Rare Disease Research Articles

Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation

Background. The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry. Data on the prevalence of СEB in Russian Federation is scattered, while data on life expectancy and mortality for this this disease is absent. This article presents medical and epidemiological data on children with СEB in Russian Federation. Objective. The aim of the study is to analyze clinical and epidemiological features of children with СEB in Russian Federation. Methods. We have performed analysis of the clinical and epidemiological features among pediatric population of Russian Federation with СEB using the “Registers of Genetic and Other Rare Diseases” of the “Butterfly Children” charitable foundation. Results. There are 491 children with СEB in Russian Federation as of 2024 according to the national registry data from “Registers of Genetic and Other Rare Diseases” of the “Butterfly Children” charitable foundation. The ratio of boys and girls was 1.08:1, that is relevant to the global data. The prevalence of CEB in children aged from 0 to 17 years in Russian Federation is 15.48 cases per 1,000,000 children as of January 1, 2024. The highest number of children with CEB were revealed in the Republic of Dagestan — 54 (11%) children, which is apparently due to the high rate of consanguineous marriages (50%). Other regions with high prevalence are Moscow Region (n = 28, 5.7%), Moscow (n = 25, 5.1%), Saint Petersburg (n = 26, 5.2%) and Krasnodar Territory (n = 23, 4.6%). Largest age group of children (from 12 to 18 years) includes 146 patients with mean age of 14.32 ± 1.72 years. The most common form of CEB is dystrophic one — 261 patients, the next one is simplex — 191 patients, then junctional form — 31 patient, and Kindler syndrome — 8 patients. The birth rate of children with CEB by year during the period from 2019 to 2023 (per 100,000 children born): 2019 — 1.42, 2020 — 2.09, 2021 — 2.65, 2022 — 2.76 and 2023 — 1.74. The arithmetic mean birth rate of children with CEB over a five-year period was 2.13 cases per 100,000 children born. The registry contains information on 22 deceased patients, average age was 3.06 ± 4.66 (from 0 to 15 years, median 0.54 years). The highest number of fatal outcomes was observed in the Republic of Dagestan (n = 3). Junctional CBE dominates in fatal outcomes among all the CEB types — 59.1% (n = 13 cases, 0.40 ± 0.22 years). The highest mortality was observed in I age group (from 0 to 1 year), which is 65.2% (15 fatal outcomes). Multisystem organ failure resulting from sepsis was the most common cause of death in both types of CEB (junctional and dystrophic). The mortality trend in the junctional form of CEB shows a decline in mortality, while the dystrophic type shows a stable situation during 2021–2023 years — 2 fatal outcomes per year. Junctional CEB has higher mortality rate at early age: survival curve shows sharp decline in the first months of life indicating high mortality in early life. The probability of survival drops to almost 0% in the first 100 days. Higher survival rate is more specific for the dystrophic type of CEB. Conclusion. This study demonstrates the significance and necessity to create and maintain registers for rare (orphan) diseases. Registry maintenance is an effective model for real understanding of the number of patients and value of needed assistance from the government to this category of patients.

Endothelial cell-specific progerin expression does not cause cardiovascular alterations and premature death.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene that provokes the synthesis of progerin, a mutant version of the nuclear protein lamin A that accelerates aging and precipitates death. The most clinically relevant feature of HGPS is the development of cardiac anomalies and severe vascular alterations, including massive loss of vascular smooth muscle cells, increased fibrosis, and generalized atherosclerosis. However, it is unclear if progerin expression in endothelial cells (ECs) causes the cardiovascular manifestations of HGPS. To tackle this question, we generated atherosclerosis-free mice (LmnaLCS/LCSCdh5-CreERT2) and atheroprone mice (Apoe-/-LmnaLCS/LCSCdh5-CreERT2) with EC-specific progerin expression. Like progerin-free controls, LmnaLCS/LCSCdh5-CreERT2 mice did not develop heart fibrosis or cardiac electrical and functional alterations, and had normal vascular structure, body weight, and lifespan. Similarly, atheroprone Apoe-/-LmnaLCS/LCSCdh5-CreERT2 mice showed no alteration in body weight or lifespan versus Apoe-/-LmnaLCS/LCS controls and did not develop vascular alterations or aggravated atherosclerosis. Our results indicate that progerin expression in ECs is not sufficient to cause the cardiovascular phenotype and premature death associated with progeria.

