Transcript CPT-1 Update - Alaska Dietetic Association

Sugar in the Arctic:
The Arctic Variant of CPT1A
and Congenital Sucrase Isomaltase
Deficiency
Matthew Hirschfeld, MD/PhD
Maternal Child Health
Alaska Native Medical Center
Anchorage, AK
Background
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CPT1 = carnitine palmitoyltransferase
type 1
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Expressed in fibroblasts, liver, brain, skin,
skeletal muscle, kidney
CPT1A = liver isoform of CPT1
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All reported cases of human deficiency of
CPT1 are due to defect in the CPT1A isoform
Does not affect muscle, heart, brain, etc.
CPT1A
Function
• Responsible for the 1
st
and rate-limiting
step in mitochondrial fatty acid oxidation
• Located in the outer (cytosolic)
membrane of the mitochondrion
A Closer Look
Symptoms of “Classic”
CPT1A Deficiency
• Occur after prolonged fast, when
glucose and glycogen stores become
depleted
• Presents with hypoketotic
hypoglycemia, fatigue, vomiting, liver
dysfunction, and seizures
History of “Classic”
CPT1A Deficiency
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Deficiency is severe
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Less than 5% of enzyme activity
Deficiency is rare
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2004 review reported 30 cases worldwide
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First cases in Alaska diagnosed in 2004—confirmed by
skin biopsy (only method of confirming CPT1A deficiency
at the time)
Found when Alaska changed to MS/MS to perform their
newborn metabolic screens (NBMS)
Doubled the world’s cases in the first year of screening
Expanded NBMS
• Before 2004 in Alaska
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Hypothyroid
PKU
Galactosemia
MSUD
Biotinidase
CAH
Expanded NBMS
• Utilizes tandem mass spectrometry
(MS/MS) to screen for many more
diseases than before
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Currently, Alaska screens for about 50 diseases
Expanded NBMS
• After 2004
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Added amino acid and urea cycle disorders
Organic acid disorders
CF
Hemoglobinopathies
Fatty Acid Oxidation Disorders
Fatty Acid Oxidation
Disorders—NBMS
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VLCADD
SCADD
CPT1
MCADD
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One of the major drivers for expanded screening (Medium Chain
Acyl CoA Dehydrogenase Deficiency)
Fatty acid metabolism disorder that has been linked to increased
infant mortality—SIDS
The Arctic Variant
• A missense mutation (P479L) found in all
affected Alaska Native people
• Same mutation found in Canadian and Greenland
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Inuit populations, Siberian arctic populations, and in
British Columbia First Nations populations
Skin biopsy results showed that this mutation gives
20% enzyme activity
The Arctic Variant
Regulation
•P479L occurs in a region of CPT1
responsible for regulation of activity
• CPT1A is inhibited by malonyl CoA
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Malonyl CoA increases when carbohydrates are ingested
Mutation causes protein to always be “on” by not allowing
malonyl CoA to bind
Newborn Screening
• NBMS has now detected about 900
cases in Alaska since 2004
• However, we know we’re detecting the
minority of cases—about 15%
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There are actually 750 infants with the
P479L variant born per year in Alaska
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Can’t set the C0/C16+C18 ratio to detect all
cases without large number of false
positives—more later
Distribution
Percent of Native Alaskan
Newborns who are CPT1A
c.1436C>T Homozygotes
60-70%
50-59%
30-39%
20-29%
Questions Surrounding the
Arctic Variant of CPT1A
• All of the infants who had a skin biopsy had 20%
residual activity—is this enough activity to eliminate
symptoms?
• Why does this variant have such high prevalence in
Arctic populations?
• Could the Arctic variant be a contributing factor to the
higher rate of SIDS in the rural villages in
Northern/Southwest Alaska?
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Project
5 families with a child between the ages of 3-5 years
with the Arctic Variant of CPT1A flown to
Doernbecher Children’s Hospital for an 18 hour
fasting study
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Labs at 6, 12, 18 hours drawn: Chem7, insulin,
acylcarnitines, free fatty acids, lactate, pyruvate,
ketones (acetoacetate and 3-hydroxybutyrate)
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Hourly serum glucose starting at 6 hours of
fasting
MRS done to determine if fatty deposits occur in
liver
Fasting Project
Continued
• 2 of the 5 kids became symptomatic with
plasma glucose below 51
• One went below 40
• Ketones were not produced at any stage
of the fast in any kid
• Suggests that fatty acid oxidation is
fairly severely affected by the Arctic
Variant
Fasting Project
Continued
• Their livers were imaged using
magnetic resonance spectroscopy. The
hypothesis was that these kids will have
fatty livers compared to controls
because of their inability to metabolize
fats efficiently—like classic CPT1A
deficiency
• Actually, completely normal livers
Conclusions
• Even healthy 5 year olds with the Arctic
Variant of CPT1 can’t utilize fats
effectively and can become symptomatic
if fasting is prolonged
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In children who are sick, the symptoms would
occur faster and would be more severe
Questions Surrounding the
Arctic Variant of CPT1A
• All of the infants who had a skin biopsy had 10-25%
residual activity—is this enough activity to eliminate
symptoms?
