Structures already discussed alongside 3-methylcrotonyl-coa carboxylase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
RCSB Protein Data Bank · entry 8XL6 · 2.29 Å · ligand BIOTIN (BTN). Experimental structure, not a prediction.
Biotin at 10 mg or more per day normalised clinical and biochemical abnormalities in patients with biotin-responsive multiple carboxylase deficiency, a disorder that includes deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). However, in a 2005 report of a consanguineous Turkish infant with isolated MCC deficiency presenting on day two of life with encephalopathy, acidosis, and hypoglycaemia, high-dose biotin and protein-restricted diet were ineffective; the patient died at 33 days with progressive neurological deterioration. A 2012 commentary notes that among over 200 newborns with MCC deficiency detected by newborn screening, most remained asymptomatic. In a selected series of 53 screen-detected children aged 2–12 years, 13 had reported symptoms, but not all were clearly related to MCC deficiency; five had had one or more metabolic decompensations with hypoglycaemia and ketonaemia. The commentary estimates that perhaps 4–5% of MCC-deficient subjects will ever become sick, and questions whether the disorder should be included in newborn screening given the risk of medicalising asymptomatic children with diet or carnitine treatment.
Diagnosis can be complicated. A 2007 report describes two patients with confirmed isolated MCC deficiency whose urine lacked or contained only trace 3-methylcrotonylglycine, the pathognomonic marker, while 3-hydroxyisovaleric acid was elevated. Residual enzyme activities were 5–7% and 12% of median control values. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, suggesting the overall pathway was partially functional. The authors warn that relying solely on urine organic acid analysis risks misdiagnosis.
A 1940 abstract (likely misdated or misattributed) states that cardiac evaluation should be performed in MCC deficiency patients and that the disorder should be included in the differential diagnosis of dilatative cardiomyopathy. No further data on cardiac outcomes are provided in the given abstracts. What remains missing is a prospective, unselected natural history study that can reliably estimate the proportion of MCC-deficient individuals who will experience metabolic decompensation or cardiomyopathy, and a clear stratification by genotype, residual enzyme activity, or other biomarkers. Without such data, the balance between benefit and harm of screening and treatment cannot be resolved.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 1981 · 100 citations
Biotin-Responsive Carboxylase Deficiency Associated with Subnormal Plasma and Urinary Biotin
AbstractAN increasing number of patients have been diagnosed as having biotin-responsive multiple carboxylase deficiency.1 2 3 4 5 6 7 8 This genetic disorder involves defects in the metabolism of biotin and produces deficiencies of at least three biotin-containing carboxylases: propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and pyruvate carboxylase (PC). All patients have responded to oral administration of 10 mg or more of biotin per day, with normalization of the clinical and biochemical abnormalities.There appear to be two forms of the disorder: a neonatal form and a juvenile form. The neonatal form presents in the first weeks of life, with metabolic acidosis and ketosis and may . . .
https://doi.org/10.1056/nejm198104023041404Journal of Inherited Metabolic Disease · 2005 · 29 citations
Consanguineous 3‐methylcrotonyl‐CoA carboxylase deficiency: Early‐onset necrotizing encephalopathy with lethal outcome
AbstractA patient with a severe neonatal variant of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is reported. The first child of healthy consanguineous Turkish parents presented on the second day of life with dehydration, cyanosis, no sucking, generalized muscular hypotonia, encephalopathy, respiratory depression requiring mechanic ventilation, macrocephaly, severe acidosis and hypoglycaemia. Elevated C5-OH-carnitine in dried blood spot by tandem MS and elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine suggested MCC deficiency, confirmed by enzyme analysis in cultured fibroblasts. Cerebral ultrasonography and cranial CT findings revealed progressive changes such as disseminated encephalomalacia, cystic changes, ventricular dilatation and cerebral atrophy. Treatment with high-dose biotin and protein-restricted diet was ineffective and the patient died at the age of 33 days with progressive neurological deterioration. Mutation analysis revealed a homozygous mutation in the splice acceptor site of intron 15 in the MCC beta-subunit. Early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency.
https://doi.org/10.1007/s10545-005-4559-8PEDIATRICS · 2007 · 23 citations
Potential Misdiagnosis of 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Associated With Absent or Trace Urinary 3-Methylcrotonylglycine
AbstractWe report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G-->A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.
https://doi.org/10.1542/peds.2007-0674Journal of Inherited Metabolic Disease · 2015 · 18 citations · open access
3‐Methylcrotonyl‐CoA carboxylase deficiency: to screen or not to screen?
