Mutations in BTD gene causing biotinidase deficiency: a regional report

2015 ◽  
Vol 28 (3-4) ◽  
Author(s):  
Çiğdem Seher Kasapkara ◽  
Melek Akar ◽  
Mehmet Nuri Özbek ◽  
Heybet Tüzün ◽  
Bedri Aldudak ◽  
...  
Keyword(s):  
Inborn Error ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Biotinidase Deficiency ◽  
Compound Heterozygous ◽  
Metabolic Abnormalities ◽  
Base Pairs ◽  
Cutaneous Manifestations ◽  
Toxic Metabolites ◽  
Untreated Individuals

AbstractBiotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotin-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey.

scholarly journals Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures

2021 ◽  
pp. 341-346
Author(s):  
Steven D. Mitchell ◽  
Roger L. Albin ◽  
William T. Dauer ◽  
John L. Goudreau ◽  
Christos Sidiropoulos
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Clinical Symptoms ◽  
Phenotypic Diversity ◽  
Phenotypic Expression ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Epistatic Interactions ◽  
History Of ◽  
Vacuolar Protein

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the <i>vacuolar protein sorting 13A</i> (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient’s clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.

scholarly journals Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Victoria Marco Hernández ◽  
Miguel Tomás Vila ◽  
Alfonso Caro Llopis ◽  
Sandra Monfort ◽  
Francisco Martinez
Keyword(s):  
Developmental Disorders ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Autosomal Recessive Inheritance ◽  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Compound Heterozygous ◽  
Recessive Inheritance ◽  
Clinical Criteria ◽  
Febrile Seizures Plus

Dominant pathogenic variations in the SCN1A gene are associated with several neuro developmental disorders with or without epilepsy, including Dravet syndrome (DS). Conversely, there are few published cases with homozygous or compound heterozygous variations in the SCN1A gene. Here, we describe two siblings from a consanguineous pedigree with epilepsy phenotype compatible with genetic epilepsy with febrile seizures plus (GEFS+) associated with the homozygous likely pathogenic variant (NM_001165963.1): c.4513A &gt; C (p.Lys1505Gln). Clinical and genetic data were compared to those of other 10 previously published patients with epilepsy and variants in compound heterozygosity or homozygosity in the SCN1A gene. Most patients (11/12) had missense variants. Patients in whom the variants were located at the cytoplasmic or the extracellular domains frequently presented a less severe phenotype than those in whom they are located at the pore-forming domains. Five of the patients (41.7%) meet clinical criteria for Dravet syndrome (DS), one of them associated acute encephalopathy. Other five patients (41.7%) had a phenotype of epilepsy with febrile seizures plus familial origin, while the two remaining (17%) presented focal epileptic seizures. SCN1A-related epilepsies present in most cases an autosomal dominant inheritance; however, there is growing evidence that some genetic variants only manifest clinical symptoms when they are present in both alleles, following an autosomal recessive inheritance.

scholarly journals Genetics of alkaptonuria – an overview

2015 ◽  
Vol 62 (s11) ◽  
pp. 27-32
Author(s):  
Andrea Zatkova ◽  
Martina Nemethova
Keyword(s):  
Inborn Error ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Homogentisic Acid ◽  
Compound Heterozygous ◽  
Ochronotic Arthropathy ◽  
Pathogenic Variants ◽  
Gene Coding ◽  
Metabolic Block ◽  
Rare Autosomal Recessive Disease

Abstract Alkaptonuria (AKU) is the first described inborn error of metabolism and a classical example of rare autosomal recessive disease. AKU patients carry homozygous or compound heterozygous mutations of the gene coding for enzyme homogentisate dioxygenase (HGD) involved in metabolism of tyrosine. The metabolic block in AKU causes accumulation of homogentisic acid (HGA) that, with advancing age of the patient, leads to severe and painful ochronotic arthropathy. HGD gene was mapped to chromosome 3q13.3 and is composed of 14 exons. In about 400 patients, 142 pathogenic variants were reported that are listed in HGD mutations database (http://hgddatabase.cvtisr.sk/). In this review, we summarise different aspects of AKU genetics and impact of the HGD variants on enzyme function.

Clinical, biochemical and genotypical characteristics in biotinidase deficiency

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Abdurrahman Akgun ◽  
Askin Sen ◽  
Hasan Onal
Keyword(s):  
Autosomal Recessive ◽  
Vision Loss ◽  
Study Data ◽  
Biotinidase Deficiency ◽  
Enzyme Deficiency ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
The Central Nervous System

Abstract Objectives Hypotonia, lethargy, eczema, alopecia, conjunctivitis, ataxia, hearing loss, optic atrophy, cognitive retardation, and seizures can occur in patients with biotinidase deficiency, and it is inherited as autosomal recessive. The aim of this study was to evaluate the cases followed up with the diagnosis of biotinidase deficiency in our unit, in terms of clinical, biochemical and genetic analyses. Methods A total of 112 cases followed up in our centre with the diagnosis of biotinidase deficiency between August 2018–September 2020 were included in the study. Data were collected retrospectively. Results A total of 112 cases (55.4% male, mean age: 2.2 ± 2.8 years) diagnosed with biotinidase deficiency were evaluated. Diagnoses were made by newborn screening in 90.2% of the cases, by family screening in 4.5%, and by investigating symptoms in 5.4%. The most frequently (27.5%) detected mutations were c.1330G>C (p.D444H)/c.1330G>C (p.D444H) homozygous mutation, followed by (13.0%) c.1330G>C (p.D444H)/c.470G>A (p.R157H) compound heterozygous mutation, and (13.0%) c.470G>A (p.R157H)/c.470G>A (p.R157H) homozygous mutation. Biotinidase enzyme levels were found to be higher in patients with the p.D444H homozygous mutation than patients with other mutations. Biotin treatment was started in all patients with enzyme deficiency. Conclusions Since the treatment is inexpensive and easily available, it is vital to detect this disease before symptom onset, especially findings related to the central nervous system, hearing and vision loss. In patients diagnosed with enzyme deficiency, the diagnosis should be definitively confirmed by genetic analysis.

