Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Is lysosomal acid lipase activity associated with the presence and severity of coronary artery disease?

BACKGROUND: Lipid metabolism is considerably complex and there can be many critical steps in atherogenesis. The association between lysosomal acid lipase (LAL) activity and coronary artery disease (CAD) has not been elucidated in detail. We aimed to evaluate the association between LAL activity with the presence and severity of CAD in patients who are seen in daily clinical practice. METHODS: Patients who underwent coronary angiography were divided into groups according to the angiography results. Syntax scores and Gensini scores were calculated. The LAL activity was measured from dried blood spots. RESULTS: Median LAL activity values were similar in all study groups (normal coronary arteries: 0.40 nmol/punch/h; non-obstructive CAD: 0.44 nmol/punch/h; obstructive chronic CAD: 0.40 nmol/punch/h; obstructive acute coronary syndrome: 0.48 nmol/punch/h) and there was no correlation between coronary atherosclerotic burden and LAL activity (correlation coefficients Syntax score and LAL: -0.032; Gensini score and LAL: -0.030). In addition, no relationship between serum lipid levels and LAL activity was detected. CONCLUSION: The presence of CAD and its severity is not associated with the LAL activity in patients encountered in daily clinical practice.

Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.

BACKGROUND AND OBJECTIVE: Pompe disease (PD) is an inherited lysosomal storage disease that progresses with glycogen accumulation in many tissues, due to the deficiency of the acid-alpha glucosidase enzyme. Recombinant alglucosidase alfa (rhGAA) is the only disease-specific treatment option, in the form of enzyme replacement therapy (ERT). Anaphylaxis can develop with rhGAA. There is no study evaluating anaphylaxis and its management in PD in the long term. We aimed to evaluate the development of anaphylaxis and rapid drug desensitization (RDD) with rhGAA in children with PD. MATERIALS AND METHODS: All children diagnosed and followed up in our institution with PD over 12 years between January 2009 and September 2021 were evaluated for development of anaphylaxis and RDD with rhGAA from medical records. RESULTS: Fourteen patients, 64% of whom were female and diagnosed with PD (1 juvenile, 13 infantile types) during the study period included in the study. The median age at diagnosis was 3.2 months (1-40 months). The median follow-up time of the patients was 20 months (1-129 months). Thirteen patients were given rhGAA, one died before ERT. Four (30.8%) patients developed moderate to severe anaphylaxis, and RDD was applied with rhGAA. A total of 390 RDDs have been performed so far without any serious breakthrough reactions during all RDDs. CONCLUSIONS: Anaphylaxis with rhGAA is not rare and RDD with rhGAA is safe and effective in the long term.

Congenital defects of glycosylation: Novel presentations with mainly neurological involvement and variable dysmorphic features.

The pathophysiology of congenital defects of glycosylation (CDG) is complex and the diagnosis has been a challenge because of the overlapping clinical signs and symptoms as well as a large number of disorders. Isoelectric focusing of transferrin has been used as a screening method but has limitations. Individual enzyme or molecular genetic tests have been difficult to perform. In this study, we aimed to describe CDG patients who were referred to from different departments either without a preliminary diagnosis or suspected to have a genetic disorder other than CDG. The patients were diagnosed mainly with a 450 gene next-generation DNA sequencing panel for inborn errors of metabolism, which also included 25 genes for CDG. A total of 862 patients were investigated with the panel, whereby homozygous (10) or compound heterozygous (4) mutations were found in a total of 14 (1.6%) patients. A total of 13 different mutations were discovered, 10 of them being novel. Interestingly, none of the patients was suspected to have a CDG before referral. This report expands the clinical/laboratory findings in patients with CDG and stresses on the fact that CDG should be in the differential list for pediatric patients presented with nonspecific dysmorphic features and neurological delays/regression. Also, next-generation DNA sequencing with panel approach was noticed to have a significant diagnostic potential in patients presented with nonspecific neurologic and dysmorphic findings.

Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

INTRODUCTION: Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. MATERIALS AND METHODS: Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. RESULTS: Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. DISCUSSION: Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

Beneficial Effects of Modified Atkins Diet in Glycogen Storage Disease Type IIIa.

INTRODUCTION: Glycogen storage disease Type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen debranching enzyme, encoded by the AGL gene. Two clinical types of the disease are most prevalent: GSD IIIa involves the liver and muscle, whereas IIIb affects only the liver. The classical dietetic management of GSD IIIa involves prevention of fasting, frequent feeds with high complex carbohydrates in small children, and a low-carb-high-protein diet in older children and adults. Recently, diets containing high amount of fat, including ketogenic and modified Atkins diet (MAD), have been suggested to have favorable outcome in GSD IIIa. METHODS: Six patients, aged 3-31 years, with GSD IIIa received MAD for a duration of 3-7 months. Serum glucose, transaminases, creatine kinase (CK) levels, capillary ketone levels, and cardiac parameters were followed-up. RESULTS: In all patients, transaminase levels dropped in response to MAD. Decrease in CK levels were detected in 5 out of 6 patients. Hypoglycemia was evident in 2 patients but was resolved by adding uncooked cornstarch to diet. CONCLUSION: Our study demonstrates that GSD IIIa may benefit from MAD both clinically and biochemically.

Patient With Niemann-Pick Type C Presenting With a Jaw Mass Characterized With Lymph Node Involvement by Niemann-Pick Cells.

Niemann-Pick type C disease (NPC) is an autosomal recessive disorder resulting in accumulation of unesterified lysosomal cholesterol. An 8-year-old girl with NPC disease had a painless, rigid, and fixed mass measuring 3 cm in diameter located on the left angular region of mandibula. The mass biopsy showed lipid-laden phagocytic cells infiltrating the lymph node consistent with Niemann-Pick cells. In NPC, accumulation of cholesterol in tissues could be seen not only in reticuloendothelial and nervous systems, but also in all systems. Our case is important for it being the first case of NPC with submandibular lymphadenopathy characterized with NPC cell infiltration.

Advances in Immune Tolerance Induction in Enzyme Replacement Therapy.

Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

Intestinal microbiota composition of children with glycogen storage Type I patients.

AIM: Dietary therapy of glycogen storage disease I (GSD I) is based on frequent feeding, with a high intake of complex carbohydrates (supplied by uncooked cornstarch), restriction of sugars, and a lower amount of lipids. There is limited information about the dietary regimen in patients with GSD, which might affect the intestinal luminal pH and microbiota composition. The aim of this study to investigate the intestinal microbiota composition in patients with GSD receiving diet treatment. METHOD: Twelve patients who were followed up with GSD I after the diagnosis receiving diet therapy and 11 healthy children have been enrolled. Intestinal microbiota composition was evaluated by 16 s rRNA gene sequencing. RESULTS: A significant difference was found for beta-diversity between the GSD group and controls. A significantly lower abundance of Firmicutes and higher abundance of Actinobacteria was found in GSD group compared to the controls. Akkermansia, Pseudoalteromonas, Uruburella, and Castellaniella were dominant in the GSD patients at the genus level, while Faecalibacterium, Bacterioides, Gemmiger, Parabacteroides in the control group. At species level, Faecalibacterium prausnitzii decreased, and Akkermansia muciniphila were dominant in children with GSD. DISCUSSION: There is a substantial change in the composition of the gut microbiota, reduction of F. prausnitzii and an increase of A. muciniphila in children with GSD receiving consumption of uncooked cornstarch. Alterations of the intestinal microbiota might be related with the disease itself or dietary restrictions in patients with GSD, however, in certain condition, dysbiosis can negatively affect the course and make it difficult to control the disease.

A 7-year-old boy with scurvy owing to coeliac disease.

ABBREVIATIONS: ESR: erythrocyte sedimentation rate; Hb: haemoglobin; HSP: Henoch-Schönlein purpura; WCC: white-cell count.

Long-term clinical evaluation of patients with alpha-mannosidosis - A multicenter study.

BACKGROUND: Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. METHOD: Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. RESULTS: Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16-208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4-181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). CONCLUSION: The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.

