Diagnosis and management of porphyrias require appropriate biochemical testing. Tests available to practicing physicians in the US are not consistent and depend greatly on what is offered by individual laboratories. In a...Diagnosis and management of porphyrias require appropriate biochemical testing. Tests available to practicing physicians in the US are not consistent and depend greatly on what is offered by individual laboratories. In addition, harmonization, whereby results and interpretations from different laboratories are comparable, is not assured. Members of American Porphyrias Expert Collaborative (APEX) recommend that specific tests should be available to all physicians in the US for diagnosis and monitoring of porphyrias, and that harmonization of laboratory practices and results reporting across laboratories should be achieved. These efforts will lead to the development and more effective implementation of guidelines for the diagnosis and monitoring of porphyrias by both community providers and porphyria expert centers.
BACKGROUND: Patients with LCHADD/TFPD are counseled to follow a diet low in long-chain fats (LCT) and supplement with medium-chain fats (MCT) with adequate micronutrients, but there is limited data on patient implementat...BACKGROUND: Patients with LCHADD/TFPD are counseled to follow a diet low in long-chain fats (LCT) and supplement with medium-chain fats (MCT) with adequate micronutrients, but there is limited data on patient implementation of recommendations. We analyzed diet intake of LCHADD/TFPD participants twice, 2 years apart. METHODS: Participants enrolled in the longitudinal Natural History of LCHAD Retinopathy study completed a 3-day food record and supplement logs at baseline and 2 years later. Differences in %LCT and MCT intake over time, and intra-individual and population variation, were analyzed. Percentage of participants meeting estimated average requirements (EAR) for fat-soluble (A, D, E, K) and water-soluble vitamins (B1, B2, B3, C) were calculated. RESULTS: Forty participants were enrolled, 2-36 years (48% female), 25% G1528C homozygous, 68% G1528C heterozygous, and 7% TFPD. Thirty-five baseline and 38 follow-up diet records were included. Fat intake was consistent over time; baseline 13.7% LCT, 18.8% MCT, follow-up 14.7% LCT, 20.6% MCT. Intra-individual variation ranged from 22% to 32% for MCT and LCT, respectively, but both were less than the overall population variation 49% MCT and 36% LCT. An average of 38.8% of participants took a multivitamin; however, only 51% met the EAR for fat-soluble vitamins compared to 81% for water-soluble vitamins. CONCLUSIONS: LCHADD/TFPD patients are consistently consuming a low-fat diet with appropriate supplementation of MCT. Day-to-day variation in %LCT was comparable to the general population, but absolute amount of fat was lower. A greater proportion of patients are still not meeting EAR for fat-soluble vitamins compared to water-soluble vitamins.
Yılmaz-Gümüş E, Kılavuz S, Demir Ş
… +17 more, Aydoğan A, Genç E, Akar HT, Akbeyaz İH, Çakar NE, Er E, Gülbahçe A, Güneş H, Kardaş F, Kılıç M, Teke-Kısa P, Koşukcu C, Önal H, Taş İ, Türkdoğan D, Dursun A, Öztürk-Hişmi B
BACKGROUND: NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo-/alacrimia, peripheral neuropathy, and elevated transaminases. METHODS: We con...BACKGROUND: NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo-/alacrimia, peripheral neuropathy, and elevated transaminases. METHODS: We conducted a multicenter retrospective study including 15 patients from 11 families to evaluate the clinical, biochemical, and molecular features of the disease. A literature review was also performed, and phenotypic data from published patients were evaluated. RESULTS: All patients presented with developmental delay and dysmorphic facial features. Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5). Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4). Peripheral and auditory neuropathy findings were observed over time. Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10). We identified 10 distinct variants, including two novel variants c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)). Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed. CONCLUSION: Our findings expand the clinical and molecular spectrum of NGLY1 deficiency and highlight its dynamic and progressive course, supporting the need for long-term clinical follow-up. NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present.
