Treating PKU: A Half-Century of Experience
What’s Been Learned, What are some Questions
National PKU Alliance Conference
Cherry Hill, New Jersey
R. Rodney Howell, M. D.
Professor of Pediatrics, Chairman Emeritus
Member, Hussman Institute for Human Genomics
Miller School of Medicine
University of Miami
Founding Chair
HHS Secretary's Advisory Committee on Heritable Disorders
In Newborns And Children
July 27, 2012
Oslo, Norway, the Late 1920s
Harry (a young dentist) and his wife Borgny Egeland
were concerned that their 3 year old daughter was very
slow in speaking. While dealing with this concern,
Borgny recognized she was pregnant this time with a
son, later named Dag. He was early found to be very
delayed
The Egelands detected a strange musty odor which they
thought might be causing their children’s retardation.
The father who had severe asthma was said to be
unable to stay in a closed room with the children due to
the odor
They sought the help of a Chemistry Professor that had
taught Harry in Dental School, Dr. Asbjørn Følling (he
was teaching there while in medical school). The Følling
medical thesis was written on “Mechanisms of
Acidosis”
Asbjørn Følling, ca 1934
The Positive Ferric Chloride Test
Borgny was asked to bring urine samples to the Følling
laboratory; routine tests were normal but when ferric chloride was added (a test for
ketones which produces a red-brown color) the girl’s urine turned a dark green color
which faded in a few minutes
Could the positive test be drugs or herbs? All these were eliminated, still the
evanescent dark green color was present
Dr. Følling asked Mrs. Egeland to bring daily urine samples which soon totaled about
20 liters. Using laborious chemical precipitation procedures he recrystallized the
compound (he could follow its presence by the positive FeCl3 test) six times and
identified this compound as phenylpyruvic acid
Følling screened 434 mentally-retarded children using the urinary FeCl3 test and
found 8 with the same abnormality, which he termed phenylpyruvic oligophrenia, and
identified it as a defect in phenylalanine metabolism
In 1934, he published these findings, approximately 6 months after the Egelands had
contacted him!
(There is an interview with Dr. Følling posted on YouTube about this discovery)
Transient Green Color seen by Følling
Bickel and Colleagues: The First Child Treated with
a Synthetic Diet Low in Phenylalanine 1951
Diet made with casein hydrolysate treated with activated
charcoal.
tyrosine and other amino acids added and
later some phenylalanine
Child 26 months old with a phenylalanine content of 67mg
% prior to treatment; slow mental development
While on the diet urinary FeCl3 became negative; during
next six months child appeared to improve, eyes brighter,
more interest in surroundings, learned to crawl, eczema
cleared; addition of more phenylalanine to diet caused
regression
Authors concluded further trials needed; felt that diet not
very helpful to older children and they presumed best
results will occur when diet begun in infancy
(Posted on YouTube is a B & W 8mm film made by Bickel
about the treatment of this first child )
PAGE 45: A NEW WAY TO DETECT A DREADFUL DISEASE-PKU
Rural China, 1920- Description by a Mother
-A Famous Writer- of her Child later Found to have
PKU-a Condition which had not yet been described
I don’t know any blow in all my life that was a rending. It was as if my very flesh were
torn. It was beyond belief, and yet I knew I had to believe it, and shape my life around
the fact
Taking this advice, the mother identified a good care-taking institution in America
and Carol was placed at the Training School at Vineland. At Vineland, as an adult
Carol was diagnosed as having PKU
The mother, Pearl S. Buck, won the Pulitzer Prize in 1932 and the Nobel Prize in 1938
for her books about rural China where she lived for 40 years from infancy. Her most
famous book is The Good Earth was published in 1931, but was on the Oprah Book
list as recently as 2002
Her book, The Child Who Never Grew published in 1950, is the world-famous author’s
story of her daughter with PKU
Pearl S. Buck on her return to the United States became an advocate for the
developmentally delayed, and became friends with the Kennedy Family who shared
these interests. This friendship clearly help increase funding for research in
phenylketonuria, and importantly to the formation of the National Institute of Child
Health and Human Development.
