follow up of abnormal neonatal screening for inborn errors of metabolism james d. shoemaker md phd...
TRANSCRIPT
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Follow up ofFollow up of
Abnormal Neonatal ScreeningAbnormal Neonatal Screening
For Inborn Errors of For Inborn Errors of MetabolismMetabolism
James D. Shoemaker MD PhDJames D. Shoemaker MD PhD
Director, Metabolic Screening Director, Metabolic Screening LabLab
St. Louis University School of St. Louis University School of MedicineMedicine
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From:
NNSGRC
National
Neonatal
Screening
And
Genetics
Resource
Center
as of
9/25/06
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Dr. David S. Millington
Duke University, Department of Genetics
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85 dalton fragment
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Preparation of blood spots for tandem mass spectrometry:
1) Punch out spot and put in test tube
2) Swish blood spot in methanol
3) Remove paper and dry methanol under nitrogen stream
4) Add butanol and acetylchloride to make butyl esters of amino acids
5) Transfer to sample plate for automated injection
6) Compile the molecular weights of all ions that yield a fragment weighing 85 daltons
7) Subtract weight of carnitine to identify “acyl” portion of acylcarnitine
8) Scan for substances with a “neutral loss” of 102: amino acids
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Note: Disorders above detected as the amino acid precursor
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Formerly only 1 “organic acidemia” among screened disorders
Biotinidase and MSUD were not screened for in MO and IL
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Current Screening Protocol:
All MS/MS results go to Dr. Jinks
312/793-1053
Who makes the determination:
Presumptive Positive or Borderline
Straight to specialist To ordering MD
recommend repeat MS/MS on new
blood spot
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Instead of 1/9624
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2005
½ year
Of Tandem MS/MS
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Missouri 2006 Expanded Newborn Screening Results
Inborn errors detected: 18 42 “high risk” cases over 8 months
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Inborn Errors Confirmed:
20 39 since inception
0.05% vs. 0.032 % for
Illinois
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H2N – C – NH2
||
O
2 NH3 + CO2
urease
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CF3-COO - +H3N- CH2-COO - +HN-[CH2CH3]3
| Trifluoroacetate R Triethylammonium
CF3-COO - +H3N[CH2CH3]3
Triethylammonium Trifluoroacetate
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H2N-CH-COOH TMS2N-CH-COO-TMS | |
R R R-COOH R-COO-TMS
R-CH2-OH R-CH2-O-TMS
R-CH2-SH R-CH2-S-TMS
Trimethylsilylation
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Creatinine Mass Spectra; top: native, bottom: d3
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How the Metabolic Screening Lab
and Expanded Newborn Screening
Work Together:
I. MS/MS cut-offs for “significance” are set for screening purposes, that is, low, to be most sensitive, but not specific. Physiological significance may be indicated on other signs of metabolic stress available on the MSL panel.
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From first year medical school lecture on MCAD deficiency:
MSL panel reports acylglycines, not acylcarnitines.
Acylglycines are made only when pathological amounts of medium chain derivatives are present and are therefore “more abnormal”
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DNA Probe by PCR: A985G [same as K329E in the peptide], confirmed by Piero Rinaldo MD at Yale University; the most common MCAD mutation ascertained from symptomatic patients.
Medium Chain Acyl-CoA-Dehydrogenase (MCAD) is a nuclear encoded (chromosome 1p31), mitochondrial, tetrameric protein specific for the initial beta-oxidation of fatty acids of chain length 6 through 12, primarily. MCAD deficiency is the most common genetic defect of fatty acid oxidation and is one of the most common genetic disorders of people of Northern European origins. The most common mutation, A985G in exon 11, causes lysine 329 to be replaced by glutamate (K329E). The substitution of the negatively charged glutamate for the positively charged lysine disrupts the folding and assembly of the tetrameric subunits and the conformation of the FAD-binding active site. High doses of riboflavin may help to correct the folding and assembly defects (ref 24,35 ) The heterozygous frequency of the A985G mutation has been estimated as follows in various ethnic groups: Netherlands 1/59, United Kingdom 1/68, Belgium 1/77, Bulgaria 1/91, Poland 1/98, Denmark 1/101, Germany 1/116, US 1/122, (North Carolina 1/84, Pennsylvania 1/95), Sweden 1/127, France 1/140, Hungary 1/168, Turkey, 1/216, Czech Republic 1/240, Italy 1/333, Spain 1/200, Spanish gypsies 1/17, Japan: none.
