Health-related quality of life and caregiver burden of pediatric patients with inborn errors of metabolism in Japan using EQ-5D-Y, PedsQL, and J-ZBI.

PURPOSE: Inborn errors of metabolism (IEM) are known with poor long-term health concerns; however, the health-related quality of life (HRQoL) and the burden placed on families remain unclear. This study investigated the self- and proxy-reported HRQoL of pediatric patients with IEM with or without developmental disabilities and the burden placed on their caregivers. METHODS: Patients with IEM aged 8-15 years and their caregivers were asked to respond to the Pediatric Quality of Life Inventory (PedsQL), EuroQoL five-dimension questionnaire for younger populations (EQ-5D-Y), and Japanese version of the Zarit Caregiver Burden Interview (J-ZBI). We compared EQ-5D-Y scores with matched EQ-5D-Y population norms. Intraclass correlation coefficients (ICC) for self and proxy HRQoL scores of those without developmental disabilities were calculated. Correlation coefficients of HRQoL proxy responses with J-ZBI score were estimated. RESULTS: We included 66 patients with IEM (mean age, 11.5 years; males, 41.2%) in the study. The mean (± standard deviation) EQ-5D-Y scores without and with developmental disabilities were 0.957 (± 0.071) and 0.821 (± 0.175), respectively. The EQ-5D-Y scores significantly increased compared with the reference values (p < 0.01, effect size = 0.337). The ICC values were 0.331 and 0.477 for the EQ-5D-Y and PedsQL scores, respectively. HRQoL proxy scores had strong negative correlations with J-ZBI scores. CONCLUSION: The HRQoL of patients with IEM without developmental disabilities in our study was similar to that of the general Japanese population. The HRQoL of patients with IEM with developmental disabilities was low and associated with a tendency towards an increased burden of care.

Case report: Deep sequencing and long-read genome sequencing refine prior genetic analyses in families with apparent gonadal mosaicism in PIK3CD-related activated PI3K delta syndrome.

Gonadal and gonosomal mosaicism describe phenomena in which a seemingly healthy individual carries a genetic variant in a subset of their gonadal tissue or gonadal and somatic tissue(s), respectively, with risk of transmitting the variant to their offspring. In families with one or more affected offspring, occurrence of the same apparently de novo variants can be an indicator of mosaicism in either parent. Panel-based deep sequencing has the capacity to detect low-level mosaic variants with coverage exceeding the typical limit of detection provided by current, readily available sequencing techniques. In this study, we report three families with more than one affected offspring with either confirmed or apparent parental gonosomal or gonadal mosaicism for PIK3CD pathogenic variants. Data from targeted deep sequencing was suggestive of low-level maternal gonosomal mosaicism in Family 1. Through this approach we did not detect pathogenic variants in PIK3CD from parental samples in Family 2 and Family 3. We conclude that mosaicism was likely confined to the maternal gonads in Family 2. Subsequent long-read genome sequencing in Family 3 showed that the paternal chromosome harbored the pathogenic variant in PIK3CD in both affected children, consistent with paternal gonadal mosaicism. Detection of parental mosaic variants enables accurate risk assessment, informs reproductive decision-making, and provides helpful context to inform clinical management in families with PIK3CD pathogenic variants.

Successful Allogeneic Hematopoietic Cell Transplantation for Patients with IL10RA Deficiency in Japan.

BACKGROUND: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. METHODS: We retrospectively analyzed patients with IL10RA deficiency in Japan. RESULTS: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. CONCLUSION: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250).

Delineating the Clinical and Immunologic Characteristics: A Comparative Study of Inborn Errors of Immunity in Adult versus Pediatric Diagnosed.

INTRODUCTION: Inborn errors of immunity (IEIs) are rare genetic disorders primarily identified in children due to their significant effects on immune system functionality. However, an increasing number of IEI cases are being diagnosed in adults, attributed to delayed presentation or advancements in diagnostic capabilities. This study explores the clinical and immunologic distinctions between IEIs diagnosed in adulthood versus childhood, shedding light on their differential presentations, the impact of diagnostic delays, and treatment outcomes. METHODS: This study focused on 122 adult patients with IEI above 17 years old, diagnosed in adulthood or childhood. We collected comprehensive data on demographics, clinical presentations, genetic mutations, and therapeutic interventions. RESULTS: The study revealed that 72.9% of participants were diagnosed in adulthood, facing a median diagnostic delay of 96 months. Diagnostic delays were longer in adults (132 months vs. 24 months) than in children. The most common clinical manifestations at onset were recurrent infections (46.7%) and autoimmunity (18%). Predominantly antibody deficiency was the most frequently diagnosed immunodeficiency (54.9%), followed by immunodysregulation at a rate of 26.2%. A higher incidence of immune thrombocytopenia or other complications, such as hepatomegaly and enteropathy, was observed in adult-diagnosed patients with IEI. Malignancies were more prevalent in patients with adult-onset IEI compared to those with childhood-onset (18.1% vs. 5.2%). Overall, 15 different malignancies were recorded in 13 patients (10.6%), including lymphomas and cancers of the stomach, thymus, skin, breast, and colon. CONCLUSIONS: The findings highlight a considerable diagnostic delay in recognizing IEI, especially in adults, and illustrate distinct differences in disease manifestation and progression between adult-onset and delayed-diagnosis groups.