The Collaborative Study for the Treatment for
Phenylketonuria
• Large, ambitious longitudinal collaborative study instituted in
1967 to test the effects of dietary restriction of phenylalanine in
the treatment of PKU
• There were two Treatment Groups: The first whose serum
phenylalanine was targeted between 1.0-5.4 mg/100 ml, and the
second between 5.5 and 9.9 mg/100ml
• There were two control groups: Siblings with PKU who were
previously untreated, and siblings without PKU
• A sophisticated system of dietary management, monitoring,
and collection, management and analysis of the data were in
place
• Over 400 patients were in the original sample
The Collaborative Study for the Treatment for
Phenylketonuria- Some Conclusions
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Patients with classic PKU were identified by newborn screening and
began treatment soon
•
All were given the restricted diet until age 6 years, when half were
assigned to continue and half to discontinue dietary therapy
•
By age 10 years, 35% had deviated from randomization
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The effects of diagnostic, treatment and psychosocial factors on
cognitive test scores were evaluated through 12 years of age
•
After controlling for parent IQ, significant correlations were noted
between various measures of control of blood phenylalanine and
their scores on intelligence, reading, spelling and behavior tests but
not for arithmetic or language
•
These findings strongly supported the importance of early initiation
of dietary treatment and continuation of therapy throughout
childhood
The International Maternal PKU Collaborative
Study
•
Designed to determine the effect of dietary control of blood
phenylalanine during pregnancy in preventing damage to the fetus
association with untreated maternal PKU
•
Women grouped according to their mean PKU levels (µmol/L)
<360, 361-600, 601-900, or >900
•
Significant relationships were seen with elevations during the critical
gestational weeks of 0-8, and 8-12 weeks
•
Frequent, severe abnormalities in brain, fetal, and postnatal growth
were seen when phenylalanine levels were above 900 µmol/L
•
Women with PKU should begin a low-phenylalanine diet to achieve
phe levels of <360 µmol/L prior to conception and should maintain
this throughout pregnancy
Phenylketonuria:
Screening and
Management
NIH Consensus
Development
Conference
October 16-18, 2000
2000 NIH Consensus Development
Conference: Some Conclusions
•
Genetic testing for PKU has been in place for almost 40 years and has
been very successful in the prevention of several mental retardation in
thousands of children and adults. Many questions, however, remain
unanswered
•
Metabolic control is necessary across the lifespan of individuals with
PKU
•
A comprehensive, multidisciplinary, integrated system is required for
the delivery of care to individuals with PKU
•
Greatly needed are consistency and coordination among screening,
treatment, data collection and patient support programs
•
There should be equal access to culturally sensitive, age appropriate
treatment programs
2000 NIH Consensus Development
Conference: Conclusions Continued
•
Ethically sound, specific policies for storage, ownership, and
use in future studies of archived samples remaining from
PKU testing should be established
•
Research into the pathophysiology of PKU and the
relationship to genetic, neural and behavioral variation is
strongly encouraged
•
Uniform policies need to be established to remove from the
individual and the family financial barriers to the acquisition
of medical foods and modified low-protein foods, as well as
to provide access to support services required to maintain
metabolic control in individuals with PKU
2000 NIH Consensus Development
Conference, Conclusions Continued
•
To achieve optimal statistical power, as well as crosscultural applicability, it will be beneficial to use data
acquired via national and international collaboration.
•
It is recommended that Phe levels below 360 µmol/L be
achieved at least 3 months before conception
•
Research on nondietary alternatives to treatment of PKU
is strongly encouraged
•
Mutation analysis and genotype determination should be
accomplished on all persons with PKU for initial
diagnosis, genetic and management counseling, followup and long-term prognosis.
Fast Forward Twelve Years Later
The PKU Scientific Review Conference: State of the Science
and Future Research Needs
Bethesda, Maryland February 22-23, 2012
•
Working groups comprising topic experts, members of the public
and federal representatives have been formed to review the current
state of the science on difference aspects of PKU
•
Long-Term Outcomes and Management across the
Lifespan
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PKU and Pregnancy
•
Diet Control and Management
•
Pharmacologic Interventions
•
Molecular Testing, New Technologies, and
Epidemiologic Considerations
New Medication: Sapropterin
dihydrochloride (Kuvan®)
•
•
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Synthetic form of BH4, the cofactor for the PAH enzyme
FDA approval in December 2007 granted to BioMarin
Indications:
–
–
–
–
BH4-responsive PKU
No age restriction
For use in combination with a Phe-restricted diet
Requires frequent monitoring of blood Phe levels and
recommended diet management with dietitian
– Patient registries for those on Kuvan, including pregnant
women
– Approval based on 4 studies in 579 patients, 4-49 yrs old
•
Mechanism: increases activity of PAH enzyme in those with
residual enzyme function
Some Key Points Which Emerged at this Conference
from the Working Groups
• A Reinforcement of the importance of lifelong treatment for PKU
• A Refinement of the critical elements of medical, nutritional, cognitive,
emotional, behavioral, and social management of PKU throughout the lifespan,
including pregnancy
•Optimal management is essential to prevent maternal PKU syndrome
• The value of double-blind, placebo controlled studies for determining
responsiveness to therapies such as sapropterin
• An emphasis on the value of genotyping for categorization of severity of PKU
and for prediction of responsiveness for sapropterin
• A recognition of the psychosocial, insurance and other factors that influence
access to and compliance with nutrition and other therapies
• The need for more treatment options for individuals with no or minimal PAH
enzyme activity
•Work that came out of this conference will inform practice guidelines and
development of a research agenda
In a Word:
Newborn screening and treatment of phenylketonuria is one of the most
successful public health programs of the past century. NBS expansion
was recognized by the CDC as one of the most important public
health accomplishments of the first ten years of this century
These extremely effective programs have identified thousands of infants
and thereby prevented severe developmental delay
Treatments have been improved and refined since they were started just
over 60 years ago; exciting new treatments are on the horizon
There remains significant need to further refine the available programs so that
treatments can be more effective and much easier to deal with
not only from the patient’s standpoint, but also by those charged with
monitoring and treating this infants, children and adults
The next conference about PKU and its treatment, will probably be
needed much earlier than in 10 years, and will present many exciting new
programs and therapies
In Memoriam:
Richard Koch, MD
1921-2011
Følling Award
Recipient, 2009
Richard Koch
Newborn Screening for Genetic Disease in
the United States
•
Routine newborn screening has been carried out in all 50 states
since the 1970s; the programs have always been state
sponsored public health programs, arguably one of the most
successful ones
•
Conditions such as phenylketonuria, with simple, reliable
screening tests and proven treatment efficacy have been the
targets of testing
•
Over the years, congenital hypothyroidism and a handful of
other diseases were added on a state by state basis
•
As the programs grew and developed, there was extraordinary
variation from state to state and there was little systematic
evaluation of either the rationale for screening and/or the
outcomes of such screening
•
Over 4,300,000 infants are screened each year, making newborn
screening by far the most commonly performed genetic testing
in the United States
American College of Medical Genetics
Contract with HRSA on Newborn Screening
•
In 2001, the Maternal and Child Health Bureau, HRSA/HHS contracted
with ACMG to convene an expert group to evaluate the scientific and
medical information related to screening for specific conditions and to
make recommendations based on this evidence.