A very rare presentation of mitochondrial elongation factor Tu deficiency-TUFM mutation and literature review.

OBJECTIVES: The mitochondrial elongation factor Tu (EF-Tu), encoded by the TUFM gene, is a GTPase, which is part of the mitochondrial protein translation mechanism. If it is activated, it delivers the aminoacyl-tRNAs to the mitochondrial ribosome. Here, a patient was described with a homozygous missense variant in the TUFM [c.1016G>A (p.Arg339Gln)] gene. To date, only six patients have been reported with bi-allelic pathogenic variants in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis, encephalopathy, and cardiomyopathy. CASE PRESENTATION: The patient presented here had the phenotypic features of TUFM-related disease, lactic acidosis, hypotonia, liver dysfunction, optic atrophy, and mild encephalopathy. CONCLUSIONS: We aimed to expand the clinical spectrum of pathogenic variants of TUFM.

Endocrinological and metabolic profile of Gaucher disease patients treated with enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) is a lysosomal storage disease caused by glucocerebrosidase (GCase) enzyme deficiency. Gaucher cells transformed from the macrophages by progressive sphingolipid accumulation and infiltrate bone marrow, spleen, liver, and other organs. The accumulation of substrate causes inflammation, compromised cellular homeostasis, and disturbed autophagy. It has been hypothesized that this proinflammatory state of GD leads cytokines and chemokines release. As a result of inflammatory process, the cellular dysfunction caused by disruption of cellular signaling, organelle dysfunction, or autoimmune antibodies may affect endocrine profile of GD patients such as hormone levels, lipid profile, and bone mineral density status. METHODS: A total of 13 patients confirmed to have GD, 12 non-neuronopathic type and one subacute neuronopathic type, were enrolled in our study. RESULTS: The median treatment duration in the enzyme therapy was 13.33 years (9-26 years). At least one endocrinological abnormality was detected in blood tests of nine patients. Hyperinsulinism was the most common finding although fasting blood glucose levels HgbA1c levels were normal in all patients. Two patients had osteopenia, and osteoporosis was detected in two patients. Low HDL levels were detected in six patients, but HDL levels below 23 mg/dL associated with disease severity have been detected in two patients who have not receiving enzyme replacement therapy. None of patients had thyroidal dysfunction. CONCLUSIONS: This study had revealed endocrinological abnormalities in GD patients that have not led any severe morbidity in our patients. However, thyroid hormone abnormalities, insulin resistance, or lipid profile abnormalities may cause unpredictable comorbidities. Endocrinological assessment in GD patients in routine follow-up may prevent possible clinical manifestation in long term as well as can define efficacy of ERT on endocrine abnormalities.

Pterin Profiling in Serum, Dried Blood Spot, and Urine Samples Using LC-MS/MS in Patients with Inherited Hyperphenylalaninemia.

Background: Hyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 µmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA. Methods: The samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study. Results: Among the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values. Conclusion: In this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results.

Is Ultrasonography a Reliable Approach for the Evaluation of Carpal Tunnel Syndrome in Patients With Mucopolysaccharidosis?

BACKGROUND: One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination. METHODS: The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline. RESULTS: Included in the study were 27 MPS patients aged 4.5-32 years and 30 healthy control subjects aged 4.3-26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median cross-sectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of ≥1.35, 56.6% (95% CI: 437.4-74.5) sensitivity, and 89.8% (95% CI: 81.0-95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673-0.877). CONCLUSION: Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements.

The efficacy of intravenous immunoglobulin on lipopolysaccharide-induced fetal brain inflammation in preterm rats.

