ABSTRACT
Biotin (vitamin B7, or vitamin H) is a water-soluble B-vitamin that functions as a cofactor for carboxylases, i.e., enzymes involved in the cellular metabolism of fatty acids and amino acids and in gluconeogenesis; moreover, as reported, biotin may be involved in gene regulation. Biotin is not synthesized by human cells, but it is found in food and is also produced by intestinal bacteria. Biotin status/homeostasis in human individuals depends on several factors, including efficiency/deficiency of the enzymes involved in biotin recycling within the human organism (biotinidase, holocarboxylase synthetase), and/or effectiveness of intestinal uptake, which is mainly accomplished through the sodium-dependent multivitamin transporter. In the last years, administration of biotin at high/"pharmacological" doses has been proposed to treat specific defects/deficiencies and human disorders, exhibiting mainly neurological and/or dermatological symptoms and including biotinidase deficiency, holocarboxylase synthetase deficiency, and biotin-thiamine-responsive basal ganglia disease. On the other hand, according to warnings of the Food and Drug Administration, USA, high biotin levels can affect clinical biotin-(strept)avidin assays and thus lead to false results during quantification of critical biomarkers. In this review article, recent findings/advancements that may offer new insight in the abovementioned research fields concerning biotin will be presented and briefly discussed.
Subject(s)
Biotin , Biotinidase Deficiency , Biotinidase , Homeostasis , Humans , Biotin/metabolism , Biotinidase Deficiency/metabolism , Biotinidase Deficiency/diagnosis , Biotinidase Deficiency/genetics , Biotinidase Deficiency/drug therapy , Biotinidase/metabolism , Biotinidase/genetics , Holocarboxylase Synthetase Deficiency/metabolism , Carbon-Nitrogen Ligases/metabolism , Carbon-Nitrogen Ligases/genetics , Animals , Ataxia/metabolism , Ataxia/genetics , Basal Ganglia DiseasesABSTRACT
CONTEXT: Elevated 3-hydroxyisovaleryl-/2-methyl-3-hydroxybutyryl (C5-OH) acylcarnitine in blood can result from several genetic enzyme deficiencies: 3-methylcrotonyl CoA carboxylase deficiency, 3-hydroxy 3-methylglutaryl-CoA lyase deficiency, beta-ketothiolase deficiency, 2-methyl 3-hydroxybutyryl-CoA dehydrogenase deficiency, primary 3-methylglutaconic aciduria, multiple biotin-dependent carboxylase deficiencies and biotin metabolism disorders. Biochemical tests help differentiate these causes while molecular tests are usually required for definitive diagnosis. CASE DESCRIPTION: We reported an infant girl with newborn screen findings of elevated C5-OH acylcarnitine. She had further confirmational biochemical testing including plasma acylcarnitines, urine organic acids and urine acylglycines. Patient's urine organic acid profile showed markedly increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Urine acylglycine test reported a large increase of 3-methylcrotonylglycine and plasma acylcarnitine test repeated the finding of elevated C5-OH acylcarnitine together with propionyl acylcarnitine elevation. These results point to multiple biotin-dependent carboxylase deficiency. Molecular tests revealed a homozygous mutation in the holocarboxylase synthetase gene that is consistent with her biochemical test findings. This case demonstrated the critical role of newborn screen in identifying inborn errors of metabolism that may otherwise be missed and lead to severe morbidity later in life. It also showcased that both biochemical and molecular tests are essential tools in the diagnosis.
Subject(s)
Carnitine , Holocarboxylase Synthetase Deficiency , Humans , Female , Carnitine/analogs & derivatives , Carnitine/blood , Carnitine/urine , Holocarboxylase Synthetase Deficiency/diagnosis , Holocarboxylase Synthetase Deficiency/genetics , Infant, Newborn , InfantABSTRACT
A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.
