Research

10 pages, 441 KiB

Open AccessArticle

Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders

by Sandro Santa Paola, Francesco Domenico Di Blasi, Eugenia Borgione, Mariangela Lo Giudice, Marika Giuliano, Rosa Pettinato, Vincenzo Di Stefano, Filippo Brighina, Antonino Lupica and Carmela Scuderi

Genes 2024, 15(1), 134; https://doi.org/10.3390/genes15010134 - 21 Jan 2024

Viewed by 1166

Abstract

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these [...] Read more.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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28 pages, 8775 KiB

Open AccessFeature PaperArticle

Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C

by Andrew J. Tolan, Kayla L. Sanchez, Samuel D. Shin, Jacob B. White, Antonio Currais, David Soriano-Castell, Christopher G. Wilson, Pamela Maher and Salvador Soriano

Genes 2024, 15(1), 101; https://doi.org/10.3390/genes15010101 - 15 Jan 2024

Viewed by 944

Abstract

Niemann–Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that [...] Read more.

Niemann–Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic Npc1^−/− mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic Npc1^−/− mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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13 pages, 3140 KiB

Open AccessArticle

Brain Targeted AAV1-GALC Gene Therapy Reduces Psychosine and Extends Lifespan in a Mouse Model of Krabbe Disease

by Aimee R. Herdt, Hui Peng, Dennis W. Dickson, Todd E. Golde, Elizabeth A. Eckman and Chris W. Lee

Genes 2023, 14(8), 1517; https://doi.org/10.3390/genes14081517 - 25 Jul 2023

Cited by 2 | Viewed by 1354

Abstract

Krabbe disease (KD) is a progressive and devasting neurological disorder that leads to the toxic accumulation of psychosine in the white matter of the central nervous system (CNS). The condition is inherited via biallelic, loss-of-function mutations in the galactosylceramidase (GALC) gene. [...] Read more.

Krabbe disease (KD) is a progressive and devasting neurological disorder that leads to the toxic accumulation of psychosine in the white matter of the central nervous system (CNS). The condition is inherited via biallelic, loss-of-function mutations in the galactosylceramidase (GALC) gene. To rescue GALC gene function in the CNS of the twitcher mouse model of KD, an adeno-associated virus serotype 1 vector expressing murine GALC under control of a chicken β-actin promoter (AAV1-GALC) was administered to newborn mice by unilateral intracerebroventricular injection. AAV1-GALC treatment significantly improved body weight gain and survival of the twitcher mice (n = 8) when compared with untreated controls (n = 5). The maximum weight gain after postnatal day 10 was significantly increased from 81% to 217%. The median lifespan was extended from 43 days to 78 days (range: 74–88 days) in the AAV1-GALC-treated group. Widespread expression of GALC protein and alleviation of KD neuropathology were detected in the CNS of the treated mice when examined at the moribund stage. Functionally, elevated levels of psychosine were completely normalized in the forebrain region of the treated mice. In the posterior region, which includes the mid- and the hindbrain, psychosine was reduced by an average of 77% (range: 53–93%) compared to the controls. Notably, psychosine levels in this region were inversely correlated with body weight and lifespan of AAV1-GALC-treated mice, suggesting that the degree of viral transduction of posterior brain regions following ventricular injection determined treatment efficacy on growth and survivability, respectively. Overall, our results suggest that viral vector delivery via the cerebroventricular system can partially correct psychosine accumulation in brain that leads to slower disease progression in KD. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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13 pages, 1204 KiB

Open AccessArticle

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene

by Stephanie I. W. van de Stadt, Petra A. W. Mooyer, Inge M. E. Dijkstra, Conny J. M. Dekker, Divya Vats, Moin Vera, Maura R. Z. Ruzhnikov, Keith van Haren, Nelson Tang, Klaas Koop, Michel A. Willemsen, Joannie Hui, Frédéric M. Vaz, Merel S. Ebberink, Marc Engelen, Stephan Kemp and Sacha Ferdinandusse