AbstractIn this issue of the Journal a paper from Israel describes the biochemical, molecular, and clinical data of all the patients with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) diagnosed as a result of 50 months of extended newborn screening—16 newborns, 20 affected mothers, and four other family members. Based on this report of mainly asymptomatic subjects, the Israeli Ministry of Health has decided to exclude 3-MCCD from routine newborn screening. This is not the first paper to present these sorts of data. In the last 5 years six papers have reported on some follow-up of over 200 newborns with 3-MCCD detected by newborn screening. Overwhelmingly these subjects have either remained asymptomatic, or, in the few with symptoms reported, there was no clear relationship between symptoms and residual enzyme activities and some symptoms were probably not related at all to 3-MCCD. Not all were asymptomatic. Grünert et al (2012) report on 53 screen-detected children aged 2–12 years 13 of whom reportedly had symptoms. Again, not all symptoms (e.g., in a child with trisomy 21) were related to 3-MCCD, but five patients had had one or more metabolic decompensations, with hypoglycaemia and ketonaemia. This series was somewhat selective—samples were referred to a central expert laboratory for enzymatic and molecular analysis. There is also another report of metabolic decompensation in a screen-detected child. This presents a dilemma that is becoming familiar in the expanded newborn screening of today: cases of disordered biochemistry with unclear clinical significance are being detected too often for comfort. For some disorders such as short-chain acyl-CoA dehydrogenase deficiency it is now apparent, although not universally accepted, that the disorder is benign and should not be included in screening. For 3-MCCD it is a little different, as there is a clear phenotype, metabolic decompensation with hypoglycaemia, ketonaemia and severe metabolic acidosis, that is found in a few cases. Making such a diagnosis can be beneficial, as clear instructions can be given so as to avoid or greatly shorten any decompensation during intercurrent illness. However, it can also be harmful; it is apparent that following diagnosis most children are medicalized to some extent, and even asymptomatic children are likely to be treated with a low protein or low-leucine diet, and certainly with carnitine. A diet is very intrusive. A Delphi-based consensus protocol (Arnold et al 2008) showed that a hand-picked group of clinicians did not recommend a diet for asymptomatic children or mothers, but in the real world it seems that probably half or more are receiving such treatment (Lam et al 2013). We do not know what proportion of 3MCCD subjects will ever become sick—something perhaps like 4–5 %—but we should consider carefully the question: if 3-MCCD was considered today for new inclusion in a newborn screening program would it be recommended? With next-generation sequencing on the screening horizon this is a very serious question which may be repeated time and again for more and more conditions. To paraphrase a quotation attributed to Aldous Huxley—soon we will have scarcely a healthy baby left. None. This article does not contain any studies with human or animal subjects performed by the author.
https://doi.org/10.1007/s10545-015-9906-9Journal of Mass Spectrometry · 1983 · 10 citations
Identification of 3-hydroxy-3-ethylglutaric acid in urine of patients with propionic acidaemia
AbstractBy gas chromatographic mass spectrometric analysis, 3-hydroxy-3-ethylglutaric acid was identified in the urine of patients with propionyl CoA carboxylase deficiency. Simultaneously, large amounts of 3-hydroxyvaleric acid and 3-oxovaleric acid, as well as a number of metabolites previously well known in this disorder, were also found in the urine of the patients. It is suggested that formation of 3-oxovaleric acid and 3-hydroxyvaleric acid proceeds via 3-hydroxy-3-ethylglutaryl CoA as an intermediate by a mechanism similar to that of ketone body formation.