OBJECTIVE: To compare adult females with X-linked adrenoleukodystrophy to age-matched controls and to evaluate the influence of this pathology on clinical presentation and responsiveness to exercise. METHODS: 14 females...OBJECTIVE: To compare adult females with X-linked adrenoleukodystrophy to age-matched controls and to evaluate the influence of this pathology on clinical presentation and responsiveness to exercise. METHODS: 14 females with X-linked adrenoleukodystrophy and 12 age-matched controls participated in a pre-post design with a 12-week exercise intervention. Outcome measures include neurological exam; quantitative strength, sensation, and walking measures; pain and quality of life questionnaires, and 3 T imaging for white matter integrity of brain and cervical spinal cord. RESULTS: At pre-test, females with X-linked adrenoleukodystrophy were significantly worse than controls in hip strength (flexion p = 0.02, extension p = 0.008), sensation (p < 0.0001), walk speed (Timed 25 ft walk p = 0.006, Timed up and go p = 0.02, walk velocity p = 0.13), pain (p = 0.007), and quality of life (p = 0.01). Significant positive changes are found in post-training for strength (flexion p = 0.03, extension p = 0.006) and walking (Timed 25-ft walk p = 0.01, walk velocity p = 0.008). Strength is the most significant factor affecting change in walk velocity in the regression model including group, disability, and imaging. Pain is the only factor that relates to quality of life, however, post training, improved strength moderates this relationship. Age significantly contributes to weakness in X-linked adrenoleukodystrophy but not to vibratory loss. White matter integrity contributes to models of vibratory loss and predicting walking benefits from exercise. INTERPRETATION: This data identifies meaningful outcomes for clinical trials and treatment guidelines for the health of females with X-linked adrenoleukodystrophy. Sensory loss quantification is an important marker of this pathology regardless of age-related changes. Pain significantly impacts quality of life. Importantly, we show that females with X-ALD responded to exercise with improved strength and walking as much as controls, despite starting from a more impaired state.
Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyoly...Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyolysis, limiting physical activity and compromising quality of life. Despite the recognition and avoidance of known triggers such as exercise, fasting, and stress, many patients suffer unexplained periodic episodes of muscle breakdown. While avoidance of fatty meals is recommended, the impact of high-fat consumption alone on muscle biology of CPT-deficient patients is not well defined. Mice with muscle specific CPT2-deletion (Cpt2) and control littermates, were placed on control or high-fat diet (HFD) (60% kcal) for up to 8 weeks. Muscle contractility, transcriptional and protein signatures, mitochondrial metabolic capacity, and histopathology were determined. After 8 weeks on the diet, Cpt2 ex vivo muscle force production was significantly reduced by high-fat feeding in the glycolytic EDL and oxidative soleus muscles. In response to HFD, Cpt2 muscle mitochondrial respiratory capacity was significantly reduced, despite increased mitochondrial biogenesis, across various muscles. Importantly, HFD further deteriorated the structural integrity of oxidative soleus muscle in CPT2-deficient mice, characterized by reduced fiber size and the presence of ragged red fibers. Together, these data indicate that chronic high dietary fat intake exacerbates the underlying mitochondrial and myopathic dysfunction caused by CPT2 deficiency. This diet-induced worsening of muscle pathology may provide a mechanistic explanation for the symptom exacerbation experienced by individuals with CPT2 deficiency following fatty food consumption.
BACKGROUND: Pyruvate dehydrogenase deficiency (PDHD) is a rare mitochondrial disorder characterized by impaired carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. Ketogenic diet therapy (...BACKGROUND: Pyruvate dehydrogenase deficiency (PDHD) is a rare mitochondrial disorder characterized by impaired carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. Ketogenic diet therapy (KDT) is commonly used to bypass defective glucose metabolism; however, evidence guiding clinical practice remains limited. OBJECTIVE: To evaluate global clinical practice and published evidence regarding the use of KDT in children and young people with PDHD. METHODS: A combined literature review and international clinician survey were conducted. A systematic search identified studies reporting KDT use in PDHD. Two international surveys targeting registered dietitians and medical doctors collected data on clinical practice, diet initiation, monitoring, outcomes, and adverse effects. RESULTS: Forty studies describing 129 patients were identified, predominantly case reports or series. Survey responses were obtained from 41 dietitians (142 patients) and 14 physicians (64 patients) across multiple regions. All physician respondents supported referral for KDT at diagnosis regardless of genotype. Classical ketogenic diets were most commonly prescribed, though modified approaches were frequently used in clinical practice to improve feasibility and palatability. Target β-hydroxybutyrate levels typically ranged between 2 and 4 mmol/L, although treatment was frequently individualized. Findings demonstrated improvements in seizure control, motor function, cognition, and quality of life. Adverse effects were primarily gastrointestinal. CONCLUSIONS: KDT is a widely used and generally well tolerated therapeutic strategy for PDHD across genotypes and age groups, with reported clinical benefits extending beyond seizure control. Clinical practice demonstrates variability, reflecting the limited high-quality evidence base. Development of standardized but flexible clinical guidelines and further longitudinal studies are needed to optimize patient outcomes.