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How the Metabolic Screening Lab
and Expanded Newborn Screening
Work Together:
II. MS/MS provides molecular weights that are consistent with various classes of compounds, but not positive compound identification.
By contrast, GC/MS used by MSL, provides positive compound ID by retention time and mass fragmentogram.
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Leucine C6H13NO2 MW = 131.17 Hydroxyproline C5H9NO3 MW = 131.13
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How the Metabolic Screening Lab
and Expanded Newborn Screening
Work Together:
III. False positives are the hallmark of the newborn screening program in another way: the cut-offs are set so low that the heterozygous state of the newborn of a parent with a benign inborn error is detectable, leading to late-life diagnosis of the parent.
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How the Metabolic Screening Lab
and Expanded Newborn Screening
Work Together:
IV. At present, expanded newborn screening does not pick up some of the most life-threatening categories of inborn errors.
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Of 120Inborn Errors: [multiple cases]
• 12 Urea cycle• 10 S-MCAD-LCHAD• 12 MMA• 6 MSUD• 15 Tyrosinemia
(many neonatal)
• 8 Galactosemia
• 4 Cystinuria
(all over 1 y.o.)
• 3 Propionic
• 2 HMG
• 2 Renal Fanconi
• 2 Hyperoxaluria
• 3 Molybdenum Cofactor Deficiency
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MS/MS techniques for detection of orotic acid have been published, but have not been incorporated into the
panel of Illinois or Missouri.
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How the Metabolic Screening Lab
and Expanded Newborn Screening
Work Together:
V. At present, expanded newborn screening does not pick up some of the most rare types of inborn errors such as
Hawkinsinuria
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Of 74 Inborn Errors: [multiple cases]
• 9 Urea cycle• 6 MCAD-LCHAD• 6 MMA• 5 MSUD• 7 Tyrosinemia
(5 neonatal)
• 4 Galactosemia
• 4 Cystinuria
(all over 1 y.o.)
• 3 Propionic
• 2 HMG
• 2 RenalFanconi
• 2 Hyperoxaluria
• 2 Molybdenum Cofactor Deficiency
Of 120Inborn Errors: [multiple cases]
• 12 Urea cycle• 11 S-MCAD-LCHAD• 12 MMA• 6 MSUD• 15 Tyrosinemia
(many transient)
• 8 Galactosemia
• 4 Cystinuria (all over 1 y.o.)
• 3 Propionic
• 2 HMG
• 2 Renal Fanconi
• 2 Hyperoxaluria
• 3 Molybdenum Cofactor Deficiency
• 2 Cystathioninuria
Pink: not likely picked up by standard organic acid screening
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Of 120 Inborn Errors: (continued)
• 6 Glutaric I • 2
hypophosphatasia
• 4 Adrenoleukodystrophy
• 4 3-methylglutaconic
• Fumaric• 2 Pyroglutamic• 2 IminoAciduria• 2 3-met-crot
CO2ase• 2 Biotinidase
• Pyruvate Dehydrogenase,
• Proline Oxidase, • Succinic Semi-
aldehyde dehydrogenase Deficiencies
• Hartnups & Canavan’s Diseases
• Renal Glycosuria• Hawkinsinuria • FIGLU uria, • PKU • 2 Alkaptonuria• 2-Hydroxyglutaric
aciduria
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Of 11724 Samples, from 10061 Of 11724 Samples, from 10061 patientspatients
1993 Abnormal 17%1993 Abnormal 17%
120 confirmed Inborn Errors120 confirmed Inborn Errors
Total: 1.17% of patientsTotal: 1.17% of patients
49 involved non-acidic 49 involved non-acidic metabolitesmetabolites
68% increase due to urease 68% increase due to urease methodmethod compared to standard compared to standard extraction or extraction or column clean-up.column clean-up.
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SourceSource # of# of
patientspatients
% %
AbnormalAbnormal
# of Inborn # of Inborn
ErrorsErrors
% Inborn% Inborn
ErrorsErrors
GlennonGlennon
InptsInpts
23062306 24.824.8 4848 2.12.1
Glennon Glennon
Outpt.Outpt.
