short Biography of the speaker:
Dr. Nadia Al Hashmi (Oman)
Consultant in inborn error of metabolic and clinical genetic.
National genetic center Department of Child Health Royal Hospital- Oman.

The Stigma of Rare Diseases

<h3>Summary of the Presentation:&nbsp;</h3>
In this video, Prof. Tawfeg Ben Omran speaks about how to ease the acceptance of LSDs in our society and how stigma could impact diagnosis of patients or even, impact compliance/adherence to therapy.

Short Biography of the speaker:
Dr. Tawfeg Ben Omran (Qatar)
Senior consultant and Head of Clinical and Metabolic Genetics at Hamad Medical Corporation, Qatar.
Associate Professor at Weill Cornell Medical College, Qatar &amp; New York-USA.

Multidisciplinary approaches in Rare Disease Patient management

Summary of the Presentation:&nbsp;
Interviewed by Dr. Nawal Makhseed, Ms. Amal tolba, the Founder and managing director of HOPE AMC, Dubai, UAE speaks about what the rehabilitation setup should include to succeed.

Short Biography of the speaker:
Ms. Amal Tolba (UAE)
Founder of the UAE Special needs support group.
Founder and managing director of HOPE AMC, Dubai, UAE.
A proud mom of child with special needs.

Multidisciplinary approaches in Rare Disease Patient management in KSA

Short Biography of the speaker:
Ms. Wijdan Ahmed (KSA)
Advanced Clinical Specialist and Team Manager, Medical Genetics Clinic, King Faisal Specialist Hospital and Research Centre, KSA.

Lysosomal Storage Diseases from Neurology Perspective

In this video, Dr. Dina Saleh is sharing information about lysosomal storage diseases but this time, it is from neurologist perspective.

LSDs overview

Summary of the Presentation:&nbsp;
LSDs are a diverse group of diseases result from enzyme deficiencies lead to defects in lysosomal function. There are more than 50 inherited LSDs, collective incidence as high as 1:4000. Mostly inherited as autosomal recessive, thus LSDs are more prevalent in consanguineous populations. Early diagnosis is important to start the treatment and prevent complications. In this video Dr. Tawfeg will discuss the diagnosis and management of LSD, including how to recognize the common red flag symptoms and signs of LSDs.
In this video, Prof. Tawfeg Ben Omran discusses how could we diagnose and manage the lysosomal storage disorders (LSDs)

Short Biography of the speaker:
Dr. Tawfeg Ben Omran Biography:
Dr. Ben-Omran received his speciality training in clinical &amp; metabolic genetics at the Hospital for Sick Children, University of Toronto, Canada. He has obtained both FRCPS &amp; FCCMG in Medical Genetics in 2006. Currently, he is a senior consultant and Head of Clinical and Metabolic Genetics at Hamad Medical Corporation. He is an Associate Professor at Weill Cornell Medical College, Qatar &amp; New York-USA. He is also a Distinguished Visiting Scientist at Boston Children’s Hospital-USA.
He contributes to the body of published knowledge in clinical and metabolic genetics, with over 60 published articles in peer reviewed journals, book chapters and abstracts. He is reviewer for many clinical genetics journals.
He is an active clinical researcher, collaborating on projects with local, regional &amp; international communities. He is a lead primary investigator in many high profile research projects &amp; clinical trials to evaluate the long-term effects of enzyme replacement therapy in patients with different lysosomal storage disorders. His main scientific interests include genetics of brain malformation&amp; microcephaly, white matter disorders, dysmorphology, autosomal recessive disorders. In addition, Dr. Ben-Omran is an external advisor and expert for E-HOD (European registry and network for homocystinurias and methylation defects).
He is recognized as an expert in genetic disorders of the Arab population. His national &amp; international presence is clear. In 2013, he received the "Princess Aljawhara Center Award for The Best Research in Basic Genetics" the most competitive &amp; prestigious awards. He received Research Award from MRC-HMC for Homocystinuria project and Stars of Excellence Award 2011 for both Pioneering Newborn Screening &amp; specialized care of Genetic Diseases in the Middle East. Recently, awarded the Stars of Excellence in research 2014: Cutting Edge of Research in Medical Genetics.
He has memberships in many societies including: American Society of Human Genetics, European Society of Human Genetics, Society for the Study of Inborn Errors of Metabolism, Middle East Metabolic Genetic Group, the Middle East &amp; North Africa Newborn Screening Initiative, Middle Eastern Lysosomal Storage Diseases Expert Council Advisory Board, Child Health Research Advisory Committee, International Society for Prenatal Diagnosis, Chairman of Middle East Metabolic Dieticians Group &amp; Founder Member &amp; Regional Representative of SSIEM Adult Metabolic Physicians Group.

