Tag: rare diseases

Categories : GeneticsTags :

CRISPR ‘Molecular Scissors’ can Leave Gaping Holes in the Chromosome

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

The CRISPR molecular scissors have the potential to revolutionise the treatment of genetic diseases. This is because they can be used to correct specific defective sections of the genome. Unfortunately, there is a catch: under certain conditions, the repair can lead to new genetic defects – as in the case of chronic granulomatous disease. This was reported in the journal Communications Biology by a team from the University of Zurich (UZH).

Chronic granulomatous disease is a rare hereditary disease that affects about one in 120 000 people. The disease impairs the immune system, making patients susceptible to serious and even life-threatening infections. It is caused by the absence of two letters, called bases, in the DNA sequence of the NCF1 gene. This error results in the inability to produce an enzyme complex that plays an important role in the immune defence against bacteria and moulds.

The CRISPR tool works…

The research team has now succeeded in using the CRISPR system to insert the missing letters in the right place. They performed the experiments in cell cultures of immune cells that had the same genetic defect as people with chronic granulomatous disease. “This is a promising result for the use of CRISPR technology to correct the mutation underlying this disease,” says team leader Janine Reichenbach, professor of somatic gene therapy at the University Children’s Hospital Zurich and the Institute for Regenerative Medicine at UZH.

… but unfortunately, it’s not perfect

Interestingly however, some of the repaired cells now showed new defects. Entire sections of the chromosome where the repair had taken place were missing. The reason for this is the special genetic constellation of the NCF1 gene: it is present three times on the same chromosome, once as an active gene and twice in the form of pseudogenes. These have the same sequence as the defective NCF1 and are not normally used to form the enzyme complex.

CRISPR’s molecular scissors cannot distinguish between the different versions of the gene and therefore occasionally cut the DNA strand at multiple locations on the chromosome – at the active NCF1 gene as well as at the pseudogenes. When the sections are subsequently rejoined, entire gene segments may be misaligned or missing. The medical consequences are unpredictable and, in the worst case, contribute to the development of leukaemia. “This calls for caution when using CRISPR technology in a clinical setting,” says Reichenbach.

Safer method sought

To minimise the risk, the team tested a number of alternative approaches, including modified versions of CRISPR components. They also looked at using protective elements that reduce the likelihood of the genetic scissors cutting the chromosome at multiple sites simultaneously. Unfortunately, none of these measures were able to completely prevent the unwanted side effects.

“This study highlights both the promising and challenging aspects of CRISPR-based therapies,” says co-author Martin Jinek, a professor at the UZH Department of Biochemistry. He says the study provides valuable insights for the development of gene-editing therapies for chronic granulomatous disease and other inherited disorders. “However, further technological advances are needed to make the method safer and more effective in the future.”

Source: University of Zurich

Categories : Diseases, Syndromes and ConditionsTags :

International Pompe Day

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Early diagnosis is key to transformative treatment in Pompe disease

Photo by National Cancer Institute on Unsplash

15 April is recognised as International Pompe Day, a time dedicated to increasing awareness about Pompe Disease – a rare, inherited disorder that leads to progressive muscle and heart weakness. The day emphasises global awareness with the message: “Together We Are Strong.”

Pompe Disease is a condition resulting from mutations in a gene responsible for producing acid alpha-glucosidase (GAA), the enzyme necessary for breaking down glycogen, a sugar the body uses for energy.1 These mutations lead to a reduced or absent production of this enzyme, causing an accumulation of glycogen that damages muscles and the heart. The impact of the disease, including its severity and the age when symptoms appear, depends on how much the enzyme’s activity is reduced.1

Pompe Disease is classified into two types2: the infantile form, characterised by severe GAA deficiency and symptoms appearing in the first months of life1, and the late-onset form, where symptoms may start in childhood or adulthood, usually without affecting the heart.1

Early diagnosis is vital for managing Pompe Disease effectively and improving outcomes.2 Kelly du Plessis, CEO and Founder of Rare Diseases South Africa (RDSA), says: “The rise in adult diagnoses stresses the importance of recognising symptoms such as difficulty walking, frequent chest infections, fatigue, muscle weakness, and frequent falls. Symptoms in infants include feeding problems, poor weight gain, breathing difficulties, muscle weakness, an enlarged heart, floppiness, and delayed milestones.”1

Obtaining a Pompe Disease diagnosis can be challenging. Du Plessis’ own path to finding a diagnosis for her son confirms the difficulties of identifying Pompe Disease. “The journey to a diagnosis is fraught with complexity because of the many ways in which the disease presents. I urge parents to trust their intuition and seek medical counsel without delay, as early intervention is critical.”

Although there is no cure for the disease, Enzyme Replacement Therapy (ERT), available since 2006, supplies the body with a version of the GAA enzyme that people with Pompe Disease lack, and has significantly improved outcomes for patients.3

Monique Nel, Medical Advisor for Rare Diseases at Sanofi South Africa, emphasises the importance of early screening and treatment to prevent or minimise complications. “Access to ERT in South Africa has been life-changing for patients, offering improved energy levels and quality of life,” says Nel. “Starting ERT before the onset of symptoms can prevent or slow the progression of the disease. This means patients may experience fewer complications and a slower decline in their condition over time.”

