Light chain (AL) amyloidosis is a complex and rare disease characterized by low incidence and diverse clinical manifestations. At the time of diagnosis, most patients exhibit involvement of multiple organs or tissues, leading to severe illness and a poor prognosis. Therefore, early diagnosis, active treatment, and a comprehensive assessment of the disease hold paramount importance. The initial presentation of this rare condition often manifests as gastrointestinal symptoms, posing challenges in clinical identification and differential diagnosis. In this case report, we describe a 70-year-old man with AL amyloidosis, initially misdiagnosed as irritable bowel syndrome and colon polyps. Subsequently, he experienced a series of complications including renal function impairment, pulmonary nodule, pleural effusion, mediastinal lymph node enlargement, spleen enlargement, reduction of white blood cells, red blood cells and platelets, and small intestinal obstruction. Despite multiple pulmonary nodule biopsy and lymph node biopsy, as well as concurrent splenectomy and partial resection of the small intestine, a clear diagnosis remained elusive. Before admission, diarrhea was aggravated, accompanied by emaciation and fatigue. Following the completion of serum immunofixed protein electrophoresis, renal biopsy, bone marrow and rectal biopsy, a conclusive diagnosis of AL amyloidosis involving multiple organs (Mayo 2012 revision stage III) was finally confirmed after a 12-year period. Treatment with proteasome inhibitors, immunomodulators, and glucocorticoids was recommended. The patient underwent methylprednisolone treatment and was discharged after symptom improvement. However, eight months into the follow-up, the patient succumbed to multiple organ failure. The repeated misdiagnoses over the past 12 years were attributed to limited perspectives among some specialists who did not conduct a systematic and detailed medical history analysis or comprehensive physical examinations. Additionally, they did not strictly follow the principle of "monism" in diagnosis. On the contrary, early diagnosis and active treatment of the disease are of great significance to improve the prognosis.

Introduction: Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children.

Methods: Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment.

Results: These observations raise important debates on whether treating only a % of children with ASD is acceptable.

Discussion: It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.

Sleep problems are more common in people with autism spectrum disorder (ASD) as compared to the general population, and may contribute to worsening social functioning, emotional symptoms, and lower quality of life. To support healthcare professionals and researchers in the field, we provide an updated overview of sleep problems in the context of autism across the lifespan and their evidence-based management, as derived from evidence-synthesis studies and the most recent randomized controlled trials. Most studies to date have been conducted in children and adolescents with autism. Several studies suggest that behavioral interventions aiming at improving sleep hygiene and environment may be beneficial, especially when actively involving parents. Furthermore, there is an increasing body of literature showing that melatonin is an effective pharmacological option for improving sleep quality in children and adolescents with autism, in line with reports showing a reduced endogenous synthesis of this hormone. Unfortunately, studies in adults are more limited, and thus, the evidence base around non-pharmacological and pharmacological interventions remains mixed. Finally, there is a growing interest towards the use of complementary interventions or food supplements, but further studies are needed to test their effectiveness. In sum, most studies to date support the use of behavioral interventions and melatonin, especially in children and adolescents with autism. However, findings need to be validated in large-scale, rigorous and blinded trials and extended to the adult population. Non-pharmacological interventions remain the first treatment option and should adopt an individualized approach, considering individual characteristics and needs, including comorbidities, family dynamics, and sleep environment.

Despite recent advances, there is still much to be learned about the pathogenesis of Fabry disease. The categorization of GLA gene missense mutations has been complicated by the fact that some missense variants may fall into more than one category. For instance, the A143T variant may cause late-onset Fabry disease in some subjects and not result in Fabry disease in others (pseudo-deficient). Efforts to mitigate the pathobiology of α-galactosidase A deficiency should differentiate between damaging (maladaptive) consequences and compensatory (adaptive) changes. Current therapy leaves a significant unmet need, especially concerning cardiovascular complications and cardiological clinical outcomes. Non-Fabry-specific therapy is necessary and quite beneficial and must be utilized. Its contribution should be considered when trying to assess the net effect of Fabry-specific therapy. Enzyme replacement therapy (ERT) can be administered to patients independently of their GLA genotype, as it slows the decline of kidney function in most patients if initiated sufficiently early in the disease course. Migalastat has better tissue penetration than ERT, but its usefulness is restricted to patients with amenable missense GLA variants. However, it is important to realize that in a substantial proportion of common amenable mutations, migalastat increases α-galactosidase A activity level beyond the disease threshold and thus eliminates the metabolic disturbance that is at the center of Fabry disease. Substrate reduction therapy and gene therapy approaches are being developed, but these therapeutic modalities have their own limitations and difficulties.

