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.

Use of Thalamus L-Sign to Differentiate Periventricular Leukomalacia From Neurometabolic Disorders.

PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.

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.

GM1 gangliosidosis: patients with different phenotypic features and novel mutations.

OBJECTIVES: GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder caused by beta-galactosidase deficiency encoded by GLB1. It is mainly characterized by progressive neurodegeneration due to accumulation of glycosphingolipids in central nervous system and classified into 3 forms according to the age of onset and severity of symptoms. CASE PRESENTATION: In this study, we described the demographic, clinical, molecular, biochemical characteristics of 4 patients from 3 unrelated families diagnosed with GM1-gangliosidosis. The ages of the patients included in the study were between 5 months and 10 years old and all were male. All families had third degree consanguinity. Two of the patients were diagnosed as infantile type and the other two siblings were diagnosed as juvenile type. Infantile type patients had coarse facial appearance, developmental delay and early neurodegeneration. Juvenile type patients had mild motor and cognitive developmental delays at the beginning, but they did not have coarse facial features. Cherry-red macula and cardiac involvement were detected in only one infantile patient, while hepatomegaly was present in both infantile type patients. Beta galactosidase enzyme levels were extremely low in all patients and two novel variants were identified in GLB1. CONCLUSIONS: In this study, we identified four patients with different phenotypic features and two new mutations. GM1 gangliosidosis shows clinical heterogeneity according to age of onset. In some patients, developmental delay can be seen before the loss of gained functions. Therefore, this disorder should be kept in mind in patients with developmental delay who have not yet started neurodegeneration. There is no curative treatment for the disease yet, but ongoing gene therapy studies are promising for curing the disease in the future.

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.

First successful concomitant therapy of immune tolerance induction therapy and desensitization in a CRIM-negative infantile Pompe patient.

OBJECTIVES: Enzyme replacement therapy (ERT) with alglucosidase alfa (rhGAA) has changed the fatal course of infantile Pompe disease, however, development of anti rhGAA antibodies and infusion-associated reactions (IAR) restrict the tolerability and effectiveness of the treatment. CASE PRESENTATION: We describe a successful concomitant immune tolerance induction (ITI) and desensitization protocols in a cross-reactive immunologic material (CRIM) negative 7-month-old male patient. At the age of 5 months and eighth dose of the ERT, the patient developed IAR and his rhGAA specific IgE was negative however, his rhGAA specific IgG titer was as high as 12,800. ITI therapy to suppress antibody formation and a desensitization protocol was devised to be given concomitantly. At the end of 5-week therapy, his fatigue and weakness improved profoundly and a control antidrug antibody level decreased at 800. At the time of the patient's follow up, he was still on ERT with desensitization at the age of 15 months without any reactions. CONCLUSIONS: This is the first report in the literature applying concomitant ITI and desensitization protocols in a CRIM negative infantile-onset Pompe disease patient successfully, hence the importance of the case.

Familial hyperphosphatemic tumoral calcinosis in an unusual and usual sites and dramatic improvement with the treatment of acetazolamide, sevelamer and topical sodium thiosulfate.

OBJECTIVES: Familial hyperphosphatemic tumoral calcinosis is a rare disorder characterized by hyperphosphatemia with recurrent ectopic periarticular calcifications, in addition to other visceral and vascular manifestations, without any inflammatory or neoplastic disorder. The available treatment strategies are limited. Here we report an eight year old female patient with recurrent lesions under the chin, and bilateral hips which are painful and improving of the size of the lesions and hyperphosphatemia. CASE PRESENTATION: The patient was started to the treatment with peroral acetazolamide however the lesion did not regress but a new lesion appeared then we added sevelamer and topical sodium thiosulfate treatment for three months. After the three months of the combination treatment the lesions, there were no pain, no hyperphospahtemia regression/disappearance of the lesions. CONCLUSIONS: This combination treatment or topical sodium thiosulfate use only may be a novel treatment strategy for the patients prospective controlled trials are needed.