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.

Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.

Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1ß (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1ß and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.

Long-term personalized high-protein, high-fat diet in pediatric patients with glycogen storage disease type IIIa: Evaluation of myopathy, metabolic control, physical activity, growth, and dietary compliance.

Dietary lipid manipulation has recently been proposed for managing glycogen storage disease (GSD) type IIIa. This study aimed to evaluate the myopathic, cardiac, and metabolic status, physical activity, growth, and dietary compliance of a personalized diet high in protein and fat for 24 months. Of 31 patients with type IIIa GSD, 12 met the inclusion criteria. Of these, 10 patients (mean age 11.2 ± 7.4 years) completed the study. Patients were prescribed a personalized high-protein, high-fat diet, comprising 3.0-3.5 g/kg/day of protein and 3.0-4.5 g/kg/day of fat, constituting 18.5%-28% and 70.5%-75.7% of daily energy, respectively. Dietary compliance was ensured and assessed via the regular administration of questionnaires. Our results revealed consistent and significant decreases of 22%, 54%, and 30% in the creatinine kinase, creatine kinase-myocardial band, and lactate dehydrogenase levels, respectively. Echocardiography revealed improvements in the Z-scores of the left ventricular mass and interventricular septum thickness. A significant increase in body muscle mass was observed, and a higher score was achieved using the Daily Activity Questionnaire. Growth monitoring revealed an arrest in the height-SDS at the 6th and 12th months, followed by subsequent improvement at the end of the second year. A gradual and persistent decline in the periods of hypo- and hyperglycemia has been reported. Biotinidase activity decreased, whereas hepatosteatosis increased and then decreased by the end of the study. Implementing a high-protein, high-fat diet and monitoring key parameters in patients with type IIIa GSD can lead to myopathic and cardiac improvements and increased physical activity.

Long-term clinical outcomes and management of hypertriglyceridemia in children with Apo-CII deficiency.

BACKGROUND AND AIM: APO CII, one of several cofactors which regulate lipoprotein lipase enzyme activity, plays an essential role in lipid metabolism. Deficiency of APO CII is an ultra-rare autosomal recessive cause of familial chylomicronemia syndrome. We present the long-term clinical outcomes of 12 children with APO CII deficiency. METHODS AND RESULTS: The data of children with genetically confirmed APO CII deficiency were evaluated retrospectively. Twelve children (8 females) with a mean follow-up of 10.1 years (±3.9) were included. At diagnosis, the median age was 60 days (13 days-10 years). Initial clinical findings included lipemic serum (41.6%), abdominal pain (41.6%), and vomiting (16.6%). At presentation, the median triglyceride (TG) value was 4341 mg/dL (range 1277-14,110). All patients were treated with a restricted fat diet, medium-chain triglyceride (MCT), and omega-3-fatty acids. In addition, seven patients (58.3%) received fibrate. Fibrate was discontinued in two patients due to rhabdomyolysis and in one patient because of cholelithiasis. Seven (58.3%) patients experienced pancreatitis during the follow-up period. One female experienced recurrent pancreatitis and was treated with fresh frozen plasma (FFP). CONCLUSIONS: Apo CII deficiency is an ultra-rare autosomal recessive condition of hypertriglyceridemia associated with significant morbidity and mortality. Low-fat diet and MCT supplementation are the mainstays of therapy, while the benefit of TG-lowering agents are less well-defined.

Development, optimization and validation of LC-MS/MS method for the determination of DBS GALT enzyme activity.

Galactosemia is a carbohydrate metabolism disorder often caused by galactose-1-phosphate uridyl transferase (GALT) deficiency. Detecting GALT deficiency involves measuring intra-erythrocyte enzyme activity. We aimed to create a robust liquid chromatography-mass spectrometry (LC-MS/MS) method to assess GALT activity in dried blood spot (DBS) samples. We validated this method and compared it to the fluorometric approach. We investigated the impact of K2EDTA and lithium heparin tubes on enzyme activity to identify the best sample collection tube. We also assessed the reaction-stopping method. The developed approach employed [13C6]-galactose-1-phosphate as a substrate and UDP-N-acetylglycosamine as an internal standard (IS). The mean ± SD value for GALT activity of DBS samples was determined as 6.37 ± 1.96 µmol/gHb/hour. The linear range was 0.4-50 µM (2.4-310% of normal) in the DBS method. The % coefficient of variation (%CV) values were less than 15 for intra-day and inter-day repeatability studies. Over 90% recovery was achieved in recovery studies, and no ion suppression from matrix was detected. DBS samples were quite stable for 31 days under different storage conditions. Enzyme activity results reported as <3.5 U/g Hb by fluorometric method, were quantitatively determined for even very low concentrations by LC-MS/MS method.

