Çiğdem Seher Kasapkara

Key features and clinical variability of COG6-CDG.

The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.

N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia

Hyperammonemia occurs mainly in patients with branched-chain organic acidemias such as propionic, methylmalonic, and isovaleric acidemias. Its pathophysiological process is mainly via the competitive inhibition of N-acetylglutamate synthetase. Oral carglumic acid (N-carbamylglutamate) administration can correct hyperammonemia in neonates with propionic and methylmalonic acidemias, thus avoiding dialysis therapy. Isovaleric acidemia is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase. For the first time, we report a neonate with isovaleric acidemia, whose plasma ammonia concentration dropped dramatically after one oral load of carglumic acid. This experience suggests that carglumic acid could be considered for acute hyperammonemia resulting from isovaleric acidemia. However, trials with more patients are needed.

SRD5A3-CDG: A patient with a novel mutation

Congenital disorders of glycosylation (CDG) are genetic diseases with an extremely broad spectrum of clinical presentations due to defective glycosylation of glycoproteins and glycolipids. Some 45 CDG types have been reported since the first clinical description in 1980. Protein glycosylation disorders are defects in protein N- and/or O-glycosylation. Dolichol phosphate is the carrier of the N-glycan during their assembly first at the outside and subsequently at the inside of the endoplasmic reticulum (ER) membrane, and hence is a key molecule in protein glycosylation. Recently, defects have been identified in the last three steps of the dolichol phosphate biosynthesis: dolicholkinase deficiency (DK1-CDG), steroid 5alpha-reductase type 3 deficiency (SRD5A3-CDG), and dehydrodolichyl diphosphate synthase deficiency (DHDDS-CDG). We report on a patient with SRD5A3-CDG carrying a novel (homozygous) mutation. The diagnostic features of this novel inborn error of glycosylation are psychomotor retardation, nystagmus, visual impairment due to variable eye malformations, cerebellar abnormalities/ataxia, and often ichthyosiform skin lesions.

Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.

Crisponi syndrome (CS) and cold‐induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold‐induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal‐recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

Severe renal failure and hyperammonemia in a newborn with propionic acidemia: effects of treatment on the clinical course

Abstract Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, and can progress to coma if not identified and treated appropriately. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Herein, we report a case of 3-day-old neonate with PA presented with acute renal failure and metabolic acidosis was effectively treated by peritoneal dialysis and conventional methods.

BCS1L gene mutation causing GRACILE syndrome: case report

Abstract GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder.

The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency

Abstract Background: Glycogen synthase deficiency, also known as glycogenosis (GSD) type 0 is an inborn error of glycogen metabolism caused by mutations in the GYS2 gene, which is transmitted in an autosomal recessive trait. It is a rare form of hepatic glycogen storage disease with less than 30 cases reported in the literature so far. The disorder is characterized by fasting hyperketotic hypoglycemia without hyperalaninemia or hyperlactacidemia. It is a glycogenosis with lack of liver glycogen synthesis, therefore hepatomegaly is not observed in patients with glycogen synthase deficiency. Symptoms of fasting hypoglycemia in patients with glycogen storage disease type 0 (GSD0) usually appear for the first time in late infancy when weaning from overnight feeds. Seizures associated with low blood glucose may also occur, but they are rare. Clinical management is therefore based on frequent meals composed of high protein intake during the day and addition of uncooked cornstarch in the evening. Case presentation: Herein we report three new cases of liver glycogen synthase deficiency (GSD0). The first patient presented at the 4 years of age with recurrent hypoglycemic seizures. The second patient who is the brother of the first patient presented at 15 months with asymptomatic incidental hypoglycemia. Glucose monitoring in both patients revealed daily fluctuations from fasting hypoglycemia to postprandial hyperglycemia and lactic acidemia. A third patient was consulted for ketotic hypoglycemia and postprandial hyperglycemia at the 5 years of age. Conclusions: Genetic analyses of the siblings revealed homozygosity for mutation c.736C>T on the GYS2 gene confirming the diagnosis. The third patient was found to be homozygous for c.1145G>A. GSD0 is more common than previously assumed. Recognition of the variable phenotypic spectrum of GSD0 and routine analysis of GYS2 are essential for the correct diagnosis.

Aromatic L-Amino acid decarboxylase deficiency: A new case from Turkey with a novel mutation.

Aromatic L-amino acid decarboxylase (AADC), a vitamin B6-requiring enzyme that converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Deficiency of this enzyme results in developmental delay, muscular hypotonia, dystonia, involuntary movements, autonomic dysfunction, and oculogyric crises. We now report a 2-year-old Turkish boy with AADC deficiency confirmed by greatly reduced AADC activity in the plasma and by genetic studies. Mutation analysis revealed a homozygous mutation c.208C > T (p. His70Tyr) in exon 3 of the AADC gene which has not been described to date.

Could GSD type I expand the spectrum of disorders with elevated plasma chitotriosidase activity

Abstract Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. Human chitotriosidase is a recently described fully active chitinase expressed by activated macrophages. Marked elevation of chitotriosidase activity was initially observed in plasma of patients with Gaucher disease. Subsequently, elevation was also observed in various lysosomal storage disorders such as fucosidosis, galactosialidosis and glycogen storage disease type IV. The aim of the present study was to evaluate plasma chitotriosidase activity in 19 children with glycogen storage disease type I. Plasma chitotriosidase levels were found to be significantly higher in children with GSD type I than healthy age-matched controls (21.3±16.4 vs. 12.3±8.9 nmol/h/mL, p=0.04). All the patients reported here presented with hepatomegaly. Our report expands the spectrum of disorders that should be included in the differential diagnosis of patients with increased plasma chitotriosidase activity, irrespective of the mechanisms involved.

Hyaline fibromatosis syndrome resulting from a new homozygous missense mutation, p.Gly116Val, in ANTXR2

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