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1.
J Inherit Metab Dis ; 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38503330

ABSTRACT

Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in SLC25A13. The clinical manifestation is very variable and comprises three types: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD: OMIM 605814), post-NICCD including failure to thrive and dyslipidemia caused by citrin deficiency, and adult-onset type II citrullinemia (CTLN2: OMIM 603471). Frequently, NICCD can run with a mild clinical course and manifestations may resolve in the post-NICCD. However, a subset of patients may develop CTLN2 when they become more than 18 years old, and this condition is potentially life-threatening. Since a combination of diet with low-carbohydrate and high-fat content supplemented with medium-chain triglycerides is expected to ameliorate most manifestations and to prevent the progression to CTLN2, early detection and intervention are important and may improve long-term outcome in patients. Moreover, infusion of high sugar solution and/or glycerol may be life-threatening in patients with citrin deficiency, particularly CTLN2. The disease is highly prevalent in East Asian countries but is more and more recognized as a global entity. Since newborn screening for citrin deficiency has only been introduced in a few countries, the diagnosis still mainly relies on clinical suspicion followed by genetic testing or selective metabolic screening. This paper aims at describing (1) the different stages of the disease focusing on clinical aspects; (2) the current published clinical situation in East Asia, Europe, and North America; (3) current efforts in increasing awareness by establishing management guidelines and patient registries, hereby illustrating the ongoing development of a global network for this rare disease.

2.
J Pediatr Endocrinol Metab ; 36(9): 873-878, 2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37427576

ABSTRACT

OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. CASE PRESENTATION: We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake. CONCLUSIONS: Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy.


Subject(s)
Carbamoyl-Phosphate Synthase I Deficiency Disease , Urea Cycle Disorders, Inborn , Humans , Infant, Newborn , Carbamoyl-Phosphate Synthase (Ammonia)/chemistry , Carbamoyl-Phosphate Synthase (Ammonia)/metabolism , Carbamoyl-Phosphate Synthase I Deficiency Disease/metabolism , Carbamoyl-Phosphate Synthase I Deficiency Disease/therapy , Citrulline/therapeutic use , Glutamic Acid
3.
J Inherit Metab Dis ; 45(3): 605-620, 2022 05.
Article in English | MEDLINE | ID: mdl-35195902

ABSTRACT

Deficiency of the biotinidase (BTD) enzyme is an inborn error of biotin metabolism caused by biallelic pathogenic variants in the BTD gene. There are two forms, partial and profound BTD deficiency, which both can be successfully treated with pharmacological doses of biotin, justifying the inclusion of this disorder in the newborn screening in numerous countries. We investigated the BTD deficiency cohort (N = 87) in our metabolic center, as it was detected upon newborn screening since 2005, and aimed to better understand the long-term course of BTD enzyme activity and how it may relate to the patients' genetic background. We observed that individuals with partial BTD deficiency display an elevation of BTD enzyme activity with increasing age in 48% of cases-a recovery which allowed adjustment or stop of biotin supplementation in 20% of all individuals. In addition, we were able to recruit 56 patients (64%) for genetic testing, revealing 19 different variants (2 novel), and constituting 22 different genotypes. Genotype-phenotype correlations revealed that the most abundant allele in our cohort p.(Asp444His) was also the most common variant in patients displaying recovery of BTD enzyme activity. Based on our results, we recommend to retest all patients with partial BTD deficiency at the age of 5 years, as this may result in an impact on therapy. Moreover, genetic testing of BTD deficient individuals can allow prediction of the severity of BTD deficiency and of the likelihood of BTD enzyme activity recovery with age.


Subject(s)
Biotinidase Deficiency , Biotin/therapeutic use , Biotinidase/genetics , Biotinidase/metabolism , Biotinidase Deficiency/diagnosis , Biotinidase Deficiency/drug therapy , Biotinidase Deficiency/genetics , Child, Preschool , Genetic Testing , Humans , Infant, Newborn , Mutation , Neonatal Screening
4.
Neuropediatrics ; 52(2): 126-132, 2021 04.
Article in English | MEDLINE | ID: mdl-33231275

ABSTRACT

TPK deficiency due to TPK1 mutations is a rare neurodegenerative disorder, also known as thiamine metabolism dysfunction syndrome 5 (OMIM no.: 614458). Here, we report a new patient with compound heterozygous TPK1 mutations, of which one has not been described so far. The individual reported here suffered from acute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by febrile infections. Initiation of high-dose thiamine and magnesium supplementation led to a marked and sustained improvement of alertness, ataxia, and muscle tone within days. Contrary to the described natural history of patients with TPK deficiency, the disease course was favorable under thiamine treatment without deterioration or developmental regression during the follow-up period. TPK deficiency is a severe neurodegenerative disease. This case report demonstrates that this condition is potentially treatable. High-dose thiamine treatment should therefore be initiated immediately after diagnosis or even upon suspicion.


