Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood.We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6.Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype.This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.
Objective DNAJC12 encodes a J-domain co-chaperone involved in the function of aromatic amino acid hydroxylases, and its deficiency is associated with hyperphenylalaninemia (HPA) and monoamine neurotransmitter deficiency. We assessed a DNAJC12 c.131A > G (p.Asp44Gly, D44G) variant identified in a 19-year-old man who presented with mild HPA, recurrent migraine-like headaches, and phenylketonuria-like white matter changes, along with four reported clinically relevant missense variants (A62E, R72P, H102Q, and W103C), using an integrated deep learning (DL)-based approach. Methods DL-based and conventional prediction algorithms were integrated to evaluate the clinical and genetic findings, together with protein structural and pathogenic impact. Analyses incorporated AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, and ThermoMPNN. Principal component analysis (PCA) was used to characterize overall, position-level, and substitution-level pathogenicity metrics. Pathogenicity classification followed American College of Medical Genetics and Genomics and ClinGen Sequence Variant Interpretation standards. Results The J-domain was confidently modeled, and Asp44 was located within the conserved His-Pro-Asp motif. DNAJC12 missense variants may affect predicted side-chain interactions and residue-contact patterns with thermodynamic changes. PCA of aggregated pathogenicity metrics indicated that the predicted deleteriousness of p.Asp44Gly was consistent with stronger position-specific constraint. D44G was classified as a variant of uncertain significance (PM1, PM2_Supporting, and PP3_Supporting). Conclusion Our findings provide additional clinical and genetic evidence relevant to DNAJC12-related disease and support a potential functional effect of D44G, but do not establish its pathogenicity yet. DNAJC12 should be included in the genetic evaluation of patients with unexplained HPA with neurological manifestations, and D44G warrants further functional validation.
We report a 6-month-old male, born to consanguineous parents, presented with recurrent bronchopneumonia, global developmental delay, and craniofacial dysmorphism. Initial workup revealed profound T-cell lymphopenia and hypoplasia of the splenium of the corpus callosum. Whole exome sequencing (WES) identified two homozygous pathogenic variants: a mutation in C12orf57, diagnostic of Temtamy syndrome, and a mutation in STK4, confirming a primary immunodeficiency. At age 3, the patient developed a life-threatening acute hemolytic crisis with a hemoglobin nadir of 2.3 g/dL. Investigations confirmed cold agglutinin disease, validating the severe immune dysregulation predicted by the STK4 genotype. The patient responded to corticosteroid therapy and is currently awaiting hematopoietic stem cell transplantation (HSCT) from his HLA-compatible father. This report illustrates that early integration of WES in complex pediatric cases is essential to anticipate and manage severe complications, shifting the clinical focus from supportive care to curative interventions like HSCT.
Background: Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy characterized by a distinctive midbrain-hindbrain malformation, manifested by hypotonia, ataxia, developmental delay, and variable multisystem involvement. The condition exhibits marked clinical and genetic heterogeneity, with over 40 genes implicated to date. However, the mutational spectrum and phenotypic presentation of JS in Middle Eastern populations, where consanguinity is prevalent, remain poorly characterized. Methods: We retrospectively reviewed whole-exome sequencing (WES) data from patients referred to the Comprehensive Medical Genetics Center, Shiraz, Iran, between 2019 and 2024. Patients harboring variants in JS-related genes were identified, and their clinical records were analyzed to establish genotype–phenotype correlations. Results: A total of 21 cases with variants in JS-associated genes were identified. Neurological manifestations, including developmental delay/intellectual disability, speech defects, seizures, and motor impairment, were the most prevalent findings. Vision problems, renal involvement and polydactyly were also present. Molecular analysis revealed variants in 14 distinct genes, with AHI1 being the most frequently mutated (3 cases), followed by KIAA0586, CSPP1, KIAA0556, CC2D2A, and TMEM67. Eight cases carried pathogenic or likely pathogenic variants, while 12 cases had variants of uncertain significance (VUS), highlighting the diagnostic challenges in this genetically heterogeneous condition. Conclusion: This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies. The high rate of consanguinity in this cohort likely contributes to the enrichment of autosomal recessive forms. Further functional studies are warranted to clarify the pathogenicity of the numerous VUS identified, which will improve genetic counseling and prenatal decision-making for affected families.