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). PROCEDURE: In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. RESULTS: A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. CONCLUSIONS: Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.

Coexistence of Gaucher Disease and severe congenital neutropenia.

Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patient's only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow.

A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.

Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.

Molecular analysis in X-linked adrenoleukodystrophy patients: identification of a novel mutation.

X linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease characterized by progressive demyelination of the central nervous system, adrenocortical insufficiency and elevated levels of very long chain fatty acids (VLCFAs). It is caused by mutations in ABCD1 gene located at Xq28. More than 1,300 mutations have been identified to date which is unique to each patient. In this study we report the mutational analysis of 2 X-ALD patients (1 male and 1 female) showing variable clinical spectrum. The mutation analysis of the female patient revealed IVS5-6delC (c.1489-6delC) and p. P543L variations in compound heterozygous state. The male patient was found to be hemizygous for a novel mutation, p. R104P. In conclusion, while defining a novel mutation, the cases presented herein may contribute to the mutation and clinical spectrum of X-ALD.

Development of a New Amperometric Biosensor for Measurement of Plasma Galactose Levels.

Galactosemia is an inherited disease that occurs as a result of insufficient or no synthesis of some enzymes (GALT, GALK, and GALE) in galactose metabolism. Failure to make an early diagnosis, especially in newborns, can lead to severe clinical and even fatal consequences. The aim of this study is to develop a biosensor for measuring free galactose in plasma. The immobilization components of the developed free galactose biosensor are screen printed carbon electrode (SCPE), Prussian blue (PB), chitosan (CHIT), Nafion (NAF), gold nanoparticle (GNP), and galactose oxidase (GaOX). The CHIT/GaOX/NAF-GNP/GaOX/CHIT-GNP/SCPE-PB electrode showed a sensitive amperometric response to detect galactose. While the surface characterization of the biosensor was performed with cyclic voltammetry and scanning electron microscopy, the optimization and performance characterizations were made by applying an amperometry technique. The amperometric operating potential for the free galactose biosensor was determined as -0.05 V. The linear detection range for the free galactose biosensor is between 0.025 and 10 mM. This range includes galactose levels in plasma of both healthy and patients. The percent coefficient of variation values calculated for intraday and interday repeatability of the developed biosensor are below 10%. The practical use of the biosensor, for which optimization and characterization studies were carried out, was tested in 10 healthy 11 patients with galactosemia, and the results were compared with the colorimetric method. In conclusion, the unique analytical properties and effortless preparation of the new galactose biosensor developed in this study make them serious candidates for point-of-care diagnostic testing.

Experience with carnitine palmitoyltransferase II deficiency: diagnostic challenges in the myopathic form.

OBJECTIVES: Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form of CPT II deficiency at Ege University Hospital. METHODS: A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. RESULTS: Ten patients were examined for rhabdomyolysis of unknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). CONCLUSIONS: Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.

The relationship between ultrasonographically measured testicular volumes and cord blood inhibin B concentrations in healthy term male neonates.

Serum inhibin B (INHB) concentrations are associated with testicular volumes (TV) in all periods of childhood. The aim of the study was to investigate the relationship between TV measured by ultrasonography (US) and cord blood inhibin B and total testosterone (TT) concentrations, stratified by mode of delivery. In total 90 male infants were included. Testes of healthy, term newborns were evaluated by US on the third day after delivery. TV were calculated using two formulae: The ellipsoid formula [length (mm) × width (mm2) × π/6] and Lambert formula [length (mm) x width (mm) x height (mm) x 0.71]. Cord blood was taken for the determination of total testosterone (TT) and INHB. TT and INHB concentrations were evaluated according to TV percentiles (<10th, 10th-90th, >90th). There was a strong positive correlation between mean TV calculated with both formulae by percentile group (r = 0.777, r = 0.804, r = 0.846; p < 0.001). Cord blood INHB, but not TT were significantly lower in newborns with TV < 10th percentile compared to those with TV between 10 and 90th percentile and > 90th percentile (p < 0.05). There was a positive correlation between left and right TV calculated by either formula, and cord blood INHB (r = 0.212, 0.313, 0.320, 0.246,p < 0.05), not TT. There was no significant difference between hormones and TV when grouped by mode of delivery (p > 0.05). The Lambert and ellipsoid formulas are equally reliable in calculating neonatal testicular by ultrasound. INHB concentration is high in cord blood and positively correlated with neonatal TV. Cord blood INHB concentration may be an indicator for early detection of testicular structure and function disorders in neonates.

