[Holocarboxylase synthetase deficiency induced by HLCS gene mutations: a rare disease study]. / ç½•è§ç— ç ”ç©¶ï¼šHLCSåŸºå› çªå˜è‡´å ¨ç¾§åŒ–é ¶åˆæˆé ¶ç¼ºä¹ç—‡.

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.

A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis.

Biotinidase (BTD) deficiency is a rare autosomal recessive metabolic disorder caused by insufficient biotin metabolism, where it cannot recycle the vitamin biotin. When this deficiency is not treated with supplements, it can lead to severe neurological conditions. Approximately 1 in 60,000 newborns are affected by BTD deficiency. The BTD deficiency causes late-onset biotin-responsive multiple carboxylase deficiency, which leads to acidosis or lactic acidosis, hypoglycemia, and abnormal catabolism. BTD deficiency is of two types based on the amount of BTD Enzyme present in the serum. A wide range of pathogenic mutations in the BTD gene are reported worldwide. Mutations in the BTD gene lead to profound and partial BTD deficiency. Profound BTD deficiency results in a severe pathogenic condition. A high frequency of newborns are affected with the partial deficiency worldwide. They are mostly asymptomatic, but symptoms may appear during stressful conditions such as fasting or viral infections. Several pathogenic mutations are significantly associated with neurological, ophthalmological, and skin problems along with several other clinical features. This review discusses the BTD gene mutation in multiple populations detected with phenotypic features. The molecular-based biomarker screening is necessary for the disease during pregnancy, as it could be helpful for the early identification of BTD deficiency, providing a better treatment strategy. Moreover, implementing newborn screening for the BTD deficiency helps patients prevent several diseases.

Holocarboxylase synthetase deficiency induced by HLCS gene mutations: a rare disease study / 中国当代儿科杂志

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.

Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency.

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.

Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency / 浙江大学学报·医学版

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.

Delayed diagnosis of holocarboxylase synthetase deficiency in three patients with prominent skin findings.

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.

High frequency of biotinidase deficiency in Italian population identified by newborn screening.

The biotinidase (BTD) enzyme is essential for recycling biotin, a water-soluble B-complex vitamin that is the coenzyme of four carboxylases involved in fatty acid synthesis, amino acid catabolism and gluconeogenesis. If untreated, total or partial BTD deficiencies lead to an autosomal recessive inherited organic aciduria whose clinical features, mainly presenting in the first years of life, include, seizures, skin rash, and alopecia. Based on residual BTD enzyme activity it is possible to identify partial or total biotinidase deficiency. The incidence of profound and partial biotinidase deficiency worldwide is estimated to be about 1 in 60.000. We report twelve years of experience in the newborn screening of biotinidase deficiency on 466.182 neonates. When a positive screening result occurred, a clinical evaluation was made of the patient and genetic counselling was offered to the family. Molecular analysis the BTD gene was carried out in all recalled neonates. Newborn screening lead to the identification of 75 BTD deficiencies with an incidence of about 1:6.300 births, ten times higher than the reported worldwide incidence. BTD deficiency was confirmed at a genomic level in all patients, demonstrating a high frequency of the p.(Asp444His) amino acid substitution and the complex allele p.(Ala171Thr)/p.(Asp444His) in the analyzed Italian newborns. Four new mutations (two small deletions, one stop mutation and one missense mutation) and a new combined allelic alteration were identified. Our data suggests that there is a high incidence of the biotinidase defect in the Italian population, most likely due to the high frequency of certain mutations.

A case of multiple carboxylase deficiency presenting with skin lesions as the initial symptom induced by a novel mutation in the holocarboxylase synthetase gene / 中华皮肤科杂志

A male patient, who was aged 3 months and 12 days, presented with well-circumscribed erythema and scales on the scrotum, perineum, buttocks and perianal region at 1 month after birth. The lesions gradually involved the perioral and axillary regions, flexor aspect of the elbow, popliteal fossa and neck. Shortness of breath, crying, dysphoria and vomiting occurred without fever and cough 3 days before hospitalization. Laboratory examinations at admission showed metabolic acidosis, hyperlactacidemia, hyperammonemia and organic aciduria. Second-generation sequencing and Sanger sequencing of the holocarboxylase synthetase gene revealed a known mutation c.1522C>T in exon 9 and a novel mutation c.1796_1814del in exon 11. According to a guideline from the American College of Medical Genetics and Genomics, this novel mutation was ranked as a pathogenic mutation. The patient was diagnosed as multiple carboxylase deficiency. His clinical symptoms were improved after oral biotin treatment, no neurological symptoms or signs were observed.

Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.

BACKGROUND: Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records. MATERIALS AND METHODS: Selective screening for IMDs using gas chromatography-mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared. RESULTS: Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, ß-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias. CONCLUSION: The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.

Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization.