15101510 9.29.2 1111 0.70.7
CH OaklandCH Oakland 13201320 17.717.7 2727 1.791.79
Spring-Spring-
field, ILfield, IL
738738 9.89.8 44 0.50.5
SpecialtySpecialty
LabsLabs
29912991 5.35.3 1212 0.40.4
CarleCarle
ClinicClinic
160160 8.18.1 11 0.60.6
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Of 120 Inborn Errors: [more common cases]How many would be picked up by
MO-IDPH neonatal screen?• 12 Urea cycle• 11 MCAD-LCHAD• 12 MMA• 6 MSUD• 15 Tyrosinemia
(many transient)
• 8 Galactosemia
• 6 Glutaric I
• 4 Adrenoleukodystrophy
• 4 3-methylglutaconic
• 4 Cystinuria
(all over 1 y.o.)
• 3 Propionic
Answer: 65/85 of more common disorders
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Of rarer disorders: 8/35 TOTAL: 73/120 = 60.8%
Of 120 Inborn Errors: (continued)
• 3 Molybdenum Cofactor Deficiency
• 2 HMG• 2 Renal Fanconi• 2 Hyperoxaluria
• 2 hypophosphatasia• 2 Pyroglutamic• 2 IminoAciduria• 2 3-met-crot CO2ase• 2 Biotinidase • 2 Alkaptonuria
• Fumaric• Pyruvate
Dehydrogenase,• Proline Oxidase, • Succinic Semi-
aldehyde dehydrogenase Deficiencies
• Hartnups & Canavan’s Diseases
• Renal Glycosuria• Hawkinsinuria • FIGLU uria, • PKU • HHH, 2
Cystathioninuria• 2-Hydroxyglutaric
Aciduria
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Overall rate of vitamin deficiency detection
500 / 2726 = 18.3%Of very ill infants and children suspected of having inborn errors of metabolism
Will Neonatal Screening Eliminate the need for Labs like mine?
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Methionine
Homocysteine
S-Adenosyl-methionine
S-Adenosyl-homocysteine
Cystathionine
Alpha-ketobutyrate Cysteine
Serine
Tetrahydrofolate
Methyl-THF
B-6
B-6
B-12
Methylene-THF
B-6
FAD
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Recommendation:
• If an infant requires intravenous fluids, add MVI to the first bag
• Or give oral equivalent .
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Indications for ordering Organic Compound Screening
• HIGH YIELD LOW YIELD
• but sometimes necessary
• Unexplained or Recurrent:
• Acidosis Seizure Disorder
• Hypoglycemia Failure to Thrive
• Hyperammonemia Developmental Delay
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Saint Louis University School of Medicine
E.A.Doisy Department of Biochemistry and Molecular Biology
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*quinolinic acid nicotinic acid
NADH NAD+
2-acroleyl-3-aminofumarate ketoadipate CO2 + H2O
3-hydroxyanthranilic acid
pyridoxal phosphate
3-hydroxykynurenine xanthurenic acid
*kynurenine *kynurenic acid
tryptophan
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MS/MS answers the question:
What was the molecular weight of the parent ion that gave rise to this daughter ion weighing 85 (carnitine) or 102 (amino complex)
Although MS/MS happens “instantaneously” it is still a separative technique: the computer records the millisecond at which the parent ion giving rise to “daughters of 85” entered the second source and can derive its molecular weight.
So you know the molecular weight of the precursor (parent) and can identify the weight of the acyl group (acylcarnitines) or side chain (amino acids) of this molecule
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Illinois Experience in the First Year of Expanded MS/MS TestingIllinois Experience in the First Year of Expanded MS/MS Testing
How many newborns were tested July 1, 2002 – June 30, 2003?How many newborns were tested July 1, 2002 – June 30, 2003?
Over 400,000 Over 400,000
How many confirmed cases of inborn errors were found?How many confirmed cases of inborn errors were found?
73 (about 1/5500)73 (about 1/5500)
From what main category?From what main category?
All categories: amino acid, organic acid, fatty acid.All categories: amino acid, organic acid, fatty acid.
Thanks to: Dr. David Jinks PhD, Chief of Newborn ScreeningThanks to: Dr. David Jinks PhD, Chief of Newborn Screening
Illinois Department of Public Health, Chicago, ILIllinois Department of Public Health, Chicago, IL
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First Complete Year: 7/1/2002 - 6/30/2003 MS/MS Results
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Analytes detected in Missouri Expanded Screening
Yellow shading = Possibly diagnostic, not definitive
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Years before MS/MS screening in Missouri
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Year 2004
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2006 January-March
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