Subject(s)
Holocarboxylase Synthetase Deficiency , Humans , Male , Biotin/genetics , Biotin/therapeutic use , Holocarboxylase Synthetase Deficiency/genetics , Holocarboxylase Synthetase Deficiency/diagnosis , Holocarboxylase Synthetase Deficiency/drug therapy , Homozygote , Mutation , Rare Diseases/drug therapy , InfantABSTRACT
BACKGROUND: This study aimed to describe the clinical, biochemical, and molecular characteristics of Chinese patients with holocarboxylase synthetase (HLCS) deficiency, and to investigate the mutation spectrum of HCLS deficiency as well as their potential correlation with phenotype. METHODS: A total of 28 patients with HLCS deficiency were enrolled between 2006 and 2021. Clinical and laboratory data were reviewed retrospectively from medical records. RESULTS: Among the 28 patients, six patients underwent newborn screening, of which only one was missed. Therefore, 23 patients were diagnosed because of disease onset. Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness, while only four cases remained asymptomatic nowadays. The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients. Among them, the variant of c.1522C > T was the most common. CONCLUSIONS: Our findings expanded the spectrum of phenotypes and genotypes for HLCS deficiency in Chinese populations and suggested that with timely biotin therapy, patients with HLCS deficiency showed low mortality and optimistic prognosis. Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes.
Subject(s)
Holocarboxylase Synthetase Deficiency , Humans , Holocarboxylase Synthetase Deficiency/genetics , Holocarboxylase Synthetase Deficiency/diagnosis , Holocarboxylase Synthetase Deficiency/drug therapy , Biotin/therapeutic use , East Asian People , Retrospective Studies , Asian People/geneticsABSTRACT
Holocarboxylase synthetase deficiency (HSD) is a rare autosomal recessive disorder of biotin metabolism. Typical manifestations include irreversible metabolic disorders and erythroderma-like dermatitis. Most patients respond well to biotin supplementation. Psoriasis-like phenotype associated with this disease has been rarely reported in the literature and experiences with the use of biologics in patients with HSD are still lacking. We reported a rare case of recurrent psoriasis-like skin lesions in a 6-year-old child with HSD. The patient did not respond to initial therapy with high-dose oral biotin. Immunofluorescence staining showed an increased number of interleukin (IL)-17A+ cells in his skin lesions. Based on this finding, the patient was successfully treated with human anti-IL-17A monoclonal antibody (secukinumab). He did not report any side effects and remained healthy during the 2-year follow-up. We provide a comprehensive review of the reported cases of HSD with psoriasis-like dermatitis to date. The psoriasis-like phenotype of HSD is controversial in treatment and IL-17A inhibitor is an alternative therapeutic option.
Subject(s)
Dermatitis, Exfoliative , Holocarboxylase Synthetase Deficiency , Psoriasis , Male , Child , Humans , Biotin/therapeutic use , Psoriasis/complications , Psoriasis/drug therapyABSTRACT
A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.
Subject(s)
Humans , Male , Infant , Biotin/therapeutic use , Holocarboxylase Synthetase Deficiency/drug therapy , Homozygote , Mutation , Rare Diseases/drug therapyABSTRACT
Multiple carboxylase deficiency (MCD) includes autosomal recessive holocarboxylase synthetase (HLCS) deficiency and biotinidase (BTD) deficiency, which are caused by and gene mutations respectively. Neonatal screening for HLCS deficiency is based on 3-hydroxyisovaleryl carnitine in dry blood filter paper, and BTD deficiency is based on BTD activity determination. HLCS deficiency and BTD deficiency are characterized by neurocutaneous syndrome and organic aciduria, however, they are different in onset age, neurological symptoms and metabolic decompensation, which needed to be differentiated from acquired biotin deficiency or other genetic metabolic diseases. The diagnosis of the disease requires a combination of biochemical characteristics of hematuria, enzyme activity determination and genetic test. Routine biotin doses are effective for most MCD patients. This consensus is intended to benefit early screening and diagnosis of MCD.
Subject(s)
Biotinidase Deficiency , Carbon-Nitrogen Ligases , Holocarboxylase Synthetase Deficiency , Multiple Carboxylase Deficiency , Biotin/metabolism , Biotin/therapeutic use , Biotinidase Deficiency/drug therapy , Biotinidase Deficiency/therapy , Carbon-Nitrogen Ligases/genetics , Carbon-Nitrogen Ligases/metabolism , Consensus , Holocarboxylase Synthetase Deficiency/drug therapy , Holocarboxylase Synthetase Deficiency/genetics , Humans , Infant, Newborn , Multiple Carboxylase Deficiency/drug therapy , Neonatal ScreeningABSTRACT
Holocarboxylase synthetase (HLCS) catalyzes the biotinylation of five distinct biotin-dependent carboxylases and perhaps chromatin proteins. HLCS deficiency causes multiple carboxylase deficiency which results in fatal consequences unless patients are diagnosed early and treated with pharmacological doses of biotin. The objective of this study was to develop an HLCS conditional knockout (KO) mouse and assess effects of HLCS knockout on embryo survival. In the mouse, exon 8 is flanked by LoxP sites, thereby removing a catalytically important region upon recombination by Cre. HLCS conditional KO mice were backcrossed for 14 generations with C57BL/6J mice to yield Hlcstm1Jze. Fertility and weight gain were normal and no frank disease phenotypes and abnormal feeding behavior were observed in the absence of Cre. HLCS knockout was embryonic lethal when dams homozygous for both the floxed Hlcs gene and tamoxifen-inducible Cre recombinase (denoted Hlcstm1.1Jze) were injected with tamoxifen on gestational days 2.5 and 10.5. This is the first report of an HLCS conditional KO mouse, which enables studies of the roles of HLCS and biotin in intermediary metabolism.
Subject(s)
Carbon-Nitrogen Ligases , Genes, Lethal , Holocarboxylase Synthetase Deficiency , Animals , Biotin/metabolism , Biotinylation , Carbon-Nitrogen Ligases/genetics , Carbon-Nitrogen Ligases/metabolism , Holocarboxylase Synthetase Deficiency/drug therapy , Holocarboxylase Synthetase Deficiency/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , TamoxifenABSTRACT
Multiple carboxylase deficiency (MCD) includes autosomal recessive holocarboxylase synthetase (HLCS) deficiency and biotinidase (BTD) deficiency, which are caused by and gene mutations respectively. Neonatal screening for HLCS deficiency is based on 3-hydroxyisovaleryl carnitine in dry blood filter paper, and BTD deficiency is based on BTD activity determination. HLCS deficiency and BTD deficiency are characterized by neurocutaneous syndrome and organic aciduria, however, they are different in onset age, neurological symptoms and metabolic decompensation, which needed to be differentiated from acquired biotin deficiency or other genetic metabolic diseases. The diagnosis of the disease requires a combination of biochemical characteristics of hematuria, enzyme activity determination and genetic test. Routine biotin doses are effective for most MCD patients. This consensus is intended to benefit early screening and diagnosis of MCD.
Subject(s)
Humans , Infant, Newborn , Biotin/therapeutic use , Biotinidase Deficiency/therapy , Carbon-Nitrogen Ligases/metabolism , Consensus , Holocarboxylase Synthetase Deficiency/genetics , Multiple Carboxylase Deficiency/drug therapy , Neonatal ScreeningABSTRACT
Holocarboxylase deficiency (HLCSD) is caused by biallelic pathogenic variants in HLCS and is associated with poor feeding, emesis, lethargy, seizures, life-threatening metabolic acidosis, and hyperammonemia. Skin involvement in HLCSD is typically described as scaly, erythrodermic, seborrhea-like, or ichthyosiform, but there is a paucity of reports. We report three patients, including two siblings, with HLCSD and significant cutaneous manifestations including ichthyosiform dermatitis and a presentation with features of annular pustular psoriasis. In this report, we show that persistent, unexplained rash, even in the absence of other clinical findings, should warrant consideration and potential workup for HLCSD.
Subject(s)
Holocarboxylase Synthetase Deficiency , Ichthyosis , Biotin , Delayed Diagnosis , Humans , Ichthyosis/diagnosis , SeizuresABSTRACT
Multiple carboxylase deficiency organic Acidemia is a rare inherited metabolic disorder. It is autosomal recessive disorder of two types: Holocarboxylase deficiency and Biotinidase deficiency. It is the metabolic disorder resulting from deficiency of biotin as a co-enzyme or reduced activity of biotin-dependent carboxylases (propionyl CoA carboxylase, and 3-methylcrotonyl CoA carboxylase and pyruvate carboxylase). A case of two months' female child is reported, who presented with recurrent infantile seizures and skin rash since birth; and biochemically with metabolic acidosis, hyper-ammonemia (on and off) since birth with multiple hospitalization. She had past history of jaundice. One sibling's death at 2nd day of life due to similar complaints. Initial presentation of raised ammonia and lactate levels were the first indication to this organic academia, which was later proven by increased peak levels of various organic acids on urine organic acid analysis by gas chromatography-mass spectrometry. Key Words: Multiple carboxylase deficiency, Holocarboxylase synthetase deficiency, Biotinidase deficiency.
Subject(s)
Acidosis , Holocarboxylase Synthetase Deficiency , Multiple Carboxylase Deficiency , Acidosis/etiology , Biotin , Child , Female , Holocarboxylase Synthetase Deficiency/genetics , Humans , Seizures/etiologyABSTRACT
Objectives Holocarboxylase synthetase deficiency (HCSD) (OMIM #253270) is a rare inborn error of metabolism with an estimated annual incidence of 1 in 200,000 people. Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. Diagnosis is made through genetic analysis. Case presentation Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis. Her family reported that she was diagnosed as having ketotic hypoglycemia; she had five episodes of hypoglycemia and metabolic acidosis in past 4 years when her oral intake decreased during acute illness. Patient 2 was a 6-month-old female infant with normal growth and development, presenting with progressive generalized eczema and metabolic acidosis for the first time. We found that they both had hyperammonemia, hyperlactatemia, hyperketonemia, organic acids detected in urine and elevated C5OH acylcarnitine level by tandem mass spectrometry. HLCS gene analysis showed a homozygous pathogenic variant p.V363D in patient 1 and a pathogenic variant p.R508W compound with a novel splice site pathogenic variant c.2010-1G>A in patient 2. They have been on biotin treatment (10 mg/day for both of them) for more than 2 years and no more symptoms have occurred. Conclusions HCSD is a rare disease, and it can be fatal if severe metabolic acidosis occurs without timely management. Once the diagnosis is made, most of the patients with HCSD have good prognosis and normal life expectancy with biotin treatment.
Subject(s)
Acidosis/diagnosis , Carbon-Nitrogen Ligases/genetics , Holocarboxylase Synthetase Deficiency/diagnosis , Hypoglycemia/diagnosis , Acidosis/drug therapy , Acidosis/genetics , Acidosis/metabolism , Biotin/therapeutic use , Child , Female , Glucose/metabolism , Holocarboxylase Synthetase Deficiency/complications , Holocarboxylase Synthetase Deficiency/drug therapy , Holocarboxylase Synthetase Deficiency/genetics , Homeostasis , Humans , Hypoglycemia/drug therapy , Hypoglycemia/genetics , Hypoglycemia/metabolism , Infant , Mutation, Missense , Prognosis , TaiwanABSTRACT
BACKGROUND: Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in defects in several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions. CASE PRESENTATION: In this paper, we report a Chinese Han pedigree with HLCS deficiency diagnosed by using next-generation sequencing and validated with Sanger sequencing of the HLCS and BTD genes. The Chinese proband carries the common missense mutation c.1522C > T (p.Arg508Trp) in exon 9 of the HLCS gene, which generates an increased Km value for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of the HLCS gene is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation, c.638_642delAACAC (p.His213Profs*4), in the BTD gene is also identified. CONCLUSIONS: The Chinese proband carries the reported Arg508Trp variant, the novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15), which expands the mutational spectrum of the HLCS gene, and the novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4), which expands the mutational spectrum of the BTD gene. Furthermore, reversible hearing damage is rarely reported in patients with HLCS deficiency, which deserves further discussion.
Subject(s)
Asian People/genetics , Ethnicity/genetics , Holocarboxylase Synthetase Deficiency/genetics , Pedigree , Amino Acid Sequence , Base Sequence , Carbon-Nitrogen Ligases/chemistry , Carbon-Nitrogen Ligases/genetics , Female , Holocarboxylase Synthetase Deficiency/blood , Holocarboxylase Synthetase Deficiency/enzymology , Holocarboxylase Synthetase Deficiency/urine , Humans , Infant , Male , Metabolome , Mutation/genetics , Protein DomainsABSTRACT
RATIONALE: Holocarboxylase synthetase (HCLS) deficiency, especially the late-onset type, is a rare disease. Affected patients can present with irreversible metabolic acidosis and may be misdiagnosed with a glucose metabolic disorder. Prompt and correct diagnosis and treatment can reduce mortality to a great extent. PATIENT CONCERNS: We report 2 Chinese patients who were diagnosed with late-onset HCLS deficiency. The age of onset of the 2 patients was approximately 8 months. The 2 patients had skin lesions, severe profound metabolic acidosis, dyspnea, and hyperglycemia. DIAGNOSES: The results of urinary and blood organic acid analysis with gas chromatography/mass spectrometry revealed multiple carboxylase deficiency. Maple syrup urine disease and diabetic ketoacidosis could not be excluded. This finding is different from those of hypoglycemic complications reported in previous reports. Human genetic analysis eventually provided a definite diagnosis. INTERVENTIONS: Prompt oral treatment with biotin dramatically corrected the metabolic imbalances of the 2 patients, and continued oral biotin therapy was essential to the improvement of their prognoses. OUTCOMES: Their metabolic disorders were corrected within 48âhours. During long-term follow-up, the patients achieved developmental milestones. LESSONS: Late-onset HCLS deficiency may present with obvious hyperglycemia. Human genetic analysis eventually provided a definite diagnosis. Prompt treatment with biotin is vital to correct metabolic imbalances, and continued therapy is essential to the improving long-term prognoses. Their mutations were p.R508W and c.1088Tâ>âA, and these mutations might represent hot-spot genes in Chinese populations with HCLS deficiency. The variants c.1484Tâ>âG(p.L495*) and c.835Gâ>âT(p.E279x) are likely pathogenic, and more studies are needed to confirm these results.
Subject(s)
Holocarboxylase Synthetase Deficiency/diagnosis , Holocarboxylase Synthetase Deficiency/physiopathology , Acidosis/etiology , Biotin/therapeutic use , China , Dyspnea/etiology , Female , Holocarboxylase Synthetase Deficiency/complications , Holocarboxylase Synthetase Deficiency/drug therapy , Humans , Hyperglycemia/etiology , Infant , MaleSubject(s)
Dermatitis/etiology , Holocarboxylase Synthetase Deficiency/complications , Psoriasis/etiology , Skin/pathology , Adult , Dermatitis/immunology , Dermatitis/pathology , Female , Holocarboxylase Synthetase Deficiency/diagnosis , Holocarboxylase Synthetase Deficiency/genetics , Holocarboxylase Synthetase Deficiency/immunology , Humans , Psoriasis/immunology , Psoriasis/pathology , Skin/immunologyABSTRACT
INTRODUCTION: Although the overall incidence of inborn errors of metabolism is low, their early diagnosis is essential, since some of them have a specific treatment. DEVELOPMENT: We review the main treatable inborn errors of metabolism that can present as early-onset epileptic encephalopathies, together with their biochemical markers and their treatment. CONCLUSIONS: It is important to think about the possibility of an inborn error of metabolism with a specific therapy, since it is crucial for this to be started as soon as possible in order to prevent permanent neurological damage.
TITLE: Abordaje metabolico en las encefalopatias epilepticas del lactante.Introduccion. Aunque la incidencia global de los errores congenitos del metabolismo es baja, su diagnostico precoz es fundamental, ya que algunos de ellos tienen tratamiento especifico. Desarrollo. Se revisan los principales errores congenitos del metabolismo tratables que pueden cursar como encefalopatia epileptica de inicio precoz, asi como sus marcadores bioquimicos y su tratamiento. Conclusiones. Es importante pensar en la posibilidad de un error congenito del metabolismo con terapia especifica, ya que es fundamental que esta comience lo antes posible para evitar un daño neurologico permanente.
Subject(s)
Brain Diseases, Metabolic, Inborn/metabolism , Epilepsy/metabolism , Age of Onset , Biotin/therapeutic use , Brain Diseases, Metabolic/drug therapy , Brain Diseases, Metabolic/metabolism , Brain Diseases, Metabolic, Inborn/drug therapy , Brain Diseases, Metabolic, Inborn/therapy , Child, Preschool , Creatine/metabolism , Diagnostic Techniques, Neurological , Epilepsy/drug therapy , Fetal Diseases/genetics , Fetal Diseases/metabolism , Holocarboxylase Synthetase Deficiency/drug therapy , Holocarboxylase Synthetase Deficiency/metabolism , Humans , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/metabolism , Infant , Infant, Newborn , Pyridoxaminephosphate Oxidase/deficiency , Pyridoxaminephosphate Oxidase/metabolism , Pyridoxine/therapeutic use , Seizures/drug therapy , Seizures/metabolismABSTRACT
Introducción. Aunque la incidencia global de los errores congénitos del metabolismo es baja, su diagnóstico precoz es fundamental, ya que algunos de ellos tienen tratamiento específico. Desarrollo. Se revisan los principales errores congénitos del metabolismo tratables que pueden cursar como encefalopatía epiléptica de inicio precoz, así como sus marcadores bioquímicos y su tratamiento. Conclusiones. Es importante pensar en la posibilidad de un error congénito del metabolismo con terapia específica, ya que es fundamental que ésta comience lo antes posible para evitar un daño neurológico permanente (AU)
Introduction. Although the overall incidence of inborn errors of metabolism is low, their early diagnosis is essential, since some of them have a specific treatment. Development. We review the main treatable inborn errors of metabolism that can present as early-onset epileptic encephalopathies, together with their biochemical markers and their treatment. Conclusions. It is important to think about the possibility of an inborn error of metabolism with a specific therapy, since it is crucial for this to be started as soon as possible in order to prevent permanent neurological damage (AU)
Subject(s)
Humans , Infant , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic/therapy , Early Diagnosis , Epilepsy/complications , Serine/deficiency , Congenital Abnormalities/diagnosis , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Vitamins/therapeutic use , Biotin/therapeutic use , Pyridoxine/therapeutic use , Holocarboxylase Synthetase Deficiency/diagnosisABSTRACT
BACKGROUND: Holocarboxylase synthetase deficiency results in impaired activation of enzymes implicated in glucose, fatty acid and amino acid metabolism. Antenatal imaging and postnatal imaging are useful in making the diagnosis. Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. Although biochemical assays are required for definitive diagnosis, certain radiologic features assist in the diagnosis of holocarboxylase synthetase deficiency. OBJECTIVE: To review evidence regarding radiologic diagnostic features of holocarboxylase synthetase deficiency in the antenatal and postnatal period. MATERIALS AND METHODS: A systematic review of all published cases of holocarboxylase synthetase deficiency identified by a search of Pubmed, Scopus and Web of Science. RESULTS: A total of 75 patients with holocarboxylase synthetase deficiency were identified from the systematic review, which screened 687 manuscripts. Most patients with imaging (19/22, 86%) had abnormal findings, the most common being subependymal cysts, ventriculomegaly and intraventricular hemorrhage. CONCLUSION: Although the radiologic features of subependymal cysts, ventriculomegaly, intraventricular hemorrhage and intrauterine growth restriction may be found in the setting of other pathologies, these findings should prompt consideration of holocarboxylase synthetase deficiency in at-risk children.
Subject(s)
Central Nervous System Cysts/diagnostic imaging , Cerebral Hemorrhage/diagnostic imaging , Holocarboxylase Synthetase Deficiency/diagnostic imaging , Hydrocephalus/diagnostic imaging , Magnetic Resonance Imaging/statistics & numerical data , Ultrasonography, Prenatal/statistics & numerical data , Central Nervous System Cysts/epidemiology , Cerebral Hemorrhage/epidemiology , Diagnosis, Differential , Female , Holocarboxylase Synthetase Deficiency/epidemiology , Humans , Hydrocephalus/epidemiology , Infant, Newborn , Male , Prevalence , Reproducibility of Results , Risk Assessment , Sensitivity and Specificity , Whole Body Imaging/methods , Whole Body Imaging/statistics & numerical dataABSTRACT
Se presenta un caso de deficiencia de holocarboxilasa sintetasa con actividad piruvato carboxilasa normal en linfocitos en una niña de 8 años con clínica de intoxicación y sin la clásica afectación dermatológica. La identificación de 3 cambios nucleotídicos en el gen HCLS, habiendo sido descrito como mutación patogénica solo uno de ellos, podría estar relacionada con una variante leve de la enfermedad que explicaría la presentación inusual más allá de la época de lactante. El tratamiento con biotina a 40 mg/día, junto con dieta controlada en proteínas, permite un crecimiento físico y un desarrollo psicomotor normales para su edad
We report a case of holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity in the lymphocytes of an 8 year-old girl with clinical toxicity without the classic dermatological involvement. The identification of three nucleotide changes in the holocarboxylase synthetase (HLCS) gene, only one of them described as a pathogenic mutation could be related to a slight variant of the disease that would explain the unusual presentation beyond the age of infant. Treatment with biotin at 40 mg/day with protein controlled diet allows normal physical growth and psychomotor development for their age