Subject(s)
Neurodegenerative Diseases/diet therapy , Neurodegenerative Diseases/physiopathology , Thiamin Pyrophosphokinase/deficiency , Thiamin Pyrophosphokinase/genetics , Thiamine/pharmacology , Vitamin B Complex/pharmacology , Child , Dietary Supplements , Humans , Magnesium/administration & dosage , Rare Diseases , Thiamine/administration & dosage , Vitamin B Complex/administration & dosage
5.
J Mother Child ; 24(2): 32-38, 2020 Oct 02.
Article in English | MEDLINE | ID: mdl-33179600

ABSTRACT

Primary hyperammonaemia is a term to describe an elevation of ammonia in blood or plasma due to a defect within the urea cycle, which is the pathway responsible for ammonia detoxification and arginine biosynthesis. Urea cycle disorders (UCDs) are rare diseases caused by genetic defects affecting any of the six enzymes or two transporters that are directly involved in the urea cycle function.The clinical situation is variable and largely depends on the time of onset. Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. Outside the neonatal period, symptoms are very unspecific but most often neurological (with wide variability), psychiatric and/or gastrointestinal. Early identification of patients is extremely important to start effective treatment modalities immediately. The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. Long-term management of patients with UCDs consists of a low-protein diet, which needs to be balanced and supplemented to avoid deficiencies of essential amino acids, trace elements or vitamins and the use of nitrogen scavengers.The reader will find here a brief overview describing the most relevant aspects of the clinical management of UCDs in an attempt to raise awareness for this important group of rare diseases.


Subject(s)
Ammonia/blood , Hyperammonemia/complications , Hyperammonemia/diagnosis , Hyperammonemia/physiopathology , Hyperammonemia/therapy , Renal Dialysis/methods , Urea Cycle Disorders, Inborn/blood , Early Diagnosis , Female , Humans , Infant , Infant, Newborn , Male , Treatment Outcome , Urea Cycle Disorders, Inborn/diagnosis , Urea Cycle Disorders, Inborn/therapy
6.
Hum Gene Ther ; 30(9): 1093-1100, 2019 09.
Article in English | MEDLINE | ID: mdl-31084364

ABSTRACT

Cystathionine ß-synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by extremely elevated total homocysteine (tHcy) in the blood. Patients diagnosed with CBS deficiency have a variety of clinical problems, including dislocated lenses, osteoporosis, cognitive and behavioral issues, and a significantly increased risk of thrombosis. Current treatment strategies involve a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine. Here, a mouse model for CBS deficiency (Tg-I278T Cbs-/-) was used to evaluate the potential of minicircle-based naked DNA gene therapy to treat CBS deficiency. A 2.3 kb DNA-minicircle containing the liver-specific P3 promoter driving the human CBS cDNA (MC.P3-hCBS) was delivered into Tg-I278T Cbs-/- mice via a single hydrodynamic tail vein injection. Mean serum tHcy decreased from 351 µM before injection to 176 µM 7 days after injection (p = 0.0005), and remained decreased for at least 42 days. Western blot analysis reveals significant minicircle-directed CBS expression in the liver tissue. Liver CBS activity increased 34-fold (12.8 vs. 432 units; p = 0.0004) in MC.P3-hCBS-injected animals. Injection of MC.P3-hCBS in young mice, subsequently followed for 202 days, showed that the vector can ameliorate the mouse homocystinuria alopecia phenotype. The present findings show that minicircle-based gene therapy can lower tHcy in a mouse model of CBS deficiency.