Genes 2021, 12(12), 1930; https://doi.org/10.3390/genes12121930 - 30 Nov 2021

Cited by 8 | Viewed by 2991

Abstract

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a [...] Read more.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D₃-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D₃-C16:0/D₃-C22:0 ratio in the D₃-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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17 pages, 25113 KiB

Open AccessArticle

Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients

by Amanat Ali, Fatmah Saeed Ali Almesmari, Nahid Al Dhahouri, Arwa Mohammad Saleh Ali, Mohammed Ahmed Ali Mohamed Ahmed Aldhanhani, Ranjit Vijayan, Amal Al Tenaiji, Aisha Al Shamsi, Jozef Hertecant and Fatma Al Jasmi

Genes 2021, 12(9), 1334; https://doi.org/10.3390/genes12091334 - 27 Aug 2021

Cited by 2 | Viewed by 2792

Abstract

The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. [...] Read more.

The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (ETFDH:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the ETFDH:p.Gly472Arg, and ETFB:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant ETFDH:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The ETFDH:p.Arg41Leu, and ETFB:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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12 pages, 689 KiB

Open AccessArticle

Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients

by Rafael Hencke Tresbach, Fernanda Sperb-Ludwig, Rodrigo Ligabue-Braun, Tássia Tonon, Maria Teresinha de Oliveira Cardoso, Romina Soledad Heredia, Maria Teresa Alves da Silva Rosa, Bárbara Cátia Martins, Monique Oliveira Poubel, Luiz Carlos Santana da Silva, François Maillot and Ida Vanessa Doederlein Schwartz

Genes 2021, 12(1), 20; https://doi.org/10.3390/genes12010020 - 25 Dec 2020

Cited by 6 | Viewed by 3934

Abstract

Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the PAH gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from [...] Read more.

Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the PAH gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from 33 unrelated families, were analyzed through next-generation sequencing in the Ion Torrent PGM™ platform. Phenotype–genotype correlations were made based on the BioPKU database. Three patients required additional Sanger sequencing analyses. Twenty-six different pathogenic variants were identified. The most frequent variants were c.1315+1G>A (n = 8/66), c.473G>A (n = 6/66), and c.1162G>A (n = 6/66). One novel variant, c.524C>G (p.Pro175Arg), was found in one allele and was predicted as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) criteria. The molecular modeling of p.Pro175Arg indicated that this substitution can affect monomers binding in the PAH tetramer, which could lead to a change in the stability and activity of this enzyme. Next-generation sequencing was a fast and effective method for diagnosing PKU and is useful for patient phenotype prediction and genetic counseling. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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Review

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18 pages, 301 KiB

Open AccessReview

Advancements in Viral Gene Therapy for Gaucher Disease

by Akhil Kulkarni, Tiffany Chen, Ellen Sidransky and Tae-Un Han

Genes 2024, 15(3), 364; https://doi.org/10.3390/genes15030364 - 15 Mar 2024

Viewed by 1019

Abstract

Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the GBA1 gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of [...] Read more.

Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the GBA1 gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood–brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

26 pages, 858 KiB

Open AccessReview

Understanding Hypertriglyceridemia: Integrating Genetic Insights

by Mara Alves, Francisco Laranjeira and Georgina Correia-da-Silva

Genes 2024, 15(2), 190; https://doi.org/10.3390/genes15020190 - 30 Jan 2024

Viewed by 1694

Abstract

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, [...] Read more.

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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20 pages, 480 KiB

Open AccessReview

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

by Rebecca Jeyaraj, Kirsten McKay Bounford, Nicola Ruth, Carla Lloyd, Fiona MacDonald, Christian J. Hendriksz, Ulrich Baumann, Paul Gissen and Deirdre Kelly

Genes 2021, 12(11), 1837; https://doi.org/10.3390/genes12111837 - 21 Nov 2021

Cited by 8 | Viewed by 2747

Abstract

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved [...] Read more.