Extraordinary measures: what are the benefits to have such movies talking about Rare Diseases?

Summary of the Presentation:
The title of the video elaborates itself … I think that this video needs no quote
Short Biography of the speaker:
Dr. Reem Alhammad (KSA)
Assistant professor of neurology
Neuromuscular consultant
Saudi board of neurology
Neuromuscular fellowship, Mayo clinic, USA
King Saud University college of Medecine&nbsp;

<h2>What are LSDs?</h2>
Lysosomal storage disorders (LSDs) are rare genetic conditions that cause a buildup of toxic materials in your body’s cells due to enzyme deficiency. LSDs can affect organs such as the brain, spleen, liver, heart, bones, and muscles, which varies depending on the specific disorder.1 
 While there is no cure for LSDs, early diagnosis is essential to both maximize potential improvement and prevent irreversible organ damage.2

<h3>What causes LSDs?</h3>
Enzymes are a type of protein that break down certain fats or sugars and assists your cells’ lysosomes with metabolism. Genetic pathogenic variants in the gene encoding an enzyme cause most LSDs. This pathogenic variant leads to accumulation of fats and sugars in cell lysosomes, which disrupts normal function and can cause damage throughout the body.1,3

<h3>How are LSDs diagnosed?</h3>
Healthcare providers can diagnose LSDs during pregnancy or in children and adults using several diagnostic tests, including enzyme testing and genetic testing.4

<h3>What treatments are available?</h3>
Treatment of LSDs varies depending on the substances that accumulate. There is currently no cure for LSDs, but several therapeutic options exist including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), chaperone therapy, and hematopoietic stem cell transplantation (HSCT).

<h3>Types of LSDs worldwide incidence of LSDs 1 in 1,500 to 7,000 live births across &gt;50 different diseases2</h3>
Inherited 
 The majority of LSDs are inherited through an autosomal recessive manner. The three exceptions are X-linked: Fabry disease, Hunter syndrome, and Danon disease.2
Select examples of LSDs

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1120px;">
 <tbody>
 <tr>
 <td>Disease</td>
 <td>Missing Enzyme</td>
 <td>Accumulating substance</td>
 </tr>
 <tr>
 <td>ASMD</td>
 <td>acid sphingomyelinase</td>
 <td>sphingomyelin</td>
 </tr>
 <tr>
 <td>Fabry disease</td>
 <td>α-galactosidase A</td>
 <td>globotriaosylceramide (GL-3)</td>
 </tr>
 <tr>
 <td>Gaucher disease</td>
 <td>glucocerebrosidase</td>
 <td>glucocerebroside</td>
 </tr>
 <tr>
 <td>GM2 gangliosidoses</td>
 <td>β-hexosaminidase</td>
 <td>GM2 ganglioside</td>
 </tr>
 <tr>
 <td>MPS I</td>
 <td>α-L- iduronidase</td>
 <td>glycosaminoglycans (GAGs)</td>
 </tr>
 <tr>
 <td>MPS II</td>
 <td>iduronate-2-sulfatase</td>
 <td>glycosaminoglycans</td>
 </tr>
 <tr>
 <td>Pompe disease</td>
 <td>acid α-glucosidase</td>
 <td>
 glycogen</td>
 </tr>
 </tbody>
</table>