One of the main challenges in rare diseases is the unavailability of reliable estimates of prevalence and incidence. The lack of epidemiological data makes planning for therapeutic and management options challenging. Methods for estimating the prevalence and incidence of rare and genetic diseases primarily rely on the availability of accurate national patient registries or databases of birth defects. This gap is wider in Low- and Middle-Income countries (LMICs) such as India, where currently, the estimates of prevalence and incidence are either unknown or data from developed countries have to be used as a proxy. Here, we analyzed the current methods used to estimate the prevalence and incidence of rare genetic diseases to provide recommendations in the form of a decision tree to select the most feasible method, particularly in resource-constrained environments such as India. We selected ten rare diseases of shared importance to the Indo US Organization for Rare Diseases (IndoUSrare) and its Patients Alliance members for analysis. Our analysis suggests that retrospective study designs are the most commonly used method to estimate the prevalence and incidence of rare diseases. We propose a generalized decision tree or flowchart to aid epidemiology researchers during the selection of methods for estimating the prevalence and incidence of a rare or genetic disease.

The importance of establishing programs to address the challenges of patients living with rare diseases has been recognized internationally, yet many countries, especially in low- and middle-income regions, are lagging in the recognition of the challenges and needs of patients and families. To improve this situation, the Enfermedades Raras en el Caribe y America Latina (ERCAL) initiative was established in 2020 with the vision of bringing together patients, patient representatives, organizations, researchers, clinicians, regulators, and all interested stakeholders in the rare diseases ecosystem under a common collaborative platform to sum efforts to improve the lives of patients and families living with rare diseases in the Latin American and the Caribbean region. Over the last three years, we have been working consistently to establish an agenda of priorities and objectives to guide the work of the initiative and address the major challenges faced by the rare disease community in the region.

Worldwide, comprehensive newborn screening (NBS) now includes a clinical examination at birth, hearing screening, pulse oximetry measurement for congenital heart defects, and biochemical screening to identify congenital disorders early in life, preventing irreversible damage, early mortality and enhancing overall health outcomes. This article provides a comprehensive overview of biochemical NBS in South Africa, outlining the history, current status, and future plans for NBS expansion. In South Africa, NBS is fragmented, with some investigations included in neonatal health assessments. Historically, biochemical NBS pilot projects in the country in the 1960s and 1980s focused on phenylketonuria and congenital hypothyroidism (CH). Despite showing initial promise, these programmes were discontinued, largely due to competing health priorities. The current status of biochemical NBS in South Africa is discussed, both for the state and private healthcare sectors, which collectively screen approximately 0.5% of births annually. While recent clinical guidelines provide for a national biochemical NBS programme, implementation has been limited, and guideline adherence remains a challenge. A brief report of a two-day meeting held in Cape Town in February 2023 focusing on biochemical NBS for South Africa is provided. The meeting addressed the importance of NBS, technology requirements, and the need for a comprehensive demonstration project for biochemical CH NBS. Key challenges identified included early newborn post-delivery discharge, technical, logistical, and infrastructure issues, as well as limited financial and human resources. Meeting recommendations included the establishment of a National Advisory Panel for Biochemical NBS, and the development and implementation of a demonstration project for CH biochemical NBS in two provinces.

The Asia-Pacific (APAC) region, home to 60% of the global population, has the highest number of Persons Living with a rare disease (PLWRD). To promote more equitable societies, the Asia Pacific rare disease Organization (APARDO), established in 2015, has been developing its regional position to promote collaboration, increase awareness among stakeholders, explore equitable and affordable diagnosis and treatment, and improve health outcomes and quality of life for all PLWRD. The APAC region’s heterogeneous population and complex healthcare environment pose distinctive challenges in addressing rare diseases. Through conferences, webinars, and contributions to global initiatives, APARDO is fostering connectivity and providing a platform as a part of the global rare disease (RD) community to address shared challenges. The development of APARDO to strengthen its global presence as the representative of the APAC RD region is vital for a more equitable world.