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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17 pages, 1235 KiB

Open AccessReview

Successful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands

by Linda C. Zuurbier, Joep C. Defesche and Albert Wiegman

Genes 2021, 12(8), 1168; https://doi.org/10.3390/genes12081168 - 29 Jul 2021

Cited by 13 | Viewed by 3184

Abstract

The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the [...] Read more.

The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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22 pages, 1519 KiB

Open AccessReview

The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders

by Anna Papadopoulou, Evangelia Bountouvi and Fotini-Eleni Karachaliou

Genes 2021, 12(5), 734; https://doi.org/10.3390/genes12050734 - 13 May 2021

Cited by 10 | Viewed by 5416

Abstract

Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling “voyage” starts at Calcium Sensing Receptor (CaSR) localized on the surface of [...] Read more.

Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling “voyage” starts at Calcium Sensing Receptor (CaSR) localized on the surface of the parathyroid glands, which captures the “oscillations” of extracellular ionized Ca and transfers the signal downstream. Parathyroid hormone (PTH), Vitamin D, Fibroblast Growth Factor (FGF23) and other receptors or ion-transporters, work synergistically and establish a highly regulated signalling circuit between the bone, kidneys, and intestine to ensure the maintenance of Ca and P homeostasis. Any deviation from this well-orchestrated scheme may result in mild or severe pathologies expressed by biochemical and/or clinical features. Inherited disorders of Ca and P metabolism are rare. However, delayed diagnosis or misdiagnosis may cost patient’s quality of life or even life expectancy. Unravelling the thread of the molecular pathways involving Ca and P signaling, we can better understand the link between genetic alterations and biochemical and/or clinical phenotypes and help in diagnosis and early therapeutic intervention. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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23 pages, 360 KiB

Open AccessReview

Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series

by Karolina M. Stepien, Elżbieta Ciara and Aleksandra Jezela-Stanek

Genes 2020, 11(11), 1383; https://doi.org/10.3390/genes11111383 - 22 Nov 2020

Cited by 23 | Viewed by 4081

Abstract

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants [...] Read more.

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described—one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype–phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

19 pages, 838 KiB

Open AccessReview

Biomarkers of Fabry Nephropathy: Review and Future Perspective

by Tina Levstek, Bojan Vujkovac and Katarina Trebusak Podkrajsek

Genes 2020, 11(9), 1091; https://doi.org/10.3390/genes11091091 - 18 Sep 2020

Cited by 15 | Viewed by 4335

Abstract

Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. [...] Read more.

Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. Clinical presentation in individual patients varies widely, even in patients from the same family carrying the same pathogenic GLA variant. Therefore, it is reasonable to anticipate that additional genomic, transcriptomic, proteomic, and metabolomics factors influence the manifestation and progression of the disease. The aim of this article is to provide an overview of nephropathy in Fabry patients and the biomarkers currently used in the diagnosis and follow-up. Current biomarkers are associated with late signs of kidney damage. Therefore, there is a need to identify biomarkers associated with early stages of kidney damage that would enable early diagnosis, which is crucial for effective treatment and prevention of severe irreversible complications. Recent advances in sequencing and -omics technologies have led to several studies investigating new biomarkers. We will provide an overview of the novel biomarkers, critically evaluate their clinical utility, and propose future perspectives, which we believe might be in their integration. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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6 pages, 990 KiB

Open AccessCase Report

An Atypical Case of Congenital Erythropoietic Porphyria

by Bénédicte Sudrié-Arnaud, Marine Legendre, Sarah Snanoudj, Fanny Pelluard, Soumeya Bekri and Abdellah Tebani

Genes 2021, 12(11), 1828; https://doi.org/10.3390/genes12111828 - 19 Nov 2021

Cited by 2 | Viewed by 2455

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)

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