Berna Seker Yilmaz

Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B.

The autosomal co-dominant disorder familial hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, very low and low density lipoproteins. We describe an 11month-old child with failure to thrive, intestinal lipid malabsorption, hepatic steatosis and severe hypobetalipoproteinemia, suggesting the diagnosis of homozygous FHBL, abetalipoproteinemia (ABL) or chylomicron retention disease (CMRD). The analysis of candidate genes showed that patient was homozygous for a variant (c.1594 C>T) in the APOB gene causing arginine to tryptophan conversion at position 505 of mature apoB (Arg505Trp). No mutations were found in a panel of other potential candidate genes for hypobetalipoproteinemia. In vitro studies showed a reduced secretion of mutant apoB-48 with respect to the wild-type apoB-48 in transfected McA-RH7777 cells. The Arg505Trp substitution is located in the βα1 domain of apoB involved in the lipidation of apoB mediated by microsomal triglyceride transfer protein (MTP), the first step in VLDL and chylomicron formation. The patients condition improved in response to a low fat diet supplemented with fat-soluble vitamins. Homozygosity for a rare missense mutation in the βα1 domain of apoB may be the cause of both severe hypobetalipoproteinemia and intestinal lipid malabsorption.

Primary systemic carnitine deficiency: a Turkish case with a novel homozygous SLC22A5 mutation and 14 years follow-up.

Abstract Systemic primary carnitine deficiency is an autosomal recessive disorder caused by the deficiency of carnitine transporter. Main features are cardiomyopathy, myopathy and hypoglycemic encephalopathy. We report a Turkish case with a novel SLC22A5 gene mutation presented with a pure cardiac phenotype. During the 14-year follow-up study, cardiac functions were remained within a normal range with oral L-carnitine supplementation.

Twenty-seven mutations with three novel pathologenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey

Abstract Background: Biotinidase deficiency (BD) is an autosomal recessive inborn error of metabolism characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. Newborn screening for BD was implemented in Turkey at the end of 2008. Methods: In total, 203 patients who were identified among the infants detected by the newborn screening were later confirmed to have BD through measurement of serum biotinidase activity. We also performed BTD mutation analysis to characterize the genetic profile. Results: Twenty-seven mutations were identified. The most commonly found variants were c.1330G>C (p.D444H), c.1595C>T (p.T532M), c.470G>A (p.R157H), and c.198_104delGCGGCTGinsTCC (p.C33Ffs ) with allele frequencies of 0.387, 0.175, 0.165 and 0.049, respectively. Three novel pathogenic and likely pathogenic variants were identified: p.W140* (c.419G>A), p.S319F (c.956C>T) and p.L69Hfs*24 (c.192_193insCATC). We also identified three mutations reported in just one patient in the past (p.V442Sfs*59 [c.1324delG], p.H447R [c.1340A>G] and p.198delV [c.592_594delGTC]). Although all of the patients were asymptomatic under the treatment of biotin, only one patient, who had the novel c.419G>A homozygous mutation became symptomatic during an episode of acute gastroenteritis with a presentation of ketosis and metabolic acidosis. Among the screened patients, 156 had partial and 47 had profound BD. Conclusions: We determined the mutation spectra of BD from the southeastern part of Turkey. The results of this study add three more mutations to the total number of mutations described as causing BD.

A 17-Year-Old Girl with Chronic Intermittent Abdominal Pain

139 Editor’s note: Each month, this department features a discussion of an unusual diagnosis. A description and images are presented, followed by the diagnosis and an explanation of how the diagnosis was determined. As always, your comments are welcome via email at pedann@Healio.com. For diagnosis, see page 140 A17-year-old girl was admitted to our emergency department with complaints of sudden, severe, and sharp abdominal pain that began 15 days prior. On admission, she was diagnosed as having acute gastroenteritis and given metronidazole. She returned 1 week later and was diagnosed as having a urinary infection for which she was given trimethoprim. Nevertheless, she continued to experience chronic intermittent abdominal pain, vomiting, diarrhea, and an inability to tolerate food that lasted more than 20 days before she was admitted to our hospital. She went to several different medical centers seeking treatment before being admitted to our hospital for a third time. Her medical history was unremarkable except for the fact that her parents were first-degree cousins. She was healthy except for complaints of mild mental and motor retardation. She denied use of any prescription drugs and denied eating any unknown food or plants, and no one in her family had an inherited metabolic disease or a known gastrointestinal disease. On follow-up in the hospital, affective symptoms such as emotional lability, psychomotor slowness, symptoms of phobia, and crying and shouting independent of pain were added to the list of her clinical symptoms. She was given olanzapine for the psychotic symptoms. Because of her mild mental retardation, sexual abuse was also considered in the differential diagnosis but there was no evidence to confirm any abuse. Upon her latest admission to the hospital she was lethargic and disoriented. Systemic examination was insignificant. Neurologic examination revealed muscle weakness, especially in the proximal muscles. Deep tendon reflexes were absent. Hemogram, blood sugar, liver and kidney function tests, thyroid hormone levels, chest X-ray, electrocardiography, electroencephalography, and magnetic resonance imaging of central nervous system were all normal. Acute phase reactants were negative. Serum folate and vitamin B12 levels were normal. A computed tomography scan of her abdomen revealed cholelithiasis. Serum lead level was within normal limits. On the third day of her hospitalization she had generalized tonic-clonic seizures. Phenobarbital, diphenylhydantoin, and diazepam were prescribed to control the seizures. Analysis of cerebrospinal fluid showed neither an elevation in total protein levels nor an elevation in cell count. Subsequently, sustained high blood pressure was detected (via 24-hour blood pressure monitoring), and she was given oral calcium channel blocker for hypertension. During a follow-up visit in the hospital, because the medical team could not exclude the diagnosis of encephalitis, antibiotics were given in addition to antiCase Challenge

Two novel missense mutations in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (OMIM no. 605899) is an autosomal recessively inherited glycine encephalopathy, caused by a deficiency in the mitochondrial glycine cleavage system. Here we report 2 neonates who were admitted to the hospital with complaints of respiratory failure and myoclonic seizures with an elevated cerebrospinal fluid/plasma glycine ratio and diagnosed as nonketotic hyperglycinemia. We report these cases as 2 novel homozygous mutations; a missense mutation c.593A>T (p.D198 V) in the glycine decarboxylase gene and a splicing mutation c.339G>A (Q113Q) in the aminomethyltransferase gene were detected. We would like to emphasize the genetic difference of our region in inherited metabolic diseases once again.