https://doi.org/10.1002/bms.1200101202Movement Disorders Clinical Practice · 2018 · 7 citations · open access
Successful Pregnancy in a Patient with L‐Amino Acid Decarboxylase Deficiency: Therapeutic Management and Clinical Outcome
AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of biogenic amine metabolism presenting with developmental delay, hypokinetic movement disorders, hypotonia, and autonomic dysfunctions.1 We report on the successful pregnancy in a previously reported 26-year-old AADC patient with a mild phenotype (Table 1).2 Since the diagnosis at the age of 22, treatment with rotigotine, pyridoxine, and escitalopram resulted in a remarkable improvement of fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait.2 After, as consequence of behavioral disinhibition and reduced control of sexual impulses, rotigotine was replaced by a prolonged release formulation of pramipexole (up to 0.78 mg/day once a day). Selegine was added to improve diurnal fluctuation of motor symptoms (up to 7.5 mg/day after a very slow dose increasing). While MAO-inhibitors and SSRIs association is contraindicated in common neuropsychiatric disorders due to the risk of serotonin intoxication syndrome, their synergic effect may be exploited to magnify the residual enzymatic activity in the defect of serotonin synthesis, such as AADC deficiency. Compound heterozygous for the mutations p.Tyr37Thrfs*5 (c.105delC) and p.Phe237Ser (c.710 T>C) The pregnancy of our patient occurred naturally at the age of 26. Escitalopram was suspended to prevent the risk of low birth weight.3 Doses of pramipexole and selegiline could be decreased (Table 1) without obvious neurological worsening. No oculogyric crises or myoclonic jerks were observed, and limb rigidity, fatigability, and muscular weakness were well controlled. UPDRS-part III score did not change with respect the prepregnancy status (Table 1). Blood pressure remained below the normal range for the age. At the 31st week of gestation preeclampsia occurred. At the 38th week of gestation, a cesarean delivery (cardiac deceleration at cardiotocography) resulted in the birth of a vital (Apgar score 91 and 105) low birth weight (2.440 grams) and small (for gestational age) male newborn. The infant presented with transient tachypnea and hypoglycemia in the first day after birth. His growth was regular after the early introduction of artificial nursing. No significant health problems were observed in the following months. Pregnancy was previously reported in inherited neurotransmitter disorders with a less severe phenotype than AADC deficiency (35 women with autosomal dominant guanosine triphosphate cyclohydrolase 1 deficiency, one with dihydropterine reductase deficiency, and one with 6-pyrovoyl-tetrahydrobiopterin synthase deficiency).4, 5 The defect of monoaminergic neurotransmitters in AADC deficiency potentially impairs embryo-maternal interactions at preimplantation stages of early embryogenesis, which could be prevented by the treatment with drugs acting on dopaminergic axis.6 Efficacy and safety profile of pramipexole and selegiline during pregnancy and lactation are reported, in 24 and three women affected by Parkinson disease or restless legs syndrome, respectively.5, 7 Pramipexole was associated with spontaneous abortion in 3 cases (co-exposition with isotretinoin in one case) while selegiline was associated with a ventral septal defect in a twin newborn (co-exposition with L-DOPA/carbidopa and entacapone).5 The present case shows that in AADC deficiency: (a) fertility may be not impaired, (b) the course of pregnancy can be successfully managed in patients with mild phenotypes, and (c) low dosages of pramipexole and selegiline may have a good efficacy and safety profile during pregnancy. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.M.: 1A, 1B, 1C, 3A, 3B F.M.: 1B, 1C, 3A L.P.: 1A, 1B, 1C, 3A S.F.: 1A, 1B, 1C, 3A C.C.: 1C, 3B Cl.C.: 1C, 3B G.M.: 1A, 1B, 1C, 3B V.L.: 1A, 1B, 1C, 3A, 3B Ethical Compliance Statement: We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work and that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed written consent was obtained from the patient for the publication of her clinical data. Funding Sources and Conflicts of Interest: None of the authors have anything to declare. Financial Disclosures for previous 12 months: None of the authors have anything to declare.
https://doi.org/10.1002/mdc3.12622Kogyo Kagaku Zasshi · 1940 · 0 citations
Thermal reaction and hydrogenation of coal. VII. Effects of the ratio of hydrogen to coal
AbstractIn order to understand the phenotypic spectrum of this rare disorder, cardiac evaluation should be made in patients with 3-methylcrotonyl-CoA carboxylase deficiency. Biochemical and clinical investigations have also to be performed in their parents and siblings. In addition, 3-methylcrotonyl-CoA carboxylase deficiency should be included in the differential diagnosis of dilatative cardiomyopathy.
https://doi.org/10.1007/pl00008366PEDIATRICS · 2012 · 0 citations · open access
Penerapan Action Control dalam Meminimalkan Indirect Control Cost pada Minimarket X di Kupang
AbstractWe report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G-->A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.
https://doi.org/10.1542/peds.2007-0674Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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