Title: MATERNAL PKU AND OTHER METABOLIC DISORDERS
1(No Transcript)
2MATERNAL PKU LONGER TERM OFFSPRING OUTCOME
RELATED TO PRENATAL AND POSTNATAL FACTORS
- Harvey L. Levy, MD, Susan E. Waisbren, PhD,
- Fran Rohr, MS, RD, Vera Anastasoaie, Stephanie
Petrides - Boston Childrens Hospital
- Harvard Medical School
3Dr. Levy has the following disclosures
- Maternal PKU Study, NPKUA
- Maternal PKU Study, Milton Fund
- Enzyme Therapy for PKU, BioMarin
-
Pharmaceuticals - GMP therapy for PKU, FDA
- Urea Cycle Disorders, NIH
4- Dr. Charles E. Dent Richards made a chance
observation from a phenylketonuric mother at the
mental defective colony in Caterham, near London.
She had three children .. All three
children were mentally retarded from birth but
had no abnormal amino acids in their urine. We
felt that it might well have been the toxicity of
the mothers high blood phenylalanine level that
damaged their brains in utero. - From Discussion at the 23rd Ross Pediatric
Research Conference 1957 -
5(No Transcript)
6(No Transcript)
7(No Transcript)
8(No Transcript)
9- PAH
- Phenylalanine Tyrosine
- BH4
- Phenylpyruvic Acid
-
- Phenyllactic Acid Phenylacetic Acid
-
-
10(No Transcript)
11(No Transcript)
12MATERNAL PKU A PROBLEM BORN OF SUCCESS
13(No Transcript)
14(No Transcript)
15(No Transcript)
16(No Transcript)
17Aims of the Study
- Longer term medical and intellectual outcome of
the offspring - Psychological-emotional-social functioning of the
offspring - Medical-nutritional-emotional status of the
mothers - Relative roles of metabolic control in pregnancy
and postnatal maternal stimulation in offspring
outcome
18The Sample
- 27 mothers ranging from 23-48 (average age is 40)
- 48 offspring ranging from 2 months-26 years
(average age is 9 years) - 0-2 10 subjects
- 3-6 15 subjects
- 7-11 8 subjects
- 12-18 12 subjects
- gt18 3 subjects
19Measures Used In Study
- IQ (mothers and offspring)
- Executive functioning (mothers and offspring)
- Prevalence of Anxiety/Depression/ADHD (mothers
and offspring) - Physical exam (mothers and offspring)
- Home Scale--measure of home environment
(offspring) - Nutrition assessment (mothers)
- Labsincluding blood Phe (mothers)
- Photos to look at dysmorphology (mothers,
offspring, and fathers if possible)
20Offspring outcome was determined by ABAS
- ABAS- Adaptive Behavior Assessment System
- (questionnaire completed by mother that includes
10 skills areas of offspring) - ABAS correlates with offspring IQ
- n27, r0.73, plt0.0001
- ABAS correlates with offspring DQ
- n11, r0.77, p0.005
21Prenatal Metabolic Control
- Started diet prior to pregnancy 76
- In metabolic control prior to pregnancy 41
- Control during pregnancy
- Excellent 41 (11)
- On diet prior, blood phe lt 6 mg/dL throughout
- Good 35 (9)
- On diet prior, blood phe lt6 mg/dL by 10 weeks
- Fair 14 (4)
- Blood phe lt 10 mg/dL by second trimester
- Poor 10 (3)
- Blood phe in control in third trimester or never
22Maternal Postnatal Diet
- Mothers currently on diet 52 (14/27)
- On diet taking medical food and restricting phe
- Maternal Blood Phe
- Average 1176 umol/L (19 mg/dL)
- Range (386-1934) (6-32)
-
23Prenatal Treatment vs. Offspring Outcome
- Maternal Offspring ABAS
- Pre-conception 9816
- Post-conception 9222
24Current Maternal Dietary Status vs. Offspring
Outcome
- Dietary Status Offspring ABAS
- On diet 10316
- Off diet 9712
25Mothers Prenatal and Postnatal Diet vs.