•
Widely representative group (physicians, scientists, consumers, state
laboratorians, lawyers, ethicists and others) worked over a two year
period to accomplish this goal, and their report was published in 2006.
•
The group of over 70 developed principals by which conditions were
to be evaluated, reviewed available published data, expert opinion and
other materials. The two major working groups were overseen by a
steering committee.
•
The developed material was then reviewed by an independent
newborn screening external review group
•
In addition to the expert group, outside input was actively solicited
Selection Criteria of Uniform Panel
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Incidence of condition
Identifiable at birth
Burden of disease
Availability of test
Test characteristics
Availability of treatment
Cost of treatment
Efficacy of treatment
Benefits of early intervention
Mortality prevention
Diagnostic confirmation
Acute management
Simplicity of therapy
Uniform Screening Panel
• 29 primary conditions
– 20 detected by MS/MS (AA, FAO, OA)
– 3 Hemoglobinopathies (S/S, S/βThal, S/C)
– 6 others (BIOT, CAH, CF, CH, GALT, HEAR)
• 25 secondary targets
– 22 detected by MS/MS (AA, FAO, OA)
– 1 Hb-pathy (many variants counted as one)
– 2 others (GAL-epimerase, GAL-kinase)
http://www.hrsa.gov/heritabledisorderscommittee/
Authorizing Legislation
• Title XXVI of the Children’s Health Act of 2000 enacts
three sections of the Public Health Service (PHS) Act:
– Established the Advisory Committee on Heritable
Disorders in Newborns and Children (Section 1111)
– Committee first met on June 7-8, 2004
– Although Committee charge is broad, to date
committee has focused efforts on newborn screening
What is Happening to Drive Such Interest
and Expansion in Newborn Screening?
•
Newborn screening has always been technologically driven,
beginning with the discovery of the ability to screen for
phenylalanine elevations using the dried blood spot and the
bacterial inhibition assay
•
There has been an enormous discovery and understanding of new
conditions, as well as the development of many therapies, some
of which must begin early in infancy to save lives
•
The development of MS/MS has been the single major force in our
expanded ability to detect serious conditions in the newborn
infant
•
In addition to NBS expansion being driven by developing
technology, the extraordinary efforts from advocacy groups has
caused a dramatic increase in the numbers of conditions for
which screening is performed
A Major Challenge to Newborn Screening
• The acrimonious public discussion about the fate of residual
dried blood spots, led by a small but vocal group, could lead to
restrictions which could seriously damage the newborn
screening program, one of our very best public health efforts
• A key effort to calm these issues is to inform the public about
the newborn screening programs, and exactly how the residual
blood spots are used, and about their great value
• The SACHDNC has had a working group focusing on this
subject for a long time, and has in press and article addressing
the many aspects of this subject:
Committee Report: Considerations and Recommendations for National Guidance
Regarding the Retention and Use of Residual Dried Blood Spot Specimens After Newborn
Screening. Genet. Med 2011, May 19 (Epub ahead of print)
The Life Cycle of Blood Spots
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Collection
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Primary testing
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Quality control, quality assurance
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Second tier testing
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Confirmatory testing
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Education
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Metabolic autopsy
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Test development
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IRB-approved research
New Important Opportunities in Newborn Screening
The recent addition of SCID to the recommended newborn screening panel
was the first DNA-based test, i.e. measurement of TRECS in dried blood
spots; pilot studies have gone very well
The rapid developments in the area of genomics will require extensive
research and discussion of newborn screening in the context of the genomic
era
The recent ACHDNC recommendation that pulse oximetry screening for
critical cyanotic congenital heart disease (awaiting a recommendation from
the Secretary) will add an important point of care test to the panel
Point of care screening has been discussed for such conditions as
galactosemia where early answers are vital
The continued development of the newborn screening transitional research
network will provide an excellent opportunity to better understand these rare
diseases and their treatment(s)