References

<h2>Understanding&nbsp;ASMD</h2>
Historically known as Niemann-Pick disease types A, A/B, and B, acid sphingomyelinase deficiency (ASMD) is a potentially lifethreatening LSD that affects pediatric and adult patients. Deficiency in acid sphingomyelinase (ASM) enzyme activity leads to intracellular sphingomyelin accumulation that results in progressive multiorgan damage. ASMD represents a wide clinical spectrum of disease.1

Anna, Living with ASMD disease, Brazil

<h3>Genetic Profile</h3>
ASMD is an autosomal recessive LSD caused by pathogenic variants in the ASM enzyme–encoding&nbsp;gene sphingomyelin phosphodiesterase 1 (SMPD1).
Sphingomyelin helps regulate cellular processes, such as cell cycle regulation, cell signaling, and apoptosis.
When ASM activity is deficient, sphingomyelin cannot be sufficiently metabolized; it accumulates in lysosomes, particularly in macrophages and hepatocytes. This accumulation damages cells in multiple organs, leading to potentially life-threatening complications.
Males and females have an equal chance of being affected4

Type A 
 Historically known as Niemann-Pick disease type A (NPA) or infantile neurovisceral ASMD
<ul>
 <li>Onset: Early Infancy</li>
 <li>Phenotype: Rapidly progressive with acute multiorgan manifestations and neurodegeneration</li>
 <li>Life Expectancy: 2 to 3 years of age</li>
</ul>

Type A/B 
 Historically known as Niemann- Pick disease type A/B (NPA/B) or chronic neurovisceral ASMD
<ul>
 <li>Onset: Infancy to childhood</li>
 <li>Phenotype: Variably progressive with multiorgan manifestations and differing degrees of neurologic involvement</li>
 <li>Life Expectancy: Between early childhood and adulthood</li>
</ul>

Type B 
 Historically known as Niemann- Pick disease type B (NPB) or chronic visceral ASMD
<ul>
 <li>Onset: Infancy to childhood</li>
 <li>Phenotype: Chronic with multiorgan manifestations and no or only minor neurologic involvement</li>
 <li>Life Expectancy: Between childhood and late adulthood</li>
</ul>

<h3>Importance of Early Diagnosis</h3>
The rarity of ASMD, heterogeneity of its manifestations, and challenging differential diagnosis can result in delayed diagnosis and management of patients.
Early diagnosis of ASMD is critical for appropriate management.
Identifying known disease-causing alleles of ASMD allows for
<ol>
 <li>Individual genetic counseling</li>
 <li>Carrier screening for at-risk individuals</li>
 <li>Family planning</li>
</ol>

<h3>How to diagnose</h3>
A simple enzyme activity test can be performed on a DBS (dried blood spot) to indicate reduced ASM activity.
A positive DBS enzyme assay is highly indicative of ASMD, but an analysis from a whole blood sample and/or genetic testing is required to confirm the diagnosis.5

<h2>Understanding Fabry Disease</h2>
Fabry disease is a rare lysosomal storage disorder in which a deficiency of α-galactosidase A (α -Gal A) causes globotriaosylceramide (GL-3) and other substrates to accumulate in multiple cell types.1,2Accumulation of GL-3 can lead to progressive cell damage, fibrosis, pain, organ failure, and eventually, premature death if left untreated.3,4

Emma &amp; Signe, Living with Fabry disease, Denmark

<h3>Genetic Profile</h3>
Fabry is inherited in an X-linked manner. This gives females a greater chance of being affected.5&nbsp;There are over 770 pathogenic variants in the GLA gene that have been reported and they can vary in age of onset, rate of progression, organ involvement, and disease severity.1,15
<h3>Importance of Early Diagnosis</h3>
The average time from symptom onset to diagnosis is 15 years for males and 18 years for females.14&nbsp;The large delay in diagnosis is due in part to the nonspecific nature of early symptoms, heterogeneous phenotypes, and lack of disease awareness.1&nbsp;Fabry Disease is progressive and can lead to irreversible damage to major body organs. Early diagnosis is very important as it provides an opportunity to intervene early and avoid irreversible organ damage.1

