Ertugrul Kiykim

Differences in the gut microbiota of healthy children and those with type 1 diabetes

Intestinal barriers, intestinal flora, and mucosal immunity are the main factors responsible for the development of various allergic and autoimmune diseases. The aim of this study was to investigate the relationship between the intestinal flora of children and the presence of type 1 diabetes, and to determine if gut microbiota could partly explain the etiology of the disease.

Spondyloocular Syndrome – Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Spondyloocular syndrome is an autosomal‐recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss.

Hereditary tyrosinemia type 1 in Turkey: twenty year single-center experience.

Hereditary tyrosinemia type 1(HT1) is a chronic disorder leading to severe hepatic, renal and peripheral nerve damage if left untreated. Despite nitisinone treatment HT1 still carries the risks of hepatocellular carcinoma (HCC) and neuropsychological outcome.

Inherited metabolic disorders in Turkish patients with autism spectrum disorders.

Autism spectrum disorders (ASDs) are a major health problem because of their high prevalence in the general population. The pathophysiology of ASD remains unclear, although genetic defects may be detected in 10–20% of affected patients. Among these cases, the prevalence of inherited metabolic disorders (IMD) has not been extensively evaluated. IMDs responsible for ASDs are usually identified via clinical manifestations such as microcephaly, dysmorphic features, convulsions, and hepatosplenomegaly. Infrequently, patients with no additional clinical symptoms suggestive of an IMD may be diagnosed as having an idiopathic ASD. High consanguinity rates have resulted in an increased prevalence of IMDs in the Turkish population. The aim of this study was to explore the benefits of systematic screening for IMD among Turkish patients with ASDs. In our study, data were retrospectively collected for 778 children with ASDs. In all cases, the metabolic investigations included an arterial blood gas analysis, serum ammonia and lactate levels, a quantitative plasma amino acid analysis, a whole blood acylcarnitine profile via tandem mass spectrometry and a urine organic acid profile. Urinary glycosaminoglycan levels and homocysteine levels were screened in selected cases; 300 of the 778 patients with ASDs whose physical and metabolic investigations were complete and met this studys criteria were enrolled. Among the 300 children with autism, IMD were diagnosed in nine patients as follows: two patients were diagnosed with phenylketonuria, and one patient was diagnosed with partial biotinidase deficiency; one patient was diagnosed with mucopolysaccharidosis type III, and one patient was diagnosed with classical homocystinuria; one patient was diagnosed with glutaric acidemia type 1, and one patient was diagnosed with short chain acyl‐CoA dehydrogenase deficiency; one patient was diagnosed with argininemia, and one patient was diagnosed with L‐2‐hydroxyglutaric aciduria. Autism Res 2016, 9: 217–223.

Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia.

3-Methylglutaconic acid (3-MGA) is a branched-chain organic acid and derived from leucine catabolism. Abnormal metabolism in this pathway results in 3-MGA-uria which is associated with several mitochondrial disorders [1,2]. Nowadays, 5 types of the disease were described [2]. Recently, type VII of 3-MGA-uria was reported with cataracts, neurologic involvement, and neutropenia (MEGCANN) [3–5]. MEGCANN is an autosomal recessive metabolic disorder causing by CLPB gene encodes ClpB caseinolytic peptidase B homolog, amember of AAA+ proteins family containing ATP-binding sites [4,5]. Severe congenital neutropenia (SCN) exhibit a heterogeneous group of diseases causing early-onset life-threatening susceptibility to bacterial infections accompanied by lack of mature neutrophils [6]. Different studies have shown mutations in ELA2, HAX1, G6PC3, WAS, GFI1 and JAGN1 genes, which account for the different forms of hereditary SCN [6,7]. Some of the SCN types were associated with multisystemic involvement, which denotes as syndromic type like Hermansky-Pudlak syndrome type II (AP3B1) [8], Cohen syndrome (COH1) [9] and Barth syndrome — MGA-uria type II (TAZ) [10]. MEGCANN disorder affected 3-MGA metabolism was found to be related with syndromic neutropenia [3–5]. Here, we report a case with novel CLPB mutation displaying multiorgan involvement. A two-year old female was a product of healthy nonconsanguineous parents. She was admitted to our clinic at 5 months of age with fever and skin abscess localized on her chin. Severe persistent neutropenia (range: 0–400/mm) was detected with a compatible blood smear absent of granulocytes (Supplementary Table 1). Due to persistence of neutropenia bone marrow aspiration was performed and revealed normocellularity with a decrease in myeloid series and maturation arrest. G-CSFwas startedwith a favorable response, increasing neutrophil counts to 8000/mm. Although developmental milestones were appropriate at 5 months of age, she exhibited neuromotor deterioration and severe hypotonia during the follow-up (Fig. 1A-C). At 17 months of age, tonic seizures complicated with strabismus were developed. Intractable seizures were observed despite combined phenobarbital, levatiracetam, clobazam and vigabatrin therapies. Cranial magnetic resonance imaging (MRI) was strikingly showing cerebralcerebellar atrophy, bilaterally increased signaling at internal capsule

