New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases.

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.

The implementation of an enhanced clinical model to improve the diagnostic yield of exome sequencing for patients with a rare genetic disease: A Canadian experience.

The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%-57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.

Multidisciplinary and multidimensional approaches to transplantation in children with rare genetic kidney diseases.

In this review, we describe the multidisciplinary, multidimensional care required to optimize outcomes for pediatric transplant recipients with rare genetic kidney diseases. Transplant success, recipient survival, and improvement in quality of life depend on collaboration between patients, families, and a team of specialists with medical, as well as nonmedical expertise. A multidisciplinary transplant team composed of experts from medicine, surgery, nursing, nutrition, social services, transplant coordination, psychology, and pharmacology, is now standard in most transplant centers and is critical to the success of a transplant. In addition to these professionals, other specialists, such as cardiologists, urologists, geneticists, metabolic disease specialists, occupational therapists, case management, child life, chaplain, and palliative care services, have a crucial role to play in the preparation, surgery, and follow-up care, especially when a pediatric patient has a rare genetic disorder leading to renal involvement, and the need for transplantation. In order to describe this multidisciplinary care, we divide the genetic renal diseases into five subgroups-metabolic and tubular disorders, glomerular diseases, congenital anomalies of the kidney and urinary tract, ciliopathies including cystic diseases, and miscellaneous renal conditions; and describe for each, the need for care beyond that provided by the standard transplant team members.

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.

TRIM E3 Ubiquitin Ligases in Rare Genetic Disorders.

The TRIM family comprises proteins characterized by the presence of the tripartite motif composed of a RING domain, one or two B-box domains and a coiled-coil region. The TRIM shared domain structure underscores a common biochemical function as E3 ligase within the ubiquitination cascade. The TRIM proteins represent one of the largest E3 ligase families counting in human more than 70 members. These proteins are implicated in a plethora of cellular processes such as apoptosis, cell cycle regulation, muscular physiology, and innate immune response. Consistently, their alteration results in several pathological conditions emphasizing their medical relevance. Here, the genetic and pathogenetic mechanisms of rare disorders directly caused by mutations in TRIM genes will be reviewed. These diseases fall into different pathological areas, from malformation birth defects due to developmental abnormalities, to neurological disorders and progressive teenage neuromuscular disorders. In many instances, TRIM E3 ligases act on several substrates thus exerting pleiotropic activities: the need of unraveling disease-specific TRIM pathways for a precise targeting therapy avoiding dramatic side effects will be discussed.

Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity.

Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy. In this study we show that the major components of pharmaceutical gentamicin lack PTC readthrough activity but the minor component gentamicin B1 (B1) is a potent readthrough inducer. Molecular dynamics simulations reveal the importance of ring I of B1 in establishing a ribosome configuration that permits pairing of a near-cognate complex at a PTC. B1 induced readthrough at all three nonsense codons in cultured cancer cells with TP53 (tumor protein p53) mutations, in cells from patients with nonsense mutations in the TPP1 (tripeptidyl peptidase 1), DMD (dystrophin), SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), and COL7A1 (collagen type VII alpha 1 chain) genes, and in an in vivo tumor xenograft model. The B1 content of pharmaceutical gentamicin is highly variable and major gentamicins suppress the PTC readthrough activity of B1. Purified B1 provides a consistent and effective source of PTC readthrough activity to study the potential of nonsense suppression for treatment of rare genetic disorders.

The role of multidisciplinary diagnostic and therapeutic model of care in Lamb-Shaffer syndrome - case report.

This case study illustrates a multidisciplinary diagnostic and therapeutic model of care for a 7-year-old male with Lamb-Shaffer syndrome (LAMSHF). LAMSHF is an ultra-rare genetic neurodevelopmental disorder, caused by heterozygous alterations in the SOX5 gene. An integrative model of therapy of cognitive functions and speech is described. The presented approach allows the development of language competences through stimulation of basic cognitive functions, which allows the learning of the abstract rules of an inflected language. A surprising, unexpected improvement in the cognitive functioning of the child was observed (both in terms of reasoning and speech), as well as an increase in his independence. The clinically important problem of the need for continued stimulation of cognitive development, in spite of the unfavourable prognosis associated with LAMSHF, is highlighted.

