Tanyel Zubarioglu

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.

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.

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.

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

Coagulation Disturbances in Patients with Argininemia

Background: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. Methods: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. Results: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. Conclusions: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms.

A Rare Leukoencephalopathy: Succinate Dehydrogenase Deficiency

70 Dear Editor, A male patient was admitted with delay in motor development. He was born from healthy consanguneous parents after a normal pregnancy and birth as the third son of the family. There were no features in his family history. It was reported that the delay in motor development became obvious after he had an infection with high fever when he was 10 months old. He still could not sit or walk without help. There was a decrease in tonus, his deep tendon reflexes were hypoactive, he could not speak and could only follow objects with his eyes. Biochemical tests including total blood count, electrolyte levels, liver enzyme levels, kidney function tests, levels of muscle enzymes, blood glucose count, and lipid profile were normal. Metabolic tests including plasma ammonia levels, cantitative amino acid analysis, acylcarnitine profile with tandem mass spectometry, organic acid analysis in urine, and very long chain fatty acid levels were normal. Lactate levels were slightly elevated (35.5 ug/dL). The enzyme activities of arylsulfatase A and beta galactosidase were normal. The nerve conduction study and electroencephalogram results were normal. T2-weighted brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensities including the corpus callosum (Figure 1a). Corticospinal tractus seemed hyperintense in capsula interna crus posterior, mesencephalon and pons (Figure 1a, 1b). Cranial MRI revealed hyperintensity of the middle cerebellar peduncles (Figure 1c) and nuclei of the thalamus (Figure 1a). Mitochondrial DNA analyses performed on a peripheral blood sample and muscle biopsy showed no pathology. Genetic testing performed on the patient’s blood sample revealed a mutation in the SDHB gene, which diminishes the activity of complex 2 of the mitochondrial respiratory chain (c.143A>T p.Asp48Val). Rehabilitation partially improved the motor development of the patient and he could sit with support, but he could not walk in his examination when he was aged 6 years. He had spastic tetraparesis predominantly in the lower extremities. He could understand spoken words and build sentences containing a few words. He was started on coenzyme q10, vitamin B12, and baclofen, and his clinical status was stable. Complex 2 enzyme ‘succinate dehydrogenase (SDH)‘ defects of mitochondrial respiratory chain and oxidative phosphorylation system are very rare (2%), which is why succinate dehydrogenase deficiency is a rare cause of leukoencephalopathy. The SDH complex is coded by the nuclear genome. It has 4 subunits including SDHA, SDHB, SDHC, and SDHD and 4 assembly factor proteins (1). The clinical presentation is variable and infantile-onset leukoencephalopathy is a frequent clinical feature (2,3). MR spectroscopy shows a succinate peak, which is a specific

Screening of free carnitine and acyl-carnitine status in patients with Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring self-limited fever, abdominal pain and chest pain caused by serositis. FMF mainly affects Middle-East populations with a high prevalence in Sephardic Jews, Turkish, Arabs and Armenians. Carnitine is an important molecule in cellular energy metabolism. Secondary carnitine deficiency can be detected in chronic diseases by either renal loss or increased needs.

Screening for inherited metabolic disorders in patients with Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autosomal recessive auto-inflammatory disease, presenting with recurrent episodes of fever and polyserositis. Diagnosis of FMF is may be challenging especially in pediatric population. Mitochondrial fatty acid oxidation disorders and porphyrias can present with periodic abdominal and muscle pain. Incidence of both FMF and inherited metabolic disorders (IMD) are increased in Turkish patients partially due to high consanguinity rates.

Lessons from two cases: is Fabry disease the correct diagnosis?

Fabry disease (FD) is an X linked inherited lysosomal storage disorder with complex multisystem involvement; it is caused by deficiency of the lysosomal enzyme α-galactosidase. Deficient enzyme activity leads to a wide spectrum of clinical manifestations consisting of dermatological, ophthalmological, cardiovascular, and urinary and central nervous system findings. As a result, FD should be considered in the differential diagnosis of many systemic diseases. Diagnosis of FD can arise from careful clinical and instrumental investigations, together with family history data and accurate interpretation of genetic and enzymatic analyses. Lack of knowledge on clinical findings of the disease and inept investigation methods unfortunately result in erroneous diagnosis. We present two patients who were referred to our clinic with a suspicion of ED and finally diagnosed as glycogen storage disorder type III and ornithine transcarbamylase deficiency, respectively.