The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases.

Na<sup>+</sup>/K<sup>+</sup> Ratio in Blood Serum as a Criterion of Human Functional State

The article discusses the physiological significance of the Na+/K+ ratio in blood serum as a criterion of a person’s functional state. Normally, in an adult, the ratio is 32.2 ± 0.5, it increases in a healthy person under the influence of extreme factors (space flight (cosmonauts, astronauts), long-term strict bedrest, etc.), with Covid-19 disease, and some orphan diseases in children. The issue of Na+/K+ in blood serum is being discussed, but not between the K+-rich cell and the Na+-dominated extracellular environment. The Na+/K+ ratio in blood serum is considered as an important parameter of a person’s physiological state and, depending on the numerical value, as an indicator of the functional state from normal to overload, severe complications to the prognosis of death.

Elevated incidence of infant botulism in a 17-county area of the Mid-Atlantic region in the United States, 2000-2019, including association with soil types.

Infant botulism occurs more frequently in 17 counties within and adjacent to the Delaware and Raritan River watersheds. This study should alert physicians and pediatricians in the area to the higher likelihood of encountering cases of this otherwise rare disease that manifests with constipation, poor feeding, loss of head control, weak suck/cry, generalized weakness, and descending bilateral paralysis.

The first case of primary malignant melanoma of the esophagus to achieve pathologic complete response after preoperative ipilimumab + nivolumab followed by resection.

Primary malignant melanoma of the esophagus is a rare disease with a poor prognosis. Surgical resection is common, but there is no consensus on perioperative treatment. Studies have reported the efficacy of programmed cell death-1 inhibitors (e.g., nivolumab, pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 agents (e.g., ipilimumab) in treating malignant melanoma. Here, we present the first case of primary malignant melanoma of the esophagus with lymph node metastases treated with nivolumab and ipilimumab followed by resection, achieving a pathologic complete response. A 75-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a black, elevated lesion in the mid-thoracic esophagus. Biopsy confirmed primary malignant melanoma of the esophagus, showing tumor cells with melanin deposition, positive for HBM45 and S-100 staining. Computed tomography showed enlarged lymph nodes in the subclavian and mediastinum regions, suggesting metastases. After two courses of preoperative chemotherapy with ipilimumab and nivolumab, which significantly shrank the tumor, the patient underwent robot-assisted subtotal esophagectomy and 3-field lymph node dissection. Histopathological examination revealed no tumors or lymph node metastases, confirming a pathologic complete response. Given the rarity and poor prognosis of primary malignant melanoma of the esophagus, this case provides valuable insights for treatment strategies.

Blueberry Muffin Baby Syndrome in a Patient with Congenital Leukemia: Clinical Case

Background. Blueberry muffin baby syndrome in newborns is characterized by diffuse nodular skin lesions and it is difficult for diagnosis due to diverse etiology. Etiological factors include congenital infections, intrauterine hemolytic disease, multifocal vascular abnormalities, and neoplastic conditions. Congenital neonatal leukemia is rare disease and it is usually revealed during the first month of life. Clinical case description. This clinical case presents a patient with congenital acute myeloid leukemia and severe skin manifestations. Treatment has included risk-adapted chemotherapy with subsequent allogeneic hematopoietic stem cell transplantation from a haploidentical donor (father). Conclusion. The significance of multidisciplinary approach in management of patients with congenital leukemias consist of timely determination of the disease variant, prognostic risk group, and initiation of programmed treatment.

Elucidating the roles of SOD3 correlated genes and reactive oxygen species in rare human diseases using a bioinformatic-ontology approach.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

Proteus Syndrome: Description of Two Clinical Cases

Background. Proteus syndrome is extremely rare congenital multisystem disease with high variability in clinical manifestations. Its prevalence is unknown, there are less than 200 cases in the world literature. The syndrome is a classic example of somatic mosaicism, and all target drugs for its management are based on it. Clinical case description. This article describes two clinical cases with somatic variants of the nucleotide sequence in the AKT1 gene, mosaic form, revealed by the NGS method. Target drug (mTOR-inhibitors group) was assigned in one case. Conclusion. The description of the phenotypic features of patients with Proteus syndrome is crucial as this pathology is very rare. It is necessary to increase the awareness of clinicians about this disease to develop a plan for dynamic follow-up with consideration to life-threatening complications (malignant tumors and thrombembolia risk). Genetic verification of Proteus syndrome is mandatory nowadays as target therapy is actively developed and implemented, thus, revision of clinical guidelines is recommended.