Offspring ABAS
Excellent Control Not Excellent Control
On Diet n10 11218 lt850 n14 9715 lt853
Off Diet n8 1027 lt850 n13 8920 lt854
26Conclusions
- Longer term follow-up of offspring from treated
maternal PKU pregnancies confirms that outcome is
usually within normal limits - Offspring outcome is not only IQ but also
function (social, behavioral) as measured by
ABAS - Optimal offspring outcome requires not only
prenatal metabolic control but also postnatal
stimulation - Good postnatal stimulation requires maternal
continuation of diet
27(No Transcript)
28(No Transcript)
29 Effects of Glycomacropeptide, Amino Acid
Casein Diets on Osteopenia in PKU Mice
- Denise M. Ney, PhD, RD
- Professor of Nutritional Sciences
- Waisman Center
- University of Wisconsin-Madison
30Disclosure
- D Ney is a co-inventor on US Patent Application
US-2010-0317597, GMP Medical Foods for
Nutritional Management of PKU, which is held by
the Wisconsin Alumni Research Foundation and
licensed to Cambrooke Foods, LLC. A percentage
of all royalty payments is awarded to the
inventors. - D Ney has received consulting income from
Cambrooke Foods and BioMarin. -
31UW-Madison PKU Bone Research Team
Denise Ney Robert Blank Sangita
Murali Patrick Solverson
- Funding National PKU Alliance USDA Hatch
Grant -
32Background
- PKU is associated with low bone mass, or
osteopenia, and fractures in early adulthood. - 57 of 28 patients had osteopenia/osteoporosis
- Perez-Dueñas et al. Acta Paediatr 91800, 2002
- Reduced bone mineral density (BMD) in PKU is
present from an early age onward and it cannot be
predicted by plasma phe levels. - 20 of 53 patients studied had osteoporosis
- de Groot et al. Mol Genet Metab 101566, 2012
-
33What causes skeletal fragility in PKU?
- The fundamental question is whether reduced BMD
is inherent to PKU or secondary to its dietary
management. - In order to isolate the contributions of the PKU
genotype itself and dietary treatment of PKU we
have conducted a factorial experiment in PKU
mice.
34Objective Design
- To determine how the PKU genotype and the source
of dietary protein affect growth, body
composition and bone development.
35PKU WT Mice Housed With Same Sex Littermates
?phe GMP ?phe AA ?phe Casein
36GMP is a natural whey protein produced when
making cheese. Pure GMP contains no phe.
37Growth
Solverson, P et al Am J Physiol Endocrinol Metab
302E885-95, 2012
38Metabolic Phenotyping Platform
?Food water intake ?O2 consumption
CO2 production
39PKU mice show increased energy expenditure with
casein diet
40GMP Diet Normalizes Food Intake in PKU Mice
Values with different letter superscripts are
significantly different, plt0.05
41AA Diet Increases Kidney Workload in both WT and
PKU Mice
Values with different letter superscripts are
significantly different, plt0.05
42 Does PKU increase energy needs?
- Resting energy expenditure is 5-10 higher in
adolescent females with PKU than that predicted
by standard equations. - J Am Diet Assoc 110922-25, 20101
- Am J Clin Nutr 62797-804, 1995
- Reduced growth occurs in children with PKU
- Mol Genet Metab 10199-109, 2010
- J Pediatr 261-11, 2002
43Dual Energy X-Ray Absorptiometry (DXA)
44PKU mice show reduced whole-body bone
mineralization compared to WT mice
45Femur Strength 3 Point Loading Test
Loading force being applied to a mouse femur
46Load-Displacement Curve
Displacement, mm
47PKU mice show bones that are brittle and break
easily
48PKU mice show reduced femoral bone mineralization
compared to WT mice
49How the casein, AA and GMP diets affect bone size
and strength?
50GMP Increases Bone Size in PKU WT Mice
Casein
AA
GMP
51GMP Improves Bone Strength in PKU and WT Mice
Compared with AA Diet
52Summary
-
- PKU mice have femora that are
- brittle and weak. This suggests
- defects in both collagen synthesis
- and mineralization.
- GMP increases bone size and strength femora
tolerate a higher max load before fracture
compared with the AA diet. - How does GMP work to improve bone strength in
mice?
53What causes skeletal fragility in PKU?
- Inherent to PKU genotype and/or
- Secondary to management with an AA diet.
- Answer both genotype and diet
54Conclusion
- Skeletal fragility is inherent to the PKU
genotype and is attenuated by a GMP compared with
an AA diet in mice. - Future research is needed to determine if
improved low-phe diets containing GMP reduce
skeletal fragility in human PKU. -
-
55Take Home Message How can bone health be
improved in PKU?
-
- Follow a low-phe diet to improve growth and bone
development - Include weight bearing exercise each day
56(No Transcript)