Diagnosis of Inborn Errors of Metabolism from Blood Spots by Acylcarnitines and Amino Acids Profiling Using Automated Electrospray Tandem Mass Spectrometry

Rashed, Mohamed S.; Özand, Pinar; Bucknall, Martin P.; Little, Douglas

doi:10.1203/00006450-199509000-00009

Cited by 314 publications

(178 citation statements)

References 8 publications

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“…Blood samples were collected between the third and sixth days of life on Whatman 903 filter paper, and the analysis of amino acids and acylcarnitines, as butyl esters (Rashed et al 1995), was performed using two API 2000 triple quadrupole tandem mass spectrometers. Methionine quantification allows the detection of cystathionine b-synthase deficiency, as well as hypermethioninemia due to MAT I/III deficiency.…”

Section: Methodsmentioning

confidence: 99%

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Martins

Marcão²,

Bandeira

et al. 2012

JIMD Reports

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Methionine adenosyltransferase deficiency (MAT I/III deficiency) is an inborn error of metabolism resulting in isolated hypermethioninemia, and usually inherited as an autosomal recessive trait, although a dominant form has been reported in several families.During the last 6 years, approximately 520,000 newborns were screened in the Portuguese Newborn Screening Laboratory by MS/MS, and 21 cases of persistent hypermethioninemia were found. One case was confirmed to be a deficiency of cystathionine b-synthase and 20 cases were confirmed by MAT1A gene analysis to have an elevation of methionine due to MAT I/III deficiency, which indicates an incidence for this condition of 1/26,000. Twelve of the MAT I/III deficient newborns, belonging to 11 families, were identified in the northern region of Portugal and sent to the same treatment center, where they are under follow-up. Clinical, biochemical, and genetic characteristics of individuals from these 11 families are presented. Plasma methionine and homocysteine concentrations were found to be moderately increased in all newborns, and molecular analysis revealed that they all were heterozygous for R264H mutation. Normal growth, development, and neurological examination were observed in all cases, and cerebral MRI performed in six cases revealed myelination abnormalities in one case. Plasma methionine concentration for all 12 cases was always below 300 mM, and they are all on a normal diet for their age. AbbreviationsAdoMet S-adenosylmethionine CNS Central nervous system MAT Methionine adenosyltransferase MRI Magnetic resonance imaging MS/MS Tandem mass spectrometry

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Section: Methodsmentioning

confidence: 99%

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Martins

Marcão²,

Bandeira

et al. 2012

JIMD Reports

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“…The assay was modified to accommodate a reduced sample size (10 μl), and use of a microplate reader for measurement of optical density at 550 nm. Serum acylcarnitine analysis was performed by using electrospray tandem mass spectrometry [23][24][25]. Urinary organic acid analysis was performed as described previously [26].…”

Section: Biochemical Analysismentioning

confidence: 99%

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

You

Kerner

et al. 2008

Molecular Genetics and Metabolism

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Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial β-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5 − 11.5. Also, while there were normal percentages of CPT-1b+/−pups born from both male and female CPT-1b+/− mice crossed with wild-type mates, the number of CPT-1b+/− pups from CPT-1b+/− breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated ∼50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/− male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/− mice had ∼60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/− mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, ∼7% CPT-1b+/− mice (n=30) developed fatal hypothermia following a 3 hr cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6 hr), significantly more CPT-1b+/− mice developed fatal hypothermia (52% CPT-1b+/− mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/− mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.

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“…Phe and Tyr plasma concentrations were measured using tandem mass spectrometry (MS/MS) in the Laboratory of Inborn Errors of Metabolism of SGM/HCPA, as described by Rashed et al [25]. All measurements were made in duplicate, and the mean of the two measurements was calculated.…”

Section: Combined Phe and Bh 4 Loading (Test 2)mentioning

confidence: 99%

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

Nalin

Perry

Sitta

et al. 2011

Molecular Genetics and Metabolism

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INTRODUCTION:Recent studies showed that phenylalanine (Phe) plasma concentrations may decrease in some patients with hyperphenylalaninemia (HPA) due to phenylalanine hydroxylase (PAH) deficiency, after the administration of tetrahydrobiopterin (BH(4)). OBJECTIVE: To determine responsiveness to a single dose of BH(4) administered according to an innovative protocol using a combined Phe and BH(4) loading test in Brazilian phenylketonuria (PKU) patients. METHODS: Patient age should be 4 years, and median Phe plasma concentration 600 mol/L when following dietary restrictions. Participants received a simple Phe loading test using 100mg/kg L-Phe (Test 1) and a combined Phe+BH(4) loading test using 100mg/kg L-Phe and 20mg/kg/BH(4) (Test 2). Blood samples were collected at baseline and 3, 11 and 27 h after Phe ingestion (T0, T1, T2 and T3). Responsiveness was defined as: criterion A: plasma Phe reduction of 30% at T1 and T2 for Tests 1 and 2; criterion B: plasma Phe reduction of 30% at T1 and T3 for Tests 1 and 2; and criterion C: at least 30% difference of the areas under the Phe curve for Tests 1 and 2. RESULTS: Eighteen patients (median age 12 yrs; 8 classical PKU; 10 mild PKU) participated in the study. Six patients (2 classical PKU; 4 mild PKU) were classified as responsive according to at least one of the criteria. Responsiveness was concordant when criteria A + B we compared with criterion C (kappa = 0.557; p = 0.017). Of the patients whose genotype was available (n = 16), six had data about BH(4)-responsiveness genotypes described in the literature, which were in agreement with our findings. CONCLUSION: The comparison of simple Phe loading and combined Phe + BH(4) loading seems to be an optimal method to evaluate responsiveness to BH (4) Introduction: Recent studies showed that phenylalanine (Phe) plasma concentrations may decrease in some patients with hyperphenylalaninemia (HPA) due to phenylalanine hydroxylase (PAH) deficiency, after the administration of tetrahydrobiopterin (BH 4 ). Objective: To determine responsiveness to a single dose of BH 4 administered according to an innovative protocol using a combined Phe and BH 4 loading test in Brazilian phenylketonuria (PKU) patients. Methods: Patient age should be ≥4 years, and median Phe plasma concentration ≤600 μmol/L when following dietary restrictions. Participants received a simple Phe loading test using 100 mg/kg L-Phe (Test 1) and a combined Phe + BH 4 loading test using 100 mg/kg L-Phe and 20 mg/kg/BH 4 (Test 2). Blood samples were collected at baseline and 3, 11 and 27 h after Phe ingestion (T0, T1, T2 and T3). Responsiveness was defined as: criterion A: plasma Phe reduction of ≥30% at T1 and T2 for Tests 1 and 2; criterion B: plasma Phe reduction of ≥30% at T1 and T3 for Tests 1 and 2; and criterion C: at least 30% difference of the areas under the Phe curve for Tests 1 and 2. Results: Eighteen patients (median age 12 yrs; 8 classical PKU; 10 mild PKU) participated in the study. Six patients (2 classical PKU; 4 mild PKU) were classified a...

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Diagnosis of Inborn Errors of Metabolism from Blood Spots by Acylcarnitines and Amino Acids Profiling Using Automated Electrospray Tandem Mass Spectrometry

Cited by 314 publications

References 8 publications

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

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