Some of the key benefits of ERT include:

Improvement in muscle function: ERT helps to break down glycogen, preventing its harmful accumulation in muscle cells. Patients often experience improvements in muscle strength and function2, which can enhance mobility and daily living activities.

Enhanced respiratory function: Many individuals with Pompe Disease suffer from respiratory complications due to muscle weakness. ERT can lead to improved respiratory function2, reducing the need for ventilatory support and decreasing the frequency of respiratory infections.

Cardiac benefits: In the infantile form of Pompe Disease, heart enlargement and dysfunction are significant concerns. ERT has been shown to improve heart function2, which can be life-saving for infants affected by the disease.

“By addressing some of the primary symptoms of Pompe Disease, ERT can significantly improve the quality of life for patients,” says Nel. “This includes increased energy levels, reduced fatigue, and the ability to participate more fully in social, educational, and professional activities.”

“We also encourage healthcare professionals to consider Pompe Disease when evaluating patients with muscle weakness, respiratory issues, or unexplained cardiac symptoms, to ensure early diagnosis. Early diagnosis facilitates timely intervention and treatment, optimising patient outcomes and quality of life.”

For more information, visit: www.rarediseases.co.za

References:

1. National Institute of Neurological Disorders and Stroke. Pompe disease. N.d. Available at: https://www.ninds.nih.gov/health-information/disorders/pompe-disease#, accessed 9 April 2024.
2. Bhengu, L, et al. Diagnosis and management of Pompe disease. South African Medical Journal, 2014; 104(4):273-274.
3. Ficicioglu, C, et al. Newborn screening for Pompe disease: Pennsylvania experience. International Journal of Neonatal Screening, 2020; 6: 89.

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Pompe Disease – Early Diagnosis and Treatment are Crucial

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Photo by CDC on Unsplash

Pompe disease (PD) is an autosomal-recessively inherited neuromuscular disease that can be fatal if it is not diagnosed and treated early.1 Due to lack of acid alpha-glucosidase (GAA), there is progressive intracellular accumulation of glycogen, which can severely damage the muscles and heart.1

PD can present from early infancy into adulthood, with variable rates of disease progression.1 Severity is determined by age of onset, organ involvement, including the degree of muscle involvement (skeletal, respiratory, and cardiac), and rate of progression.1

Classification1

PD is classified into two groups: infantile and late-onset.

Infantile form:

• Classic infantile PD is most severe and rapidly progressive, and is characterised by prominent cardiomegaly, hepatomegaly, muscular weakness and hypotonia. Death results from cardiorespiratory failure in <1 year, if not treated.

• Infantile variant form (non-classic, in the <1-year group that has slower progression and less severe or absent cardiomyopathy).

Late-onset form:

• Childhood/juvenile or muscular variant (heterogeneous group) presenting later than infancy and typically excluding cardiomyopathy.

• Adult-onset form characterised by slowly progressive myopathy predominantly involving skeletal muscle and presenting as late as the 2nd – 6th decade of life.

Signs and symptoms

In infants, symptoms begin in the first months of life, with feeding problems, poor weight gain, breathing difficulties, profound hypotonia, and cardiomegaly.2 Many infants with PD also present with macroglossia.2

Kelly du Plessis, CEO and Founder of non-profit organisation, Rare Diseases SA (RDSA), says that the difficulty for both parents and healthcare professionals is that PD shows itself in many ways. “There is not one specific thing that you can pinpoint. My child, who is a PD sufferer, took longer to reach his milestones, and got slower as time progressed. It is better to be overcautious than under-cautious because early identification is critical to a positive outcome, and the damage done up until diagnosis cannot be undone.”

Du Plessis says that RDSA is also seeing many more adults being diagnosed with PD lately, and describes a few of the signs and symptoms: “In adults these include difficulty walking, particularly up stairs or inclines, recurring chest infections, being very fatigued, finding that their arms are getting weaker when they try to reach something on a top shelf, and falling over quite often owing to lower muscle tone and foot drop. Healthcare professionals need to be aware of this link with PD – because early intervention is critical to outcomes.”

Diagnosis

While making an early diagnosis is imperative to optimise disease management and outcomes,1 many patients experience a diagnostic odyssey.3

Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “The diagnostic odyssey for PD can be quite long and complicated, as the symptoms can be similar to those of other conditions, and the disease is quite rare. The journey to diagnosis can take years, and many patients go through a battery of tests and specialists before finally receiving a correct diagnosis.”

In the United States it was reported that before implementation of newborn screening, there was, on average, a 3-month delay in diagnosing infantile-onset PD after the onset of symptoms.3 In late-onset PD, symptoms may begin any time from infancy to adulthood.3 In paediatric onset cases, on average: symptom onset occurs at approximately 6 years of age, yet diagnosis is generally made around 18 years of age, with a potential 12-year delay in diagnosis.3 The average age of symptom onset in adult-onset PD is 35 years, with a 7-year delay in diagnosis after symptom onset.3

Adds Nel: “In South Africa, we do enzyme activity testing via a dried blood spot test to measure the activity of the alpha-glucosidase enzyme. If the enzyme activity is low, it suggests that the individual may have PD. Genetic testing is currently performed abroad. This involves analysing a person’s DNA to look for mutations in the GAA gene. If two mutated copies of the GAA gene are found, it confirms a diagnosis of PD.”

Treatment

Enzyme replacement therapy (ERT) is available for all forms of PD, and has dramatically changed patient outcomes.3 This life-changing therapy is more effective when started before the onset of symptoms.3

Since the end of 2012, ERT (as alglucosidase alfa) has been registered with the South African Health Products Regulatory Authority (SAHPRA) for use in PD patients.1 Patients with infantile-onset PD who receive ERT have significantly prolonged survival, decreased cardiomegaly, and improved cardiac and skeletal muscle function.1 Cardiac response appears to be good, irrespective of the stage of disease at initiation of ERT, while the skeletal muscle response appears more variable.1 The best skeletal muscle response occurs when ERT is administered prior to skeletal muscle damage.1

Says Nel: “Early screening for PD and prompt treatment is crucial to prevent or delay the onset of disease complications. Therefore, healthcare providers must consider PD as a potential differential diagnosis when evaluating patients with muscle weakness, respiratory difficulties, and other related symptoms.”

Says du Plessis: “With medication, you see a difference in the patients within weeks, and they have a lot more energy. RDSA advocates as much as is necessary to get patients approved for medication, since this treatment changes their lives and quality of life – and in fact saves their lives. We need to do everything we can now, with the treatments we have today, to keep these patients as healthy as possible, so that they can benefit from the treatments that come tomorrow.”

For more information, visit: www.rarediseases.co.za

References

1. Bhengu, L, et al. Diagnosis and management of Pompe disease. South African Medical Journal 2014;104(4):273-274.

2. National Institute of Neurological Disorders and Stroke. Pompe disease. N.d. Available at: https://www.ninds.nih.gov/health-information/disorders/pompe-disease#, accessed 7 April 2023.

3. Ficicioglu, C, et al. Newborn screening for Pompe disease: Pennsylvania experience. Int J Neonatal Screen 2020;6(4):89.

Categories : Diseases, Syndromes and ConditionsTags :

Tackling the Challenges of Lysosomal Storage Diseases Diagnosis and Treatment

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Source: NCI

A disease is defined as ’rare’ when it affects fewer than 1 in 2000 people,1 and there are currently more than 7000 known rare diseases (lysosomal storage diseases), affecting more than 300 million people worldwide.1-2 Most (70–80%) lysosomal storage diseases are genetic and inherited, while some may be acquired, and 70% are exclusively paediatric in onset.2

Patients with lysosomal storage diseases present unique challenges to healthcare professionals (HCPs), including diagnostic delays and a lack of information, expertise, and treatment options for many lysosomal storage diseases. Appropriate referrals to specialists, timely diagnosis and treatment, coordinated cross-functional care, and assisting patients in obtaining the proper support are vital roles for HCPs in enhancing quality of life for lysosomal storage disease patients and their families.3,4

Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “We understand that HCPs may face difficulties when it comes to the diagnosis of a lysosomal storage disease, and that a coordinated approach to diagnosis and care for people living with lysosomal storage diseases is needed. Lysosomal storage diseases deserve the same amount of time, resources and dedication to finding effective treatments and therapies as any other condition. This is a mission that Sanofi strives to uphold every day, to help HCPs to improve diagnosis, especially as we are starting to see more patients diagnosed with lysosomal storage diseases in both the public and private sectors.”

“Sanofi is focused on education around innovative treatment and research efforts that improve real-world outcomes, investing in education and research to better manage and understand these conditions, and identifying areas requiring more attention,” says Nel.

In the 10 years of its existence, patient advocacy group Rare Diseases SA has made great strides in advocacy for lysosomal storage disease patients. Founder and CEO, Kelly du Plessis, says: “We need to acknowledge that local doctors and healthcare practitioners may have limited knowledge and experience of lysosomal storage diseases. What we would like to see is that they are upskilled on the following three aspects: knowing that lysosomal storage diseases exist, knowing the impact that these have on the patient, and knowing where to refer a patient who they think may have a rare condition. If we can tick these three boxes, great strides will have been made for the diagnostic odyssey that patients with lysosomal storage diseases go through.”

Says du Plessis: “Most importantly, we need a lysosomal storage disease policy to be recognised and enforced in SA, and we need National Treasury to assign a budget to treat these patients so that once an official diagnosis is made, they can receive immediate care. There is also a need for mechanisms to escalate product registration where there are no existing products or alternatives available for lysosomal storage disease patients.”