Case report on activated PI3K-delta syndrome.

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) [OMIM 615513] is an inborn error of immunity with autosomal dominant inheritance caused by a pathogenic variant in the PIK3CD gene. The prevalence ratio of APDS is < 1: 1,000,000 newborns. The main clinical features of APDS are sinopulmonary infections, benign lymphoproliferation, autoinflammatory disease, and a major risk of lymphoid neoplasms. CLINICAL CASE: A 17-year-old female with a history of pneumonia at 9 months of age subsequently developed recurrent respiratory tract infections, bronchiectasis, perforated otitis media, unilateral tonsillar lymphoid hyperplasia, pansinusitis, recurrent oral candidiasis, and chronic rhinitis. Laboratory studies reported persistent leukopenia and lymphopenia, low CD4 lymphocyte subpopulation, and persistently elevated immunoglobulin M immunoglobulin studies with values up to 692 mg/dL. An inborn error of immunity next-generation sequencing and multiplex ligation-dependent probe amplification analysis detected a heterozygous pathogenic variant in the PIK3CD gene, compatible with APDS. Treatment with monthly injectable gamma globulin and prophylactic antibiotics was started, allowing better control of the infectious processes. CONCLUSION: This is the second case of APDS reported in Mexico in the literature. It is important to be aware of this condition to make a timely diagnosis, which requires a high clinical suspicion and immunological and genetic studies to provide adequate treatment and prevent complications.

INTRODUCCIÓN: El síndrome de la Fosfoinositida 3-cinasa delta activado (Activated Phosphoinositide 3-kinase δ síndrome, APDS) [OMIM 615513] es un error innato de la inmunidad con patrón de herencia autosómica dominante causada por una variante patogénica heterocigota del gen PIK3CD. Su prevalencia es < 1: 1,000,000 nacidos vivos. Las principales manifestaciones clínicas son infecciones sinopulmonares, linfoproliferación benigna, autoinmunidad y aumento del riesgo de malignización linfoide. CASO CLÍNICO: Femenino de 17 años de vida con antecedentes de neumonía a los 9 meses de edad, posteriormente infecciones de vías respiratorias recurrentes, bronquiectasias, otitis media perforada, hiperplasia linfoide de amigdala unilateral, pansinusitis, candidiasis oral recurrente y rinitis crónica. Los estudios de laboratorio reportaron leuco linfopenia persistente, subpoblación linfocitaria con CD4 baja y estudios de inmunoglobulinas con IgM persistentemente elevada con valor de hasta 692 mg/dl. Se realizó estudio molecular de secuenciación de siguiente generación (NGS por sus siglas en inglés Next-Generation Sequencing) y amplificación de sondas dependientes de ligandos múltiples (MLPA por sus siglas en inglés Multiplex Ligation-dependent Probe Amplification) dirigido a errores innatos de la inmunidad que detectó una variante patogénica en estado heterocigoto en el gen PIK3CD, compatible con APDS. Se inició tratamiento con gammaglobulina intravenosa mensual y antibiótico profiláctico, permitiendo mejor control de los procesos infecciosos. CONCLUSIONES: Este es el segundo caso reportado en la literatura de APDS en México, por lo que es importante su conocimiento para poder realizar un diagnóstico oportuno, para el cual se requiere una alta sospecha clínica, además de estudios inmunológicos y genéticos, con la finalidad de otorgar el tratamiento adecuado y prevenir complicaciones.

Transitions of Care in Patients With Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are a group of inherited conditions caused by damaged monogenic variants that result in impairment and/or dysregulation within the immune system. IEI are typically diagnosed in infancy or early childhood, with clinical presentations that include increased susceptibility to infections, immune dysregulation, autoinflammation, bone marrow failure, and/or malignancy. Historically, transitions of care experienced by patients with IEI have not been well described in the literature. However, with treatment advances extending the long-term survival of patients, this has become a primary area of research. It is crucial to establish guidelines and recommendations specific to the transition of patients with IEI. Transitions may include patients who naturally progress from pediatric to adult care, from inpatient to outpatient settings, or from their established health care team to a new team (ie, moving from one geographic area to another). This narrative review summarizes the current data on transitions of care and describes the health care challenges and patient-related barriers impacting transitions of care. Frameworks with practical guidance on how health care practitioners can better manage care transitions faced by patients with IEI are presented.

Seizure Characteristics and EEG Features in Intoxication Type and Energy Deficiency Neurometabolic Disorders in the Pediatric Intensive Care Unit: Single-Center Experience Over 10 Years.

BACKGROUND: Acute metabolic crises in inborn errors of metabolism (such as urea cycle disorders, organic acidemia, maple syrup urine disease, and mitochondrial disorders) are neurological emergencies requiring management in the pediatric intensive care unit (PICU). There is a paucity of data pertaining to electroencephalograms (EEG) characteristics in this cohort. We hypothesized that the incidence of background abnormalities and seizures in this cohort would be high. Neuromonitoring data from our center's PICU over 10 years are presented in this article. METHODS: Data were collected by retrospective chart review for patients with the aforementioned disorders who were admitted to the PICU at our institution because of metabolic/neurologic symptoms from 2008 to 2018. Descriptive statistics (χ2 test or Fisher's exact test) were used to study the association between EEG parameters and outcomes. RESULTS: Our cohort included 40 unique patients (8 with urea cycle disorder, 7 with organic acidemia, 3 with maple syrup urine disease, and 22 with mitochondrial disease) with 153 admissions. Presenting symptoms included altered mentation (36%), seizures (41%), focal weakness (5%), and emesis (28%). Continuous EEG was ordered in 34% (n = 52) of admissions. Twenty-three admissions were complicated by seizures, including eight manifesting as status epilepticus (seven nonconvulsive and one convulsive). Asymmetry and focal slowing on EEG were associated with seizures. Moderate background slowing or worse was noted in 75% of EEGs. Among those patients monitored on EEG, 4 (8%) died, 3 (6%) experienced a worsening of their Pediatric Cerebral Performance Category (PCPC) score as compared to admission, and 44 (86%) had no change (or improvement) in their PCPC score during admission. CONCLUSIONS: This study shows a high incidence of clinical and subclinical seizures during metabolic crisis in patients with inborn errors of metabolism. EEG background features were associated with risk of seizures as well as discharge outcomes. This is the largest study to date to investigate EEG features and risk of seizures in patients with neurometabolic disorders admitted to the PICU. These data may be used to inform neuromonitoring protocols to improve mortality and morbidity in inborn errors of metabolism.

Decreased T-cell response against latent cytomegalovirus infection does not correlate with anti-IFN autoantibodies in patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inborn error of immunity affecting both multiple endocrine organs and susceptibility to candidiasis, each with an autoimmune basis. Recently, high titer neutralizing anti-type I interferon (IFN) autoantibodies have been linked with increased severity of SARS-CoV-2 and varicella zoster virus infections in APECED patients. Examining immunity against cytomegalovirus (CMV), we found a higher prevalence of anti-CMV IgG antibodies in patients with APECED (N = 19) than in 44 healthy controls (90% vs 64%, p = 0.04); the similar difference in their IgG levels did not achieve significance (95 ± 74 vs 64 ± 35 IU/mL, ns.). In contrast, the frequency of CMV-specific T cells was lower (804 ± 718/million vs 1591 ± 972/million PBMC p = 0.03). We saw no correlations between levels of anti-CMV IgG and anti-IFN antibodies in APECED patients or in a separate cohort of patients with thymoma (n = 70), over 60% of whom also had anti-IFN antibodies. Our results suggest a dysregulated response to CMV in APECED patients and highlight immunodeficiency to viral infections as part of the disease spectrum.

Severe Acute Motor Exacerbations (SAME) across Metabolic, Developmental and Genetic Disorders.

Acute presentation of severe motor disorders is a diagnostic and management challenge. We define severe acute motor exacerbations (SAME) as acute/subacute motor symptoms that persist for hours-to-days with a severity that compromise vital signs (temperature, breath, and heart rate) and bulbar function (swallowing/dysphagia). Phenomenology includes dystonia, choreoathetosis, combined movement disorders, weakness, and hemiplegic attacks. SAME can develop in diverse diseases and can be preceded by triggers or catabolic states. Recent descriptions of SAME in complex neurodevelopmental and epileptic encephalopathies have broadened appreciation of this presentation beyond inborn errors of metabolism. A high degree of clinical suspicion is required to identify appropriately targeted investigations and management. We conducted a comprehensive literature analysis of etiologies. Reported triggers are described and classified as per pathophysiological mechanism. A video of six cases displaying multiple SAME with diverse outcomes is provided. We identified 50 different conditions that manifest SAME, some associated with developmental regression. Etiologies include disorders of metabolism: energy substrate, amino acids, complex molecules, vitamins/cofactors, minerals, and neurotransmitters/synaptic vesicle cycling. Non-metabolic neurodegenerative and genetic disorders that present with movement disorders and epilepsy can additionally manifest SAME. A limited number of triggers are grouped here, together with an approach to investigations and general management strategies. Several neurogenetic and neurometabolic disorders manifest SAME. Identifying triggers can help in certain cases narrow the differential diagnosis and guide the expeditious application of targeted therapies to minimize adverse developmental and neurological consequences. This process may inform pathogenesis and eventually improve our understanding of the mechanisms that lead to the development of SAME. © 2024 International Parkinson and Movement Disorder Society.

Case report of renal manifestations in X-linked agammaglobulinemia.

Introduction: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disorder characterized by recurrent infections, severe hypogammaglobulinemia, and a deficiency of circulating B cells. While the hallmark clinical manifestations of XLA typically include the respiratory, dermatological, and gastrointestinal systems, renal involvement is infrequent. In this article, we report two cases of XLA with concurrent renal disease, supplemented with a review of documented cases. Case description: The two cases described involve twin brothers, both presenting with respiratory tract infections and renal manifestations. Subsequent genetic testing confirmed the diagnosis of XLA. The younger brother exhibited improvement following intravenous immunoglobulin (IVIG) therapy and anti-infection treatment. Due to financial constraints, the older brother received only anti-infection and symptomatic treatments. Seven months after discharge, the older brother developed nephritis. However, he showed improvement following IVIG treatment. Conclusion: Immune profiling and genetic testing should be considered in male children with recurrent infections to facilitate the effective diagnosis of XLA. Regular monitoring is also imperative to detect and treat immune-mediated renal diseases in patients with XLA.

Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.

Introduction: Leigh syndrome is a rare mitochondrial disorder characterized by subacute necrotizing encephalomyelopathy, resulting from defects in mitochondrial respiratory enzymes or pyruvate dehydrogenase complex. Symptoms can manifest in infancy, childhood, or adulthood. We present a case of a 7-month-old girl initially misdiagnosed with septic shock but was later found to have Leigh encephalomyelopathy due to MT-ATP6 deficiency. Case Presentation: A 7-month-old girl was admitted with fever, drowsiness, and wheezing, initially diagnosed with septic shock. She had a history of parental consanguinity and hypotonia. Physical examination revealed unconsciousness, miotic pupils, and respiratory distress. Initial laboratory tests showed significant metabolic acidosis and elevated lactate, creatine kinase, and ammonia levels. The patient was treated for sepsis and shock, but her condition worsened with elevated lactate and liver transaminases, eventually leading to hypertrophic cardiomyopathy and multiorgan failure. Her basic metabolic scans showed extremely low citrulline levels, whole-exome sequencing analysis did not show any pathologic change in nuclear genome, and mitochondrial genome analysis revealed an MT-ATP homoplasmic variant. She passed away on the 22nd day of hospitalization. Discussion/Conclusion: While mitochondrial disorders are broadly acknowledged for their phenotypic diversity, it is essential to note that specific disorders, such as Leigh syndrome, display distinctive presentations with varying degrees of severity. Factors such as the percentage of homoplasmy contribute to the variability in manifestations. Notably, MT-ATP6-associated Leigh syndrome is predominantly characterized by an early onset, typically occurring before the age of 2 years. Low citrulline levels have been observed in approximately 90% of patients with MT-ATP6-related disorders, distinguishing them from other mitochondrial disorders. The exact mechanisms underlying this specific metabolic alteration are not fully understood, but it could be linked to disruptions in the mitochondrial energy production process. The mitochondria are essential for various metabolic pathways, including the urea cycle, where citrulline is involved. The association between low citrulline levels and MT-ATP6-related disorders raises the possibility of using citrulline as a potential biomarker for disease identification. MT-ATP6 defects should be kept in mind in cases with mitochondrial disease and low plasma citrulline levels.

Clinicogenetic characterization of cerebrotendinous xanthomatosis in Brazil.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

IPINeT Ped-unPAD Study: Goals, Design, and Preliminary Results.