Background:Mucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is a group of rare autosomal recessive lysosomal storage disorders caused by deficiency of enzymes involved in heparan sulfate degradation, encoded by SGSH (type A), NAGLU (type B), HGSNAT (type C), or GNS (type D). Progressive lysosomal accumulation leads to neurodegeneration, cognitive decline, behavioral disturbances, and premature death. Despite a global pooled birth prevalence of ∼0.76 per 100,000 live births, MPS III remains substantially underdiagnosed in Latin America. To date, only a single MPS IIIB case has been molecularly confirmed in Mexico, with no reported cases of MPS IIIA or IIIC. Methods:Two adolescent patients with progressive neurodevelopmental deterioration were evaluated at a tertiary genetics center in Yucatán, Mexico. Assessment included structured clinical history, neuroimaging, conventional karyotyping, and whole-exome sequencing (WES), with variants classified per ACMG/AMP guidelines. Results:Case 1 (MPS IIIC): a 15-year-old male presented with speech delay, progressive loss of ambulation and self-feeding, sleep disturbances, and hyperactivity. WES identified a homozygous pathogenic HGSNAT variant (NM_152419.3): c.234 + 1G > A, a previously described Iberian-associated allele. Case 2 (MPS IIIA): a 15-year-old female presented with neurological regression from age 4, refractory generalized seizures, and profound intellectual disability. WES identified two compound heterozygous SGSH variants (NM_000199.5): c.233 T > G (p.Leu78Arg) and c.368 A > G (p.Lys123Arg), both classified as likely pathogenic and, to our knowledge, not previously reported in the literature or genomic databases. Conclusions:These cases are consistent with the first reported diagnoses of MPS IIIA and MPS IIIC in Mexico, supported by concordant clinical and molecular findings and indicating the presence of at least three MPS III subtypes in the country. The two SGSH variants represent candidate novel alleles, with enzymatic and functional confirmation pending. The identification of these variants and of a recurrent Iberian-associated HGSNAT allele in non-consanguineous patients underscores the likely underdiagnosis of MPS III in Mexico and the diagnostic value of WES in resource-limited settings.
Glycogen storage disease type Ib (GSD-Ib) engenders neutropenia and severe neutrophil dysfunction, leading to recurrent infections and inflammatory complications. Recent studies have identified intracellular accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) as a key mechanism underlying neutrophil impairment and have suggested therapeutic benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower plasma levels of its precursor 1,5-AG. In this study, we performed a four-year longitudinal evaluation of empagliflozin therapy in a genetically confirmed GSD-Ib infant, contributing to the growing body of long-term data on empagliflozin treatment in GSD-Ib. Routine laboratory parameters and key neutrophil effector functions were assessed before and during treatment, as well as in two additional GSD-Ib patients with and without therapy. Empagliflozin therapy resulted in complete restoration of neutrophil function, including reactive oxygen species (ROS) production and bactericidal activity. Notably, neutrophil extracellular trap (NET) formation and neutrophil survival recovered to levels comparable to healthy donors. These functional improvements occurred in conjunction with reduced plasma 1,5-AG levels, supporting the concept that GSD-Ib neutrophils are sensitive to physiological 1,5-AG concentrations. Functional recovery and normalization of neutrophil survival observed in vitro, was paralleled by improvement of absolute neutrophil counts to low-normal levels in vivo. Clinically, treatment was associated with a substantial reduction of severe infections. Collectively, these findings further support that empagliflozin corrects neutrophil dysfunction in GSD-Ib and demonstrate its potential to improve long-term clinical outcome across the lifespan, from infancy through adulthood.
