Month: April 2023

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 : GastrointestinalTags :

An Elusive Relationship Between The Gastrointestinal Immune System and Caffeine

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Certain gut microorganisms are thought to contribute to the development of inflammatory conditions such as inflammatory bowel disease (IBD), but the sequence of events leading from microbes to immune cells to disease remains elusive. A new study published in Immunity explores exactly what leads to the generation of Th17 cells, an important subtype of cells in the intestine, and uncovers some of the underappreciated molecular players and events that lead to cell differentiation in the gut. One of those players is the purine metabolite xanthine – high levels of which are found in caffeinated foods such as coffee, tea and chocolate.

“One of the concepts in our field is that microbes are required for Th17 cell differentiation, but our study suggests that there may be exceptions,” said co-lead auhor Jinzhi Duan, PhD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine at Brigham and Women’s Hospital,. “We studied the underlying mechanisms of Th17 cell generation in the gut and found some surprising results that may help us to better understand how and why diseases like IBD may develop.”

While illuminating the steps leading to Th17 cell differentiation, the researchers unexpectedly discovered a role for xanthine in the gut.

“Sometimes in research, we make these serendipitous discoveries – it’s not necessarily something you sought out, but it’s an interesting finding that opens up further areas of inquiry,” said senior author Richard Blumberg, MD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine. “It’s too soon to speculate on whether the amount of xanthine in a cup of coffee leads to helpful or harmful effects in a person’s gut, but it gives us interesting leads to follow up on as we pursue ways to generate a protective response and stronger barrier in the intestine.”

Interleukin-17-producing T helper (Th17) cells are thought to play a key role in the intestine. The cells can help to build a protective barrier in the gut, and when a bacterial or fungal infection occurs, these cells may release signals that cause the body to produce more Th17 cells. But the cells have also been implicated in diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and IBD.

Duan, co-lead author Juan Matute, MD, Blumberg and colleagues used several mouse models to study the molecular events that lead to the development of Th17 cells. Surprisingly, they found that Th17 cells could proliferate even in germ-free mice or mice that had been giving antibiotics wiping out bacteria. The team found that endoplasmic reticulum stress in intestinal epithelial cells drove Th17 cell differentiation through purine metabolites, such as xanthine, even in mice that did not carry microbes and with genetic signatures that suggested cells with protective properties.

The authors note that their study was limited to cells in the intestine. It’s possible that crosstalk between cells in the gut and other organs, such as the skin and lung, may have an important influence on outcomes. They also note that their study does not identify what causes Th17 cells to become pathogenic, and that further exploration is needed, including studies that focus on human-IBD Th17 cells.

“While we don’t yet know what’s causing pathogenesis, the tools we have developed here may take us a step closer to understanding what causes disease and what could help resolve or prevent it,” said Blumberg.

Source: Brigham and Women’s Hospital

Categories : Cardiovascular Disease Diet and NutritionTags :

The Effectiveness of Salt Restriction in Primary Aldosteronism

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Results from a clinical trial published in the Journal of Internal Medicine reveal several health benefits of moderate salt restriction in patients on standard medical treatment for primary aldosteronism/ These included lowered blood pressure and reduced depressive symptoms. 

Primary aldosteronism – when adrenal glands produce excess aldosterone – is a common cause of secondary hypertension. The combination of aldosterone excess and high dietary salt intake leaves affected patients with a higher risk of cardiovascular disease than patients with hypertension from other causes. Mineralocorticoid antagonists are the main treatment of primary aldosteronism, but these medications do not completely normalise patients’ elevated cardiovascular risk.

Because elevated aldosterone and high dietary salt intake have detrimental effects on patients’ health, investigators wanted to find out whether salt restriction might benefit patients. In the non-randomised single-arm Salt CONNtrol trial that included 41 patients, moderate salt restriction reduced blood pressure and depressive symptoms without detectable adverse effects.

“The study shows that a moderate dietary salt restriction is feasible, when combined with a dedicated smartphone app for continuous motivation, and has a strong antihypertensive effect in patients with primary aldosteronism,” said corresponding author Christian Adolf, MD, of Ludwig Maximilian University of Munich, in Germany. “Our findings will help to improve care for patients with primary aldosteronism and, likely, also for subgroups of patients with essential hypertension.”

