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1.
Metab Brain Dis ; 36(6): 1411, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34106389

ABSTRACT

A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8.

2.
Metab Brain Dis ; 36(6): 1405-1410, 2021 08.
Article in English | MEDLINE | ID: mdl-34014443

ABSTRACT

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.


Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , HSP40 Heat-Shock Proteins/deficiency , Phenylalanine/blood , Amino Acid Metabolism, Inborn Errors/complications , Biopterins/analogs & derivatives , Biopterins/therapeutic use , Child , Developmental Disabilities/genetics , Female , Genetic Variation , Humans , Infant, Newborn , Intellectual Disability/genetics , Male , Muscle Hypotonia/genetics , Neurotransmitter Agents/therapeutic use , Phenylalanine Hydroxylase/genetics , Protein Isoforms/genetics
4.
J Inherit Metab Dis ; 42(2): 381-388, 2019 03.
Article in English | MEDLINE | ID: mdl-30701556

ABSTRACT

MBOAT7 gene codes O-acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild-to-moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome-wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173-54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.


Subject(s)
Acyltransferases/genetics , Brain/pathology , Epilepsy/genetics , Intellectual Disability/genetics , Membrane Proteins/genetics , Phospholipids/metabolism , Brain/diagnostic imaging , Child , Child, Preschool , DNA Mutational Analysis , Family , Female , Homozygote , Humans , Infant , Male , Mutation , Neuroimaging , Pedigree , Phenotype , Turkey
5.
J Pediatr Endocrinol Metab ; 31(6): 681-687, 2018 Jun 27.
Article in English | MEDLINE | ID: mdl-29715191

ABSTRACT

BACKGROUND: Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. METHODS: We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition. RESULTS: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously. CONCLUSIONS: Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.


Subject(s)
Alstrom Syndrome/genetics , Mutation , Proteins/genetics , Adolescent , Alstrom Syndrome/diagnosis , Alstrom Syndrome/pathology , Cell Cycle Proteins , Child , DNA Mutational Analysis , Early Diagnosis , Female , Humans , Male , Pedigree , Retrospective Studies , Siblings , Young Adult
6.
Brain Dev ; 40(6): 458-464, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29544888

ABSTRACT

Hereditary spastic paraplegias (HSPs) are a group of genetic disorders resulting in pyramidal tract impairment, predominantly in lower limbs. KIF1C gene has recently been identified as one of the genetic causes of HSP and associated with pure or complicated HSP. We present three patients with complicated HSP from two unrelated families, who had early onset progressive cerebellar signs and developed pyramidal tract signs during follow-up. Whole exome sequencing in these patients followed by segregation analysis identified novel truncating KIF1C mutations (c.463C> T; p.R155∗ and c.2478delA; p.Ala828Argfs∗13). Neuroimaging findings showed cerebral and upper cervical spinal atrophy, bilateral symmetrical pyramidal tract involvement, and focal cerebral white matter lesions. Patients with KIF1C mutations may present with cerebellar signs and pyramidal findings may emerge later, therefore complicated HSP should be considered in the differential diagnosis of unidentified cases with cerebellar dysfunction.


Subject(s)
Kinesins/genetics , Mutation , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Brain/diagnostic imaging , Disease Progression , Family , Female , Humans , Male , Phenotype , Spastic Paraplegia, Hereditary/diagnostic imaging , Spastic Paraplegia, Hereditary/physiopathology , Spinal Cord/diagnostic imaging , Young Adult
7.
Am J Med Genet A ; 173(11): 2954-2967, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28884960

ABSTRACT

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.


Subject(s)
Lysosomal Storage Diseases/genetics , Mucopolysaccharidosis VI/genetics , N-Acetylgalactosamine-4-Sulfatase/genetics , Adolescent , Adult , Child , Child, Preschool , Enzyme Replacement Therapy , Female , Gene Frequency , Genetic Association Studies , Humans , Infant , Infant, Newborn , Lysosomal Storage Diseases/enzymology , Lysosomal Storage Diseases/pathology , Lysosomal Storage Diseases/therapy , Male , Mucopolysaccharidosis VI/enzymology , Mucopolysaccharidosis VI/pathology , Mucopolysaccharidosis VI/therapy , Quality of Life , Turkey/epidemiology , Young Adult
8.
Metab Brain Dis ; 32(5): 1389-1393, 2017 10.
Article in English | MEDLINE | ID: mdl-28752220

ABSTRACT

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.