Background:Inherited ocular disorders are a leading cause of early-onset visual impairment, particularly in populations with high consanguinity such as Iran, where a substantial proportion of affected individuals remain without a molecular diagnosis after conventional evaluation. We aimed to determine the diagnostic yield and variant spectrum of whole-exome sequencing (WES) in Iranian probands with congenital or early-onset ocular disorders that were genetically unresolved by prior testing. Methods:Thirty unrelated probands were recruited consecutively (July-September 2024). Genomic DNA underwent exome capture (Agilent SureSelect V7) and paired-end sequencing (Illumina NovaSeq 6000). Reads were cleaned with SOAPnuke, aligned with BWA-MEM, and variants were called with GATK HaplotypeCaller and DeepVariant, filtered by GATK VQSR, and annotated against public and Iranian-specific databases (GEMIRAN, IRANOM). Variants were classified per ACMG/AMP criteria. Diagnostic yield was defined as the proportion of probands with a causative or candidate variant concordant with phenotype. Results:A causative or strong candidate variant concordant with the phenotype was identified in 21 of 30 probands (diagnostic yield 70.0%; 95% CI 50.6-85.3%). Pathogenic or likely-pathogenic variants were found in established genes including ABCA4, USH2A, RP1, CRB1, CEP290, GUCY2D, CYP1B1 and TYR. Among the identified genotypes, 54% were homozygous and 12% hemizygous (X-linked), consistent with consanguinity in 11/30 (36.7%) families; 35% were single heterozygous findings in autosomal-recessive genes, interpreted as incomplete genotypes pending detection of a second allele. Onset was infantile in 73% of probands. Conclusions:WES is an effective first-tier test for congenital and early-onset ocular disorders in the Iranian population, resolving roughly 70% of previously undiagnosed probands. Single-allele findings in recessive genes indicate that complementary copy-number and structural-variant analysis, deep-intronic assessment, periodic reanalysis, and reflex whole-genome sequencing are needed to maximise yield and support accurate genetic counselling.
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with multisystemic involvement. We report a 68-year-old asplenic man with late-onset ASMD and severe interstitial lung disease, chronic respiratory failure, and markedly reduced diffusion capacity. Treatment with olipudase alfa resulted in significant clinical, functional, and biomarker improvement despite advanced age and disease severity. This case supports the benefit of enzyme replacement therapy in patients with complex, late-presenting ASMD.
Congenital disorders of glycosylation (CDGs) are rare metabolic diseases characterized by clinical heterogeneity, yet the molecular basis for their tissue-specific manifestations remains poorly understood. Because affected tissues are rarely accessible for biopsy, the baseline transcriptional and regulatory landscape of CDG-causative genes in healthy human tissues offers a valuable, complementary perspective on tissue vulnerability. Here, we performed an in silico study of the expression, allelic regulation, expression quantitative trait loci (eQTLs), and associations with immune cell compositions of 12 CDG-causative genes across healthy human tissues using multi-omics datasets from the Adult GTEx project. The selected panel includes the most prevalent multisystem CDGs (PMM2-, ALG6-, ALG1-, SLC35A2-, ALG13-, SRD5A3-, MAN1B1-, DPAGT1-CDG), three immune-relevant CDGs classified as inborn errors of immunity (MOGS-, PGM3-, VPS13B-CDG), and the autosomal recessive form of GNE-CDG (GNE-CDG (ar); GNE myopathy) as a tissue-restricted contrast.CDG-causative genes were broadly but heterogeneously expressed, with substantial inter-individual variation. Tissues frequently affected in the corresponding disorders did not consistently display the highest baseline gene expression, underscoring that higher gene expression alone is a poor indicator of tissue susceptibility.Allele-specific analyses revealed five distinct allelic expression patterns across individuals and identified tissue-specific deviations from balanced biallelic expression for several genes, most notably SRD5A3, PGM3, VPS13B, and GNE.Tissue-specific eQTLs affecting CDG genes were frequently located in intronic enhancers of unrelated genes or intergenic regions, revealing a complex, predominantly distal regulatory architecture. Several eQTLs overlapped GWAS Catalog traits and ClinVar entries relevant to the corresponding CDG phenotypes, including PMM2 eQTLs associated with reduced PMM2 gene levels.Finally, correlations between CDG-causative gene expression and immune cell composition recapitulated known immune phenotypes from blood and suggested additional tissue-dependent roles for glycosylation in immune modulation, that warrant functional validation.Together, these findings demonstrate that CDG-causative genes operate within diverse transcriptional, allelic, and regulatory contexts across human tissues. Our in silico framework provides an interpretable candidates and foundational reference for interpreting tissue vulnerability in CDG and underscore the need for global analyses to fully understand organ-specific disease mechanisms.