Pompe disease is a lysosomal disorder associated with respiratory muscle weakness and a high risk of sleep-disordered breathing (SDB). The impact of enzyme replacement therapy (ERT) on respiratory parameters remains insu...Pompe disease is a lysosomal disorder associated with respiratory muscle weakness and a high risk of sleep-disordered breathing (SDB). The impact of enzyme replacement therapy (ERT) on respiratory parameters remains insufficiently analyzed. The aim of the study was to retrospectively review the polysomnographic/polygraphic (PSG/PG) characteristics and longitudinal trajectories of 22 children with Pompe disease in an era of universal access to ERT in France. Nineteen patients had Infantile-Onset Pompe disease (IOPD) and three had Late-Onset Pompe disease (LOPD). For the IOPD subgroup, the median age at diagnosis was 2 (0-8) months and ERT was started at 2.5 (0.5-10) months. Seven patients had mild obstructive sleep apnea (OSA) with one patient having associated hypercapnia and one patient had moderate OSA. For the LOPD subgroup, the median age at diagnosis was 36 (0-48) months and ERT was started at 39 (0-52) months. One patient had moderate OSA with hypercapnia. Of the IOPD patients, after their baseline PSG/PG, two patients were weaned from NIV and two patients were initiated on long-term NIV. Among the LOPD patients, one patient continued NIV after his baseline PSG/PG. Regarding follow-up PSG/PG for the IOPD patients, one patient was successfully weaned from NIV, and one continued long-term NIV. Our findings suggest that, in a cohort of patients receiving ERT, nocturnal respiratory function is largely preserved, and that early diagnosis and prompt initiation of ERT may mitigate the progression of respiratory disease, which has historically been associated with a poor prognosis.
Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal...Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.
Pseudodeficiency alleles pose a significant challenge to Pompe disease (PD) newborn and high-risk screening by causing false-positive enzyme reductions without clinical manifestations. The clinical significance of the GA...Pseudodeficiency alleles pose a significant challenge to Pompe disease (PD) newborn and high-risk screening by causing false-positive enzyme reductions without clinical manifestations. The clinical significance of the GAA c.[752C > T;761C > T] haplotype, frequently identified in East Asian screening programs, remains uncertain. We conducted a retrospective review of the Chinese PD high-risk screening program, identifying 22 individuals from 11 independent families carrying this haplotype. PD phenotypes occurred exclusively when the haplotype was coupled with two pathogenic variants in trans (one in cis). Crucially, individuals homozygous for the haplotype or carrying it in trans with a single pathogenic variant remained asymptomatic, despite dried blood spot (DBS) GAA activity falling below the diagnostic threshold (34% of the lower normal limit). Computational structural modeling corroborated these clinical observations, revealing minimal conformational alterations that preserve the integrity of the catalytic site. Furthermore, the haplotype is markedly enriched in East Asian populations (allele frequencies: 0.259% for c.752C > T and 0.263% for c.761C > T) compared to other ethnic groups. Collectively, these clinical, structural, and population data support the classification of the GAA c.[752C > T;761C > T] haplotype as a pseudodeficiency allele. Genotyping to identify this haplotype is essential to prevent misdiagnosis and avoid unnecessary treatment in East Asian populations.