Clinical and neuroradiological approach to fucosidosis in a child with atypical presentation

Fucosidosis is a rare lysosomal storage disease with clinical presentation of developmental retardation, coarse facial features, hepatosplenomegaly, dysostosis multiplex, and angiokeratomas. Here, a 7-year-old female patient with progressive dystonic movement disorder and loss of acquired motor skills is presented. Coarse facial feature and abnormal globuspallidus signaling in brain magnetic resonance imaging (MRI) led the patient to be investigated in terms of fucosidosis despite absence of hepatosplenomegaly, dysostosis multiplex, and angiokeratomas. Markedly decreased enzyme activity of alpha-fucosidosis led to the correct diagnosis. Conclusion: Various neurological findings have recently been reported in fucosidosis. However, neuroimaging findings have not been studied in detail except a few studies. It is critically important to discuss the wide neuroradiological spectrum of the disease and to highlight fucosidosis in differential diagnosis of bilateral pallidalhypointensity on T2-weighted images in brain MRI. In addition, description of atypical clinical findings of fucosidosis should avoid clinicians from diagnostic delay.

Cobalamin C defect-hemolytic uremic syndrome caused by new mutation in MMACHC

Atypical hemolytic uremic syndrome (aHUS) is mostly linked to defects in the regulation of alternative complement pathway, but a rare form is caused by an inherited defect of cobalamin 1 metabolism. Cobalamin C (cblC) deficiency is an autosomal recessive disorder of vitamin B12 metabolism that results from mutations in methylmalonic aciduria and homocysteinuria (MMACHC). The most severe form of cblC deficiency and the associated high mortality rate are mostly observed in neonates or in infants <6 months of age. Early diagnosis of cblC deficiency leads to early treatment and an improved prognosis. We describe the case of a 6‐year‐old girl with cblC disorder, who presented with severe multiorgan involvement at the age of 5 months and who was successfully treated with vitamin B12, betaine, coenzyme Q10 and l‐carnitene, and who had a new homozygous mutation of MMACHC.

Screening Mucopolysaccharidosis Type IX in Patients with Juvenile Idiopathic Arthritis

Mucopolysaccharidosis is a group of lysosomal disorders of a deficiency of specific enzyme required for glycosaminoglycan degradation. Mucopolysaccharidosis type IX is the rarest form of mucopolysaccharidosis. To date, only four patients have been reported. The first reported patient had mild short stature and periarticular soft tissue masses; the other reported patients are clinically indistinguishable from juvenile idiopathic arthritis. In the present study, we screened mucopolysaccharidosis type IX among patients with juvenile idiopathic arthritis with hyaluronidase enzyme assay. One hundred and eight patients with JIA and 50 healthy age-matched control subjects were enrolled in the study. Among all patients, none had deficient hyaluronidase activity. Though serum Hyal-1 activity was significantly increased in JIA patients, compared with control subjects (p < 0.000), no correlation was found between CRP, ESR, and Hyal-1 activity (p = 0.187). In conclusion, the data reported in our study indicates that systemic metabolic investigation for hyaluronidase activity is not recommended in all patients with JIA.