OBJECTIVE: Interleukin-1 is accepted as one of the major cytokines; it is involved in inflammatory processes and systemic fetal inflammatory response that is triggered by maternal lipopolysaccharide (LPS) injection. Because it is an antiinflammatory agent, we investigated (in the brain damage of rat pups) the role of intravenous immunoglobulin (IVIG) in decreasing interleukin-1 beta (IL-1ß) expression and caspase 3 activity that was induced by maternal LPS administration. STUDY DESIGN: Dams were divided into 3 groups. Pyrogen-free saline solution (NS) was administered intraperitoneally to group 1; LPS (0.3 mg/kg) suspension in NS was administered to groups 2 and 3 at 19 days of gestation. Two hours after the first injection, a second injection of NS was administered intravenously to group 1 (NS + NS), of IVIG was administered intravenously to group 2 (LPS + IVIG), and of NS was administered intravenously to group 3 (LPS + NS). Hysterectomy was performed in one-half of the dams 2 hours after the second injection and in the other one-half of the dams 22 hours after the second injection. Pups were delivered, and the brains were extracted just after delivery. IL-1ß expression and caspase 3 activity were determined in brain tissues. RESULTS: For the pups at 4 hours, the IL-1ß expression of group 2 was significantly lower than groups 1 and 3. For the pups at 24 hours, the IL-1ß expression of group 2 was significantly lower than group 3 but was similar to group 1. For the pups at 24 hours, caspase 3 activity of groups 1 and 2 were significantly lower than group 3. CONCLUSION: Maternal IVIG administration decreased IL-1ß expression and caspase 3 activity in the brain tissue of rat pups, which had been induced by maternal LPS-administration.

Endocrinological, immunological and metabolic features of patients with Fabry disease under therapy.

OBJECTIVES: Fabry disease is an X-linked lysosomal disorder caused by decreased or absent alpha galactosidase enzyme. The enzyme deficiency leads to progressive accumulation of globotriaosylceramide (Gb-3) and its deacetylated form lyso-Gb3 in various tissue lysosomes that results in primarily lysosomal deterioration and subsequently mitochondrial, endothelial, and immunologic dysfunctions. METHODS: The endocrinological, metabolic, immunological and HLA status of 12 patients were evaluated. RESULTS: A total of 11 patients (91.6 %) had immunologic and/or endocrinologic abnormalities. fT4, anti-TPO, and anti-TG levels were increased in 1, 2, and 2 patients, respectively. Three patients had elevated proinflammatory cytokines. ANA profile, p-ANCA and c-ANCA were positive in 1, 1, and 2 patients, respectively. Tissue transglutaminase antibody was negative in all patients however P5 was diagnosed with Celiac disease at the age of 12 and on gluten free diet. All patients had distinct types of HLA apart from 2 patients with anti-TG and anti-TPO positive and there was no relationship between the HLA types and the autoimmunity biomarkers. CONCLUSIONS: FD may have impact on endocrinologic and immunologic abnormalities even in the patients under ERT, therefore prevalence of these abnormalities may be higher in ERT naïve patients. However, apparently, they are less likely to cause clinical symptoms. Certain HLA alleles may contribute to the direct impact of immunological pathogenesis in FD by developing abnormal autoimmune biomarkers. To the best of our knowledge, this is the first study investigating HLA status of FD patients; therefore further studies are needed to elucidate the underlying mechanism of action.

A possibly new autoinflammatory disease due to compound heterozygous phosphomevalonate kinase gene mutation.

BACKGROUND: Mevalonate kinase (MVK) plays a role in cholesterol and non-sterol isoprenoid biosynthesis and its deficiency-related diseases are caused by bi-allelic pathogenic mutations in the MVK gene, (MVK), which leads to rare hereditary autoinflammatory diseases. The disease may manifest different clinical phenotypes depending on the degree of the deficiency in the enzyme activity. The complete deficiency of the enzyme activity results in the severe metabolic disease called mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentations called hyper-immunoglobulin D syndrome (HIDS). Serum immunoglobulin (Ig) D and urine mevalonic acid levels may be increased during inflammatory attacks of HIDS. CASE PRESENTATION: Herein, for the first time in the literature, we present a 6-year-old male patient who suffered from recurrent episodes of fever, polyarthritis, skin rash, diarrhea, abdominal pain, and inflammatory bowel disease-like manifestations with elevated levels of serum IgD, and urine mevalonic acid. Eventually we detected compound heterozygous mutations in the phosphomevalonate kinase (PMVK) gene coding the second enzyme after mevalonate kinase in the mevalonate pathway. CONCLUSION: For patients presenting with HIDS-like findings, disease exacerbations and persistent chronic inflammation, and having high urinary mevalonic acid and serum IgD levels, raising suspicion in terms of MVK deficiency (MVKD), it is recommended to study all mevalonate pathway enzymes, even if there is no mutation in the MVK gene. It should be kept in mind that novel mutations might be seen such as PMVK gene.

