Objective Inherited metabolic disorders (IMDs) are heterogeneous genetic diseases whose observed spectrum is influenced by population characteristics, newborn screening (NBS), and diagnostic pathways.This study aimed to characterize confirmed IMDs diagnosed through NBS and symptomatic referrals at a tertiary center in Eastern Türkiye and estimate the regional burden of selected disorders. Methods This retrospective study included patients evaluated between September 2022 and September 2024. IMDs were confirmed by biochemical and/or molecular genetic analyses. Population and live-birth data from the defined referral region were used to estimate regional and NBS-based birth prevalence. Results Among 9603 patients evaluated, 828 (8.6%) had a confirmed IMDs; 580 (70.0%) were identified through NBS, 230 (27.8%) through symptomatic referral, and 18 (2.2%) through family screening. Vitamin and cofactor metabolism (43.8%) and amino acid metabolism disorders (35.7%) predominated. Biotinidase deficiency was the most frequent disorder (n = 360, 43.4%), including 316 (87.8%) partial and 44 (12.2%) profound cases. Neurological manifestations were the most frequent presentation among symptomatic patients (23.2%). Based on 61,409 estimated live births, estimated birth prevalence was 1:627 for the hyperphenylalaninemia/phenylketonuria spectrum and 1:543 for biotinidase deficiency. Minimum estimated regional prevalence was 1.07 and 0.97 per 100,000 for mucopolysaccharidoses and alkaptonuria, respectively. Conclusion NBS and symptom-based evaluation are complementary diagnostic pathways for IMDs. The observed disease spectrum reflects the influence of screening strategies, while symptomatic referrals reveal broader clinical and genetic heterogeneity.
Alpha-mannosidosis (AM) is a rare lysosomal storage disease with heterogeneous disease manifestations and a continuous spectrum of severity. The only specific treatment for AM is enzyme replacement therapy with velmanase alfa (VA). The focus of this analysis was to assess changes in physician-reported clinical manifestations of AM following VA treatment, using data from Étoile Alpha, a multicenter, non-interventional registry of AM patients treated with VA in France. The cohort included 16 patients (7 females [43.7%]) and 9 males [56.3%]), with a median (range) age at VA initiation and duration of VA treatment of 15.7 (6.1–49.4) and 3.3 (1.1–9.2) years, respectively. Clinical outcomes, including 3-minute stair climb test, 6-minute walk test, forced expiratory volume in 1 second and forced vital capacity, showed numerical improvements from baseline to the last assessment. VA treatment was associated with significant (p < 0.0001) improvements in overall physician-assessed health assessment scores, encompassing motor, quality of life and psychological domains. Across all individual clinical manifestations, VA led to either improvement or stability, with no deteriorations reported. Lower patient age at inclusion, diagnosis and at VA initiation were significantly (p < 0.05) associated with improvement of clinical manifestations. To complement these clinical data, physician-reported narratives recorded before and after VA treatment were evaluated using natural language processing. Sentiment analysis revealed that all pre-treatment narratives were negative, with shifting to positive sentiment in 81.3% of cases following treatment. This analysis highlights the varied clinical manifestations associated with AM and underscores the potential benefits of early intervention with enzyme replacement therapy.
Objective To provide key considerations and best practices for restarting pegvaliase based on real-world experiences of healthcare professionals managing individuals with phenylketonuria (PKU). Methods An in-person advisory board with 11 experienced PKU practitioners identified strategies for restarting pegvaliase after a treatment pause. The advisors presented real-world restart cases detailing treatment history, reasons for discontinuation, restart approach, and outcomes, followed by discussions about best practices for clinical decision-making. Results Among 11 restart cases, reasons for treatment discontinuation included adverse events (AEs) (3 cases), limited blood phenylalanine (Phe) response (4 cases), clinical trial participation (1 case), and pregnancy (3 cases). Time off treatment ranged from 3 to 64 months. Eight cases restarted pegvaliase with an expedited titration schedule, while 2 cases resumed with a slowed approach and 1 case used the standard titration. At the time of the advisory board, 9 cases had achieved blood Phe ≤360 μmol/L, 1 case still had elevated blood Phe levels but had not yet completed titration and 1 case discontinued after 18 months on therapy.Key considerations for restarting pegvaliase after AE-related discontinuations include proactively addressing anxiety, optimizing premedications, ensuring access to on-demand medications and using a flexible, individualized titration approach. For individuals discontinuing primarily due to a limited blood Phe response, resuming at the previously tolerated dose and titrating adaptively as tolerated may be considered. For individuals desiring an expedited titration, more frequent blood Phe monitoring may be warranted to guide dietary adjustments and dosing. Life changes, individual preferences and social determinants of health should inform timing and resources for restart. For pregnancy-related discontinuations restart decisions should be made collaboratively with the individual and care team (geneticist, metabolic dietitian, obstetrician, and other relevant caregivers). Conclusion Pegvaliase can help achieve blood Phe control, which may mitigate neurocognitive effects and can result in greater dietary flexibility and improved quality of life. Restarting pegvaliase is feasible for most individuals, with many having a better experience during the restart process compared with the first treatment initiation. AEs were reported (eg, injection site reactions, rash, and arthralgia) but were milder compared to the previous treatment course in most cases and some individuals responded at lower doses or after shorter treatment duration. Restarting pegvaliase should be considered as part of a shared decision-making process for individuals seeking to further optimize outcomes.