Vaia Y, Arrigoni F, Sira LB
… +24 more, Bernard G, Bertini E, Boespflug-Tanguy O, Bruschi F, Cereda C, Eichler F, Erbetta A, Ferraro S, Heidari M, Lalli L, Lambert G, Libzon S, Longo D, Moroni I, Nagy A, Nicita F, Renaldo F, Rodriguez D, Khan GS, Tavasoli AR, Winter E, Zerem A, Parazzini C, Tonduti D
INTRODUCTION: Type I Alexander Disease (AxD) is a rare leukodystrophy that can be subclassified into subtypes (Ia, Ib, Ic, and Id), in order of decreasing severity. To date, no study has correlated MRI findings with AxD...INTRODUCTION: Type I Alexander Disease (AxD) is a rare leukodystrophy that can be subclassified into subtypes (Ia, Ib, Ic, and Id), in order of decreasing severity. To date, no study has correlated MRI findings with AxD type I clinical evolution. This study aims to identify MRI features that may predict disease progression. METHODS: Patients with genetically confirmed type I AxD were recruited from multiple Leukodystrophy Centers worldwide. Clinical data were collected via RedCap, and patients were retrospectively classified by disease subtype. Leukodystrophy experts analyzed the first available MRI scans using an adapted AxD MRI scoring protocol, and imaging findings were correlated with disease subtypes. RESULTS: 47 subjects with type I AxD were enrolled. Subtype distribution included 3 Ia, 12 Ib, 8 Ic, 10 Id, 10 Ic/Id, and 4 undetermined. Risk of belonging to type Ib compared to other subtypes was significantly increased in case of involvement of parietal subcortical WM (OR = 16.1, p = 0.003), occipital deep WM (p = 0.008), temporal deep (p = 0.018), and periventricular WM (p = 0.013), body of corpus callosum (p = 0.018), genu of corpus callosum (p = 0.047) and hilar region of cerebellum (p = 0.008). Involvement of occipital periventricular WM was associated to a higher risk of being type Ic compared to type Id (p = 0.010). CONCLUSIONS: Some distinct MRI patterns on initial MRI scans may predict disease outcomes in type I AxD. These findings may help clinicians in early prognostic stratification, with key brain regions needing careful evaluation. Further studies are required to validate these findings and improve prognostic accuracy in type I AxD.
Maple syrup urine disease (MSUD) is a rare inherited disorder identified through newborn screening. Monitoring relies on using established biochemical biomarkers; however, neurodevelopmental outcomes remain variable desp...Maple syrup urine disease (MSUD) is a rare inherited disorder identified through newborn screening. Monitoring relies on using established biochemical biomarkers; however, neurodevelopmental outcomes remain variable despite metabolic control. Structural neuroimaging in MSUD has identified acute and chronic brain injury, but these approaches provide limited insight into functional brain physiology. Recent preclinical work by demonstrated altered resting-state functional connectivity in a mouse model of MSUD using functional near-infrared spectroscopy (fNIRS), suggesting that metabolic dysregulation directly impacts cortical function. The objective of this study was to translate preclinical fNIRS findings to humans with MSUD by evaluating the feasibility of fNIRS acquisition and exploring cortical hemodynamic and functional measures. fNIRS data were successfully acquired in MSUD cohort, demonstrating the feasibility of this approach in this population. Participants from two age groups (<8 years and ≥ 8 years) completed age-appropriate cognitive tasks (video tasks, and an N-back, respectively). Across both language and working memory paradigms, greater activation was observed in prefrontal regions relative to parietal and occipital areas, reflecting the cognitive demands of the tasks in both MSUD and controls. While group-level differences in hemoglobin concentration suggest potential alterations in cortical hemodynamics in MSUD. Although N-back task performance was broadly comparable between groups, differences in hemoglobin concentration suggest potential alterations in cortical hemodynamics in individuals with MSUD. These findings support the use of fNIRS as a practical and adjunctive neuroimaging modality for studying rare metabolic disorders and provide a foundation for future longitudinal studies aimed at identifying disease-specific functional biomarkers.
INTRODUCTION: GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exi...INTRODUCTION: GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. METHODS: In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. RESULTS: Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. CONCLUSIONS: Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.
BACKGROUND: Patients with Gaucher disease (GD) require lifelong monitoring of visceral involvement. The GD type 1 disease severity scoring system (GD1-DS3) is commonly used for longitudinal assessment but is clinically i...BACKGROUND: Patients with Gaucher disease (GD) require lifelong monitoring of visceral involvement. The GD type 1 disease severity scoring system (GD1-DS3) is commonly used for longitudinal assessment but is clinically intensive and not imaging-based. The goal of this study was to evaluate whether liver magnetic resonance elastography (MRE) is associated with longitudinal changes in disease severity. METHODS: This retrospective longitudinal study included patients with GD who underwent ≥1 liver MRE between April 2019 and April 2025. Clinical data were used to calculate GD1-DS3 scores, and imaging parameters including liver stiffness were extracted from MR imaging reports. Longitudinal associations between liver stiffness and GD1-DS3 scores were evaluated using linear mixed-effects models with random intercepts to account for repeated measurements, adjusting for age, sex, treatment group, spleen stiffness, and time. RESULTS: Forty-two individuals (90.5% type 1 GD) with 77 MRE examinations were analyzed. Over time, GD1-DS3 scores decreased modestly (0.24 units per year, p = 0.036). Liver stiffness was independently associated with disease severity: Each 1 kPa increase in liver stiffness corresponded to a 0.53-unit increase in GD1-DS3 score (p < 0.01) after adjustment for covariates. Liver stiffness remained a significant predictor of GD1-DS3 severity independent of time. CONCLUSIONS: Liver stiffness independently predicted GD1-DS3 severity after adjusting for time and covariates. These findings support liver MRE as a valuable noninvasive imaging biomarker for longitudinal monitoring of hepatic involvement and composite clinical severity in patients with GD.
With the expanding treatment landscape for phenylketonuria (PKU), there is a growing need for a reliable, non-invasive method to quantify residual phenylalanine hydroxylase (PAH) activity and to determine disease severit...With the expanding treatment landscape for phenylketonuria (PKU), there is a growing need for a reliable, non-invasive method to quantify residual phenylalanine hydroxylase (PAH) activity and to determine disease severity to guide individualized treatment strategies. The C-Phenylalanine (Phe) breath test (C-PBT) has the potential to measure in vivo oxidation of Phe by quantifying conversion of C-Phe to CO. Although the C-PBT has previously been used in PKU, its test-retest reliability in PAH deficient individuals has not been studied. The aim of this study was to assess the test-retest reliability of the C-PBT in individuals with PAH deficiency and to evaluate the association between C-Phe oxidation parameters and disease severity. To establish preliminary reference values and to optimize protocol, 10 healthy adults underwent the C-PBT once. Subsequently, 10 individuals with varying severities of PAH deficiency completed the test twice. After an overnight fast, all participants received an oral dose of 6 mg/kg C-Phe. Both area under the curve (AUC) and the maximum C-Phe oxidation showed a good-to-excellent test-retest reliability, expressed as an ICC of 0.93 (95% CI 0.71-0.98) and 0.91 (95% CI 0.68-0.98) respectively. When stratifying for the genotypic phenotype value (GPV), it was shown that a lower GPV was associated with lower oxidation parameters in comparison to higher GPV levels. These findings support the C-PBT as a reliable, easy to perform, non-invasive measure of in vivo PAH function that could potentially aid in the interpretation of PAH variants and the assessment of treatment response. TAKE HOME MESSAGE: The C-Phenylalanine breath test shows good-to-excellent test-retest reliability in adults with phenylalanine hydroxylase deficiency, supporting its potential role as a non-invasive measure of in vivo PAH activity that may aid individualized treatment in PKU.