Background:Glycogen Storage Disease Type I (GSD I) is an inherited metabolic disorder characterized by impaired hepatic glucose production due to defects in gluconeogenesis and glycogenolysis. Two subtypes are recognized: GSD Ia (G6PC) and GSD Ib (SLC37A4). Genotype-phenotype correlations and long-term outcomes in Southeast Asia remain insufficiently characterized. This study aimed to describe the clinical, biochemical, and molecular features of Vietnamese children with GSD I and evaluate treatment outcomes . Methods:Twenty-four patients from 19 families diagnosed at the Vietnam National Children's Hospital between 2016 and 2025 were included. All underwent genetic testing. Clinical characteristics and laboratory parameters were collected at diagnosis and during follow-up . Results:Twelve distinct variants were identified, including eight in G6PC and four in SLC37A4, with one novel variant (c.1193G > A). The most common G6PC variants were c.518 T > C, c.356 A > T, and c.648G > T, while c.706_708delGTG predominated in SLC37A4. The median age at symptom onset was 4 months, and 70% of patients presented with hepatomegaly. Elevated liver enzymes and lactate levels were observed in all cases, and 88.2% had hypertriglyceridemia. Dietary adherence was generally poor despite uncooked cornstarch therapy. During follow-up, patients with GSD Ia developed complications including short stature, hepatic adenoma, pancreatitis, hypertension, kidney stones, and cirrhosis, while all GSD Ib patients experienced neutropenia and required empagliflozin for recurrent infections . Conclusion:Hepatomegaly with elevated liver enzymes, lactate, and triglycerides is a common presentation of GSD I. Variant distribution may differ across populations, and complications can occur at any age.
Introduction:A male infant presented at three months of age with generalized ataxia, hypotonia, aspiration of liquids and recurrent generalized seizures. He was treated with levetiracetam and phenobarbital. Methods: Extensive testing, including whole genome sequencing was done. Results:He had two known pathogenic variants in the HMBS gene: p.R167Q [maternal] and p.T35M [paternal]. Plasma and urine exhibited high concentrations of 5-aminolevulinic acid, porphobilinogen, and uroporphyrin 1. Activity of hydroxymethylbilane synthase in red blood cells of the child was markedly reduced [18 nmol uroporphyrin/ g hemoglobin /h; reference range: 60-335]; it was ∼50% of normal in parents. The findings supported the diagnosis of biallelic severe HMBS deficiency with severe disease phenotype. A 5-day course of intravenous heme led to no observable clinical improvement. Orthotopic liver transplantation at the age of 15 months led to only mild transient improvement. Developmental delays and seizures persisted. MRI scans of the brain showed progressive white matter volume loss, cystic changes, and multifocal supratentorial signal abnormalities. He died at 88 months of age. Findings at autopsy of the brain showed patchy gliosis and leukodystrophy. We also review 11 previously reported cases. Conclusion:No effective disease-modifying therapy currently exists for biallelic HMBS deficiency. Substantial neurological injury is present by the time of diagnosis and seems irreversible.
The mitochondrial intermediate peptidase (MIP) catalyzes the post-import removal of an N-terminal octapeptide from a subset of nuclear-encoded mitochondrial proteins. While the mechanistic role of this processing remains unclear, biallelic MIPEP variants have been linked to respiratory chain dysfunction and mitochondrial disease. Patients expressing these variants most often presented with cardiomyopathy, variable neurological defects, and early mortality. Here, we report the identification and functional characterization of a homozygous MIPEP variant in a patient presenting with a comparatively milder clinical phenotype involving global developmental delay, infantile epileptic spasms syndrome, and hypotonia. Analyses of patient-derived fibroblasts revealed reduced MIP abundance and impaired processing of established MIP substrates MRPL12, NDUFV2, and ATP5F1. Expression of wild-type MIPEP restored these defects, confirming the pathogenic nature of the variant. Thus, our findings expand the genetic and phenotypic spectrum of MIPEP-linked disease.