The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotin-dependent carboxylases. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In human cells, biotin-dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotin is attached to apocarboxylases by a biotin ligase: holocarboxylase synthetase (HCS) in mammalian cells and BirA in microbes. Despite their evolutionary distance, these proteins share structural and sequence similarities, underscoring their importance across all life forms. However, beyond its role in metabolism, HCS participates in the regulation of biotin utilization and acts as a nuclear transcriptional coregulator of gene expression. In this review, we discuss the function of HCS and biotin in metabolism and human disease, a putative role for the enzyme in histone biotinylation, and its participation as a nuclear factor in chromatin dynamics. We suggest that HCS be classified as a moonlighting protein, with two biotin-dependent cytosolic metabolic roles and a distinct biotin-independent nuclear coregulatory function.

Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited metabolic disorder that can be easily and effectively treated with pharmacological doses of the vitamin, biotin. Untreated children with profound biotinidase deficiency may exhibit neurological, cutaneous and cellular immunological abnormalities, specifically candida infections. To better understand the immunological dysfunction in some symptomatic individuals with biotinidase deficiency, we studied various aspects of immunological function in a genetically engineered knock-out mouse with biotinidase deficiency. The mouse has no detectable biotinidase activity and develops neurological and cutaneous symptoms similar to those seen in symptomatic children with the disorder. Mice with profound biotinidase deficiency on a biotin-restricted diet had smaller thymuses and spleens than identical mice fed a biotin-replete diet or wildtype mice on either diet; however, the organ to body weight ratios were not significantly different. Thymus histology was normal. Splenocyte subpopulation study showed a significant increase in CD4 positive cells. In addition, in vitro lymphocyte proliferation assays consistently showed diminished proliferation in response to various immunological stimuli. Not all symptomatic individuals with profound biotinidase deficiency develop immunological dysfunction; however, our results do show significant alterations in cellular immunological function that may contribute and/or provide a mechanism(s) for the cellular immunity abnormalities in individuals with biotinidase deficiency.

[Delayed onset holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity]. / Deficiencia de holocarboxilasa sintetasa de presentación tardía con actividad piruvato carboxilasa normal.

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.

Clinical analysis and long-term follow-up of multiple carboxylase deficiency in 15 children / 中华实用儿科临床杂志

Objective Multiple carboxylase deficiency(MCD) is an autosomal recessively inherited defect of organic acid metabolism.The underlying mechanism is biotinidase(BT) or holocarboxylase synthetase(HLCS) deficiency.The authors reported 15 cases of MCD(clinical characteristics,diagnosis and treatment) and outcomes of long-term follow-up.Methods The clinical data of 15 patients with MCD admitted to Guangzhou Women and Children's Medical Center between Aug.2001 and Feb.2013 were analyzed.The diagnosis was confirmed by urinary organic acid analysis with gas chromatography/mass spectrometry (GC/MS),blood enzymatic determination and gene analysis.The patients consisted of 12 male and 3 female.The onset age ranged from newborn infants to 16 months.Results 1.Remarkable elevations of urinary lactate,3-oxy-butyric acid,3-OH-isovalerate,methylcitrate,3-methylcrontonylglycine,3-OH-propionate were detected in all of 15 cases.Fourteen cases with HLCS deficiency and 1 case with BT deficiency were confirmed by gene analysis.2.Most of patients with HLCS deficiency presented in the neonatal period or early infancy.The main clinical manifestations were skin rash (14 cases),tachypnea (9 cases),developmental retardation (8 cases),vomiting(5 cases),poor feeding (3 cases),developmental regradation (1 case),convulsion (1 case).Laboratory evaluation showed persistent metabolic acidosis and varied degree of ketosis,lactic acidosis,hyperuricacidemia,ammoniemia and hypoglycemia.Biotin was given to 13 patients in 10 mg/d and their metabolic disorders were corrected within 48 h,except one who gave up treatment and died.Treatment with Biotin in 5 mg/d provided clinical stability and normal neurodevelopmental outcome on follow-up for 3-11 (6.47 ± 2.70) years.3.One patient with BT deficiency presented with severe neurological symptoms(impaired consciousness,limbs trembling,tachypnea with irregular respiratory rhythm) at 16 months old.Demyelination of corpus callosum was evident on magnetic resonance imaging.Biotin treatment was given to him on the second of onset,and 1-year follow-up indicated significant improvement of his clinical symptoms,but the right limb weakness did not completely recover.Conclusions The main clinical features of HLCS deficiency include frequent skin rash,tachypnea,and metabolic disorders.BT deficiency may produce variable neurologic manifestations including demyelination of corpus callosum.Urinary organic acid analysis with GC/MS is critical to the early diagnosis of MCD.Prompt biotin treatment is recommended to correct metabolic derangements and continued therapy is essential to the improvement of long-term prognosis.Delayed commencement of therapy in BT deficiency can result in irreversible neurological damage.