Aromatic L-amino acid decarboxylase (AADC), encoded by DDC gene, catalyzes the final step in dopamine and serotonin biosynthesis. Pathogenic DDC variants cause AADC deficiency, a severe neurometabolic disorder. This stud...Aromatic L-amino acid decarboxylase (AADC), encoded by DDC gene, catalyzes the final step in dopamine and serotonin biosynthesis. Pathogenic DDC variants cause AADC deficiency, a severe neurometabolic disorder. This study aimed to elucidate previously uninvestigated DDC variant combinations: p.Pro47Ala/p.Arg447Cys and p.Cys261Phe/p.Gly354Ser, with respect to structural and functional characteristics. Recombinant heterodimeric and homodimeric AADC proteins were expressed in Escherichia coli and purified. Enzymatic activity was quantified via ion-pair reversed-phase HPLC with photodiode detection, while structural changes were analyzed using circular dichroism and molecular modelling. Functional characterization revealed that p.Pro47Ala, p.Gly354Ser, and p.Arg447Cys homodimers showed marked loss of activity towards both L-DOPA (88%, 97% and >99%, respectively) and L-5-hydroxytryptophan (88%, 99%, >99%, respectively), whereas p.Cys261Phe retained substantial activity (82% for L-DOPA and 75% for L-5-hydroxytryptophan). Kinetic analysis indicated a mild to severe decrease in substrate affinity for all homodimers, particularly for p.Arg447Cys. Furthermore, heterodimeric combinations showed positive complementation effects on decarboxylase reaction for both heterodimers. Surprisingly, p.Cys261Phe/p.Gly354Ser also restored the wild-type activity with L-DOPA and regained 43% of L-5-hydroxytryptophan activity, whereas p.Pro47Ala/p.Arg447Cys was 15% and 10% active towards L-DOPA and L-5-hydroxytryptophan with respect to the wild-type. Our results indicate that the pathogenicity of AADC variants depends on structural combination, complementation effects in heterodimeric species, and residual activity of homodimers, highlighting the complexity of polypeptide chain interactions in compound heterozygotes.
BACKGROUND: Conserved oligomeric Golgi (COG) deficiencies are rare congenital disorders of glycosylation characterized by severe multisystem involvement. Recurrent inflammatory episodes have been reported but remain poor...BACKGROUND: Conserved oligomeric Golgi (COG) deficiencies are rare congenital disorders of glycosylation characterized by severe multisystem involvement. Recurrent inflammatory episodes have been reported but remain poorly understood and are likely underrecognized. METHODS: We describe three patients with COG6 or COG7 deficiency presenting recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). In parallel, we conducted a systematic review of the literature to assess the frequency and characteristics of inflammatory manifestations in COG deficiency. RESULTS: All three patients experienced recurrent febrile episodes associated with biological features of HLH. In two cases, these episodes were followed by neurological deterioration and onset of epilepsy. Early or prophylactic corticosteroid therapy during febrile episodes appeared to mitigate both the severity and neurological impact of inflammatory flares. The literature review identified recurrent, unexplained, and poorly tolerated febrile episodes in approximately 40% of reported patients. Only one additional case of fully documented HLH was identified. However, multiple reports described partial or suggestive HLH features, supporting the hypothesis that hyperinflammatory manifestations are underdiagnosed in this population. CONCLUSION: COG deficiencies, especially COG6 and COG7, may be complicated by recurrent and potentially severe hyperinflammatory episodes, including HLH, with significant neurological consequences. These findings suggest a link between glycosylation defects and immune dysregulation. Early recognition and preventive anti-inflammatory strategies are recommended.
van Kuilenburg ABP, Mandel H, Moady TA
… +21 more, Sloma R, Fedida A, Leen R, Jansen-Meijer J, Paperna T, Sheffer VF, Dobritzsch D, Hochwald O, van der Wel NN, Grootemaat AE, Chulsky S, Rootman MS, Eran A, Yousef MA, Dinwiddie A, Manor J, van Karnebeek CDM, Kalfon L, Hershkovitz T, Tal G, Falik Zaccai TC
The clinical and genetic features of ataxia with isolated vitamin E deficiency (AVED) patients in Chinese are remain not well understood. We enrolled 120 unrelated probands with clinically suspected autosomal recessive c...The clinical and genetic features of ataxia with isolated vitamin E deficiency (AVED) patients in Chinese are remain not well understood. We enrolled 120 unrelated probands with clinically suspected autosomal recessive cerebellar ataxia (ARCA) at the Department of Neurology, China-Japan Friendship Hospital between 2014 and 2024. all probands underwent Whole-exome sequencing (WES), with candidate variants validated by Sanger sequencing and family cosegregation analysis. In silico pathogenicity analysis, including protein structure homology modeling and multispecies conservation analysis, was performed for novel variants. Plasma vitamin E levels were measured using high-performance liquid chromatography with diode array detection(HPLC-DAD). We identified 4 probands with biallelic TTPA variants, accounting for 3.33% of the ARCA cohort. Three probands were from consanguineous families, and 1 was from non- consanguineous family. The median age at onset was 15years (range 14-23years), with gait instability/ataxia as the universal initial symptom. Core clinical features included cerebellar ataxia (4/4), dysarthria (4/4), areflexia (2/4), scoliosis (4/4), foot deformity (3/4), and head titubation (3/4). Brain MRI revealed cerebellar atrophy in 3 patients, and all had markedly reduced serum vitamin E levels. We identified 2 novel missense variants (c.265C>A(p.P89T) and c.790A>G(p.M264V)). All patients received high-dose vitamin E supplementation, with 3/4 improved ataxia symptoms at 2-years follow-up. Our findings expand the clinical and genetic spectrum of AVED in China and support early evaluation of plasma vitamin E status and TTPA variants in patients with unexplained sporadic or recessive ataxia, as well as proactive screening of siblings and other at-risk relatives, even before symptom onset.