The m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene is a rare cause of mitochondrial cardiomyopathy (MCM). We report a Japanese family with this variant across three generations, demonstrating a wide clinical spectrum ranging from asymptomatic carriers to lethal infantile cardiomyopathy. The proband was a newborn male infant who developed severe hypertrophic obstructive cardiomyopathy, generalized hypotonia, and profound lactic acidosis (43.9 mmol/L) shortly after birth. Despite intensive care, the patient died at 11 days of age due to multiorgan failure. Autopsy revealed diffuse cardiac hypertrophy and abnormal mitochondria. Genetic analysis showed 98% heteroplasmy of the m.3303C > T variant in multiple tissues. Family screening revealed variant loads ranging from 6% to 100% in seven relatives, with clinical manifestations only appearing when the variant load exceeded 90%. One maternal uncle with 100% muscle heteroplasmy died at the age of 7 years from mitochondrial myopathy. Other family members with variant loads below 90% were asymptomatic. This study demonstrates that the m.3303C > T variant exhibited, within this family, an exceptionally high threshold effect, with severe phenotypes manifesting only at very high heteroplasmy levels (>90%), and highlights the importance of family screening for genetic counseling.
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.
Type I collagen is the most abundant form of collagen and forms the organic component of bone. Pathogenic variants in genes encoding its constituent polypeptide chains, COL1A1 and COL1A2, can result in autosomal dominant osteogenesis imperfecta and other connective tissue disorders. Although osteogenesis imperfecta is clinically well-described, the molecular basis of clinical heterogeneity among patients is not well understood. We undertook a global proteomic approach to uncover alterations in osteogenesis imperfecta patient bone-derived stromal cells as well as their secretome. We performed multiplexed tandem mass tag (TMT)-based proteomics analysis of cells from three patients along with three controls to investigate global changes in the proteome of these cells as well as their secretome. This was combined with analysis of proline hydroxylation to catalog the modification of type I collagens in this disorder. We observed significant changes in both the cellular and secreted proteomes including the levels of proteins involved in osteoblast proliferation such as nitric oxide synthase-interacting protein (NOSIP), secreted frizzled-related protein 1 (SRFP1) and transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1) as well as others involved in endoplasmic reticulum homeostasis such as protein disulfide isomerase A6 (PDIA6) and reticulophagy regulator 3 (RETREG3). Notably, a number of alterations were observed in proline hydroxylation in intracellular collagens - COL1A1 and COL1A2. These findings expand our current understanding of the cellular pathophysiology in osteogenesis imperfecta and could lead to the identification of novel therapeutic targets.
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.
CACNA1C-related disorder (CRD), a severe multisystem disorder caused by variants of CACNA1C gene, presents significant diagnostic and management challenges due to its rarity and variable expressivity. This study leverages a detailed longitudinal case report and comprehensive literature review to expand the phenotypic spectrum of CRD with Timothy syndrome (TS) features associated with the CACNA1C NM_001129830.1: c.3061 T > C (p.Cys1021Arg) variant. We describe an individual with CRD exhibiting a severe multisystem phenotype including classic features like syndactyly, profound neurological symptoms, and cardiac arrhythmias. Critically, our detailed clinical and genetic analysis identified previously undocumented features for this specific variant: cerebral infarction, as well as a combined T-cell and B-cell immunodeficiency characterized by specific lymphocyte dysregulation. These novel findings necessitate refined diagnostic protocols and tailored management strategies. By redefining CRD with TS features as a profoundly multisystem disorder, this expanded understanding facilitates improved prognostication, genetic counseling, and targeted therapeutic interventions, aiming to transform management from unpredictable complications into predictable, preventable components, ultimately enhancing quality of life and survival.
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.