Mild Aromatic L-Amino Acid Decarboxylase Deficiency: As A Reason For Hypoketotic Hypoglycemia In A 4-Year-Old Girl.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a disease in which neurological findings are dominant due to deficiencies in neurotransmitter synthesis; hypoglycemia caused by autonomic dysfunction is one of the symptoms that may be encountered. Here we report a mild AADC deficiency presenting with hypoglycemia without a neurological sign. A 4-year-old girl presented with recurrent hypoglycemia. Her growth and development were normal. Plasma insulin and cortisol values were normal in the sample at the time of hypoglycemia. The C8:1-Carnitine elevation was detected in the acylcarnitine profile. The clinic exome panel was performed with the suggestion of a fatty acid oxidation defect. However, a homozygous variant in the DDC gene was detected. On top of that, CSF neurotransmitter analysis revealed low 5-hydroxy indol acetic ( 5 HIAA ) and homovanillic acid ( HVA ) and high 3-O-methyl-dopa and methyltetrahydrofolate ( 5 MTHF ) consistent with AADC deficiency. Plasma AADC enzyme activity was low. The episodes of hypoglycemia were treated with uncooked cornstarch. Our case emphasizes that AADC deficiency should be considered in patients with hypoglycemia.

Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG.

OBJECTIVES: Congenital Glycosylation Disorders (CDG) are a large group of inherited metabolic diseases with multi-organ involvement. Herein, we aimed to expand the clinical characteristics of patients with CDG based on our experience with diagnoses and follow-up of CDG patients from different subtypes. METHODS: The clinical and laboratory findings from the last 15 years were reviewed retrospectively in Ege University Child Metabolism and Nutrition Department. RESULTS: There were 8 (57.2 %) females and 6 (42.8 %) males. Diagnoses of the patients were PMM2-CDG (n=4), PGM1-CDG (n=2), DPAGT1-CDG (n=2), SRD5A3-CDG (n=2), MPI-CDG (n=1), POMT2-CDG (n=1), B3GALNT2-CDG (n=1), DPM1-CDG (n=1). The clinical findings of the patients were dysmorphia (85.7 %), developmental delay (85.7 %), intellectual disability (85.7 %), ocular abnormalities (64.2 %), skeletal malformations (64.2 %), failure to thrive (57.1 %), microcephaly (57.1 %), hepatomegaly (35.7 %), hearing loss (35.7 %), seizures (28.5 %), gastrointestinal symptoms (21.4 %), endocrine abnormalities (21.4 %), and cardiac abnormalities (7.1 %). Laboratory findings were abnormal TIEF (92.8 %), abnormal liver enzymes (64.2 %), decreased protein C (64.2 %), decreased antithrombin III (64.2 %), decreased protein S (42.8 %), hypogammaglobulinemia (35.7 %), cerebellar hypoplasia (28.5 %), CK elevation (7.1 %), and hypoglycemia (7.1 %). CONCLUSIONS: This study contributes to the literature by sharing our ultra-rare DPM1-CDG case with less than 20 cases in the literature and expanding the clinical and molecular characteristics of other CDG patients. Hyperinsulinemic hypoglycemia, short stature, hypothyroidism, growth hormone deficiency, hypogammaglobulinemia, pericardial effusion, elevated CK, congenital myasthenia, and anorectal malformation were unique findings that were observed. Cerebello-ocular findings accompanying multi-organ involvement were an essential clue for a possible CDG.

COVID-19 and Vaccination Status in Lysosomal Storage Diseases: A Single-Center Experience.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) causes significant morbidity and mortality in individuals with chronic disease. There is not enough information about the course of coronavirus disease in lysosomal storage diseases. This study aimed to evaluate coronavirus disease vaccination status and the impact of coronavirus disease on lysosomal storage disease. MATERIALS AND METHODS: The study included 87 lysosomal storage disease patients. The patients' diagnoses were Gaucher, mucopolysaccharidosis I, II, IVA, VI, VII, Fabry, and Pompe. A questionnaire assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, coronavirus disease symptoms, and vaccine status was administered in person or by phone calls. RESULTS: The number of coronavirus disease positive patients was 8 (9.1%). Only 2 patients were treated in the intensive care unit. Other coronavirus disease patients had mild symptoms and stayed in-home quarantine. Patients over 12 years of age could receive a COVID-19 vaccine. 63.5% of those aged ≥12 years were vaccinated. CONCLUSION: Lysosomal storage disease patients did not have an increased risk of COVID-19 compared to the healthy population, despite the chronic inflammatory disease. Vaccination of lysosomal storage disease patients will be protective against severe coronavirus disease.

Severe perinatal hypophosphatasia case with a novel mutation. / Un caso de hipofosfatasia perinatal grave con una mutación novedosa.