<h3>How to diagnose</h3>
An initial diagnosis for Fabry Disease can be made through an α-GAL enzyme assay. This can be an enzyme assay using plasma, leukocytes or skin cultured cells. Another common and easy way to test for α-GAL activity is a DBS (dried blood spot) assay.12
Enzyme assays that show a reduced or absent level of α-GAL should be followed up through a DNA analysis to confirm diagnosis and identify the specific GLA gene mutation. Plasma lyso- GL3 can also be used as a biomarker to confirm diagnosis of Fabry Disease, especially in male patients.17
Genetic testing and counseling should be offered to all relevant family members.13

<h3>Inheritance pattern</h3>
X-linked Inheritance

GLA&nbsp;mutation
No&nbsp;GLA&nbsp;mutation
Affected mothers have a 50% risk of passing along the defective gene (Xr) to their children, regardless of gender

<h3>Time to diagnosis</h3>
Male and female patients in the Fabry Registry were diagnosed 15 and 18 years, respectively, after onset of first symptoms1

<h2>Understanding Gaucher Disease</h2>
Gaucher disease (pronounced go-shay) is the most common lysosomal storage disorder. It is caused by a deficiency in the enzyme glucocerebrosidase. Insufficient enzyme activity in Gaucher patients results in progressive accumulation of glucocerebroside in the macrophages. Clinical symptoms arise due to the displacement of normal cells by lipid engorged Gaucher cells. Accumulation occurs in organs throughout the body, typically the bone marrow, liver, and spleen.1,2,3

Pawan, Living with Gaucher disease, India

<h3>Genetic Profile</h3>
Gaucher disease is inherited in an autosomal recessive manner. If both parents are carriers of the diseasecausing allele, their child has a 25% chance of being affected with Gaucher disease. Males and females have an equal chance of being affected.3,6
More than 480 pathogenic variants in the GBA gene are associated with Gaucher disease. N370S [N409S], L444P [L483P], 84GG, and IVS2+1 are the most common pathogenic variants of the GBA gene.8
Homozygosity for L444P (c.1448T&gt;C) is associated with neuronopathic form of the disease and occurs in more than 70% of GD3 patients.8&nbsp;Worldwide prevalence of neuronopathic Gaucher disease varies substantially by region: East Asia and Middle East 12- 55%, North America and Europe 5%.9-12

<h3>Importance of Early Diagnosis</h3>
Delays in diagnosis of Gaucher disease are common. A patient with Gaucher disease may experience a delay of up to 10 years.7 
 Gaucher disease is progressive, yet almost 25% of patients do not get timely access to appropriate disease management because of delays in diagnosis.2

<h3>How to diagnose</h3>
A simple enzyme activity test can be performed on a DBS (dried blood spot).
A positive DBS enzyme assay is highly indicative of Gaucher disease, but an analysis from a whole blood sample is required to confirm the diagnosis.7

<h3>Phenotypes of Gaucher Disease</h3>
PATTERN Gaucher disease is a phenotypic continuum with a spectrum of clinical presentations.13,14&nbsp;Symptoms can present in early childhood in a severe form or in adulthood in a mild form.4

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1120px;">
 <tbody>
 <tr>
 <td>
 &nbsp;</td>
 <td>TYPE 1 
 Non-neuronopathic</td>
 <td>TYPE 2 
 Acute neuronopathic</td>
 <td>TYPE 3 
 Chronic neuronopathic</td>
 </tr>
 <tr>
 <td>Neurological effects</td>
 <td>None</td>
 <td>Severe</td>
 <td>Moderate to severe</td>
 </tr>
 <tr>
 <td>Symptom onset</td>
 <td>Any age</td>
 <td>First year of life</td>
 <td>Childhood</td>
 </tr>
 <tr>
 <td>Course</td>
 <td>Progressive</td>
 <td>Rapidly progressive</td>
 <td>Progressive</td>
 </tr>
 </tbody>
</table>