EBSTEINS ANOMALY: A RARE CARDIAC DISORDER UNVEILED BY SUDDEN ARRHYTHMIA IN A PREVIOUSLY STABLE ADULT

Ebsteins anomaly (EA) is a rare congenital heart disease which occurs in approximately 1 in 200,000 live births and represents less than 1% of all cases of congenital heart disease(1). AE is a rare cardiopathy of the right ventricle that originates in an embryological peculiarity of the tricuspid valve responsible for over-apical implantation of the septal leaflet of the tricuspid valve (2). We report the case of a 47-year-old patient with asymptomatic EA, admitted with junctional tachycardiaat 200bpm and haemodynamic instability. Due to this instability, we administred a synchronous external electric shock at 150 joules after sedation. The patient immediately recovered regular sinus rhythm and achieved haemodynamic stability. Echocardiographic evaluation supported the of EA, showing apical displacement of the tricuspid valve and a mitro-tricuspid mismatch of 11.6 mm/m2, The septal leaflet exhibited reduced mobility, attached to the interventricular septum, and the right atrium was dilated due to right ventricular atrialization. The clinical presentation of EA varies from neonatal respiratory distress to right heart failure and rhythm disorders in adolescents and adults. Some cases exhibit exceptionally long survival. Management of EA depends on its anatomical form and clinical presentation (3). Patients with minor tricuspid valve displacement are often asymptomatic and do not require specific treatment, Surgery is indicated when the patient is symptomatic or when arrhythmias or echocardiographic changesare detected (4).This clinical presentation highlights the rarity of such cases in our practice.

Management Strategy for Patients With Idiopathic Recurrent Pericarditis. Position Statement of the Experts of the Russian Society оf Cardiology and Eurasian Association of Therapists

Pericarditis as an inflammatory heart disease is rarely discussed in the cardiology community. The latest European guidelines on pericarditis were published in 2015, and Russian clinical guidelines are dated 2022. However, in recent years, a number of publications have appeared that have forced the scientific community to take a fresh look at this problem. This is mainly due to a change in the paradigm of the treatment of idiopathic recurrent pericarditis (IRP) registered in the Russian Federation as a rare (orphan) disease. According to most experts, IRP is an underestimated cardiac disease, which, due to the lack of specific symptoms and the physicians' alertness regarding the IRP diagnostics, is rarely the subject of scientific discussions. The issues of diagnosis and therapy of IRP in light of the latest reports became the matter under discussion for a group of leading Russian experts chaired by Corresponding Member of the Russian Academy of Sciences, Professor G.P. Arutyunov.

A case of resistant granuloma faciale successfully treated with ablative fractional carbon dioxide laser

ABSTRACT Granuloma faciale is a benign and rare skin disease, which usually presents as well-defined red-purple asymptomatic plaques or nodules on the face but can also present extra-facially. It poses a significant therapeutic challenge, with varying degrees of success reported by a range of medical and surgical treatments. We describe a 41-year-old lady with biopsy-confirmed facial granuloma faciale, affecting her nose, cheeks, upper lip, and forehead, who had failed a variety of medical treatments, UVB phototherapy, and pulsed dye laser. She was successfully treated with ablative fractional CO2 laser, with a sustained response, without recurrence or complications maintained for 1 year.

Hirayama Disease in a Young Male: A Case Report

Hirayama disease is a rare benign neurological disease that affects the anterior horn of the spinal cord at C5 to T1, mainly at C7 and C8 due to imbalance growth between the vertebral column and the dura mater leading to microcirculatory disturbances in the anterior portion of the spinal cord due to overstretched cord, especially during flexion of the neck causing unilateral or rarely asymmetrically bilateral upper limb weakness and muscle wasting.It is a case of a 21-year-old boy presented with weaknesses in his left hand and forearm for 2 years which aggravates during cold weather and flexion of the neck. A plain x-ray of the neck and MRI of the cervical spine were conducted which show the features of Hirayama disease.

