Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study.

BACKGROUND Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. CASE REPORT The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK - C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as "with unknown clinical significance". CONCLUSIONS According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Neutrophil functions in patients with neutropenia due to glycogen storage disease type 1b treated with empagliflozin.

Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) are caused by the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) in granulocytes. The antidiabetic drug empagliflozin reduces the concentration of 1,5-anhydroglucitol (1,5 AG), thus restoring neutrophil counts and functions, leading to promising results in previous case reports. Here, we present a comprehensive analysis of neutrophil function in seven GSD1b patients and 11 healthy donors, aiming to evaluate the immediate (after 3 months) and long-term (after 12 months) efficacy of empagliflozin compared to the reference treatment with granulocyte-colony stimulating factor (G-CSF). We found that most patients receiving G-CSF remained neutropenic with dysfunctional granulocytes, whereas treatment with empagliflozin increased neutrophil counts and improved functionality by inhibiting apoptosis, restoring phagocytosis and the chemotactic response, normalizing the oxidative burst, and stabilizing cellular and plasma levels of defensins and lactotransferrin. These improvements correlated with the decrease in serum 1,5-AG levels. However, neither G-CSF nor empagliflozin overcame deficiencies in the production of cathelicidin/LL-37 and neutrophil extracellular traps. Given the general improvement promoted by empagliflozin treatment, patients were less susceptible to severe infections. G-CSF injections were therefore discontinued in six patients (and the dose was reduced in the seventh) without adverse effects. Our systematic analysis, the most extensive reported thus far, has demonstrated the superior efficacy of empagliflozin compared to G-CSF, restoring the neutrophil population and normal immune functions. EudraCT 2021-000580-78.

Preservative-free Bimatoprost 0.01% Ophthalmic Gel for Glaucoma Therapy. A Phase III Randomized Controlled Trial.

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel) compared with preserved bimatoprost 0.01% (PB 0.01%). DESIGN: Phase III, international, multicenter, randomized, 2-parallel group, investigator-masked, 3-month treatment duration. METHODS: Patients with glaucoma or ocular hypertension were randomized after a 7 week run-in/washout period to receive once-daily PFB 0.01% gel (n=236) or PB 0.01% (n=249) for 3 months. The primary efficacy measure was change from baseline in IOP at Week 12. Safety measures included adverse events (AEs) and assessment of conjunctival hyperemia. RESULTS: Mean change from baseline in IOP at Week 12 in the PFB 0.01% gel and PB 0.01% were -9.72±2.97 mmHg and -9.47±3.06, respectively at 8 am, -9.41±3.03 and -9.19±3.12 mmHg at 10 am, and -8.99±3.36 and -8.54±3.44 mmHg at 4 pm. Noninferiority of PFB 0.01% gel to PB 0.01% was demonstrated at Week 12 based on predetermined criteria (upper 95% confidence interval margin of 1.5 mmHg at all timepoints). The most frequently reported AE was conjunctival hyperemia; 13 (5.5%) patients with PFB 0.01% gel and 17 (6.8%) patients with PB 0.01%. The percentage of patients experiencing a worsening from baseline in conjunctival hyperemia score was lower with PFB 0.01% gel compared to PB 0.01% at Week 6 (20.1% vs 29.3%, respectively) and Week 12 (18.3% vs 30.4%, respectively). CONCLUSIONS: PFB 0.01% ophthalmic gel has the same efficacy in lowering IOP as PB 0.01% and demonstrated less aggravation of conjunctival hyperemia at Week 6 and Week 12.

Metabolic encephalopathies in children: A pragmatic diagnostic approach based on literature analysis.

Inborn errors of metabolism (IEM) in the general population are rare diseases. However, from the perspective of general pediatrics and pediatric intensive care units (PICUs), they are becoming a significant challenge both diagnostically and therapeutically. Clinically, there is a useful division of IEMs with neurological manifestations into 2 categories: acute and progressive encephalopathies. The extent of individual IEMs in these 2 groups varies, requiring different diagnostic strategies. Despite progress in development of diagnostic tools in IEM, initial diagnosis is made on the basis of basic laboratory tests, neuroradiological findings and metabolic screening. In settings of shortage of diagnostic resources and under time pressure, rational decisions should be made based on available clinical data. The text discusses diagnostic aspects of IEM presenting as metabolic encephalopathies, highlighting their significance in the context of general pediatric care and intensive care units (ICUs), and the challenges associated with diagnosis. It should be noted that the paper does not include a discussion of epileptic encephalopathies of IEM etiology, although some cases of metabolic encephalopathies may also present initially as epileptic encephalopathy.