<h2>Understanding GM2 Gangliosidoses</h2>
GM2 gangliosidoses comprise rare, neurodegenerative lysosomal storage disorders, primarily Tay-Sachs disease and Sandhoff disease, caused by deficiency of β-hexosaminidase.
Accumulation of GM2 occurs primarily within neurons and progressively destroys nerve cells in the brain and spinal cord, leading to neurodegenerative symptoms.1,2,3

Zoe, Living with GM2 gangliosidoses, USA

Late-onset forms of the disease include debilitating and progressive proximal muscle weakness and imbalance.18

<h3>Genetic Profile</h3>
GM2 gangliosidoses are inherited in an autosomal recessive manner. If both parents are carriers of the disease-causing allele, their child has a 25% chance of being affected. 
 Males and females have an equal chance of being affected.17
<h3>Importance of Early Diagnosis</h3>
The average time from symptom onset to diagnosis for late-onset GM2 gangliosidoses is 16 years. The large delay in diagnosis is due in part to the nonspecific nature of early symptoms and lack of disease awareness. GM2 gangliosidoses are progressive and can lead to irreversible damage to major body organs.18

<h3>Clinical subtypes of GM2 gangliosidoses10,13-15</h3>
Subtypes of GM2 gangliosidoses are categorized according to age at onset.

Infantile onset: 0−2 years
Infantile form is aggressive and leads to premature death at approximately 4 years of age

Juvenile onset: 2−10 years
Death is likely mid-to late-teens

Late-onset: teens to early adulthood
Variable clinical course and life expectancy

<h3>How to diagnose</h3>
Diagnosis of GM2 gangliosidoses can be accomplished by measurement of Hex A or Hex B enzyme activity.
Confirmatory diagnosis is recommended by detection of two pathogenic variants in&nbsp;HEXA&nbsp;or&nbsp;HEXB&nbsp;.16

<h3>Incidence and high-risk populations</h3>
Incidence is likely to be underestimated due to misdiagnosis and delayed diagnosis resulting from limited disease awareness.4-12
<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1120px;">
 <tbody>
 <tr>
 <td colspan="2" rowspan="1" style="text-align: center;">Incidence</td>
 <td>Carrier frequency</td>
 <td>High risk populations</td>
 </tr>
 <tr>
 <td>Tay-Sachs disease</td>
 <td>
 <ul>
 <li>1 in 320,000 in general population</li>
 <li>1 in 3900 births in unscreened Jewish populations</li>
 </ul></td>
 <td>
 <ul>
 <li>1 in 300 in general population</li>
 <li>1 in 30 in Ashkenazi Jewish</li>
 <li>1 in 14 in French Canadian</li>
 </ul></td>
 <td>
 <ul>
 <li>Ashkenazi Jewish</li>
 <li>French Canadian</li>
 <li>Irish</li>
 <li>Pennsylvania Dutch (old order Amish)</li>
 <li>Cajun communities (e.g., Louisiana)</li>
 </ul></td>
 </tr>
 <tr>
 <td>Sandhoff disease</td>
 <td>
 <ul>
 <li>1 in 422,000</li>
 </ul></td>
 <td>&nbsp;</td>
 <td>
 <ul>
 <li>No ethnic association</li>
 </ul></td>
 </tr>
 </tbody>
</table>

<h2>Understanding MPS I</h2>
The mucopolysaccharidoses (MPS) are a group of rare, genetic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down storage molecules called glycosaminoglycans (GAGs).1
MPS I, one of the seven types of MPS, results from deficiency of α-L-iduronidase (IDUA) due to pathogenic variants in the IDUA gene.1

Kali, Living with MPS I, USA

<h3>Genetic Profile</h3>
MPS I is an autosomal recessive disorder; over 250 pathogenic variants have been described in the literature.1,4
Genotype - phenotype correlations have been established for some pathogenic variants, but others are novel.5
There is a higher prevalence of severe MPS I in the Irish Traveller Community, due to homozygous W402X pathogenic variants.6

<h3>Importance of Early Diagnosis</h3>
Diagnosis of MPS I is often delayed, due to the non-specific nature of symptoms.9&nbsp;Early diagnosis and intervention is essential to prevent or minimize irreversible organ damage an improve long-term clinical outcomes.10
Diagnosis of Family screening can help siblings of those with MPS I receive an accurate diagnosis and early management.11&nbsp;MPS I newborn screening has gained increasing importance as the evidence base for early intervention and improved outcomes has been clearly demonstrated.8

<figure class="table" style="width:1120px;">
 <table>
 <tbody>
 <tr>
 <td>
 Severe → Attenuated
 MPS I presents as a&nbsp;disease spectrum,&nbsp;ranging from the severe phenotype to the attenuated phenotype2</td>
 </tr>
 </tbody>
 </table>
</figure>

<h3>How to diagnose</h3>
A simple urine test to look for abnormally high levels of GAGs (heparan sulfate and dermatan sulfate) can be ordered.1
Diagnosis is confirmed via enzyme assay and genetic testing.2,9

<h3>Inheritance Pattern</h3>
Autosomal Recessive Inheritance

<h3>For more information</h3>
<a href="https://www.mps1disease.com/" target="_blank">https://www.mps1disease.com/</a> <a href="https://mpssociety.org/" target="_blank">https://mpssociety.org/</a> <a href="https://www.mpsreference.eu/" target="_blank">https://www.mpsreference.eu/</a>

<h2>Understanding MPS II</h2>
The mucopolysaccharidoses (MPS) are a group of rare, genetic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down storage molecules called glycosaminoglycans (GAGs).1
MPS II, also known as Hunter Syndrome, one of the seven types of MPS, results from deficiency of iduronate-2-sulfatase (IDS) due to the pathogenic variants in the IDS gene.1

David, Living with MPS II, Australia

<h3>Genetic Profile</h3>
MPS II is an X-linked recessive disorder that almost exclusively affects males.1
Heterozygous MPS II females (carriers) are generally asymptomatic or not heavily affected.1
More than 300 pathogenic variants in the IDS gene have been reported. Genotype – phenotype correlations are difficult to establish, but if established, help to better understand the disease.6
Pathogenic variants that result in complete absence of IDS activity lead to a severe phenotype.1,6

<h3>Importance of Early Diagnosis</h3>
Diagnosis of MPS II is often delayed, due to the non-specific nature of symptoms.7&nbsp;Early diagnosis and intervention is essential to prevent or minimize irreversible organ damage and improve long-term clinical outcomes.7
MPS II newborn screening has gained increasing importance as the evidence base for early intervention and improved outcomes has been clearly demonstrated.8

<figure class="table" style="width:1120px;">
 <table>
 <tbody>
 <tr>
 <td>
 Severe → Attenuated
 MPS II presents as a&nbsp;disease spectrum,&nbsp;ranging from the severe (neuronopathic) phenotype to the attenuated (non-neuronopathic) phenotype.3</td>
 </tr>
 </tbody>
 </table>
</figure>

<h3>How to diagnose</h3>
A simple urine test to look for abnormally high levels of GAGs (heparan sulfate and dermatan sulfate) can be ordered.1
Diagnosis is confirmed via enzyme assay and genetic testing.9

<h3>Inheritance Pattern</h3>
X-Linked Recessive Inheritance

Affected mothers have a 50% risk of passing along the defective gene (Xr) to their children, regardless of gender

<h3>For more information</h3>
<a href="https://mpssociety.org/" target="_blank">https://mpssociety.org/</a> <a href="https://www.mpsreference.eu/" target="_blank">https://www.mpsreference.eu/</a>