Snyder-Robinson syndrome (SRS) is an X-linked polyaminopathy caused by pathogenic variants in the spermine synthase (SMS) gene, resulting in impaired spermine synthesis, accumulation of spermidine, and widespread cellula...Snyder-Robinson syndrome (SRS) is an X-linked polyaminopathy caused by pathogenic variants in the spermine synthase (SMS) gene, resulting in impaired spermine synthesis, accumulation of spermidine, and widespread cellular dysfunction. Although mitochondrial impairment has been implicated in SRS, the impact of SMS deficiency on cellular energy metabolism has not been systematically characterized. In the present study, we performed high-throughput metabolic profiling of 29 patient-derived lymphoblastoid cell lines using Biolog Phenotype Mammalian Microarrays. SRS cells exhibited broad metabolic rewiring, including reduced utilization of galactose, and compensatory increases in the metabolism of d-fructose, maltose, maltotriose, and a- keto-glutaric acid. They also showed attenuated metabolic responses to ionic perturbations and blunted sensitivity to insulin and glucagon, indicating defects in both mitochondrial substrate preference and signal-dependent metabolic regulation. Treatment with phenylbutyrate (PBA), previously shown to modulate polyamine catabolism, partially restored metabolic flexibility and normalized several impaired nutrient pathways. These findings highlight global energy metabolism dysregulation as a hallmark of SRS and support PBA as a promising therapeutic candidate for correcting bioenergetic defects in this disorder.
BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Sepiapterin, the most recently FDA-approved therapeutic for PKU, is indicated for sepiapterin-respo...BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Sepiapterin, the most recently FDA-approved therapeutic for PKU, is indicated for sepiapterin-responsive PKU in individuals >1 month of age. Real-world experience is needed to characterize clinical impact across patient subsets. METHODS: A retrospective chart review was conducted for PKU patients at Lurie Children's Hospital prescribed sepiapterin from August 2025 through January 2026. Baseline characteristics, genotypic phenotype values (GPV), historical sapropterin responsiveness, and treatment outcomes were analyzed. RESULTS: Of 63 patients prescribed sepiapterin, 53 initiated treatment. The cohort included 34 sapropterin-responsive, 12 non-sapropterin-responsive, and 7 treatment-naïve patients. Of 50 patients who submitted blood samples, 76% (n = 38) responded to sepiapterin. Mean Phe reductions were 46% (GPV ≤2.7), 53% (GPV 2.8-6.6), and 41% (GPV >6.6). Notably, a mean 46% reduction occurred in sapropterin-responsive patients already receiving sapropterin. Within the non-sapropterin responsive cohort 27% (3/11) had a mean blood Phe reduction ≥15% (16%-76%; mean 56%). Dietary liberalization occurred in 64% of patients, with 88% increasing natural protein intake and 5 patients discontinuing medical nutrition therapy. The discontinuation rate was 10% due to inadequate response. Side effects were predominantly gastrointestinal (loose stools 8%, abdominal pain 9%). CONCLUSIONS: Real-world experience with sepiapterin demonstrates a 76% response rate in the group of PKU patients tested which included a disproportionate number of sapropterin-responsive subjects. Clinical benefit was observed in individuals across the PKU severity spectrum, including a proportion of patients with classical PKU and those historically non-responsive to cofactor therapy. The favorable safety profile and potential for dietary liberalization support sepiapterin as a valuable treatment option for individuals with PKU.