Relationship between Bone Mineral Density and Selected Parameters of Calcium-Phosphate Economy with Dietary Management and Metabolic Control in Polish Pediatric Patients with Classical Homocystinuria-A Preliminary Study.

BACKGROUND: Classical homocystinuria (HCU) is an inborn defect of methionine metabolism caused by a deficiency of the enzyme cystathionine ß-synthase (CBS). The main symptoms of classical homocystinuria are lens subluxation, bone lesions, vascular disease and developmental delay/intellectual disability. The treatment method for HCU is a methionine-poor diet supplemented with amino acid preparations. The aim of the study was to examine the relationship of dietary factors, metabolic compensation and selected skeletal parameters in patients with HCU. METHODS: Bone mineral density measurements (DXA) were performed in pediatric patients with HCU, and blood levels of selected amino acids, minerals and vitamins, as well as dietary nutritional value, were analyzed. RESULTS: A total of 11 patients with HCU whose median age was 9.3 years were enrolled in the study. The median DXA total body less head of HCU patients was -0.4 z-score, and the lumbar spine was -1.4 z-score. Despite supplementation, calcium intake was below the age norm. Average vitamin D3 intake was in line with recommendations, but 36% of patients had reduced blood levels. Bone mineral density depended on blood levels of 25-hydroxyvitamin D, homocysteine and methionine, as well as on BMI, age and intake of natural protein (R2 = 98.5%, p = 0.015; R2 = 86.7%, p = 0.0049) and protein from an amino acid preparation (r = 0.69, p = 0.026). CONCLUSION: The results of the study indicate the need for regular densitometry in patients with HCU and also the use of additional calcium and vitamin D3 supplementation. It is also necessary to perform a comprehensive analysis of the diet and metabolic controls.

S100B Protein but Not 3-Nitrotyrosine Positively Correlates with Plasma Ammonia in Patients with Inherited Hyperammonemias: A New Promising Diagnostic Tool?

Individuals with inherited hyperammonemias often present developmental and intellectual deficiencies which are likely to be exaggerated by hyperammonemia episodes in long-term outcomes. In order to find a new, systemic marker common to the course of congenital hyperammonemias, we decided to measure the plasma level of S100 calcium-binding protein B (S100B), which is associated with cerebral impairment. Further, we analyzed three mechanistically diverged but linked with oxidative-nitrosative stress biochemical parameters: 3-nitrotyrosine (3-NT), a measure of plasma proteins' nitration; advanced oxidation protein products (AOPP), a measure of protein oxidation; and glutathione peroxidase (GPx) activity, a measure of anti-oxidative enzymatic capacity. The plasma biomarkers listed above were determined for the first time in congenital hyperammonemia. Also, the level of pro- and anti-inflammatory mediators (i.e., IL-12, IL-6, IL-8, TNF-α, IL-1ß, and IL-10) and chemokines (IP-10, MCP-1, MIG, and RANTES) were quantified. S100B was positively correlated with plasma ammonia level, while noticeable levels of circulating 3-NT in some of the patients' plasma did not correlate with ammonia concentration. Overall, the linear correlation between ammonia and S100B but not standard oxidative stress-related markers offers a unique perspective for the future identification and monitoring of neurological deficits risk-linked with hyperammonemia episodes in patients with inherited hyperammonemias. The S100B measure may support the development of therapeutic targets and clinical monitoring in these disorders.

Perinatal manifestations of congenital disorders of glycosylation-A clue to early diagnosis.

N-glycosylation defects-isolated or mixed with other glycosylation defects-are the most frequent congenital disorders of glycosylation and present mostly in childhood, with a specific combination of non-specific phenotypic features. The diagnosis, however, is often delayed. The aim of this study is to describe the perinatal phenotype of congenital disorders of N-glycosylation. We present an analysis of perinatal symptoms in a group of 24 one-center Polish patients with N-glycosylation defects-isolated or mixed. The paper expands the perinatal phenotype of CDGs and shows that some distinctive combinations of symptoms present in the perinatal period should raise a suspicion of CDGs in a differential diagnosis.

Clinical characteristics and long-term outcomes of patients with glycogen storage disease type 1b: a retrospective multi-center experience in Poland.

Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by a deficiency of microsomal glucose-6-phosphate (G6P) transport protein across the endoplasmic reticulum membrane. Patients with GSD 1b have hypoglycemia episodes, lactate acidosis, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, neutropenia and in imaging studies hepatomegaly and/or nephromegaly. The primary goals of treatment are to maintain proper blood glucose levels and to increase the number of properly functioning neutrophils. The aim of the study was a retrospective analysis of the clinical picture and treatment results of pediatric patients with type 1b glycogen storage disease from Poland. The study included 13 patients from 3 clinical centers, with a median age at diagnosis as 5 months. In 11/13 patients, the diagnosis was confirmed by molecular test, by the presence of pathogenic variants on both alleles of the SLC37A4 gene. Ten out of 13 patients developed the first symptoms in the form of severe infection (sepsis and/or pneumonia) already in the neonatal-infant period. A hypoglycemia episode was observed before diagnosis in 8/13 patients, of which 4/8 patients presented symptoms in the form of generalized relaxation and/or seizures. Two patients developed hypertension, and 4/13 required long-term treatment of inflammatory bowel disease.

The fibroblast growth factor 21 concentration in children with mitochondrial disease does not depend on the disease stage, but rather on the disease genotype.

ABSTRACT: The fibroblast growth factor 21 (FGF21) is a new biomarker of mitochondrial diseases (MD). FGF21 concentration may be used to define the severity of mitochondrial disease. AIM OF THE STUDY: The study objective was to verify if the FGF21 concentration in paediatric patients with MD was correlated with the disease severity and stage and to assess the correlation between FGF21 levels and the genetic background of MD. MATERIAL AND METHODS: The disease stage in MD subjects was determined on the basis of the International Paediatric Mitochondrial Disease Scale (IPMDS) and the concentrations of FGF21, lactic and pyruvic acids, alanine and creatine kinase in serum were assessed in those patients. RESULTS: The median age of children with MD (n = 32) was 33 months (range: 2-213), in the control group (n = 21) the median age was 42 months (range: 8-202). The concentrations of FGF21, lactic acid and pyruvic acid were higher in MD patients than in the control group. No correlation between the disease severity (IPMDS) and serum FGF21 concentration was found. The FGF21 concentration was higher in patients whose MD resulted from nuclear gene damage (nDNA), median FGF21 = 1022 (84-8873) pg/ml, than in patients with MD resulting from mitochondrial damage (mtDNA), median FGF21 = 736 (188-2906) pg/ml, or with an abnormal variant in the PDHA1 gene, median FGF21 = 58 (25-637) pg/ml. CONCLUSIONS: There is no correlation between the stage of MD and FGF21 level. Higher FGF21 values are seen in patients whose MD results from an abnormal nDNA variant rather than mtDNA damage.

Sodium-glucose cotransporter type 2 channel inhibitor: Breakthrough in the treatment of neutropenia in patients with glycogen storage disease type 1b?

Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by biallelic mutations in the SLC37A4 gene encoding microsomal glucose-6-phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. Ineffective G6P transport into the ER leads to hypoglycaemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hepato- and/or nephromegaly. Clinical manifestations of the disease include recurrent, severe infections and inflammatory bowel (Crohn-like) caused by neutropenia and diminished bactericidal and fungicidal activity of neutrophils. Granulocyte colony-stimulating factor (G-CSF) administration is currently a standard therapy to prevent adverse effects of neutropenia, but the treatment is associated with a high risk of severe side effects. On the other hand, short-treatment with sodium-glucose cotransporter type 2 inhibitor - empagliflozin (EMPA) was reported to act directly on the mechanism of neutropenia and neutrophil dysfunction in GSD 1b. We observed significant improvement in clinical and laboratory parameters after introducing EMPA to treatment, that is reduced frequency of infections, lower number of bowel movements, and improved postoperative wound healing. EMPA is effective in the treatment of neutropenia in our GSD 1b patients, which allows for dose reduction and even withdrawal of G-CSF. We did not observe any significant side effects of EMPA treatment in our patients.

COVID-19 Pandemic and Patients with Rare Inherited Metabolic Disorders and Rare Autoinflammatory Diseases-Organizational Challenges from the Point of View of Healthcare Providers.

COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one year of coronavirus pandemic has impacted the treatment of patients with IMD and AD in Poland. Surveys were distributed to all healthcare providers that coordinate the treatment of IMD and AD patients. Thirty-two responders (55%) answered the survey. They provide care to 1726 patients with IMD/AD, including 246 patients on dedicated treatment. In 35% of units, the regular appointments were disrupted, primarily because of patient infection. In 18 hospitals, remote visits were implemented, but only 66.6% of patients used this form of consultation. In 14/32 hospitals, administration of the therapy was delayed (median: 17.4 days). Forty-four patients suffered from SARS-COV-2 infection, in majority with mild symptoms. However, four adult patients developed complications, and one died following a SARS-COV-2 infection. Although most hospitals managed to maintain regular visits during the pandemic, more comprehensive implementation of telemedicine and switch to oral therapy or home infusions would be a reasonable solution for the current epidemic situation.