Partnerships with various stakeholders are paramount in terms of bringing innovative medicines and access to treatment to lysosomal storage disease patients. Says Nel: “For more than 40 years, Sanofi has been a pioneer in science and innovation, rallying its people and resources to help improve the lives of those living with lysosomal storage diseases. Through its commitment to faster diagnoses, innovative treatments, sustainable access and integrated support along the patient journey, Sanofi strives to enable more fulfilling futures.”

Sanofi continues to build on its scientific understanding and strives to develop more therapies with the potential to improve the lives of those living with lysosomal storage diseases and beyond.5 Says Nel: “Sanofi’s lysosomal storage disease patient registries represent one of the largest collections of real-world data for lysosomal storage diseases amassed over the past 30 years. It has a presence in 65 countries, with more than 920 participating sites and over 18,000 patients enrolled. These registries help researchers to publish the latest information on real-world outcomes, showcasing innovative treatments and ongoing research for people living with lysosomal storage diseases.”

Sanofi also has a Rare Humanitarian Programme, which has been running for 32 years and provides humanitarian support to people living with lysosomal storage diseases.Says Nel: “This isan integral part of Sanofi’s mission to develop sustainable healthcare systems, increase access, and improve standards of care for lysosomal storage diseases worldwide. Over 1,000 people in over 70 countries are currently receiving access to free therapy.6

“By building meaningful connections with all stakeholders through various platforms, we continuously strive to transform the practice of medicine, sharing experiences and breaking down barriers,” says Nel.

A useful resource for HCPs and patients is the list of lysosomal storage diseases maintained by the Genetic and Rare Diseases Information Center (GARD) of the US National Institutes of Health.7           

References

1.   NIH. Genetic and Rare Disease Information Center. FAQs About Rare Diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed January 2022.

2.   Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165–173.

https://doi.org/10.1038/s41431-019-0508-0.

3.    Elliott E, Zurynski Y. Rare diseases are a ‘common’ problem for clinicians. Aust Fam Physician. 2015 Sep;44(9):630. http://www.ncbi.nlm.nih.gov/pubmed/26488039.

4.    Dudding-Byth T. A powerful team: the family physician advocating for patients with a rare disease. Aust Fam Physician. 2015 Sep;44(9):634. http://www.ncbi.nlm.nih.gov/pubmed/26488040. NIH.

5.   Sanofi Your Health webpage. Rare Disease. https://www.sanofi.com/en/your-health/specialty-care/rare-diseases. Accessed February 2023.

6.   Sanofi. The Sanofi Genzyme Rare Humanitarian Program turns 30. Available at: https://www.sanofi.com/en/about-us/our-stories/the-sanofi-genzyme-rare-humanitarian-program-turns-30. Accessed February 2023.

7.   Genetic and Rare Disease Information Center. Browse by disease. Available at: https://rarediseases.info.nih.gov/diseases. Accessed February 2023.

Categories : Diseases, Syndromes and Conditions General InterestTags :

Celine Dion Reveals Her Rare Disease Diagnosis

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Celine Dion in 2008. Photo by Anirudh Koul. CC2.0

Canadian singer Celine Dion has revealed that she has been diagnosed with a very rare neurological disease called Stiff Person Syndrome (SPS), BBC News reports. The disease causes muscle spasms, interfering with daily activities. Injuries can be sustained from falls caused by spasms experienced while walking.

The 54-year-old singer had been battling with muscle spasms, and since the disease interferes with her singing, she has cancelled all of her concerts scheduled for 2023, putting them off to 2024.

SPS is an extremely rare disease, thought to affect only one in a million individuals. As such, relatively little is known about it and what causes it, although it is associated with autoimmune disorders and often misdiagnosed as Parkinson’s disease.

After a hiatus from 2014 to be with her husband while he battled cancer, she returned to the stage in 2019 with her new album Courage. This tour had a number of cancellations due to the COVID pandemic.

Speaking on an Instagram post, Dion said that she had “a great team of doctors working alongside me to help me get better” and had the support of her “precious children”.

The singer explained: “I’m working hard with my sports medicine therapist every day to build back my strength and my ability to perform again, but I have to admit it’s been a struggle.

“All I know is singing. It’s what I’ve done all my life and it’s what I love to do the most.

“I miss you so much. I miss seeing all of you [and] being on the stage, performing for you.

“I always give 100 per cent when I do my show but my condition is not allowing me to give you that right now.”

What is stiff person syndrome?

According to the National Institute for Neurological Disorders, SPS is characterised by “fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms. Abnormal postures, often hunched over and stiffened, are characteristic of the disorder. People with SPS can be too disabled to walk or move, or they are afraid to leave the house because street noises, such as the sound of a horn, can trigger spasms and falls. SPS affects twice as many women as men.”

A definitive diagnosis can be made by measuring the level of glutamic acid decarboxylase (GAD) antibodies in the blood, which is elevated in people with SPS. GAD is the rate-limiting enzyme that catalyses the conversion of glutamate to GABA

As for management, the symptoms can be well controlled. Pharmacological treatment includes IVIg, anti-anxiety drugs, muscle relaxants, anti-convulsants, and pain relievers.

