ABSTRACT
Acute liver failure (ALF) is a clinical condition characterized by the abrupt onset of coagulopathy and biochemical evidence of hepatocellular injury, leading to rapid deterioration of liver cell function. In children, ALF has been characterized by raised transaminases, coagulopathy, and no known evidence of pre-existing chronic liver disease; unlike in adults, the presence of hepatic encephalopathy is not required to establish the diagnosis. Although rare, ALF has a high mortality rate without liver transplantation (LT). Etiology of ALF varies with age and geographical location, although it may remain indeterminate in a significant proportion of cases. However, identifying its etiology is crucial to undertake disease-specific management and evaluate indication to LT. In this position statement, the Liver Disease Working Group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) reviewed the most relevant studies on pediatric ALF to provide recommendations on etiology, clinical features and diagnostic work-up of neonates, infants and children presenting with ALF. Recommendations on medical management and transplant candidacy will be discussed in a following consensus conference.
Subject(s)
Liver Failure, Acute/diagnosis , Acetaminophen/adverse effects , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Italy , Liver Failure, Acute/blood , Liver Failure, Acute/etiology , Liver Failure, Acute/therapyABSTRACT
The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients' organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients' health and the mid- and long-term effects of the pandemic on their wellbeing.
Subject(s)
COVID-19/complications , Metabolic Diseases/complications , Rare Diseases/complications , SARS-CoV-2 , COVID-19/epidemiology , Data Collection , Europe/epidemiology , Genetic Predisposition to Disease , Health Personnel , Health Services Accessibility , Humans , Metabolic Diseases/classification , TelemedicineABSTRACT
Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
Subject(s)
Adaptive Immunity , Autophagy/immunology , DNA/metabolism , Endosomes/metabolism , Immunity, Innate , Lysosomes/metabolism , Proteins/metabolism , RNA/metabolism , Agenesis of Corpus Callosum/genetics , Agenesis of Corpus Callosum/immunology , Autophagy-Related Proteins , B-Lymphocytes/immunology , Biological Transport , Cataract/genetics , Cataract/immunology , Cell Line , Humans , Lysosomal Membrane Proteins , Mutation , Proteins/genetics , Toll-Like Receptor 9/metabolism , Vesicular Transport ProteinsABSTRACT
Congenital disorders of glycosylation (CDG) are due to defective glycosylation of glycoconjugates. Conserved oligomeric Golgi (COG)-CDG are genetic diseases due to defects of the COG complex subunits 1-8 causing N-glycan and O-glycan processing abnormalities. In COG-CDG, isoelectric focusing separation of undersialylated glycoforms of serum transferrin and apolipoprotein C-III (apoC-III) allows to detect N-glycosylation and O-glycosylation defects, respectively. COG5-CDG (COG5 subunit deficiency) is a multisystem disease with dysmorphic features, intellectual disability of variable degree, seizures, acquired microcephaly, sensory defects and autistic behavior. We applied matrix-assisted laser desorption/ionization-MS for a high-throughput screening of differential serum O-glycoform and N-glycoform in five patients with COG5-CDG. When compared with age-matched controls, COG5-CDG showed a significant increase of apoC-III0a (aglycosylated glycoform), whereas apoC-III1 (mono-sialylated glycoform) decreased significantly. Serum N-glycome of COG5-CDG patients was characterized by the relative abundance of undersialylated and undergalactosylated biantennary and triantennary glycans as well as slight increase of high-mannose structures and hybrid glycans. Using advanced and well-established MS-based approaches, the present findings reveal novel aspects on O-glycan and N-glycan profiling in COG5-CDG patients, thus providing an increase of current knowledge on glycosylation defects caused by impairment of COG subunits, in support of clinical diagnosis. Copyright © 2017 John Wiley & Sons, Ltd.
Subject(s)
Adaptor Proteins, Vesicular Transport/blood , Congenital Disorders of Glycosylation/blood , Biomarkers/blood , Case-Control Studies , Child , Congenital Disorders of Glycosylation/diagnosis , Glycosylation , High-Throughput Screening Assays/methods , Humans , Polysaccharides/blood , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.
Subject(s)
Acidosis, Lactic/genetics , Anemia, Sideroblastic/genetics , Electron Transport Complex I/genetics , Microphthalmos/genetics , Acidosis, Lactic/complications , Acidosis, Lactic/physiopathology , Anemia, Sideroblastic/complications , Anemia, Sideroblastic/physiopathology , Child , DNA, Mitochondrial/genetics , Electron Transport Complex I/deficiency , Genetic Predisposition to Disease , Humans , Male , Microphthalmos/physiopathology , Mutation , Pedigree , Phenotype , Tyrosine-tRNA LigaseABSTRACT
INTRODUCTION: Adenosine kinase deficiency (ADK deficiency) is a recently described disorder of methionine and adenosine metabolism resulting in a neurological phenotype with developmental delay, muscular hypotonia, and epilepsy as well as variable systemic manifestations. The underlying neuropathology is poorly understood. We have investigated MRI and (1)H-MRS changes in ADK deficiency in order to better understand the in vivo neuropathologic changes of ADK deficiency. METHODS: Systematic evaluation of 21 MRIs from eight patients (age range 9 days-14.6 years, mean 3.9 years, median 2.7 years) including diffusion-weighted imaging in six and (1)H-MRS in five patients. RESULTS: Brain maturation was delayed in the neonatal period and in infancy (6/6), but ultimately complete. White matter changes occurring in five of eight patients were discrete, periventricular, and unspecific (4/5), or diffuse with sparing of optic radiation, corona radiata, and pyramidal tracts (1/5). Choline was low in white matter spectra (3/3), while there was no indication of low creatine in white matter or basal ganglia (5/5), and diffusion was variably decreased or increased. Central tegmental tract hyperintensity was a common finding (6/8), as was supratentorial atrophy (6/8). CONCLUSIONS: MRI changes in ADK deficiency consist of delayed but ultimately completed brain maturation with later onset of mostly unspecific white matter changes and potentially transient central tegmental tract hyperintensity. Immaturity on neonatal MRI is consistent with prenatal onset of disease and reduced choline with lower membrane turnover resulting in delayed myelination and deficient myelin maintenance.
Subject(s)
Adenosine Kinase/deficiency , Brain Diseases, Metabolic/enzymology , Brain Diseases, Metabolic/pathology , Brain/metabolism , Brain/pathology , Magnetic Resonance Imaging/methods , Proton Magnetic Resonance Spectroscopy/methods , Adenosine Kinase/metabolism , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Molecular Imaging/methods , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4-CL) ratio. We report a 6-year-old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4-CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0-0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.
Subject(s)
Barth Syndrome/genetics , Cardiomyopathy, Dilated/genetics , Transcription Factors/genetics , Transcription, Genetic , Acidosis, Lactic/genetics , Acidosis, Lactic/physiopathology , Acyltransferases , Barth Syndrome/blood , Barth Syndrome/physiopathology , Cardiolipins/blood , Cardiomyopathy, Dilated/physiopathology , Child , Exons/genetics , Female , Heterozygote , Humans , Hypoglycemia/genetics , Hypoglycemia/physiopathology , Lysophospholipids/blood , Male , MutationSubject(s)
Benzoates/adverse effects , Glucuronosyltransferase/genetics , Iron Chelating Agents/adverse effects , Multidrug Resistance-Associated Proteins/genetics , Thalassemia/genetics , Triazoles/adverse effects , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Benzoates/blood , Benzoates/therapeutic use , Child, Preschool , Deferasirox , Female , Humans , Iron Chelating Agents/therapeutic use , Multidrug Resistance-Associated Protein 2 , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Thalassemia/blood , Thalassemia/drug therapy , Triazoles/blood , Triazoles/therapeutic useABSTRACT
BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1. METHODS: Five HT1 patients (age between 5 and 53 months) with different types of presentation were evaluated before and during the first 2 weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function. RESULTS: Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48h, while the other markers of renal dysfunction showed an improving trend over 2 weeks. CONCLUSIONS: NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.
Subject(s)
Cyclohexanones/therapeutic use , Kidney Tubules/physiopathology , Nitrobenzoates/therapeutic use , Tyrosinemias/drug therapy , Biomarkers/blood , Biomarkers/urine , Child, Preschool , Cyclohexanones/pharmacology , Female , Humans , Infant , Kidney Tubules/drug effects , Male , Nitrobenzoates/pharmacology , Retrospective Studies , Treatment Outcome , Tyrosinemias/metabolism , Tyrosinemias/physiopathologyABSTRACT
BACKGROUND: Glycogen storage disease type 1 (GSD1) is a rare and genetically heterogeneous metabolic defect of gluconeogenesis due to mutations of either the G6PC gene (GSD1a) or the SLC37A4 gene (GSD1b). Osteopenia is a known complication of GSD1. OBJECTIVES: The aim of this study was to investigate the effects of poor metabolic control and/or use of GSD1-specific treatments on bone mineral density (BMD) and metabolism in GSD1 patients. METHODS: In a multicenter, cross-sectional case-control study, we studied 38 GSD1 (29 GSD1a and 9 GSD1b) patients. Clinical, biochemical and instrumental parameters indicative of bone metabolism were analyzed; BMD was evaluated by dual-emission X-ray absorptiometry and quantitative ultrasound. RESULTS: Both GSD1a and GSD1b patients showed reduced BMD compared with age-matched controls. In GSD1a patients, these abnormalities correlated with compliance to diet and biochemical indicators of metabolic control. In GSD1b patients, BMD correlated with the age at first administration and the duration of granulocyte colony-stimulating factor (G-CSF) therapy. CONCLUSIONS: Our data indicate that good metabolic control and compliance with diet are highly recommended to improve bone metabolism in GSD1a patients. GSD1b patients on G-CSF treatment should be carefully monitored for the risk of osteopenia/osteoporosis.
Subject(s)
Bone Diseases, Metabolic/chemically induced , Bone Diseases, Metabolic/metabolism , Bone and Bones/metabolism , Glycogen Storage Disease Type I/metabolism , Granulocyte Colony-Stimulating Factor/therapeutic use , Adolescent , Bone Density , Bone Diseases, Metabolic/epidemiology , Case-Control Studies , Child , Cross-Sectional Studies , Female , Glycogen Storage Disease Type I/diet therapy , Glycogen Storage Disease Type I/drug therapy , Glycogen Storage Disease Type I/epidemiology , Growth Disorders/chemically induced , Growth Disorders/epidemiology , Growth Disorders/metabolism , Humans , Male , Patient Compliance/statistics & numerical dataSubject(s)
Crigler-Najjar Syndrome/therapy , Liver Transplantation/methods , Liver Transplantation/statistics & numerical data , Metabolic Diseases/therapy , Child , Decision Making , Ethics, Medical , Family , Humans , Liver Transplantation/trends , Referral and Consultation , Time Factors , Tissue and Organ ProcurementABSTRACT
AIM: To investigate adherence to dietary treatment and quality of life (QoL) in patients with phenylketonuria (PKU). METHODS: In the setting of a tertiary paediatric hospital, 41 early-treated patients affected by PKU aged more than 3 years old were enrolled in a cross-sectional study. Three-days dietary assessment, QoL questionnaires for patients<18 years old (Child Health Questionnaire) and Short Form for adults were completed. RESULTS: Of 41 patients, 23 (56.1%) were considered adherent to the dietary prescriptions as their phenylalanine intake was less than prescribed. Phenylalanine intake was significantly in excess of prescribed if mothers had a lower level of education. Adherence was not correlated with age. Metabolic control was obtained in 41.5-51.2% of the patients depending on the target. QoL was reduced in children and adolescents. There was no significant correlation between adherence and QoL, except for the domains of Global Health and Family Activities (ρ=0.42 and 0.46, respectively). The overall agreement between adherence and metabolic control varied according to different targets of metabolic control (51.2-65.9%). CONCLUSIONS: It is necessary to improve the adherence to diet and the QoL in children and adolescents affected by PKU.
Subject(s)
Patient Compliance , Phenylketonurias/diet therapy , Quality of Life , Adolescent , Child , Child, Preschool , Female , Humans , Male , Phenylalanine/blood , Phenylketonurias/blood , Young AdultSubject(s)
Patient Care Team , Rare Diseases , Child , Humans , Rare Diseases/diagnosis , Rare Diseases/therapyABSTRACT
Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis of glycans and in the attachment of glycans to lipids and proteins. Actually, some 42 CDG are known including defects in protein N-glycosylation, in protein O-glycosylation, in lipid glycosylation, and in multiple and other glycosylation pathways. Most CDG are multisystem diseases and a large number of signs and symptoms have already been reported in CDG. An exception to this is deafness. This symptom has not been observed as a consistent feature in CDG. In 2008, a novel defect was identified in protein N-glycosylation, namely in RFT1. This is a defect in the assembly of N-glycans. RFT1 is involved in the transfer of Man(5)GlcNAc(2)-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. According to the novel nomenclature (non-italicized gene symbol followed by -CDG) this defect is named RFT1-CDG. Recently, three other patients with RFT1-CDG have been reported and here we report two novel patients. Remarkably, all six patients with RFT1-CDG show sensorineural deafness as part of a severe neurological syndrome. We conclude that RFT1-CDG is the first 'deafness-CDG'. CDG should be included in the work-up of congenital, particularly syndromic, hearing loss.
Subject(s)
Congenital Disorders of Glycosylation/complications , Congenital Disorders of Glycosylation/metabolism , Hearing Loss, Sensorineural/etiology , Membrane Glycoproteins/metabolism , Congenital Disorders of Glycosylation/genetics , Female , Glycosylation , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/metabolism , Humans , Infant , Infant, Newborn , Lipopolysaccharides/biosynthesis , Male , Membrane Glycoproteins/genetics , MutationABSTRACT
Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Biomarkers/analysis , Methylmalonyl-CoA Mutase/deficiency , Adolescent , Adult , Age of Onset , Amino Acid Metabolism, Inborn Errors/epidemiology , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/mortality , Child , Child, Preschool , Cobamides/deficiency , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Methylmalonyl-CoA Mutase/genetics , Outcome Assessment, Health Care , Prognosis , Survival Analysis , Young AdultABSTRACT
In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, succinate semialdehyde dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134-147 ms; normal <118 ms. We hypothesize that elevated GABA in ocular tissue of SSADH patients leads to a use-dependent downregulation of the major GABAergic receptor in eye, GABA(C), and that the VEP recordings' abnormalities, as evidenced by P100 latency and/or amplitude measurements, may be reflective of abnormalities within visual systems. This is a preliminary finding that may suggest the utility of performing VEP analysis in a larger sample of SSADH-deficient patients, and encourage a neurophysiological assessment of GABA(C) receptor function in Aldh5a1(-/-) mice to reveal new pathophysiological mechanisms of this rare disorder of GABA degradation.
Subject(s)
Amino Acid Metabolism, Inborn Errors/physiopathology , Evoked Potentials, Visual , Succinate-Semialdehyde Dehydrogenase/deficiency , Adult , Amino Acid Metabolism, Inborn Errors/enzymology , Amino Acid Metabolism, Inborn Errors/genetics , Caproates/urine , Child , Child, Preschool , Developmental Disabilities , Female , Humans , Hydroxybutyrates/urine , Male , Mutation , Succinate-Semialdehyde Dehydrogenase/geneticsABSTRACT
Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.
Subject(s)
DNA, Mitochondrial/genetics , Mutation/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Adolescent , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Organ SpecificitySubject(s)
Brain Diseases, Metabolic/complications , Brain/drug effects , Dystonic Disorders/drug therapy , Dystonic Disorders/etiology , Succinate-Semialdehyde Dehydrogenase/deficiency , Vigabatrin/therapeutic use , Adolescent , Brain/enzymology , Brain/physiopathology , Brain Diseases, Metabolic/enzymology , Brain Diseases, Metabolic/physiopathology , Dystonic Disorders/enzymology , Epilepsy/enzymology , Epilepsy/etiology , Extremities/physiopathology , GABA Agents/therapeutic use , Gene Expression Regulation, Enzymologic , Humans , Hydroxybutyrates/metabolism , Intellectual Disability/enzymology , Intellectual Disability/etiology , Italy , Male , Muscle, Skeletal/innervation , Muscle, Skeletal/physiopathology , Mutation, Missense/genetics , Succinate-Semialdehyde Dehydrogenase/genetics , Treatment Outcome , gamma-Aminobutyric Acid/metabolismABSTRACT
3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and leucine metabolism. The disease is caused by mutations in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL). To date 26 different mutations have been described. A (betaalpha)(8) TIM barrel structure has been proposed for the protein, and almost all missense mutations identified so far localize in the beta sheets that define the inside cavity. We report an Italian patient who bears homozygously a novel HL mutation, c.608G > A (p. G203E) in beta sheet six. A structural model of the mutated protein suggests that glutamic acid 203 impedes catalysis by blocking the entrance to the inner cavity of the enzyme. Loss of functionality has been confirmed in expression studies in E. coli, which demonstrate that the G203E mutation completely abolishes enzyme activity. Beta sheet six and beta sheet two are the two protein regions that accumulate most missense mutations, indicating their importance in enzyme functionality. A model for the mechanism of enzyme function is proposed.