Sensorineural hearing loss in GSD type I patients. A newly recognized symptomatic association of potential clinical significance and unclear pathomechanism.

OBJECTIVE: Glycogen storage disease (GSD) type I is an inborn error of carbohydrates metabolism characterized by inability to convert glucose-6-phosphate to glucose. It presents with serious liver and metabolic complications, as well as in type Ib with severe infections due to neutropenia. So far, the sensorineural hearing impairment has not been reported in these patients. Bilateral, sensorineural hearing impairment was diagnosed in four unrelated GSDI patients. Congenital origin of hearing loss and descending audiometric curves warranted the need for future investigations. METHODS: Hearing status was assessed in entire group of 40 children with GSD type I. Then, molecular testing, massive parallel sequencing was performed in the four probands and their parents in order to find possible genetic background of auditory dysfunction in these patients. RESULTS: Pathogenic variants in G6PC and SLC37A4 related to the phenotypes of GSDI subtype Ia and subtype Ib were detected, each in two probands, respectively. No change in the genes involved in auditory pathway dysfunction was found. CONCLUSIONS: Sensorineural hearing loss appears to be associated with GSDI in approximately one out of ten cases. Careful assessment and monitoring of auditory functions of patients with GSDI is recommended.

Early treatment of biotin-thiamine-responsive basal ganglia disease improves the prognosis.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder associated with pathogenic variants in SLC19A3 gene. The clinical picture includes symptoms of subacute encephalopathy (e.g. confusion, dysphagia, dysarthria, and seizures), which respond very well to early treatment with thiamine and biotin. METHOD: A retrospective review of clinical characteristics, magnetic resonance imaging and molecular findings in 3 patients with BTBGD. RESULTS: The first symptoms in all patients occurred at 12-24 months of age and they had subacute encephalopathy, ataxia and dystonia. The baseline magnetic resonance imaging demonstrated abnormal signal intensity in the basal ganglia with atrophy and necrosis of the basal ganglia during follow-up in two patients. One patient was diagnosed and the treatment was initiated after a long period from symptoms onset and he is currently severely affected, with dystonia, quadriparesis and seizures. The other two patients were diagnosed early in life and are currently stable on treatment, without the clinical symptoms. Genetic testing demonstrated pathogenic variants in SLC19A3 gene. CONCLUSION: To avoid diagnostic errors and delayed or incorrect treatment, BTBGD must be recognized early. Adequate prompt treatment gives the chance of significant clinical improvement. Unexplained encephalopathy and MRI abnormalities including bilateral abnormal signal in the basal ganglia should alert the clinician to consider BTBGD in the differential, and the treatment with biotin and thiamine should be introduced immediately.

Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.

N-acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel noncoding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427-222G>A and NM_153006.2:c.427-218A>C reside in the 547 bp-long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor α. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.-3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.-3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing noncoding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

Epilepsy in Mitochondrial Diseases-Current State of Knowledge on Aetiology and Treatment.

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

Hepatic glycogen storage diseases: pathogenesis, clinical symptoms and therapeutic management.

Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. The first symptoms of the disease usually appear during the first months of life and are thus the domain of pediatricians. Due to the fairly wide access of the authors to unpublished materials and research, as well as direct contact with the GSD patients, the article addresses the problem of actual diagnostic procedures for patients with the suspected diseases. Knowledge and awareness of the problem among physicians seem insufficient, and research on the diagnosis and treatment of GSD is still ongoing, resulting in a heterogeneous GSD typology and a changing way of its diagnosis and treatment.

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up.

BACKGROUND: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical, and molecular findings of CDG patients, and to present the long-term follow-up. MATERIAL AND METHODS: A single-center study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation was performed. RESULTS: Among 32 patients included into the study, there were 12 PMM2-CDG, 3 ALG13-CDG, 3 ALG1-CDG, 1 ALG3-CDG, 3 MPI-CDG, 1 PGM1-CDG, 4 SRD5A3-CDG, 1 DPAGT1-CDG, 3 ATP6AP1-CDG, 1 ATP6V0A2-CDG. The phenotypic and genotypic spectrum during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between asialo-Tf and tetrasialo-Tf, as well as between disialo-Tf and tetrasialo-Tf. Within CDG type I, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG was assessed and we found that % of asialo-Tf, monosialo-Tf, and disialo-Tf was significantly lowered, whereas tetrasialo-Tf and pentasialo-Tf rose, coming closer or falling into the reference range. CONCLUSIONS: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM1-CDG patient, improved patients' clinical picture and Tf isoform profiles.

The potential of dietary treatment in patients with glycogen storage disease type IV.

There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension.