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.

Positive effects of ketogenic diet on weight control in children with obesity due to Prader-Willi syndrome.

OBJECTIVE: Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Prevention and management of obesity, which represents the main cause of morbidity and mortality in these patients, is essential. Ketogenic diet (KD) is used in the treatment of various disorders, however knowledge of its effect in PWS is lacking. The present study assesses the characteristics of patients with PWS who were on KD. DESIGN AND PATIENTS: This is a retrospective, cross-sectional descriptive study investigating the subjects with PWS, who had received KD for at least 6 months. RESULTS: Ten patients with PWS [median age 52.5 (47-77) months] complied with KD. The median treatment period was 16.5 [11-52] months. Of the daily calorie, 75%-85% were from fat, and 15%-25% from protein + carbohydrate. The baseline body weight standard deviation (SD) score before diet therapy was 2.10 [-1.11-4.11], whereas it was 0.05 [-0.92-1.2] at final evaluation (p = .007). The baseline median BMI SD score before diet therapy was 3.05 [-0.21-3.72], whereas it was 0.41 [-0.87-1.57] at final evaluation (p = .002). The height SD score remained unchanged. Mild hypercholesterolaemia was the most common biochemical abnormality during treatment with KD. CONCLUSION: Our results indicate that KD might have a favourable effect on weight management in PWS.

A challenging etiology of myopathy: The late-onset Pompe disease.

Pompe disease is a rare metabolic disorder that is characterized by the deficiency of the acid aglucosidase. As a result, glycogen accumulates in several tissues including motor neurons, skeletal, cardiac, and smooth muscles. The course of the disease varies according to the type of mutations, and the clinical phenotype can be affected by the enzyme levels. Late-onset Pompe disease (LOPD) is a challenging issue for clinicians as it has a milder phenotype with later onset of symptoms and slower disease progression. One of the most important differentials in the diagnosis of LOPD is inflammatory myositis as both diseases have some common clinical and laboratory features. Herein, we presented a 30-year-old female patient initially diagnosed as polymyositis and treated with immunosuppressive therapy without a benefit on her symptoms and later diagnosed as LOPD.

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

BACKGROUND: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs. OBJECTIVE AND METHODS: To document neuroimaging data in six patients with PNPT1 highlighting novel findings. RESULTS: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection. CONCLUSION: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

Efficacy of Phenylalanine- and Tyrosine-Restricted Diet in Alkaptonuria Patients on Nitisinone Treatment: Case Series and Review of Literature.

INTRODUCTION: Nitisinone used in alkaptonuria (AKU) can result in keratopathy due to strongly increased tyrosine levels. METHODS: This study aimed to investigate nutritional status and changes in plasma tyrosine and phenylalanine and urinary homogentisic acid (u-HGA) levels in 8 adult AKU patients (mean age, 56.3 ± 4.7 years) who were on tyrosine/phenylalanine-restricted diet together with 2 mg/day nitisinone. RESULTS: The treatment period was 23.4 ± 6.9 months. Daily dietary protein intake was restricted to 0.8-1.0 g/kg/day. Daily tyrosine intake was restricted to 260-450 mg/day for females and 330-550 mg/day for males. Tyrosine/phenylalanine-free amino acid supplements accounted for an average of 56.1% of daily protein intake. The following assessments were performed: anthropometric and plasma tyrosine level measurements every 2 months; ophthalmological examination every 6 months, and nutritional laboratory analyses and measurements of plasma amino acids and u-HGA once in a year. It was targeted to keep the plasma tyrosine level <500 µmol/L. The plasma tyrosine level was <100 µmol/L before the treatment in all patients and around a mean of 582.5 ± 194.8 µmol/L during the treatment. The diet was rearranged if a plasma tyrosine level of >700 µmol/L was detected. The u-HGA level before and after the 1st year of treatment was 1,429.3 ± 1,073.4 mmol/mol creatinine and 33.6 ± 9.5 mmol/mol creatinine, respectively. None of the patients developed keratopathy or experienced weight loss and protein or micronutrient deficiency. CONCLUSION: AKU patients should receive tyrosine/phenylalanine-restricted diet for reducing plasma tyrosine level to the safe range. Tyrosine/phenylalanine-free amino acid supplements can be safely used to enhance dietary compliance. Keratopathy and nutrient deficiency should be frequently monitored.

Lipemia Retinalis Diagnosed Incidentally After Laser Photocoagulation Treatment for Retinopathy of Prematurity

A preterm infant who underwent bilateral laser photocoagulation for the treatment of stage 3 retinopathy of prematurity (ROP) is presented because she was incidentally diagnosed with grade 3 lipemia retinalis by dilated fundoscopy at post-laser 2 weeks. Meticulous ophthalmologic examination is imperative in premature newborns for not only ROP screening but also detecting any concomitant ocular abnormalities, which can be sight-threatening or even life-threatening.

Role of surveillance screening in detecting tumor recurrence after treatment of childhood cancers.