Background: An unclassified primary antibody deficiency (unPAD) is a widely heterogeneous clinical entity, recently identified within the spectrum of Inborn Errors of Immunity (IEIs). Since unPAD has been traditionally considered as a mild condition, it has incorrectly received little attention, resulting in the paucity of extensive and comparable studies describing its natural history. To address the gaps in characterizing, understanding, and managing pediatric unPAD patients, the Italian Primary Immunodeficiency Network (IPINet) Ped-unPAD study has recently been launched. Methods: Seventeen IPINeT Centers have expressed interest to participate, and data collection is still on-going. Hereby, we anticipate preliminary key issues emerging from the first 110 enrolled patients, attending three IPINet Centers. Results: A proportion of unPAD patients have experienced a severe infectious phenotype, which required hospitalization in a quarter of patients and antibiotic prophylaxis or Immunoglobulin Replacement Therapy in approximately 10% of patients. In this partial cohort, a mean follow-up (FU) of 5 years confirmed unPAD diagnosis in fifty percent of cases, with the remaining being reclassified as the Transient Hypogammaglobulinemia of Infancy (25%) and other IEIs (25%), such as a Common Variable Immunodeficiency, Selective IgA deficiency, Selective IgM deficiency, and IgG3 subclass deficiency. Conclusions: Despite a phenotype overlap at diagnosis, clinicians should be aware that unPAD is a mutable condition that deserves comprehensive evaluation and long-term monitoring to dissect the final diagnosis for optimal treatment.

Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Breastfeeding in PKU and Other Amino Acid Metabolism Disorders-A Single Centre Experience.

In addition to the numerous immunological and nutritional benefits that breast milk offers to infants, its proportion in the diet must be limited or even excluded in the case of inborn errors of amino acid metabolism (IEM). The objective of the study was to expand knowledge about breastfeeding and the degree of contribution of breast milk to the feeding of infants with IEM before and after the introduction of expanded newborn screening. A retrospective single-centre study was conducted on 127 infants born between 1997 and 2020: 66 with phenylketonuria (PKU), 45 with other IEM (non-PKU), all diagnosed through newborn screening (NBS), and 16 non-PKU diagnosed through selective screening (SS). The time of initiation of dietary treatment and the proportion of breast milk in the diet, both expressed and breastfed, with or without intake control, were analysed at 1, 3, and 6 months after birth. For 47% of the newborns in Groups 1 and 2, the dietary treatment was started before the 10th day of life; in Group 3, the dietary treatment was started after the 10th day of life for all children. During the first month of life, the proportion of infants receiving breast milk was higher in the NBS-PKU (74%) and the NBS non-PKU (80%) groups, compared with 38% in the SS non-PKU infants. In the subsequent months of life, the proportion of infants receiving human milk (either from the breast or a bottle) declined in all groups. This decline occurred more in bottle-fed rather than directly breast-fed infants. Our observations indicate that the model of feeding from a bottle with expressed milk may have had an adverse effect on maintaining lactation and may have contributed to a faster transition to formula milk. Maintaining lactation and extending the period of feeding the infant with human milk in the first 6 months of life is possible by breastfeeding on demand, under regular biochemical monitoring: preferably weekly in PKU infants, and at least every 2-4 weeks in infants with other IEM.

The importance of geographic and sociodemographic aspects in the characterization of mucopolysaccharidoses: a case series from Ceará state (Northeast Brazil).

Geographic and sociodemographic aspects may influence the natural history and epidemiology of mucopolysaccharidoses (MPS). The main objective in this work was to evaluate the clinical, molecular, and geographic profile of MPS in a population from Ceará (Northeast Brazil). For this, we have performed a descriptive cross-sectional study based on clinical evaluation, interviews with patients and/or family members, and review of medical records of 76 MPS patients. MPS II was the most common type, with the most affected individuals presenting missense pathogenic variants. Patients with MPS I proved to be the most severe clinical phenotype, presenting the first symptoms (mean: 7.1 months; SD = 4.5) and being diagnosed earlier (2.2 years; SD = 2.1) in comparison with the other types. In addition, we have shown that 13 individuals with MPS VI were born of consanguineous marriages in small, nearby cities, in a place where geographical isolation, consanguinity, and clusters of genetic diseases were previously reported. Ten of these individuals (at least, seven different families) presented a rare pathogenic variant in the ARSB gene, c.1143-8T > G in homozygosity, previously reported only among Iberian and South American patients. The results presented here provide a comprehensive picture of MPS in an important state of the Brazilian Northeast, a region that concentrates many risk factors for rare genetic diseases, such as endogamy, inbreeding, and reproductive isolation. We discuss the possible evolutionary processes and biosocial dynamics that can help to explain this finding in terms of population medical genetics and public health.