CASE REPORT: AUTOIMMUNE HEPATITIS IN A 29-YEAR-OLD FEMALE WITH RECURRENT PREGNANCY LOSS

Autoimmune hepatitis (AIH) is a rare chronic liver disease characterized by a wide spectrum of symptoms ranging from asymptomatic to jaundice, which can be confusing in diagnosis because of their non-specificity and the presence of laboratory changes. This case report presents a 29-year-old woman with AIH and past history of repetitive pregnancy losses. She has been diagnosed with various problems such as two rounds of failed in vitro fertilization, five miscarriages and secondary amenorrhea. A liver biopsy proved AIH, and appropriate prednisolone and azathioprine therapy resulted in a positive change in her liver status. Early diagnosis and right management of AIHresulted in significant clinicalimprovement and normalization of liver function tests.

Case report of the successful treatment of a rare complication of pulmonary vein stenting: atrial rupture and stent detachment

Pulmonary vein stenosis (PVS) is a relatively rare pulmonary vascular disease in clinical practice, and radiofrequency ablation (RFA) is a common cause of pulmonary vein stenosis. Owing to its nonspecific symptoms and irregular follow-up, PVS is often misdiagnosed. In severe cases, intervention is needed, with the main treatment options being pulmonary vein stenting and/or balloon dilation, both of which carry risks of serious complications. We report a patient with severe pulmonary vein stenosis who experienced right atrial wall rupture and stent detachment during an interventional procedure. Through active intraoperative intervention, we successfully avoided serious complications.

C3 glomerulonephritis with genetically confirmed C3 deficiency in a pediatric patient: a case report

Complement component 3 glomerulonephritis (C3GN) is a rare kidney disease characterized by complement dysregulation that results in prominent complement component 3 (C3) deposition in the kidneys. The clinical course of C3GN varies from mild hematuria to progressive chronic kidney disease. In most patients, C3GN is driven by acquired factors, namely, autoantibodies that target C3 or C5 convertases. Genetic variations in complement-related genes are less frequent. We report the case of a 9-yearold Korean boy who presented with microscopic hematuria and a persistently low C3 level and had biopsy findings of C3GN, with the presence of a C3 gene mutation: a frameshift mutation associated with C3 deficiency. However, the patient did not exhibit any other symptoms of complement deficiency. Direct DNA sequencing of his family members revealed the same genetic mutation in his father and older brother. This case report is significant because there are very few such reports worldwide concerning gene mutations related to C3 deficiency to be discovered in patients with C3GN. Explaining C3GN pathogenesis is challenging; therefore, additional research is required in the future.

The Role of Newborn Pulse Oximetry Screening for Detecting Critical Congenital Heart Defects: A Narrative Review.

Critical congenital heart diseases are life-threatening, with a high morbidity rate and mortality among newborns; in fact, a newborn discharged from the hospital with undiagnosed heart disease may experience severe complications during the initial days or weeks of their life, necessitating emergency care and even death. Among all kinds of critical congenital heart disease, coarctation of the aorta is one of the most difficult to diagnose because it only becomes noticeable a few days after birth, when patients have already been discharged from the hospital. This underlines the importance of having a reliable diagnostic tool to discover these diseases. The identification of some of these patients can be achieved through newborn screening with pulse oximetry, but only a small number are diagnosed. Hence, the objective of this review was to determine the value of pulse oximetry screening for the early detection of congenital heart defects in newborns, with a focus on coarctation of the aorta. A literature search was conducted between December 2023 and February 2024 using four electronic databases: Pubmed, Google Scholar, Embase, and Scopus to identify studies that evaluated the efficacy of pre- and post-discharge neonatal ductal saturation monitoring for the diagnosis of critical congenital heart defects before discharge. Twenty research studies with a large number of patients, demonstrating moderate sensitivity and high specificity of pulse oximetry test in detecting critical heart defects, especially coarctation of the aorta, were selected and analyzed. Many confirmations have been found of how good the specificity of screening is, reaching an average value of 99.9% in each study analyzed. The problem still lies in the sensitivity of the screening, which is not as good as the specificity, never reaching 90% in any of the studies analysed. So, it is crucial to keep up with efforts to improve the efficacy of the pulse oximetry screening method.