• Why does this variant have such high prevalence in
Arctic populations?
• Could the Arctic variant be a contributing factor to the
higher rate of SIDS in the rural villages in
Northern/Southwest Alaska?
Traditional Diet
Permanent Ketosis
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Arctic populations traditionally eat a diet of 80%
fat, 15% protein, and less than 5%
carbohydrate (mostly from muscle glycogen)
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Essentially a ketogenic diet, and their bodies get used to
functioning without much glucose
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Fatty-acid oxidation generates ketones to be used for energy
Spares the small amount of glucose present for the brain
Ketogenic Diet When
Ketogenesis Is Not Working Well?
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The Arctic variant of CPT-1A might be
advantageous to people observing a traditional
diet because of its insensitivity to malonyl-CoA
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If a ketogenic diet has to be interrupted due to
lack of fatty foods, the sudden disruption
causes severe weakness, nausea, and
headaches
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Overcome by eating more carbohydrates,
which are not readily available in the Arctic
Ketogenic Diet When
Ketogenesis Is Not Working Well?
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Non ketogenic diet most common at the end of
winter, when low-fat meat is consumed--more muscle
glycogen
If the Arctic variant of CPT1A is not inhibited by
malonyl CoA with carbohydrate ingestion, then
ketogenesis would tend to continue, and the malaise
would occur less frequently and less severely
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Could allow for increased survival in a unforgiving
environment
Also
• Marine mammals have high levels of n-3
polyenoic fatty acids, which increases
the transcription of the CPT1A gene
• These fatty acids are passed into
breast milk
• May off-set the 80% drop in activity
Possible New Study
• Compare people with the Arctic Variant
who have a traditional diet vs. a more
Western diet and compare symptoms,
labs, and fasting ability.
Questions Surrounding the
Arctic Variant of CPT1A
• All of the infants who had a skin biopsy had 10-25%
residual activity—is this enough activity to eliminate
symptoms?
• Why does this variant have such high prevalence in
Arctic populations?
• Could the Arctic variant be a contributing factor to the
higher rate of SIDS in the rural villages in
Northern/Southwest Alaska?
CPT1A and SIDS
Infant mortality rates (IMR) 1992-2004
Region
# Deaths
IMR
Northern
Southwest
Anchorage Bowl
Gulf Coast
Interior
Southeast
83
123
425
84
140
79
12.1*
10.8*
6.3
6.2
6.2
6.2
Distribution
Percent of Native Alaskan
Newborns who are CPT1A
c.1436C>T Homozygotes
60-70%
50-59%
30-39%
20-29%
Phenotype of the
Arctic Variant
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Looked at all Alaska Native infant deaths from
2006-2010
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110 deaths
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46 homozygous for the Arctic Variant
Case control study comparing to 395 Alaska Native controls from
the same time period
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119 were homozygous for the Arctic Variant
Comparison of Arctic
Variant to Controls
CPT1A homozygous among
cases
CPT1A homozygous among
controls
Odds ratio (95% CI)
Adjusted* odds ratio (95%
CI)
All study subjects
46 of 110 (42%)
119 of 395 (30%)
1.7 (1.1, 2.6)
1.8 (1.1, 2.9)
Limited to homozygous
variant and heterozygous
cases
46 of 79 (58%)
119 of 269 (44%)
1.8 (1.1, 2.9)
2.3 (1.3, 4.0)
Limited to residents of
Western and Northern
Alaska
38 of 58 (66%)
112 of 185 (51%)
1.8 (0.98, 3.3)
2.5 (1.3, 5.0)
All study subjects
39 of 94 (41%)
112 of 377 (30%)
1.7 (1.1, 2.7)
1.8 (1.1, 2.9)
Limited to homozygous
variant and heterozygous
cases
39 of 69 (56%)
112 of 258 (43%)
1.7 (0.99, 2.9)
2.2 (1.2, 3.9)
Limited to residents of
Western and Northern
Alaska
33 of 48 (69%)
88 of 154 (51%)
2.2 (1.1, 4.2)
3.0 (1.4, 6.3)
All birth weights
Normal birth weights
*Adjusted for maternal education, a composite variable combining marital status and presence of the father’s name on the birth certificate, and maternal prenatal alcohol and tobacco use.