Epidural Block in a Patient With Melkersson-Rosenthal Syndrome: A Case Report.

This case report describes the first known application of an epidural block for labor analgesia in a patient with Melkersson-Rosenthal syndrome (MRS), a rare disorder that may present sudden and threatening airway complications. A tailored epidural protocol effectively mitigated symptom exacerbation, facilitating a complication-free vaginal delivery. This report not only enriches the sparse literature on anesthesia in patients with MRS but also provides a crucial review of perioperative considerations for administering either general or regional anesthesia in similar cases.

A Cross-Sectional Study of Quality of Life in Patients Enrolled in the Romanian Hereditary Angioedema Registry.

BACKGROUND: Hereditary angioedema (HAE) is a rare potentially life-threatening genetic disorder characterized by recurrent episodes of angioedema without wheals that can affect any part of the body. The unpredictability of the attacks and the risk of passing the disease to the offspring result in significant physical and emotional burdens for patients, with a negative impact on quality of life. Data about the health-related quality of life in HAE patients from Romania are scarce. This study aimed to evaluate the disease-specific quality of life in patients with HAE from Romania and to determine associated factors. METHODS: The study included adult patients with HAE enrolled in the Romanian HAE Registry. Disease-specific quality of life was measured using the Hereditary Angioedema Quality of Life questionnaire, a cross-culturally adapted, internationally validated structured survey. RESULTS: The survey was completed by 94 patients (64.9% females; 35.1% males). The mean age of the participants was 44.9 years (SD 14.1). Most patients (88.3%) had type I HAE and were from urban areas (63.8%). The mean ages at symptom onset and diagnosis were 15.1 (SD 11.1) and 36.1 (SD 14.1) years, respectively. The mean diagnosis delay was 20.5 years (SD 14.2). In the evaluated period, all patients had at least one vial of on-demand treatment at home, and 10 were on long-term prophylaxis treatment. The general and dimensional quality of life scores were slightly above the median values of the reference scales. While the general score was not associated with sex or residence, a statistically significant, negative, weak correlation was detected with diagnostic delay. CONCLUSION: The results suggest that despite the availability of on-demand treatment for all patients, there is a need for other diagnostic and therapeutic interventions to improve the management of the disease and the quality of life for HAE patients from Romania.

Pyloric Stenosis in a Patient with CEDNIK Syndrome.

We present a rare neurocutaneous genetic disorder where patients develop a combination of cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma, commonly known as CEDNIK syndrome. It is an autosomal recessive inheritance involving the SNAP29 protein, mapped to the 22q11.2 gene. Phenotypic variation is seen with this disease, with clinical manifestation of developmental milestone delays ranging in severity. With only a handful of documented cases, available research, management of the syndrome, and prognosis are not well established. As CEDNIK syndrome has systemic implications, care coordination between specialists is essential in improving patient outcomes. Particularly important is preventing patients from meeting the criteria of failure to thrive, a commonly reported issue. In this case, we present a four-month-old male with a past medical history of pyloric stenosis status/post pyloromyotomy who has failure to thrive, gastroesophageal reflux disease, profound hypotonia, and delayed progression of developmental milestones. Additionally, the case is complicated by idiopathic pyloric stenosis, further contributing to the patient's failure to thrive. We aim to discuss the pathophysiology of this syndrome, explore the timeline of disease progression, as well as compare our case to the current literature.

An Unusual Presentation of Succinic Semialdehyde Dehydrogenase Deficiency: A Fatal Case of Severe Progressive Seizures in a Four-Month-Old Infant.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare genetic condition with approximately 450 patients reported worldwide, inherited in an autosomal recessive manner affecting gamma-aminobutyric acid (GABA) metabolism, characterized by varied clinical features. We report a fetal case of a four-month-old female infant presenting with severe, progressive seizures leading to fatality. Despite aggressive medical interventions, including multiple antiepileptic medications and a ketogenic diet, the patient's condition deteriorated rapidly. Genetic testing revealed a homozygous mutation in the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene. This present case emphasizes the difficulties in controlling SSADH deficiency and emphasizes the necessity for additional studies on successful therapy approaches.

Estimating prevalence of rare genetic disease diagnoses using electronic health records in a children's hospital.

Rare genetic diseases (RGDs) affect a significant number of individuals, particularly in pediatric populations. This study investigates the efficacy of identifying RGD diagnoses through electronic health records (EHRs) and natural language processing (NLP) tools, and analyzes the prevalence of identified RGDs for potential underdiagnosis at Cincinnati Children's Hospital Medical Center (CCHMC). EHR data from 659,139 pediatric patients at CCHMC were utilized. Diagnoses corresponding to RGDs in Orphanet were identified using rule-based and machine learning-based NLP methods. Manual evaluation assessed the precision of the NLP strategies, with 100 diagnosis descriptions reviewed for each method. The rule-based method achieved a precision of 97.5% (95% CI: 91.5%, 99.4%), while the machine-learning-based method had a precision of 73.5% (95% CI: 63.6%, 81.6%). A manual chart review of 70 randomly selected patients with RGD diagnoses confirmed the diagnoses in 90.3% (95% CI: 82.0%, 95.2%) of cases. A total of 37,326 pediatric patients were identified with 977 RGD diagnoses based on the rule-based method, resulting in a prevalence of 5.66% in this population. While a majority of the disorders showed a higher prevalence at CCHMC compared with Orphanet, some diseases, such as 1p36 deletion syndrome, indicated potential underdiagnosis. Analyses further uncovered disparities in RGD prevalence and age of diagnosis across gender and racial groups. This study demonstrates the utility of employing EHR data with NLP tools to systematically investigate RGD diagnoses in large cohorts. The identified disparities underscore the need for enhanced approaches to guarantee timely and accurate diagnosis and management of pediatric RGDs.

Familial Deep Vein Thrombosis in a Child With Antithrombin III Deficiency: A Case Report.

Deep vein thrombosis (DVT) is caused by a clot (thrombus) formed in the deep veins, usually the legs. The incidence of DVT is notably less prevalent in children than in adults. Here, we present a rare case of DVT in an eight-year-old female child with a significant family history involving the untimely death of the maternal aunt. The child presented with pain and edema in the left lower limb causing immobilization without any obvious cause. The clinical features suggested the possibility of DVT. On further evaluation and radiological investigations, the diagnosis of DVT was confirmed. A complete thrombophilia workup was done showing antithrombin (AT) III deficiency. The patient was then started on low-molecular-weight heparin, leading to improvement in the symptoms. Oral rivaroxaban was continued for the patient on discharge.

i-Dent: A virtual assistant to diagnose rare genetic dental diseases.

Rare genetic diseases are difficult to diagnose and this translates in patient's diagnostic odyssey! This is particularly true for more than 900 rare diseases including orodental developmental anomalies such as missing teeth. However, if left untreated, their symptoms can become significant and disabling for the patient. Early detection and rapid management are therefore essential in this context. The i-Dent project aims to supply a pre-diagnostic tool to detect rare diseases with tooth agenesis of varying severity and pattern. To identify missing teeth, image segmentation models (Mask R-CNN, U-Net) have been trained for the automatic detection of teeth on patients' panoramic dental X-rays. Teeth segmentation enables the identification of teeth which are present or missing within the mouth. Furthermore, a dental age assessment is conducted to verify whether the absence of teeth is an anomaly or a characteristic of the patient's age. Due to the small size of our dataset, we developed a new dental age assessment technique based on the tooth eruption rate. Information about missing teeth is then used by a final algorithm based on the agenesis probabilities to propose a pre-diagnosis of a rare disease. The results obtained in detecting three types of genes (PAX9, WNT10A and EDA) by our system are very promising, providing a pre-diagnosis with an average accuracy of 72 %.

A 29-Year-Old Patient With Patau Syndrome: A Case Report on Medical Management.

Patau syndrome (trisomy 13) is a chromosomal abnormality with multiple malformations due to an additional copy of chromosome 13. This genetic condition has a systemic impact on the development of the human body, which can result in, but is not limited to, microphthalmia, microcephaly, low-set ears, cleft palate, cardiac abnormalities, and abdominal wall defects. It is associated with severe physical and intellectual disabilities and a limited lifespan. Here, we present a 29-year-old female with a high suspicion of the mosaic form of Patau syndrome. She decided to opt for an elective robotic-assisted vaginal hysterectomy (RAVH) due to worsening menorrhagia and recurrent miscarriages. In addition, the importance of medical interventions from surgery to anesthesia is discussed, with their role in improving the quality of life of the patient.