Recurrence of carbamoyl phosphate synthetase 1 (CPS1) deficiency in Turkish patients: Characterization of a founder mutation by use of recombinant CPS1 from insect cells expression

Carbamoyl phosphate synthetase 1 (CPS1) deficiency due to CPS1 mutations is a rare autosomal-recessive urea cycle disorder causing hyperammonemia that can lead to death or severe neurological impairment. CPS1 catalyzes carbamoyl phosphate formation from ammonia, bicarbonate and two molecules of ATP, and requires the allosteric activator N-acetyl-L-glutamate. Clinical mutations occur in the entire CPS1 coding region, but mainly in single families, with little recurrence. We characterized here the only currently known recurrent CPS1 mutation, p.Val1013del, found in eleven unrelated patients of Turkish descent using recombinant His-tagged wild type or mutant CPS1 expressed in baculovirus/insect cell system. The global CPS1 reaction and the ATPase and ATP synthesis partial reactions that reflect, respectively, the bicarbonate and the carbamate phosphorylation steps, were assayed. We found that CPS1 wild type and V1013del mutant showed comparable expression levels and purity but the mutant CPS1 exhibited no significant residual activities. In the CPS1 structural model, V1013 belongs to a highly hydrophobic β-strand at the middle of the central β-sheet of the A subdomain of the carbamate phosphorylation domain and is close to the predicted carbamate tunnel that links both phosphorylation sites. Haplotype studies suggested that p.Val1013del is a founder mutation. In conclusion, the mutation p.V1013del inactivates CPS1 but does not render the enzyme grossly unstable or insoluble. Recurrence of this particular mutation in Turkish patients is likely due to a founder effect, which is consistent with the frequent consanguinity observed in the affected population.

Neonatal nonketotic hyperglycinemia: diffusion-weighted magnetic resonance imaging and diagnostic clues.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder, which is caused by a defect in the glycine cleavage system. Characteristic findings of this metabolic encephalopathy include generalized hypotonia, seizures, apneic attacks, lethargy, and coma. In this paper, we present the case of a 3-month-old male patient with NKH who presented with atypical clinical features in whom suggestive magnetic resonance imaging (MRI) findings lead to the correct diagnosis. A 3-month-old male patient was admitted to our pediatric nutrition and metabolism unit with complaint of generalized hypotonia. He was the first child of consanguineous parents and his prenatal, natal, and postnatal history was uneventful. He had no history of seizures. Feeding difficulty was noted. His physical examination revealed generalized hypotonia. He had spontaneous eye opening but during the examination, it was observed that he was not aware of his environment. He had no head control. Hematological and biochemical investigations including liver function and muscle specific enzymes, electrolyte levels, and renal functions were found normal. Acylcarnitine profile and urinary organic acid analysis were unremarkable. Plasma lactate and ammonia levels were in normal ranges. Brain diffusion-weighted MRI imaging revealed bilateral symmetrical diffusion restriction in the corona radiata, the posterior limb of the internal capsule and ventral brainstem corresponding to the course of the corticospinal tract, which was suggestive for the diagnosis of NKH (Fig. 1). Despite the absence of seizures, which is an important clinical finding in NKH, the disease was considered in the differential diagnosis based on MRI imaging and the existence of an altered level of consciousness. Plasma and cerebrospinal fluid (CSF) amino acid analyses were performed for definite diagnosis, and both plasma and CSF glycine levels were found remarkably elevated (890 and 131.3 lmol/L, respectively) with a typically high CSF-to-plasma glycine ratio (0,14). Definite diagnosis of NKH was based on characteristic biochemical findings. Although he had not an obvious sign of seizure, electroencephalography was performed and hypsarrhythmia pattern, which was compatible with the disease, was detected. Dextrometorphan and sodium benzoate therapies were started once the diagnosis was made. However, he became progressively lethargic and his condition continued to deteriorate. He died 2 months after the beginning of the treatment. Nonketotic hyperglycinemia is an autosomal recessive disorder, which is characterized by a rapid neurological & Tanyel Zubarioglu tanyel0554@yahoo.com