Work continues for better treatments; so far rituximab proved ineffective. At present, research is focused on aetiology and the role of anti-GAD antibodies.

Categories : Diseases, Syndromes and ConditionsTags :

International Gaucher Day on 1 October Highlights Need For Greater Attention on Rare Diseases

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Photo by Cottonbro on Pexels

Currently, there are an estimated 6000–8000 rare diseases, which affect 350 million people worldwide.1 One such rare condition is Gaucher Disease (GD) – a lysosomal storage disorder (LSD).  GD is a rare genetic disorder, passed down from parents to children (inherited) in an autosomal recessive manner. 

GD is one of the most common LSDs with a prevalence in the general population of ~1 per 100 000 and ~1/855 in the Ashkenazi Jewish population.2 As with many rare conditions, diagnosis of GD may present a significant challenge to non-GD specialities, owing to the wide variability in age, severity, type of clinical manifestation and lack of awareness of the early signs and symptoms of GD among non-specialist physicians.3 One in 6 patients with GD reported a diagnosis delay of 7 years or more after first consulting a doctor.3

International Gaucher Day on 1 October, therefore, aims to improve patients’ quality of life through greater awareness and earlier diagnosis of GD amongst healthcare professionals.

GD arises from an inherited deficiency of an enzyme called glucocerebrosidase, normally found within the lysosomes of cells, due to mutations in the GBA gene.4 This enzyme is responsible for breaking down a fatty substrate, glucocerebroside, into glucose and a simpler fat molecule (ceramide).4 Patients with GD have a progressive build-up of glucocerebroside within the lysosomes, particularly of macrophages, resulting in enlarged cells known as ‘Gaucher’ cells.4

These ‘Gaucher’ cells accumulate in organs throughout the body, predominately affecting the bone marrow, liver, and spleen.4 There are three types of GD, based on the presence and severity of neurological involvement.4 Type 1, known as the non-neuronopathic GD  characterised by haematological abnormalities such as thrombocytopenia, leukopenia and anaemia, hepatomegaly and/or splenomegaly, bone crises and/or osteoporosis, and fatigue.4  Phenotypically, there is a wide spectrum of disease manifestations, ranging from asymptomatic to severe type 1 child-onset disease.5,6 Type 2, the acute neuronopathic form, is the rarest and most severe form of GD.  It includes the rapid progression of severe neurological abnormalities early in life, leading to death in infancy or early childhood.4,6 Type 3, the chronic form, encompasses multiple phenotypes.  Type 3 typically occurs during the paediatric years and varies in severity: patients have the same symptoms as in type 1, plus some neurological involvement that generally appear later in life, such as abnormal eye movement, ataxia, seizures and dementia.4

Anaemia, thrombocytopenia, enlargement of the liver and/or spleen, and skeletal abnormalities (osteopenia, lytic lesions, pathological fractures, chronic bone pain, bone crisis, bone infarcts, osteonecrosis and skeletal deformities) are typical manifestations of type 1 GD, the most prevalent form of the disease.5 However, the severity and coexistence of different symptoms are highly variable, and GD patients are often misdiagnosed as having other malignant haematological conditions.4

Although GD is rare, clinicians are encouraged to maintain a high index of suspicion with patients presenting with atypical symptoms, and should consider testing for rare diseases where other haematological pathologies have been excluded4 or when testing for them. Such patients may be referred to a GD specialist or be tested through North West University (NWU), where global pharmaceutical company Sanofi and the NWU Centre of Human Metabolomics, headed by Prof Chris Vorster, have partnered to test for the most common lysosomal storage disorders in South Africa, including GD, using dried blood spot samples.

Says Prof. Vorster: “Rare conditions such as GD require the cooperation of a multidisciplinary team in order to find and treat them. Interventions can improve a patient’s quality of life through improvement or restoration of their physical function, so that they may carry out regular daily activities. The NWU Centre of Human Metabolomics provides internationally competitive metabolomic analytic services, and electronic results may be sent by high priority straight to healthcare practitioners, speeding up diagnosis.”

Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “We understand the difficulty that healthcare professionals face when it comes to diagnosing patient with GD. It requires a coordinated approach to diagnosis and care for people living with the condition. Early diagnosis of GD, and the initiation of treatment will delay the occurrence of irreversible complications, and improve the patient’s quality of life. We therefore direct the attention of healthcare providers to the RD Nexus platform, which is Sanofi’s dedicated platform for rare diseases, at www.RDNexus.com. This platform offers educational materials, road maps to a differential diagnosis and how to test a patient for these conditions.”