Hypophosphatasia (HPP) is a rare inherited disorder caused by mutations in the ALPL gene. Mineralization defect in bones and teeth, abnormal respiratory function, seizures, hypotonia, bone pain, and nephrocalcinosis can be observed. Clinical forms are usually recognized based on age at diagnosis and severity of features. We present an infant with an enlarged anterior fontanelle, soft calvarium, fractures, respiratory distress, and seizures. Biochemical analysis showed hypercalcemia, normal serum phosphate, and low serum alkaline phosphatase (ALP) levels. X-ray showed hypomineralization, fractures, and callus formations. Plasma pyridoxal 5'-phosphate (PLP) was 762 mg/L (NV : 5-50) and urine phosphoethanolamine (PEA) was 1015 mmol/L (NV : 15-341) and ALPL gene analysis showed two compound heterozygous mutations, one of which is a novel one. Early diagnosis and treatment of perinatal HPP may improve outcomes and might have a positive impact on survival.

La hipofosfatasia es un trastorno hereditario raro causado por mutaciones en el gen ALPL. Causa defectos en la mineralización ósea y dental, función respiratoria anormal, convulsiones, hipotonía, dolor óseo y nefrocalcinosis. Las formas clínicas se reconocen según la edad al diagnóstico y la gravedad. Presentamos el caso de una lactante con fontanela anterior agrandada, bóveda craneal blanda, fracturas, dificultad respiratoria y convulsiones. El análisis bioquímico mostró hipercalcemia, fosfato sérico normal y fosfatasa alcalina sérica baja. La radiografía mostró hipomineralización, fracturas y callos. La concentración plasmática de piridoxal-5'-fosfato era de 762 mg/l (intervalo normal: 5-50) y la concentración de fosfoetanolamina en orina era de 1015 mmol/l (intervalo normal: 15-341). El análisis del gen ALPL mostró dos mutaciones heterocigotas compuestas, una de las cuales es novedosa. El diagnóstico y tratamiento tempranos de la hipofosfatasia perinatal podría mejorar los resultados y tener un impacto positivo en la sobrevida.

Two siblings with galactose mutarotase deficiency: Clinical differences.

Galactose mutarotase (GALM) deficiency is an inherited metabolic disease caused by the deficiency of the first enzyme in the Leloir pathway. GALM deficiency was first reported in 2018. To date, eight cases have been reported. We are presenting two siblings with GALM deficiency; one patient presented with cataracts and her brother was asymptomatic. We evaluated the first case due to a cataract at 3 months old. She had elevated galactose and galactose-1-phosphate and normal galactose-1-phosphate uridylyltransferase (GALT) activity. Genetic analysis and other laboratory and clinical findings excluded galactokinase-1 (GALK1) and UDP-galactose 4'-epimerase (GALE) deficiencies. She had a homozygous mutation p. Gly277Arg (c.829G>A) in the GALM (NM_138801) gene. She was 3 years old at the last visit, and her physical examination was normal, except for cataracts. The same mutation was found to be homozygous in the patient's asymptomatic sibling during family screening. He had normal blood galactose and galactose-1-phosphate. This study highlights the importance of evaluating the whole galactose metabolism in terms of GALM deficiency in patients with cataracts.

Primary Carnitine Deficiency as a Treatable Cause of Heart Failure in Young Patients.

Non-ischemic dilated cardiomyopathy is the most common subgroup of heart failure in young adults. Several metabolic defects could be the underlying etiology in these young heart failure patients. However, most cases are considered idiopathic. Primary carnitine deficiency is an overlooked inherited metabolic disease causing cardiomyopathy in these patients. Oral carnitine replacement therapy could prevent primary carnitine deficiency patients from progressing to advanced heart failure and life-threatening arrhythmias. In this case report, we present an index primary carnitine deficiency case and his brother's diagnosis and successful treatment period to draw attention to primary carnitine deficiency as a treatable cause of heart failure in young adults.

Persistent moderate methylmalonic aciduria in a patient with methylmalonyl CoA epimerase deficiency.

BACKGROUND: Methylmalonyl CoA epimerase (MCE) deficiency was first reported in 2006 and only a few cases have been reported so far. The clinical spectrum of MCE deficiency ranges from asymptomatic to lifethreatening metabolic decompensation attacks. CASE: Herein we report a patient diagnosed with MCE deficiency with recurrent acute metabolic ketoacidosis attacks and moderate MMA-uria that persisted in periods without decompensation. At presentation, organic acid profiles were dominated by increased 3 hydroxybutyrate. CONCLUSIONS: 3-Oxothiolase deficiency as a main ketolysis defects disorder was initially suspected. However, the subsequently repeated organic acid analyses demonstrated mild and persistent elevation of methylmalonic acid. This report provides a new phenotype of the clinical and biochemical characterization of MCE deficiency.