Acid sphingomyelinase deficiency (ASMD) type B is frequently complicated by interstitial lung disease without validated circulating pulmonary biomarkers. In this retrospective longitudinal study of five patients treated with enzyme replacement therapy, plasma KL-6 was evaluated in relation to CT-based severity, DLCO, and treatment response. Higher pre-treatment KL-6 concentrations were observed with higher exploratory CT severity grades, and KL-6 levels generally decreased or remained stable during follow-up. A transient rise occurred during SARS-CoV-2 infection. KL-6 may reflect dynamic alveolar epithelial injury in ASMD.
Albinism is characterized by generalized hypopigmentation and ocular features resulting from impaired melanin biosynthesis. Most known pathogenic variants are rare (MAF < 0.001) and found in coding regions. The role of non-coding variants, especially those with higher allele frequencies, is generally not investigated. Our next generation sequencing panel that includes the entire sequence of five major albinism genes (TYR, OCA2, SLC45A2, GPR143 and HPS1) identified compound OCA2 heterozygosity in a patient with a rare (MAF:0,0003) coding variant, NM_000275.3:c.1025 A > G;p.(Tyr342Cys) and a more common intronic variant, NM_000275.3:c.574-19 A > G (MAF:0,0087, with 80 homozygotes in the control population GnomADv4.1.0). In silico prediction tools indicated that this intronic variant could alter splicing. RT-PCR analysis on RNA extracted from the patient's blood revealed the skipping of exons 6 and 7, which resulted in the in-frame deletion of 78 amino acids. Protein modelling suggested that this deletion disrupts the GOLD-like domain and leads to the loss of conserved N-glycosylation sites, likely impairing protein folding and intracellular trafficking. These findings provided strong evidence for a deleterious effect on OCA2 function. Therefore, the variant was classified as likely pathogenic, allowing to establish the diagnosis in the patient. The relatively high allele frequency of this variant suggests that it behaves as a hypomorphic allele leading to disease in a compound heterozygous state. This underscores that intronic variants outside the canonical splice sites must be taken in consideration and functionally tested, and that common variants should not be systematically discarded in the diagnosis of albinism, and, similarly, of other rare diseases.
Congenital Disorder of Glycosylation type Ib (MPI-CDG) is a rare autosomal recessive metabolic disorder caused by deficiency of mannose-6-phosphate isomerase, resulting in impaired N-glycosylation. Unlike other CDG subtypes, MPI-CDG is not associated with neurodevelopmental impairment and is effectively treated with oral D-mannose supplementation. However, evidence guiding management during pregnancy is scarce, and D-mannose is generally avoided due to limited safety data.We describe the long-term course and pregnancy outcomes of a woman diagnosed with MPI-CDG in infancy. She was treated with oral D-mannose throughout childhood with good clinical response but demonstrated intermittent non-compliance in adulthood, complicated by hepatic fibrosis, protein-losing enteropathy, osteoporosis, anaemia, and musculoskeletal manifestations. She had two pregnancies without D-mannose supplementation.The first pregnancy was complicated by microcytic anaemia, hypoalbuminemia, pregnancy-induced cholestasis, and emergency caesarean section. A male infant was delivered and later diagnosed with Hirschsprung disease, requiring surgical correction with good outcome. Postpartum assessment of the mother demonstrated progression of liver disease to cirrhosis (F4). The second pregnancy proceeded with fewer complications and resulted in emergency caesarean delivery of a healthy female infant with normal postnatal glucose control and growth.This case contributes to the limited literature on pregnancy in MPI-CDG and illustrates that successful pregnancies are possible despite advanced multisystem disease and cessation of D-mannose therapy. It highlights the importance of multidisciplinary care, close hepatic and nutritional monitoring, and the need for further studies to clarify the safety and role of D-mannose supplementation during pregnancy.