For more information on GD and other rare diseases, visit: www.RDNexus.com

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505568/pdf/EMMM-11-e10486.pdf Accessed September 2022.
  2. Burrow TA et al. Prevalence and management of Gaucher disease. Paediatric Health, Medicine and Theraeutics 2011;2:59-73.
  3. Revel-Wilk S, et al. How we manage Gaucher Disease in the era of choices. British Journal of Haematology 2018;182:467-480.
  4. CPD Gaucher. Gaucher Disease. Medical Chronicle June 2020:30-32.
  5. Linari S, Castaman G. Clinical manifestations and management of Gaucher disease. Clinical Cases in Mineral and Bone Metabolism 2015;12(2):157-164.
  6. Roshan Lal T and Sidransky E. The spectrum of neurological manifestations associated with Gaucher Disease. Diseases 2017;5,10.
Categories : Diseases, Syndromes and Conditions Medical Research & TechnologyTags :

Sanofi’s Rare Disease Database Aids Healthcare Practitioners

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Image source: CDC/Unsplash

Sanofi’s rare disease database that helps healthcare practitioners tackle their unique challenges – and knowing that treatments are available directly improves patients’ wellbeing. This comprehensive database has also aided rare disease research.

Johannesburg, 28 February 2022: Patients with rare diseases present unique challenges to healthcare practitioners (HCPs). Obstacles to caring for them include diagnostic delays and a lack of information, expertise, and treatment options for many rare diseases. HCPs play a vital role in enhancing the quality of life for patients and families living with a rare disease by making appropriate referrals to specialists, helping to coordinate care, and assisting patients in obtaining the proper support.1,2

A disease is defined as ‘rare’ when it affects fewer than 1 in 2000 people.3

Over 7000 rare diseases have been described to date, affecting over 350 million people worldwide.3,4 While most (70-80%) of rare diseases are genetic and inherited, some may be acquired, and 70% are exclusively paediatric in onset.5

Recent surveys showed that those living with rare diseases had a significantly higher prevalence of anxiety and depression compared to the general population.5,6 Levels of high stress can become even worse for carers when the person they are supporting has a diagnosis with no available treatment option.5,6

Monique Nel, Medical Advisor – Rare Diseases at Sanofi says: “Sanofi has been dedicated to researching and developing innovative treatments for rare diseases for 40 years. Currently, Sanofi has one of the largest rare diseases pipelines in the industry, across multiple diseases and modalities.7”

“Our rare disease patient registries have grown to represent one of the largest collections of real-world data for rare diseases collected over the past 30 years. We have a presence in 68 countries worldwide, with more than 920 participating sites and more than 17 800 patients enrolled.”

These registries have helped researchers to publish studies describing the underlying biology of disease, identify risk factors impacting treatment outcomes, and share guidelines for monitoring and treatment.

A further useful resource for HCPs and patients is the list of rare diseases maintained by the Genetic and Rare Diseases Information Center (GARD) of the US National Institutes of Health.8          

Says Nel: “We understand the difficulty that healthcare professionals face when it comes to patient diagnosis of a rare disease, and that a coordinated approach to diagnosis and care for people living with rare diseases is needed. Rare diseases deserve the same amount of time, resources and dedication to finding effective treatments and therapies as any other conditions, which is a mission that Sanofi strives to promote every day, to help HCPs to improve diagnosis.”

References:

  1. Elliott E, Zurynski Y. Rare diseases are a ‘common’ problem for clinicians. Aust Fam Physician. 2015 Sep;44(9):630. http://www.ncbi.nlm.nih.gov/pubmed/26488039
  2. Dudding-Byth T. A powerful team: the family physician advocating for patients with a rare disease. Aust Fam Physician. 2015 Sep;44(9):634. http://www.ncbi.nlm.nih.gov/pubmed/264880401. NIH.
  3. Genetic and Rare Disease Information Center. FAQs About Rare Diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases
  4. Bogart KR, Irvin VL. Health-related quality of life among adults with diverse rare disorders. Orphanet J Rare Dis. 2017 Dec 7;12(1):177. doi: 10.1186/s13023-017-0730-1. PMID: 29212508; PMCID: PMC5719717.
  5. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165–173. https://doi.org/10.1038/s41431-019-0508-0
  6. National Alliance for Caregiving. Rare Disease Caregiving in America. Available at: https://www.caregiving.org/wp-content/uploads/2020/05/NAC-RareDiseaseReport_February-2018_WEB.pdf
  7. Sanofi Your Health webpage. Rare Disease. https://www.sanofi.com/en/your-health/specialty-care/rare-diseases
  8. National Institutes of Health, Genetic and Rare Diseases Information Center. Caring for your patient with a rare disease.  Available at: https://rarediseases.info.nih.gov/guides/pages/122/caring-for-your-patient-with-a-rare-disease
Categories : Diseases, Syndromes and ConditionsTags :

Study Shows New Possibilities of Treating Rare Ossifying Disease

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Source: National Cancer Institute on Unsplash

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterised by anomalous bone growth at the site of even minor injuries. It results in what some term a “second skeleton,” which locks up joint movement and even making breathing difficult. However, new research shows that forming extra-skeletal bone might not be the only driver of the disease. Impaired muscle tissue regeneration allows unwanted bone to form instead of muscle regeneration after injury.

This study was published in NPJ Regenerative Medicine.

“While we have made great strides toward better understanding this disease, this work shows how basic biology can provide great insights into appropriate regenerative medicine therapies,” said the study’s lead author, Foteini Mourkioti, PhD. “From the lab, we’re now able to show that there is potential for a whole new realm of therapies for patients with this devastating condition.”

About 15 years ago, researchers discovered that a mutation in the ACVR1 gene was responsible for FOP. In that study, the team found that the mutation changed cells within muscles and connective tissues, causing them to behave like bone cells and create new, extraneus bone.

“However, while investigations of how the FOP mutation alters the regulation of cell fate decisions have been extensively pursued in recent years, little attention has been paid to the effects of the genetic mutation on muscle and its impact on the cells that repair muscle injuries,” Shore said. “We were convinced that pursuing research in this area could provide clues not only for preventing extra bone formation but also for improving muscle function and regeneration, bringing new clarity to FOP as a whole.”

The researchers studied muscle from mice with the same mutation in the ACVR1 gene that people with FOP have. They focused on two specific types of muscle tissue stem cells: fibro-adipogenetic progenitors (FAPs) and muscle stem cells (MuSCs). Typically, muscle injury repair requires a careful balance of these two cell types. Injured tissue responds by an expansion of FAP cells, which are assigned to recruit muscle stem cells that will regenerate the damaged muscle tissue. After about three days, FAPs die off, their job done. At the same time, MuSCs transition toward a more mature, differentiated state, called muscle fibre, essential to organised movement of our muscles.

In the mice with the ACVR1 mutation being studied, apoptosis – the process through which FAP cells die as a part of proper muscle regeneration – had slowed significantly, leading to a high presence of FAPs past their usual lifespan, altering their balance with the MuSCs. The injured tissue also showed a diminished capacity for muscle stem cell maturation and, as a result, muscle fibres were considerably smaller in mice carrying the ACVR1 mutation compared to muscle fibres in mice lacking the mutation.

“The prolonged persistence of diseased FAPs within the regenerating muscle contributes to the altered muscle environment in FOP, which reduces muscle regeneration and allows the over-abundant FAPs to contribute to the formation of extra-skeletal bone,” Mourkioti said. “This provides a completely new perspective on how excess extra-skeletal bone is formed – and how it could be prevented.”

The current targets for treating FOP focus on slowing extra-skeletal bone growth. This research may provide a pivotal new direction. “We propose that therapeutic interventions should consider promoting the regenerating potential of muscles together with the reduction of ectopic bone formation,” the authors wrote. “By addressing both stem cell populations and their roles in the origin of FOP, there is the possibility of greatly enhanced therapies.”

Source: University of Pennsylvania School of Medicine

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Up to Five Times Higher Costs for Those with Rare Diseases

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By studying medical and insurance records indicates health care costs for people with a rare disease, researchers have found that these have been underestimated and are three to five times greater than the costs for people without a rare disease.

The findings, appearing in the Orphanet Journal of Rare Diseases, provides new evidence of the impact rare diseases could have on public health, suggesting that medical costs for individuals with rare diseases are on par with those for cancer and heart failure.  

“There needs to be greater public awareness of the large and growing medical footprint of rare diseases in society,” said senior author Anne Pariser, MD, director of the NCATS Office of Rare Diseases Research. “Only about 10% of rare diseases have an FDA-approved therapy for their treatment. The findings underscore an urgent need for more research, and earlier and more accurate diagnoses of and interventions for these disorders.”

Most of the 7000 to 10 000 known rare diseases disproportionately affect children, adolescents and young adults. Individually, most rare diseases might affect only a few hundred to a few thousand people around the world. Rare diseases however are collectively common, affecting an estimated 4% of the world’s population. Many of these diseases have a genetic cause, are serious or life-threatening and are hard to diagnose and treat.

The pilot study used International Classification of Diseases (ICD) codes, which designate a disease diagnosis and other methods, to determine those individuals with rare diseases and their direct medical costs for 14 rare diseases in four health care systems compared to non-rare disease patients of a similar age.

The 14 rare diseases represented a diverse set of disorders differing in prevalence, organ systems affected, age of onset, clinical course, and availability of an approved treatment or specific ICD code. These rare diseases include sickle cell disease, muscular dystrophy and eosinophilic esophagitis.

The analysis showed wide variations of rare diseases prevalence in the different health care systems, possibly due in part to geographic differences, as well as the use of public versus private insurance, which may include different patient group representation. Some genetic diseases can also have a higher prevalence in certain regions, due to demographic make-up.

With the Eversana health care system database, the cost per patient per year (PPPY) for those with a rare disease, ranged from $8 812 to $140 044 for rare diseases patients compared to $5862 for those without a rare disease. The NCATS data indicated PPPY costs ranging from $4859 to $18 994 for rare diseases patients versus $2211 for those without a rare disease.

Using patient medical records, the researchers also traced the diagnostic journeys of four people with a rare disease, including two individuals who had a form of Batten disease, an inherited neurological disorder, and two others with cystic fibrosis. These journeys provided detailed descriptions of direct medical costs, such as for hospitalisations and procedures for these diseases, and provided insights into patient clinical management before and after disease diagnosis.

Analysis of medical records also revealed that rare diseases patients often shared commanilities in symptoms (eg, seizures, infections, and developmental delay) and characteristics, which could aid in earlier diagnosis and treatmen. As many receive a rare disease diagnosis at a young age and because most rare diseases are serious conditions, rare disease patients are likely to require hospital time and incur greater medical expenses over a lifetime.

Such commonalities among rare disease patients could point to the potential use of machine learning techniques on health care system databases to improve diagnoses, said study co-author Joni L. Rutter, PhD, NCATS Acting Director.

The researchers would also like to determine whether these methodologies could be scaled to thousands of other known rare diseases.

“Ultimately, to improve the lives of people with rare diseases,” said Dr Rutter, “we need to find innovative ways, including new technologies, to help shorten the lengthy diagnostic odysseys so many patients and families experience and make more treatments available faster.”

Source: National Center for Advancing Translational Sciences

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Rare Diseases in South Africa: A Neglected Topic

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An article in Spotlight examines the challenges faced by South Africans with rare diseases.

A rare disease is a health condition affecting a small number of people compared with other diseases commonly identified in the population. According to the World Health Organization (WHO), there are between 5000 and 8000 known rare diseases worldwide, affecting an estimated 400 million people.

According to the advocacy group Rare Disease South Africa (RDSA), about 3.6 million people in SA have a rare disease. In South Africa, the ability to diagnose a rare disease is hindered by a lack of capacity and resources, according to research, putting the time to diagnosis for rare diseases in general higher than the estimated 5.5 to 7.5 years in high-income countries.
“There is still low recognition of genetic disorders among specialists. And when they are recognised, testing remains expensive and requires sophisticated levels of training which are relatively limited,” says Prof Karen Fieggen, a medical geneticist at the University of Cape Town (UCT).

According to her, costs, skills, training, and human resource factors are all barriers to effective testing and diagnosis. But she says the rationale to build an effective system is solid.

“We have capable people and expertise to build this system, but until you invest in it, it won’t be big enough to be self-sustaining,” she says.

Prof Fieggen acknowledges that resources are stretched in the public sector, where specialists who carry out genetic testing for rare diseases must meet the needs of a larger part of the population. However, she notes, “there’s no guarantee you’re better off in the private sector”.

“There are very few genetic referral options, and none of the medical geneticists are kept in work full time,” she says. In Cape Town, for example, she says that all patients seeking genetic testing had to come to the private sector until recently. “We have the capacity to train seven specialists a year, but posts aren’t available for them to take,” she says.

At one per 4.5 million population, available medical geneticists in the public healthcare sector fall far short of the 21 per 2 million recommended by the WHO. These services are also spread unevenly through the country. The country’s heavy burden of HIV and TB is partly responsible for this lack of coverage.

While healthcare training must focus on these public health needs, Prof Fieggen says rare diseases need a sensible approach. “It doesn’t help to throw huge resources at something that will have minimal management impact,” she says. “But the way in which rare diseases have been relatively ignored isn’t constructive.”

Helping the recognition of rare diseases and referral pathways in physician training may make a difference. “One thing that could be instilled in training is to recognise that if things are atypical in their presentation, there should be a discussion with a referral centre,” says Associate Professor Ian Ross, a senior consultant endocrinologist at UCT and Groote Schuur Hospital.

Only 2.5-5% of rare diseases have approved treatments, some of which are prohibitively expensive.

The most expensive drug in the world is Zolgensma (generic name onasemnogene abeparvovec), a once-off treatment costing a mind-blowing USD $2.1 million (R 30m). Used to treat inherited spinal muscular atrophy, where infants with the condition are unlikely to see their second birthday. However, even this is available through the UK’s National Health Service, which struck a deal to bring prices down.

Du Plessis says these drugs are not on the essential medicines list because of the small group of patients they would serve. “The essential medicines list is dedicated to treatments that are procured in large numbers. Rare diseases will never be mass-market drugs.”

Such drugs can be purchased by hospital pharmacists so they can be available at a certain hospital, making for a haphazard situation.
To help address this inequality, RDSA held a Rare Disease Symposium on 25 August, inviting feedback on a draft policy framework from various medical sector and political stakeholders.

The framework has a definition for rare disease in SA, namely a condition affecting one in 2000 people or fewer. It also recommends including rare diseases in the NHI benefit package. The NHI bill also includes a Benefits Advisory Committee, which will determine what diseases get coverage,

However, Dr Nicolas Crisp, Acting Director General for Health, said that the NHI would not ring-fence funding. As medical insurance will be done away with, it will be crucial to secure funding for those extremely expensive drugs unaffordable to the private sector.

Source: Spotlight