Source: Wiley

Categories : Obstetrics & GynaecologyTags :

Lower-dose Hormonal Contraceptives may be Possible, Study Suggests

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Photo: Reproductive Health Supplies Coalition on Unsplash

The dosage of hormones in common contraceptives could be reduced by as much as 92% and still effectively suppress ovulation, according to a computational model from University of the Philippines Diliman which is described in PLOS Computational Biology.

Constant dosage and nonconstant dosage comparison. The shaded regions in Panels (A), (C), and (E) indicate the minimum total constant dosage of exogenous estrogen and/or progesterone over 28 days that lowers maximum P4 concentration to 4.99 ng/mL. The shaded region below u1 (area under the curve or AUC) in Panel (B) is the total nonconstant dosage of exogenous E2 which suppresses the P4 level to 4.43 ng/mL, a reduction by about 92% of the total dosage in (A). Panel (D) illustrates the total nonconstant dosage of exogenous P4 that reduces maximum P4 to 4.66 ng/mL, a reduction by about 43% of the total dosage in (C). Panel (F) shows the combined nonconstant doses of exogenous E2 and P4 that gives a maximum P4 level of 4.31 ng/mL. Credit: Gavina et al., 2023, PLOS Computational Biology, CC-BY 4.0 (creativecommons.org/licenses/by/4.0/)

A normal menstrual cycle involves multiple phases which are regulated by the endocrine system and influenced by levels of various hormones. The most contraceptive approaches, including pills, injectables and implants, involve the administration of exogenous oestrogen and/or progesterone to block ovulation.

In the new study by Brenda Lyn A. Gavina, PhD student, and her collaborators, researchers used data on hormone levels in 23 women aged 20 to 34 with normal menstrual cycles.  The team developed computational models depicting the interactions between various hormone levels as well as the impacts of exogenous hormones.

The model provided evidence that it is possible to reduce the total dose by 92% in oestrogen-only contraceptives, or the total dose by 43% in progesterone-only contraceptives, and still prevent ovulation. By combining oestrogen and progesterone, the doses of each hormone could be reduced even further. In addition, the model showed the importance of timing the hormones during the cycle, pointing toward ways that exogenous oestrogen and progesterone could be given during only certain phases of the menstrual cycle rather than at steady constant doses.

“These results may give clinicians insights into optimal dosing formulations and schedule of therapy that can suppress ovulation,” the authors say.

Source: EurekAlert!

Categories : Cardiovascular Disease Emergency MedicineTags :

Better Survivor Outcomes One Year after Cardiac Arrest When Bystanders Perform Defibrillation

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Pexels Photo by Freestocksorg

Survivors of out-of-hospital cardiac arrest (OHCA) who received initial bystander defibrillation with a nearby automated external defibrillator (AED) reported better outcomes at 12 months after arrest compared with those initially defibrillated by paramedics, according to a new study from Monash University which appears in Heart.

The retrospective study recruited adult non-traumatic OHCA with initial shockable rhythms between 2010 and 2019. Survivors at 12 months after arrest were invited to participate in structured telephone interviews. Outcomes were identified using the Glasgow Outcome Scale-Extended (GOS-E), EuroQol-5 Dimension (EQ-5D), 12-Item Short Form Health Survey and living and work status-related questions.

Of 6050 patients, 3211 (53.1%) had a pulse on hospital arrival, while 1879 (31.1%) were discharged alive. Survival rates were highest with bystander defibrillation (52.8%), followed by dispatched first responders (36.7%) and paramedics (27.9%). Of the survivors, 1802 (29.8%) survived to 12-month post-arrest; of these 1520 (84.4%) were interviewed. 1088 (71.6%) were initially shocked by paramedics, 271 (17.8%) by first responders and 161 (10.6%) by bystanders. Bystander-shocked survivors reported higher rates of living at home without care (87.5%), upper good recovery (GOS-E=8) (41.7%) and EQ-5D visual analogue scale (VAS) ≥ 80 (64.9%) compared with first responder and paramedics, respectively. After adjustment, initial bystander defibrillation was associated with higher odds of EQ-5D VAS ≥ 80 (adjusted OR (AOR) 1.56), good functional recovery (GOS-E ≥ 7) (AOR 1.53), living at home without care (AOR 1.77) and returning to work (AOR 1.72) compared with paramedic defibrillation.