Subject(s)
Leigh Disease/genetics , Mitochondrial Diseases/genetics , Mitochondrial Proteins/genetics , Ribosomal Proteins/genetics , Brain/diagnostic imaging , Cardiomegaly/diagnostic imaging , Cardiomegaly/genetics , Developmental Disabilities/genetics , Genotype , Humans , Infant , Leigh Disease/diagnostic imaging , Leigh Disease/psychology , Magnetic Resonance Imaging , Male , Mitochondrial Diseases/diagnostic imaging , Mitochondrial Diseases/physiopathology , Muscle Hypotonia/genetics , Mutation
9.
Clin Dysmorphol ; 26(1): 1-12, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27547915

ABSTRACT

We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p. R498W missense mutation in the VPS33A gene might be responsible for this novel disease. Segregation analysis in family members and mutation prediction tools' results also supported the damaging effect of the missense mutation on the function of the Vps33a protein, which plays a role in the vesicular transport system. Electron microscopic studies of the cornea of the proband showed findings supportive of dysfunction in vesicular transport. The clinical phenotype and genetic studies support the suggestion that the siblings most probably have a novel disease very likely caused by a VPS33A gene defect.


Subject(s)
Genetic Association Studies , Lysosomal Storage Diseases/diagnosis , Lysosomal Storage Diseases/genetics , Mutation , Phenotype , Vesicular Transport Proteins/genetics , Biopsy , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Child, Preschool , Facies , Fatal Outcome , Female , Humans , Infant , Pedigree , Radiography , Siblings , Syndrome , Tomography, X-Ray Computed
10.
Turk J Med Sci ; 46(2): 404-8, 2016 Feb 17.
Article in English | MEDLINE | ID: mdl-27511503

ABSTRACT

BACKGROUND/AIM: This study aimed to identify IDUA gene mutations in Turkish patients morphologically (phenotypic) diagnosed with MPS type I. It also sought to discuss the possible effects of detected mutations on alpha-L-iduronidase enzyme function based on current knowledge. MATERIALS AND METHODS: Genetic analysis was carried out in 15 patients using direct DNA sequencing. Moreover, segregation analysis was performed among family members to predict the pathogenic effect of novel mutations, and computational programs were used to predict their functional impact. RESULTS: Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well. CONCLUSION: Our results revealed heterogeneity in the mutation spectrum of Turkish patients. Six of the mutations, including the novel ones, have never before been reported in the Turkish population. Moreover, 5 patients who were phenotypically diagnosed with MPS type I could not be confirmed by genetic analysis, indicating the importance of the molecular characterization of MPS subtypes.


Subject(s)
Mutation , Genetic Testing , Humans , Iduronidase , Mucopolysaccharidosis I , Polymorphism, Genetic
11.
Eur J Pediatr ; 174(8): 1077-84, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25754625

ABSTRACT

UNLABELLED: The incidence of biotinidase deficiency in Turkey is currently one of the highest in the world. To expand upon the information about the biotinidase gene (BTD) variations in Turkish patients, we conducted a mutation screening in a large series (n = 210) of probands with biotinidase deficiency, using denaturing high-performance liquid chromatography and direct DNA sequencing. The putative effects of novel mutations were predicted by computational program. Twenty-six mutations, including six novels (p.C143F, p.T244I, c.1212-1222del11, c.1320delG, p.V457L, p.G480R) were identified. Nine of the patients were symptomatic at the initial clinical assessment with presentations of seizures, encephalopathy, and lactic acidemia. The most common mutation in this group of symptomatic patients was c.98-104 del7ins3. Among the screened patients, 72 have partial and 134 have profound biotinidase deficiency (BD) of which 106 are homozygous for BTD mutations. The common mutations (p.R157H, p.D444H, c.98-104del7ins3, p.T532M) cumulatively accounted for 72.3% of all the mutant alleles in the Turkish population. CONCLUSION: The identification of common mutations and hot spot regions of the BTD gene in Turkish patients is important for mutation screening in the Turkish population and helps to ascertain carriers, may have impact on genetic counseling and implementing prevention programs.