A Patient with a Novel RARS2 Variant Exhibiting Liver Involvement as a New Clinical Feature and Review of the Literature.

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodevelopmental disorder that is characterized by decreased brainstem and cerebellum volume. Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease associated with autosomal recessive inheritance that results from mutations in the RARS2 gene. In this case report, we describe a new clinical presentation with a novel RARS2 pathogenic variant. We report here on 2 siblings who presented with neonatal lactic acidosis, microcephaly, growth retardation, persistent seizures, and cholestasis with a previously undefined RARS2 pathogenic variant. In our literature review, we evaluated the clinical features and pathogenic variants of 34 patients reported in 16 publications since the initial identification of RARS2 pathogenic variants in PCH6 in 2007. Both siblings were detected with c.1564G>A (p.Val522Ile), a novel homozygous pathogenic variant of the RARS2 gene. Imaging revealed advanced cerebral atrophy and cerebellar hypoplasia, while the basal ganglia and pons were preserved. At follow-up, the elevations in liver function test results and cholestasis had regressed while the LDH and GGT elevations persisted. Both siblings showed microcephaly on follow-up and started to suffer seizures. Severe developmental delay and nutritional problems were observed, and both died in infancy. RARS2 pathogenic variant is a mitochondrial disease that causes severe mental, motor, and developmental retardation, as well as short life expectancy. Our patients are the first cases with liver involvement in PCH6 and a novel homozygous RARS2 pathogenic variant to be reported in the literature. This additional phenotype can be considered as making a valid contribution to the literature.

Fructose 1,6 bisphosphatase deficiency: outcomes of patients in a single center in Turkey and identification of novel splice site and indel mutations in FBP1.

OBJECTIVES: Fructose 1,6 bisphosphatase (FBPase) deficiency is a rare autosomal recessively inherited metabolic disease. It is encoded by FBP1, and the enzyme catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose 6-phosphate. Patients with recurrent episodes of metabolic acidosis, hypoglycemia, hypertriglyceridemia, and hyperketonemia are present. METHODS: In this study, we describe the clinical, biochemical, and molecular genetic features of six unrelated Turkish patients from six different families who were genetically diagnosed with FBPase deficiency in our clinic between 2008 and 2020. Their clinical and laboratory data were collected retrospectively. Next-generation sequencing (NGS) was performed for the molecular genetic analysis. RESULTS: All patients were hospitalized with recurrent hypoglycemia and metabolic acidosis episodes. Three out of six patients were presented in the neonatal period. The mean age at diagnosis was 26 months. NGS revealed a known homozygous gross deletion including exon 2 in three patients (50%), a known homozygous c.910_911dupTT pathogenic variant in one patient (16%), a novel homozygous c.651_653delCAGinsTAA likely pathogenic variant, and another novel homozygous c.705+5G>A splice site variant. Leukocyte FBPase analysis detected no enzyme activity in the patient with homozygous c.705+5G>A splice site variant. CONCLUSIONS: We identified two novel mutations in this study. One of them is a splice site mutation which is five bases downstream of the exon, and the other one is an indel mutation. Both of the splice site and indel mutations are exceedingly rare in FBP1, and to the best of our knowledge, there are second splice site and indel variants reported in the literature. Exon 2 deletion is the most common mutation consistent with the previous reports in Turkish patients. FBPase is a frequent cause of hypoglycemia and metabolic acidosis, and the widespread use of molecular genetic analysis would contribute to the enlightenment of advanced genetic factors and possible genotype/phenotype correlation.