<h2>Understanding Infantile-onset Pompe Disease</h2>
Pompe disease is a progressive, multi-systemic, debilitating, and often life-threatening neuromuscular disorder. Pompe disease is caused by the absence or deficiency of the enzyme acid alpha-glucosidase (GAA), which is responsible for the breakdown of glycogen inside the cells. Without sufficient GAA enzyme, glycogen accumulates primarily in muscle cells, which leads to progressive loss of muscle function. Infantileonset Pompe disease (IOPD) is rapidly progressing and usually presents within the first months of life. If left untreated, IOPD is often fatal before age 1.1

Arathi, Living with Pompe disease, India

<h3>Genetic Profile</h3>
IOPD is inherited in an autosomal recessive manner. The GAA gene can have a spectrum of variants that lead to differing amounts of GAA enzyme activity.1&nbsp;Variants that leave little to no GAA enzyme activity (&lt;1% of normal) manifest as the infantile onset form of Pompe disease.2

<h3>Importance of Early Diagnosis</h3>
IOPD is rapidly progressing and early diagnosis can be crucial in providing supporting therapy. Delays in diagnosis of IOPD correlate with respiratory failure, profound motor impairment, and death.6
Newborn screening for Pompe disease can readily identify patients with IOPD. This allows immediate diagnosis and can lead to improving survival and outcomes.7
<h3>How to diagnose</h3>
A relatively quick, simple, and minimally invasive way to screen for Pompe disease is the DBS (dried blood spot) enzyme assay. A DBS is able to detect low or absent levels of the GAA enzyme.3&nbsp;Reduced GAA enzyme activity should always be followed with a second blood sample and/ or GAA gene sequencing to confirm diagnosis of Pompe disease.3

<h3>Pathogenic GAA variants can predict clinical phenotype</h3>

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1120px;">
 <tbody>
 <tr>
 <td>&nbsp;</td>
 <td>IOPD</td>
 <td>LOPD</td>
 </tr>
 <tr>
 <td>Age of onset</td>
 <td>Infancy</td>
 <td>Infancy - adulthood</td>
 </tr>
 <tr>
 <td>Progression</td>
 <td>Rapid</td>
 <td>Varying</td>
 </tr>
 <tr>
 <td>Predominant symptoms</td>
 <td>Respiratory distress, hypotonia, muscle weakness, cardiomyopathy</td>
 <td>
 Progressive proximal muscle weakness, respiratory deficit</td>
 </tr>
 </tbody>
</table>

<h2>Understanding Late-onset Pompe Disease</h2>
Pompe disease is a progressive, multi-systemic, debilitating, and often life-threatening neuromuscular disorder. Pompe disease is caused by the absence or deficiency of the enzyme acid alpha-glucosidase (GAA), which is responsible for the breakdown of glycogen inside the cells. Without sufficient GAA enzyme, glycogen accumulates primarily in muscle cells, which leads to progressive loss of muscle function.1&nbsp;Late-onset Pompe disease (LOPD) has a less rapid and more variable disease course, where symptoms may begin anywhere from infancy to adulthood.1

Andrea, Living with Pompe disease, Denmark

<h3>Genetic Profile</h3>
LOPD is inherited in an autosomal recessive manner. The GAA gene can have a spectrum of variants that lead to differing amounts of GAA enzyme activity.1&nbsp;The pathogenic variants that leave low to moderate GAA enzyme activity (1-40% of normal) manifest as the less rapid form of Pompe disease, LOPD.8

<h3>Importance of Early Diagnosis</h3>
If treated early enough, muscle damage from glycogen accumulation can be reversible. However, if left untreated, it can lead to irreversible deterioration of skeletal and respiratory muscle, disability, and premature death. The initiation of an intervention is crucial in preventing further deterioration of respiratory function and muscle, and permanent disability.4
A person with LOPD may go several years before receiving a diagnosis. Newborn screening for Pompe disease can help diagnose patients before irreversible muscle damage occurs.7

<h3>How to diagnose</h3>
A relatively quick, simple, and minimally invasive way to screen for Pompe disease is the DBS (dried blood spot) enzyme assay. A DBS is able to detect low or absent levels of the GAA enzyme.9
Reduced GAA enzyme activity should always be followed with a second, blood sample and/ or GAA gene sequencing to confirm diagnosis of Pompe Disease.9

<h3>Genotype - Phenotype Correlation</h3>

<h2>Sanofi Rare Disease Registries Program</h2>
The Sanofi Registries program is a multi-center, international, longitudinal, observational program that tracks the natural history and outcomes of people with Gaucher, Fabry, MPS I or Pompe disease.

Each Registry is specifically centered around the disease and collects real-world data.

All patients with a confirmed diagnosis are eligible to participate, regardless of their therapy status and choice of treatment. Patients may be enrolled at any time during the course of their disease, including posthumously with ethics approval.

The Registry program is non-interventional and patients receive standard of care treatment as determined by their physicians.

The Registry collects:
<ul>
 <li>Retrospective and Prospective Data</li>
 <li>Disease Signs and Symptoms</li>
 <li>Treatment Information</li>
 <li>Clinical Assessments</li>
 <li>Patient Reported Outcomes</li>
 <li>Siblings Linkage</li>
</ul>

<h3>Global Reach of Sanofi Rare Disease Registries</h3>

4&nbsp;International Boards of Advisors

1&nbsp;Rare Disease Registries Patient Council

12&nbsp;Regional Boards of Advisors

<ul>
 <li>Fabry, Gaucher, MPS I, Pompe&nbsp;4 Main Registries</li>
 <li>8 Sub Registries</li>
 <li>More Than 19,000 Patients Enrolled</li>
 <li>Presence In Over 68 Countries</li>
 <li>Over 900 Participating Sites</li>
 <li>Support From More Than 1,280 HCPs</li>
</ul>

* ePRO = electronic Patient Reported Outcomes available to sites and via patient accounts where available with IRB/EC approval 
 ** Available in 2023 for Gaucher Registry participants and in development for the other Registries

<h3>Rare disease registries’ contributions</h3>
<ul>
 <li>Increasing disease knowledge</li>
 <li>Improving patient care</li>
 <li>Fulfilling regulatory requirements</li>
 <li>Supporting healthcare policy formulation</li>
 <li>Reimbursement and access to therapy</li>
 <li>Facilitating community connections</li>
</ul>

Reference

<h2>Supporting Sustainable Access</h2>
Sanofi’s Rare Humanitarian Program&nbsp;is the first humanitarian initiative and longest-running program of its kind for people with lysosomal storage disorders. The program is focused on providing access to free treatments for people who meet the program’s criteria, who otherwise would not have access to such treatments, as well as supporting patient diagnosis, treatment monitoring, patient advocacy and physician education.
<h3>Over 30 Years</h3>
Our Rare Humanitarian Program was established in 1991 when our first treatment for Gaucher disease was approved by the U.S. FDA. Since then, it has evolved and expanded to support six different lysosomal storage disorder communities across six continents.
<h3>A Focused Approach</h3>
Our global team partners with the patient community, physicians, and Sanofi affiliates to understand and address the needs of the people we serve.
<h3>Ensuring Sustainable Care</h3>
Our program serves as a resource when access to treatment is limited; support can last anywhere from several months to a decade or more.
Through this program...
<ul>
 <li>3,550+&nbsp;people in 100+ countries have received access to free therapy.</li>
 <li>1,050+&nbsp;people in 70+ countries are currently receiving access to free therapy.</li>
 <li>375+&nbsp;people have received access to free therapy for over 10 years.</li>
 <li>150+&nbsp;new people receive access to free therapy each year.</li>
</ul>

An overview of Lysosomal Storage Disorders & Sanofi`s Commitment to the Development and Provision of Treatments

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