Subject(s)
Cystathionine beta-Synthase/genetics , DNA, Circular/genetics , Genetic Therapy , Genetic Vectors/genetics , Homocystinuria/genetics , Homocystinuria/therapy , Animals , Biomarkers , Cystathionine beta-Synthase/blood , Cystathionine beta-Synthase/deficiency , DNA, Circular/administration & dosage , Disease Models, Animal , Female , Gene Expression , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Homocystinuria/metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Phenotype , Transfection/methods , Treatment Outcome
7.
JIMD Rep ; 31: 11-14, 2017.
Article in English | MEDLINE | ID: mdl-27000017

ABSTRACT

A male patient, born in 1999, was diagnosed with ornithine transcarbamylase deficiency as neonate and was managed with a strict low-protein diet supplemented with essential amino acids, L-citrulline, and L-arginine as well as sodium benzoate. He had an extensive history of hospitalizations for hyperammonemic crises throughout childhood and early adolescence, which continued after the addition of sodium phenylbutyrate in 2009. In December 2013 he was switched to glycerol phenylbutyrate, and his metabolic stability was greatly improved over the following 7 months prior to liver transplant.

8.
J Med Genet ; 53(10): 710-9, 2016 10.
Article in English | MEDLINE | ID: mdl-27287393

ABSTRACT

BACKGROUND: Citrullinemia type 1 is an autosomal-recessive urea cycle disorder caused by mutations in the ASS1 gene and characterised by increased plasma citrulline concentrations. Of the ∼90 argininosuccinate synthetase (ASS) missense mutations reported, 21 map near the substrate (aspartate or citrulline) binding site, and thus are potential kinetic mutations whose decreased activities could be amenable to substrate supplementation. This article aims at characterising these 21 ASS mutations to prove their disease-causing role and to test substrate supplementation as a novel therapeutic approach. METHODS: We used an Escherichia coli expression system to study all potentially kinetic ASS mutations. All mutant enzymes were nickel-affinity purified, their activity and kinetic parameters were measured using tandem mass spectrometry and their thermal stability using differential scanning fluorimetry. Structural rationalisation of the effects of these mutations was performed. RESULTS: Of the characterised mutants, 13 were totally inactive while 8 exhibited decreased affinity for aspartate and citrulline. The activity of these eight kinetic mutations could be rescued to ∼10-99% of the wild-type using high l-aspartate concentrations. CONCLUSIONS: Substrate supplementation raised in vitro the activity of eight citrullinemia type 1 mutations with reduced affinity for aspartate. As a direct translation of these results to the clinics, we propose to further evaluate the use of oxaloacetate, a nitrogen-free aspartate precursor and already available medical food (anti-ageing and brain stimulating, not considered as a drug by the US Food and Drug Administration), in patients with citrullinemia type 1 with decreased aspartate affinity. Although only patients with kinetic mutations would benefit, oxaloacetate could offer a safe novel treatment.


Subject(s)
Argininosuccinate Synthase/genetics , Aspartic Acid/therapeutic use , Citrullinemia/enzymology , Argininosuccinate Synthase/metabolism , Aspartic Acid/metabolism , Aspartic Acid/pharmacology , Catalytic Domain/genetics , Citrulline/metabolism , Citrullinemia/drug therapy , Citrullinemia/genetics , Humans , Kinetics , Mutation, Missense
9.
J Inherit Metab Dis ; 38(6): 1075-83, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25896882

ABSTRACT

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD(+) depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD(+) depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD(+) depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.


Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Glutamate-Ammonia Ligase/deficiency , Glutamine/blood , Hyperammonemia/genetics , NAD/blood , NAD/deficiency , B-Lymphocytes/cytology , Cell Culture Techniques , Dietary Supplements , Fibroblasts/cytology , Glutamate-Ammonia Ligase/genetics , Humans , Point Mutation
10.
Mol Genet Metab ; 114(3): 438-44, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25639153

ABSTRACT

Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 µmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 µmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carbamoyl-Phosphate Synthase (Ammonia)/deficiency , Hematopoietic Stem Cell Transplantation/adverse effects , Hyperammonemia/etiology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Edema/etiology , Carbamoyl-Phosphate Synthase (Ammonia)/genetics , Carbamoyl-Phosphate Synthase (Ammonia)/metabolism , Carbamyl Phosphate/metabolism , Carboplatin/adverse effects , Carboplatin/pharmacology , Child, Preschool , Combined Modality Therapy , Etoposide/adverse effects , Etoposide/pharmacology , Fatal Outcome , Glutamine/blood , Hep G2 Cells , Humans , Hyperammonemia/chemically induced , Liver/enzymology , Liver/metabolism , Male , Middle Aged , Neuroblastoma/drug therapy , Ornithine Carbamoyltransferase/genetics , Oxidative Phosphorylation
11.
Orphanet J Rare Dis ; 7: 48, 2012 Jul 25.
Article in English | MEDLINE | ID: mdl-22830360