Subject(s)
Biotinidase Deficiency/diagnosis , Biotinidase Deficiency/genetics , Biotinidase/genetics , Mutation , Neonatal Screening/methods , Acidosis, Lactic/genetics , Biotinidase Deficiency/physiopathology , Brain Diseases/genetics , Chromatography, High Pressure Liquid , DNA/genetics , Exome , Family , Female , Homozygote , Humans , Incidence , Infant, Newborn , Male , Pedigree , Seizures/genetics , Sequence Analysis, DNA/methods , Turkey/epidemiology
12.
Eur J Med Genet ; 57(10): 596-601, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25220015

ABSTRACT

We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype-phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234 + 3G > C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456 + 2T > C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype-phenotype correlation could be determined. One of the cases with the novel c.234 + 3G > C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.


Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Isovaleryl-CoA Dehydrogenase/deficiency , Adolescent , Adult , Child , Child, Preschool , Consanguinity , Female , Genetic Heterogeneity , Genotype , Humans , Infant , Isovaleryl-CoA Dehydrogenase/genetics , Male , Mutation , Phenotype , RNA Splicing , Turkey , Young Adult
13.
DNA Cell Biol ; 33(12): 876-83, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25148430

ABSTRACT

Leber congenital amaurosis (LCA) causes severe visual impairment and blindness very early in life. Mutant alleles of several genes acting in different pathways, of which all have critical roles for normal retinal function, were involved in LCA development. The purpose of this study was to use genome-wide genotyping to identify LCA-causing loci in two Turkish families. Genome-wide genotyping and haplotype analysis were performed for prioritization of candidate genes for mutation screening in families with LCA. Identified informative critical choromosomal regions obtained by homozygosity mapping from the families were searched for overlapping of any LCA causative genes. Corresponding clinical phenotypes of the patients with identified mutations were evaluated. In this study, two families were shown to be linked to two different LCA loci covering retinol dehydrogenase 12 (RDH12) and aryl-hydrocarbon-interacting protein-like1 (AIPL1) genes. Mutation screening revealed a novel p.Gln141* mutation in the AIPL1 gene and a previously described p.Thr49Met mutation in the RDH12 gene in a homozygous state. Our patients with the RDH12 mutation had the distinct macular coloboma sign, and the patient with the AIPL1 mutation developed microphthalmia and severe widespread retinal pigment epithelial atrophy, in contrast to previously reported cases. It is currently evident that mutation screening needs to be done in at least 18 genes known to be associated with LCA. Thus, homozygosity mapping is an alternative technique to improve the molecular diagnosis in LCA, which is a group of genetically and clinically heterogeneous diseases causing retinal degeneration. The patients without mutation in known genes may further be analyzed by using next-generation sequencing.


Subject(s)
Alcohol Oxidoreductases/genetics , Carrier Proteins/genetics , Eye Proteins/genetics , Leber Congenital Amaurosis/genetics , Adaptor Proteins, Signal Transducing , Base Sequence , Child , Child, Preschool , Chromosome Mapping , Consanguinity , DNA Mutational Analysis , Female , Genome-Wide Association Study , Homozygote , Humans , Male , Mutation, Missense , Pedigree , Polymorphism, Single Nucleotide
15.
J Hum Genet ; 58(10): 675-8, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23924834

ABSTRACT

Classical galactosemia is an inherited recessive disorder of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT), which is caused by mutations in the GALT gene. In this study, 56 Turkish patients diagnosed with galactosemia were screened for GALT gene mutations using Affymetrix resequencing microarrays. Eleven types of mutations were detected in these patients, including two novel mutations (R258G and G310fsX49) and nine recurrent mutations. We detected six patients who were homozygous for the E340* mutation and for N314D, L218L silent substitutions (Duarte-1 variant) in this study. The haplotype E340*, N314D and L218L has been reported only in Turkish patients, which suggests that the E340* mutation is specific for our population and might be spread by a Turk ancestor. In patients, the Duarte-1 allele was found with a frequency of 10.71%, whereas the Duarte-2 allele was not detected. Duarte-1 and Duarte-2 alleles were found to be present at a frequency of 2.3% and 1.4%, respectively, in the screening of 105 healthy individuals. Considering all detected mutations, it is a very important finding that exons 6 and 10 of the GALT gene account for 79% of all mutant alleles in the Turkish population. The most common mutation is Q188R, with a frequency of 55.35%.


Subject(s)
Asian People/genetics , Galactosemias/epidemiology , Galactosemias/genetics , Genetic Variation , UTP-Hexose-1-Phosphate Uridylyltransferase/genetics , Alleles , Exons , Gene Frequency , Gene Silencing , Homozygote , Humans , Mutation , Oligonucleotide Array Sequence Analysis , Phenotype , Sequence Analysis, DNA , Turkey
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