Clinicopathological Features of Pakistani Patients with Anti Aquaporin-4 (Aqp-4) Antibody Positive Neuromyelitis Optica Spectrum Disorder (NMOSD): A Comparison with Local, Regional and International StudiesOPTICA SPECTRUM DISORDER(NMOSD)-A COMPARISON WITH LOCAL, REGIONAL AND INTERNATIONAL STUDIES

Objective: To characterize clinicopathological characteristics of patients with anti AQP-4 antibody positive Neuromyelitis Optica Spectrum Disorder in local population in order to facilitate clinicians in timely diagnosis and treatment of this rare debilitating illness. Study Design: Cross-sectional study. Place and Duration of Study: Department of Immunology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, from Jun 2021 to Dec 2022. Methodology: The study included 369 individuals presenting at Armed Forces Institute of Pathology for serum anti AQP-4 antibody testing by indirect immunofluorescence. Commercial Anti Aquaporin-4 Indirect Immunofluorescence Test Slides along with control serum (EUROIMMUN Medizinische Labordiagnostika AG, Lubeck, Germany) were used and immune-fluorescence was observed using immunofluorescent microscope BA-310. Results: Out of 369 patients who were tested for Anti Aquaporin-4 antibody, 168(45.5%) were females and 201(54.5%) were males. Total 9(2.43%) patients tested positive including 5(55.5%) females and 4(44.4%) males (p=0.947). Most prevalent core clinical characteristics among patients with Neuromyelitis Optica Spectrum Disorder were optic neuritis 7(77.8%), acute myelitis 7(77.8%) and area postrema syndrome 6(66.6%). Common presenting core clinical characteristics were area postrema syndrome 4(44.4%) and acute myelitis 4(44.4%). Average diagnostic delay in our study was 2.7±3.2 years. Conclusion: By keeping high index of suspicion for presenting core clinical characteristics (area postrema syndrome and acute myelitis) clinicians may be able to diagnose and treat this rare disease timely hence decrease average diagnostic delay and prevent associated morbidity and mortality.

Epidemiological characterization of rare diseases in Brazil: A retrospective study of the Brazilian Rare Diseases Network

BackgroundThe Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019.ResultsThe survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF.ConclusionThis study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

Segregation of the COL6A2 Variant (c.1817-3C>G) in a Consanguineous Saudi Family with Bethlem Myopathy

Introduction: Bethlem myopathy is a rare genetic disease caused by a variant mapped to 21q22, which harbors the collagen type VI alpha 2 chain (COL6A2) and collagen type VI alpha 1 chain (COL6A1) genes, and 2q37, which harbors the collagen type VI alpha 3 chain (COL6A3) gene. Disease onset can occur at any age, and the symptoms are related to those of muscular dystrophy. Since Bethlem myopathy is a rare disease, no previous studies have been conducted in Arab countries, including Saudi Arabia. Its variable presentation of nonspecific muscular contractions and severity represents a diagnostic dilemma. Case presentation: Here, we report a Saudi pediatric patient, who is 9 years old (proband), brought to the pediatric clinic of King Saud’s Hospital by his mother. The boy presented with difficulty standing, walking, and running with his classmates and unaffected siblings. He has a younger sibling, aged 6 years old, who reported having a limping gait and difficulty bending his right knee. Laboratory results for the proband were unremarkable except for a slight increase in creatine kinase (CK). Whole-exome sequencing (WES) was performed for five family members, including the proband and his symptomatic brother, their mother and two asymptomatic siblings. A very rare 3′ splice site acceptor intronic variant, NM_001849.4: c.1817-3C>G, located three nucleotides before exon 25, was identified in COL6A2. Bioinformatics tools (SpliceAI, dbscSNV, FATHMM-MKL, and MaxEntScan) predicted this variant as pathogenic. The proband and his 6-year-old sibling presented a homozygous genotype for the variant, whereas the mother and one asymptomatic sibling were heterozygous, and the other sibling carried homozygous wild-type alleles. Conclusions: This is the first study to report a case of Bethlem myopathy confirmed by WES in Saudi Arabia and all Arab nations. The identified variant is rare, and its segregation pattern suggests autosomal recessive inheritance. The segregation pattern and bioinformatics tool results may qualify this variant to be annotated as pathogenic, addressing the reported uncertainty of its classification. Our findings contribute to linking and filling the knowledge gap of diagnosing and managing patients with collagen VI-related myopathies, providing greater clinical and genetic understanding to the existing knowledge.