scholarly journals An Atypical Case of Congenital Erythropoietic Porphyria

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1828
Author(s):  
Bénédicte Sudrié-Arnaud ◽  
Marine Legendre ◽  
Sarah Snanoudj ◽  
Fanny Pelluard ◽  
Soumeya Bekri ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Inborn Error ◽  
Autosomal Recessive ◽  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Hydrops Fetalis ◽  
Intravascular Hemolysis ◽  
Atypical Case ◽  
Congenital Erythropoietic Porphyria

Congenital erythropoietic porphyria (CEP, OMIM #606938) is a severe autosomal recessive inborn error of heme biosynthesis. This rare panethnic disease is due to a deficiency of uroporphyrinogen III synthase (or cosynthase). Subsequently, its substrate, the hydroxymethylbilane is subsequently converted into uroporphyrinogen I in a non-enzymatic manner. Of note, uroporphyrinogen I cannot be metabolized into heme and its accumulation in red blood cells results in intramedullary and intravascular hemolysis. The related clinical symptoms occur most frequently during antenatal or neonatal periods but may also appear in late adulthood. The main antenatal clinical presentation is a non-immune hydrops fetalis. We report here two cases of antenatal CEP deficiency and a review of the reported cases in the literature.

scholarly journals Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures

2021 ◽  
Vol 12 (1) ◽  
pp. 65
Author(s):  
Konrad Kaminiów ◽  
Magdalena Pająk ◽  
Renata Pająk ◽  
Justyna Paprocka
Keyword(s):  
Intellectual Disability ◽  
Vitamin B6 ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Neonatal Seizures ◽  
Semialdehyde Dehydrogenase ◽  
Phenotypic Spectrum ◽  
Neonatal Onset ◽  
Toxic Metabolites ◽  
Refractory Seizures

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase (mutation in ALDH7A1 gene), more commonly known as antiquitin (ATQ). ATQ is one of the enzymes involved in lysine oxidation; thus, its deficiency leads to the accumulation of toxic metabolites in body fluids. PDE is characterized by persistent, recurrent neonatal seizures that cannot be well controlled by antiepileptic drugs but are responsive clinically and electrographically to daily pyridoxine (vitamin B6) supplementation. Although the phenotypic spectrum distinguishes between typical and atypical, pyridoxine-dependent is true for each. Diagnosis may pose a challenge mainly due to the rarity of the disorder and the fact that seizures may not occur until childhood or even late adolescence. Moreover, patients may not demonstrate an obvious clinical or electroencephalography response to the initial dose of pyridoxine. Effective treatment requires lifelong pharmacologic supplements of pyridoxine, and dietary lysine restriction and arginine enrichment should improve prognosis and avoid developmental delay and intellectual disability. The purpose of this review is to summarize briefly the latest reports on the etiology, clinical symptoms, diagnosis, and management of patients suffering from pyridoxine-dependent epilepsy.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

Trimethylaminuria (‘fish-odour syndrome’): A study of an affected family

1988 ◽  
Vol 74 (3) ◽  
pp. 231-236 ◽  
Author(s):  
Makram Al-Waiz ◽  
Riad Ayesh ◽  
Stephen C. Mitchell ◽  
Jeffrey R. Idle ◽  
Robert L. Smith
Keyword(s):  
Oral Administration ◽  
Inborn Error ◽  
Autosomal Recessive ◽  
Oral Challenge ◽  
Recessive Trait ◽  
Autosomal Recessive Trait ◽  
Challenge Dose ◽  
The Third ◽  
The Family ◽  
Body Odour

1. Beginning with a single propositus, who had been previously diagnosed at the age of 10 as suffering from trimethylaminuria (fish-odour syndrome), both her parents and two sisters were investigated biochemically with respect to their ability to N-oxidize trimethylamine (TMA), both when derived from the diet and when administered exogenously. 2. Both the propositus and a second sister were markedly deficient in their ability to N-oxidize TMA, both when derived from the diet and when given as such; furthermore, both siblings readily developed the symptoms of fish-odour syndrome as characterized by a strong objectionable breath and body odour shortly after the oral administration of TMA (300 mg). 3. At this dose level of TMA, neither of the parents nor the third sister showed any evidence of impaired N-oxidation ability nor did they experience any ‘fish-odour’ symptoms. 4. With an oral challenge of 600 mg of TMA, both the parents showed a clear impairment of N-oxidation capacity which was not seen in six healthy unrelated volunteers. Both parents experienced a fish-odour syndrome at this level of TMA challenge. 5. The family data support the hypothesis that trimethylaminuria is an inborn error in the ability to N-oxidize TMA which is inherited as an autosomal recessive trait. Furthermore, experience with this family suggests that an oral challenge dose with 600 mg of TMA may be used to identify carriers of the condition.

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