Practical Tips on Epidermolysis Bullosa for Caregivers: Part 2.

The heritable condition epidermolysis bullosa (EB) is a rare but potentially devastating and life-threatening condition that is characterized primarily by cutaneous fragility, manifested when the dermis and epidermis fail to adhere properly. EB has no cure, and because of its rarity, few healthcare professionals have experience in treating it. Most families with an EB child are forced to rely on family caregiving which can be disruptive to family routines but, more importantly, place enormous time and emotional and financial burdens on the family. EB can be extremely painful, and families are often caught in the bind of trying to manage overwhelming financial burdens in an effort to help their children cope with excruciating pain. For many years, the nonprofit organization NoBabyBlisters.org has worked on five continents with families caring for EB children. Many of these families reside in under-developed nations with hot climates and limited healthcare resources. Over time, the healthcare professionals with NoBabyBlisters.org have worked with EB families both internationally and in the United States to develop a series of simple tips or "hacks" that may provide relief or great benefit to these children. The objective of this article is to share these field-tested tips with a wider audience. This is not a scientific study or a systematic review and is offered as a companion article to an earlier article on the same subject.

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study.

BACKGROUND: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. RESULTS: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. CONCLUSIONS: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.

Uncommonly Missed Diagnosis of Methylmalonic Acidemia (MMA) in Adults and Usefulness of Testing for MMA in Cases of Seizures/Neuropathy/Weakness/Ataxia.

Methylmalonic acidemia (MMA) is a genetic condition affecting cobalamin metabolism causing elevated serum and urine methylmalonic acid without B12 deficiency. MMA presents with ketoacidotic hyperammonemic coma in newborns and can result in neonatal death or severe neurological disability. Rarely, this diagnosis is missed, or patients do not present until later in life. Presentation of this life-threatening condition is variable in adults. Improvement is rapid with IV cobalamin and a specialized diet. This case is intended to increase clinician's awareness of the late presentation of this disease and the importance of high clinical suspicion and prompt diagnosis. We present a case of a 32-year-old man with seizures, polyneuropathy, ataxia, and memory loss which were unexplained until diagnosis with MMA. We aim to help clinicians understand the variable presentation and diagnostic work-up of MMA to prevent catastrophic missed diagnoses. After an extensive work-up, the patient was found to have methylmalonic acidemia and was promptly treated with high dose vitamin B12 and a specialized diet with low protein including restricted isoleucine, threonine, methionine, and valines as well as a high caloric content. The patient showed significant clinical improvement with this treatment. To our knowledge, this is the first case of MMA presenting with these symptoms in a medically stable adult. The patient was adopted from abroad and therefore, lacked access to normal newborn screenings, further complicating diagnosis. We aim to demonstrate to clinicians the importance of considering this diagnosis in patients in whom symptoms may be suggestive, particularly if they lack access to genetic or metabolic screening.

Clinical Disease States Related to Mutations of the NOD2 Gene: A Case Report and Literature Review.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a protein encoded by the NOD2 gene and plays an important role in the immune system. NOD2 is an intracellular pattern recognition receptor (PRR) responsible for the recognition of pathogens as well as the activation of many biochemical processes within cells of the host immune system. Mutations of the NOD2 gene can significantly impact the host's immune response against a variety of pathogens. In addition to immunodeficiency, mutations of the NOD2 gene have also been linked with several atopic diseases and autoimmune conditions such as rheumatoid arthritis and Crohn's disease (CD). There is also a distinct set of autoinflammatory conditions that are now classified as NOD2-associated autoinflammatory diseases (NAID). We present a case of a 63-year-old female with common variable immunodeficiency, eosinophilic asthma, and rheumatoid arthritis who was found to have a NOD2 mutation on genetic testing. As genetic testing continues to gain popularity, several disease states that were previously thought to be unrelated are now being recognized as originating from a common genetic defect.