Comparison of the
Causes of Infant Mortality
Cause of death
Homozygous variant
(n=46)
Heterozygous or homozygous wildtype
(n=66)
OR (95%CI)
SIDS or asphyxia of unknown etiology
14
32
0.50 (0.22 to 1.1)
Infectious disease
12
7
2.9 (1.0, 8.0)
Congenital anomaly
8
12
0.91 (0.34, 2.4)
Injury
5
6
1.2 (0.38, 3.6)
Phenotype of the
Arctic Variant
• Other findings in babies homozygous for
the Arctic Variant
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More likely to have been diagnosed with an
infectious disease before the clinical illness leading
to their death
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Pneumonia was the strongest association
More likely to have been hospitalized before
their death
Conclusions
• Looks like the presence of the Arctic
Variant of CPT1A could be the reason
for the difference in infant mortality
between Northern/SW Alaska the rest of
the State
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The Arctic Variant doesn’t cause death, but
contributes when the baby has an infectious issue
Not associated with SIDS, as originally
hypothesized
Next Steps
• Is education enough?
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No!
• Do we need to identify all of these kids,
given the data relating the Arctic Variant
to infant mortality?
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Yes!
Change the NBMS
• If we lower the cutoff value for the
NBMS, we will pick up many more kids
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But also a lot of false positives
• Instead, we’re going to be using PCR on
all NBMS cards to truly identify all kids
with the Arctic Variant
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The Oregon Public Health Lab and State of Alaska
are looking at the logistics
Recommendations for
Parents
• Symptoms include:
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Poor feeding
Lethargy
Jitteriness
Seizures
Inconsolability
Other symptoms of low blood sugar…..
Recommendations
for Parents
• Until the NBMS is 100% sensitive, all
babies from Western and Northern
Alaska should be considered to be
positive for the Arctic Variant
• Most babies never have any issues with
the Arctic Variant of CPT1A
• Well babies almost NEVER have
issues
Recommendations for
Parents
• If your baby is sick, your baby shouldn’t
go more than 6-8 hours without being
able to drink breast milk, formula, or
Pedialyte
• If your baby is going to have surgery,
you should tell the doctor that your baby
has the Arctic Variant of CPT1A
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People with Artic Variant shouldn’t be fasted for long
periods of time
Other Effects
• In Greenland Inuit people, homozygotes
for the Arctic variant have higher levels
of HDL
• Unknown if this affects
cardiovascular disease
Unknown
• Does the Arctic variant of CPT1A play a
role in other adult disease?
• Diabetes
Resources
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You Tube video—sent by the State to all families with a child diagnosed
by NBMS
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Handout—very detailed
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http://www.newbornscreening.info/Parents/fattyaciddisorders/CPT1A
V.html
Alaska Dispatch News article
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https://www.youtube.com/watch?v=g-JRZ7PO3yk&feature=youtu.be
http://www.adn.com/article/20141129/clues-emerging-about-arcticgene-diet-and-health
American Indian Living with Dr. David DeRose
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http://stream.publicbroadcasting.net/production/mp3/nv1/local-nv11039242.mp3
But Wait…..
Congenital Sucrase Isomaltase
Deficiency (CSID)
• Sucrase Isomaltase enzyme complex is
missing from small intestine
• Can’t break down sucrose into fructose
and lactose
• Can’t break starch down completely
due to decreased isomaltase activity
CSID
• Autosomal recessive
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Frameshift mutation that causes absence of enzyme
Can now send a blood test to the University of
Washington to test for the Alaska Native-specific
mutation
• Results in osmotic diarrhea when
weaned from breast milk/formula, or
table foods are introduced
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Has a varied phenotype, ranging from severe diarrhea
with FTT to more of an irritable bowel syndrome
picture
More CSID
• Prevalence
• 0.2% of the general population
• 5-10% of Greenland/Canadian Inuit
people
• Unknown at this time in Alaska Native
people—but we’re finding out it’s
probably similar to the
Greenland/Canadian Inuit people
CSID Treatment
• Diet control—Avoid foods with processed
sugar and foods high in sucrose and
starch
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Peas, beets, onions, pastas, breads, potatoes, honey
Alaska Native Traditional Diet is actually perfect for
CSID control
• In the absence of diet control, Sucraid
can be used
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Very expensive, and needs to be taken with every
meal and snack
Thanks—Arctic
Variant
CPT1A
Oregon Health & Sciences
University
Alaska Native Medical
Center
David Koeller
Melanie Gillingham
Bill Lambert
Cary Harding
Sarah Lowe
Terry Powell
Doug Eby
Samantha Maloney
All Pediatric Staff
State of Alaska DHSS
Thalia Wood
Stephanie Birch
Brad Gessner
University of Manitoba
Cheryl Greenberg
Fatty Acid Oxidation