OBJECTIVE: As the survival rates in children with cancer reach up to 80%, this improvement in survival increases the number of patients under follow-up. After cancer treatment is completed, patients are taken to follow-up surveillance to ensure the early detection of recurrence and the late effects of treatments. The frequency and necessity of surveillance screening tests are controversial. This study aimed to assess the efficacy of surveillance screening in the detection of recurrence. MATERIAL AND METHODS: The files of 533 children who were diagnosed as having cancer at our pediatric oncology clinic between 2004 and 2013 were retrospectively evaluated. We looked at outcomes after recurrence, the timing and pattern of recurrence, the presence of symptoms during recurrence, physical examination findings, tumor marker levels, laboratory findings, and radiologic tests. RESULTS: Of the 63 patients with recurrence, 23 were symptomatic and 40 were asymptomatic at the time of the recurrence. Tumor location and time of the recurrence did not affect the post recurrence survival. The median post-recurrence survival for patients was 13 (range, 1-98) months. The median post-relapse survival was 10 (range, 1-73) months in patients with symptomatic recurrence, and 16 (range, 1-98) months in patients with asymptomatic recurrence. It was determined that patients in whom recurrence was identified with surveillance tests had longer post-relapse survival time. The 5-year survival rate of 23 patients with symptomatic recurrence was 12.2%; this rate was 49.5% in asymptomatic patients (p<0.05). CONCLUSIONS: It should be considered that surveillance testing offers the benefit of prolonging post recurrence survival.

Inborn errors of immunity and metabolic disorders: current understanding, diagnosis, and treatment approaches.

Inborn errors of metabolism consist of a heterogeneous group of disorders with various organ systems manifestations, and some metabolic diseases also cause immunological disorders or dysregulation. In this review, metabolic diseases that affect the immunological system and particularly lead to primary immune deficiency will be reviewed. In a patient with frequent infections and immunodeficiency, the presence of symptoms such as growth retardation, abnormal facial appearance, heart, skeletal, lung deformities, skin findings, arthritis, motor developmental retardation, seizure, deafness, hepatomegaly, splenomegaly, impairment of liver function tests, the presence of anemia, thrombocytopenia and eosinophilia in hematological examinations should suggest metabolic diseases for the underlying cause. In some patients, these phenotypic findings may appear before the immunodeficiency picture. Metabolic diseases leading to immunological disorders are likely to be rare but probably underdiagnosed. Therefore, the presence of recurrent infections or autoimmune findings in a patient with a suspected metabolic disease should suggest that immune deficiency may also accompany the picture, and diagnostic examinations in this regard should be deepened.

Clinical and molecular characteristics and time of diagnosis of patients with classical galactosemia in an unscreened population in Turkey.

Classical galactosemia is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in the GALT gene. With the benefit of early diagnosis by newborn screening, the acute presentation of galactosemia can be prevented. In this study, we describe the clinical phenotypes, time of diagnosis and GALT genotypes of 76 galactosemia patients from Turkey, where the disease is not yet included in the newborn screening program. The median age at first symptom was 10 days (range 5-20), while the median age at diagnosis was 30 days (range 17-53). Nearly half of the patients (36 patients, 47.4%) were diagnosed later than age 1 month. Fifty-eight individuals were found to have 18 different pathogenic variants in their 116 mutant alleles. In our sample, Q188R variant has the highest frequency with 53%, the other half of the allele frequency of the patients showed 17 different genotypes. Despite presenting with typical clinical manifestations, classical galactosemia patients are diagnosed late in Turkey. Due to the geographical location of our country, different pathogenic GALT variants may be seen in Turkish patients. In the present study, a clear genotype-phenotype correlation could not be established in patients.

Severe hyperchylomicronemia in two infants with novel APOC2 gene mutation.

Background Familial apo C-II deficiency is a rare hereditary disorder frequently caused by lipoprotein lipase (LPL) and APOC2 gene mutations. To date, less than 30 patients with familial apo C-II deficiency with 24 different mutations have been identified in the literature. Here, we describe two familial chylomicronemia syndrome cases in infants with two novel mutations of the APOC2 gene. Case presentation Case 1, a 46-day-old female, was admitted to our hospital for evaluation due to the lipemic appearance of the blood sample. A clinical examination revealed hepatomegaly and lipemia retinalis. Triglyceride level of 6295 mg/dL was decreased with a strict low-fat diet, medium-chain triglycerides (MCT) oil-rich formula and omega-3 fatty acid supplementation. Due to low adherence to the diet, TG elevation was detected and fresh frozen plasma (10 mL/kg/day) was administered for 2 days. A novel homozygous p.Q25X (c.73C>T) mutation in the APOC2 gene was detected. Case 2, a 10-month-old female patient, referred to our center for the differential diagnosis of hyperlipidemia as her blood sample could not be assessed due to its lipemic appearance. Laboratory examinations showed a TG level of 4520 mg/dL which was reduced with a low-fat diet, MCT oil-rich formula and omega-3 fatty acid supplementation. Hepatosteatosis and splenomegaly were determined using abdominal sonography. A novel homozygous IVS2+6T>G (c.55+6T>G) mutation in the APOC2 gene was identified. Conclusions We describe two novel homozygous mutations (p.Q25X [c.73C>T] and IVS2+6T>G [c.55+6T>G]) in the APOC2 gene in infants with hyperchylomicronemia. To the best of our knowledge, Case 1 is the youngest patient with familial apo C-II deficiency in the literature to date.