ABSTRACT

Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine deficiency and has been described in three patients with epileptic encephalopathy. There is no established treatment for this condition.Here, we describe a therapeutic trial consisting of enteral and parenteral glutamine supplementation in a four year old patient with GS deficiency. The patient received increasing doses of glutamine up to 1020 mg/kg/day. The effect of this glutamine supplementation was monitored clinically, biochemically, and by studies of the electroencephalogram (EEG) as well as by brain magnetic resonance imaging and spectroscopy.Treatment was well tolerated and clinical monitoring showed improved alertness. Concentrations of plasma glutamine normalized while levels in cerebrospinal fluid increased but remained below the lower reference range. The EEG showed clear improvement and spectroscopy revealed increasing concentrations of glutamine and glutamate in brain tissue. Concomitantly, there was no worsening of pre-existing chronic hyperammonemia.In conclusion, supplementation of glutamine is a safe therapeutic option for inherited GS deficiency since it corrects the peripheral biochemical phenotype and partially also improves the central biochemical phenotype. There was some clinical improvement but the patient had a long standing severe encephalopathy. Earlier supplementation with glutamine might have prevented some of the neuronal damage.


Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Amino Acids/metabolism , Glutamate-Ammonia Ligase/deficiency , Glutamine/administration & dosage , Brain/pathology , Child , Humans , Magnetic Resonance Imaging
12.
J Inherit Metab Dis ; 35(5): 761-76, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22170564

ABSTRACT

Δ(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia). Here we report a new P5CS-deficient patient presenting the complete clinical/metabolic phenotype and carrying p.G93R and p.T299I substitutions in the γ-glutamyl kinase (γGK) component of P5CS. The effects of these substitutions are (1) tested in mutagenesis/functional studies with E.coli γGK, (2) rationalized by structural modelling, and (3) reflected in decreased P5CS protein in patient fibroblasts (shown by immunofluorescence). Using optical/electron microscopy on skin biopsy, we show collagen/elastin fiber alterations that may contribute to connective tissue laxity and are compatible with our angio-MRI finding of kinky brain vessels in the patient. MR spectroscopy revealed decreased brain creatine, which normalized after sustained arginine supplementation, with improvement of neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy. Morphological and functional studies of fibroblast mitochondria show that P5CS deficiency is not associated with the mitochondrial alterations observed in Δ(1)-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations).


Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/therapy , Arginine/therapeutic use , Ornithine-Oxo-Acid Transaminase/deficiency , Amino Acid Metabolism, Inborn Errors/enzymology , Amino Acid Metabolism, Inborn Errors/metabolism , Amino Acid Sequence , Humans , Infant , Male , Models, Molecular , Molecular Sequence Data , Ornithine-Oxo-Acid Transaminase/metabolism , Phenotype
13.
J Hum Genet ; 54(6): 331-4, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19373259

ABSTRACT

Transcobalamin II (TC II) is a plasma transport protein for cobalamin. TC II deficiency can lead to infant megaloblastic anemia, failure to thrive and to neurological complications. This report describes the genetic work-up of three patients who presented in early infancy. Initially, genomic investigations did not reveal the definite genetic diagnosis in the two index patients. However, analysis of cDNA from skin fibroblasts revealed a homozygous deletion of exon 7 of the TC II gene caused by the mutation c.940+303_c.1106+746del2152insCTGG (r.941_1105del; p.fs326X) in one patient. The other patients were siblings and both affected by an insertion of 87 bp on the transcript which was caused by the homozygous mutation c.580+624A>T (r.580ins87; p.fs209X). Additional experiments showed that cDNA from lymphocytes could have been used also for the genetic work-up. This report shows that the use of cDNA from skin fibroblasts or peripheral lymphocytes facilitates genetic investigations of suspected TC II deficiency and helps to avoid false-negative DNA analysis.


Subject(s)
Anemia, Megaloblastic/diagnosis , DNA, Complementary/genetics , RNA/genetics , Transcobalamins/deficiency , Transcobalamins/genetics , Anemia, Megaloblastic/genetics , Child , DNA, Complementary/metabolism , Female , Fibroblasts/metabolism , Follow-Up Studies , Humans , Infant, Newborn , Lymphocytes/metabolism , Male , Prognosis , RNA/metabolism , Skin/cytology , Skin/metabolism
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