Background:Arimoclomol has been approved in the US for the treatment of Niemann-Pick disease type C (NPC) in patients aged ≥2 years, in combination with miglustat. This multicenter, open-label substudy of the phase 2/3 NPC-002 trial (NCT02612129) evaluated the safety, pharmacokinetics (PK) and impact on clinical status outcomes of arimoclomol in infants with NPC 6-<24 months of age. Methods:Infants with NPC aged 6-<24 months received arimoclomol in addition to their standard of care management for up to 36 months. The dosing regimen used for patients <24 months differed from the regimen recommended in the FDA label. The primary endpoint was safety and tolerability of arimoclomol; secondary endpoints were changes in clinical status (physical examination and Bayley III developmental scores), biomarkers, and PK. Results:Five patients (three females, two males; aged 14-23 months at screening) were enrolled; four remained in the study >12 months; arimoclomol exposure ranged from 72 to 1109 days. All patients received concomitant miglustat. Across 108 reported adverse events (AEs), most were considered mild or moderate in severity and non-serious. A total of 15 serious AEs were reported for two patients. Two AEs in one patient (elevated alanine/aspartate aminotransferases) were considered probably related to arimoclomol and resolved within 51 days; the patient was withdrawn from the substudy. No clinically significant changes were observed in hematology, kidney ultrasound imaging, or vital signs. Mean arimoclomol exposure over the first 8 h post-dose (1378.3-2988 h∙μg/L) was comparable to levels in NPC patients aged 2-19 years. Changes in Bayley III scores and biomarkers varied between individuals. Conclusion:Arimoclomol was well tolerated in infants initiating treatment before 2 years of age, with no new safety signals. PK profiles support the dosing regimen used. These findings suggest that early initiation of arimoclomol could be considered for the 6-24-month population. Further investigation in larger cohorts is warranted to elucidate the impact of arimoclomol in NPC patients under 2 years of age.
Newborn screening (NBS) for Fabry disease (FD) is highly effective at detecting FD prior to symptom onset. This initiative is currently being implemented worldwide. We previously reported results for 599,711 newborns from the first large-scale NBS program for FD in Japan, from August 2006 to December 2018. In this study, we provide additional data from January 2019 to September 2022. A total of 782,591 newborns were screened, and 29 variants, including 18 pathogenic variants and 11 variants of uncertain significance (VUS), were detected in 77 newborns (57 males and 20 females). Thirty-five male and 14 female newborns with pathogenic variants in GLA were identified. Twenty-two male and six female newborns with VUS in GLA were also identified. At the most recent follow-up, 5 of the 35 hemizygous patients manifested symptoms or signs and were receiving enzyme replacement therapy. The estimated frequency of patients with FD, including individuals with pathogenic variants or VUS identified in this study, was 1 in 7730, whereas that of patients with pathogenic variants was 1:12,436. FD-related cardiac and renal tissue damage are present before the onset of FD symptoms, such as limb pain. These findings highlight the importance of early diagnosis using NBS and regular monitoring.
Objectives:Acid sphingomyelinase deficiency (ASMD) is an inherited autosomal recessive disease caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene, which encodes acid sphingomyelinase (ASM). ASMD has 3 broad phenotypes (type A, type A/B, and type B) characterized by the age of onset, symptomatology, and the rapidity of disease progression. The diagnosis of ASMD can be delayed or missed because of the wide spectrum of severity and its variable manifestations. Analysis of genotype-phenotype correlations can help to determine ASMD disease type and inform management. Here, we describe the clinical presentation of 47 patients with ASMD referred to a single center in Iraq since 2007, whose diagnosis was confirmed by gene sequencing and ASM activity. Study design:This was a retrospective observational cohort study of patients diagnosed with ASMD in Iraq. Results:The cohort included 47 patients with ASMD. A positive family history and consanguinity were noted in 66% and 98% of these cases, respectively. Hepatosplenomegaly, anemia, and thrombocytopenia were present in 100%, 79%, and 44% of patients, respectively. Notably, dysmorphic features were observed in 23% of cases. Thirteen SMPD1 variants were present in this cohort, the most common of which were c.1556A > G (p.Tyr519Cys), c.740delG (p.Gly247Alafs*10), c.967A > C (p.Ser323Arg), and c.1267C > T (p.His423Tyr). Three of the variants identified were novel, specifically c.967A > C (p.Ser323Arg), c.1579A > G (p.Asn527Asp), and c.905C > T (p.Thr302Ile). Conclusions:Physicians assessing infants and children who present with hepatosplenomegaly or anemia and dysmorphic features should have a high index of suspicion for ASMD, particularly in regions with high rates of consanguineous unions.
Background:Monogenic causes of focal segmental glomerulosclerosis (FSGS) are increasingly recognized, but data from highly consanguineous Middle Eastern populations remain limited. This study explored the diagnostic yield and descriptive genotype-phenotype correlations of a targeted gene panel in Iraqi patients with biopsy-proven FSGS from a cohort enriched for familial, early-onset, and consanguineous disease. Methods:Thirty consecutive patients with histologically confirmed FSGS underwent next-generation sequencing using a 98-gene renal disease panel. Variants were classified according to ACMG guidelines and interpreted with clinical and histopathological findings. Exploratory analyses compared variant-positive and variant-negative patients and assessed simple clinical predictors of a positive genetic result. Results:Pathogenic variants were identified in 10 of 30 patients (33.3%) in COL4A3 (n = 2), COL4A4 (n = 3), JAG1 (n = 3), and NPHS2 (n = 2). Two novel frameshift variants were detected in COL4A4 (c.3109_3110delCT) and JAG1 (c.1713delC). Variant-positive patients had earlier disease onset than variant-negative patients (20.6 ± 7.2 vs. 30.1 ± 11.6 years; p = 0.022). In this small, enriched cohort, a simple triage rule based on age of onset <25 years, extrarenal manifestations, or family history showed 100% sensitivity and negative predictive value, but requires external validation before clinical use. Gene-group analyses suggested collagen IV-related disease, recessive podocytopathy, and Alagille-spectrum disease in relevant subgroups. Conclusions:In this predominantly familial and early-onset FSGS cohort, one-third of patients harbored pathogenic variants, supporting the value of gene-panel testing in selected young or syndromic patients while underscoring the need for validation in larger, more representative cohorts.
BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by progressive cyst development and renal dysfunction. While thyroid hormones (THs) are known to regulate key pathways in various kidney diseases, their role in ADPKD pathobiology and therapeutic potential remains unexplored. Here, we aimed to elucidate the role of THs in ADPKD and evaluate whether their pharmacological modulation could serve as a therapeutic strategy. METHODS:Patient-derived renal epithelial cells were used to engineer 3D polycystic tubules and to test the anti-cystogenic effects of THs and their analogs. The therapeutic efficacy of thyroxine (T4) in reducing cyst formation and delaying disease progression was assessed in vivo using PCK rats, an animal model of ADPKD. Lastly, serum THs levels were measured in 90 ADPKD patients enrolled in the REORIENTED clinical study and correlated with estimated glomerular filtration rate to explore their clinical relevance (Clinical Trial Gov NCT05646420). RESULTS:Mechanistically, thyroxine inhibits cyst growth by modulating proliferative, metabolic and ferroptotic pathways through αvβ3 integrin binding. In PCK rats, an animal model of ADPKD, T4 administration decreased kidney weight and significantly reduced macrocystic area (%, Vehicle 9.255 ± 2.654 vs. T4 1.945 ± 0.850, p < 0.05). Clinical data from ADPKD patients showed that altered TH serum levels correlate with disease severity: in the overall population of the study reverse triiodothyronine (rT3, a T3's metabolite) levels inversely correlate with renal function (R2 = 0.159, r = -0.397, p < 0.001), while free triiodothyronine (fT3) levels show a positive correlation (R2 = 0.110, r = 0.332, p < 0.01). CONCLUSIONS:This study reveals that THs contribute to ADPKD progression and identifies them as potential prognostic and therapeutic agents. By modulating multiple pathogenic pathways, THs may offer a novel, multi-targeted approach to reduce cyst growth and preserve renal function. These findings further support the development of personalized, hormone-based treatments and more refined stratification in the clinical management of ADPKD.
