Heritable Illnesses of the Navajo:
Fallout of the American Indian Wars
of the 19th Century
I have no financial relationships to
disclose
Steve Holve, MD
Objectives
• Define the founder effect
• Recognize the historical factors that led to the
founder effect in the Navajo
• Identify heritable illnesses among the Navajo
“You can observe a lot by watching”
Yogi Berra
T Kuyper
325,000 Tribal Members
US Census 2010
Late Infantile Metachromatic
Leukodystrophy
• Term AGA infant
• Normal newborn growth and development
• Loss of developmental milestones noted at 18
months- actual regression of skills
• Seizures began at 24 months of age
Late Infantile Metachromatic
Leukodystrophy
•
•
•
•
30 months- Progressive neurologic degeneration
Increasing spastic quadriparesis.
By 36 months gastrostomy tube feeding required
Multiple hospitalizations for seizure control and
recurrent pneumonia
• Death due to aspiration pneumonia at age 6 years
Metachromatic leukodystrophy
• Autosomal recessive disorder of sphingolipid
metabolism
• Deficiency of lysosomal enzyme arylsulfatase A
• Absence of ARSA leads to accumulation of
sulfatides which causes progressive
demyelination
• Occurs worldwide in 1/40,000 births
• Why 8 MLD cases in Tuba City in 18 years?
Hmmm…..That’s Odd!
Founder Effect
• a gene rare in the general population occurs in a
small, isolated, rapidly expanding population
which leads to increased gene frequency and
increased frequency of the disease in that
population
Examples of the Founder effect
• Religion - The Hutterites and the Amish
• Ethnicity - French Canadians and Ashkenazi Jews
• Geography - island populations
Captured
The Long Walk
Fort Sumner Imprisonment 18641868
Population Movement and MLD
Ancestors
Conditions Favoring the Founder Effect
in the Navajo
• Population reduction during the Long Walk from
8,000 Navajo to 4,000
• Geographic Isolation of 1,000 Navajo who fled to
western reservation
• Subsequent rapid population increase
– Navajo population increased 60 fold in 6-7
generations vs. 8 fold for U.S. population
Unique Single Base Mutation in Navajo MLD
G to A transition in first nucleotide of intron 4 in ARSA gene
Population Bottleneck in the Western
Navajo
• No MLD seen in other Athabascan groups
• No MLD seen in Eastern Navajo
• New ARSA gene frequency of MLD in western
Navajo after 1868
• Estimated gene frequency of 1/25
• Estimated incidence of MLD 1/2500 births
Yupik with MLD
• Journal of Inherited Metabolic Disease
• 1995, Volume 18, Issue 3, pp 326-332
• Metachromatic leukodystrophy among southern
Alaskan Eskimos: molecular and genetic studies
M. Pastor-Soler, E. M. Schertz, M. A. Rafi, G. de
Gala, D. A. Wenger
• Same single base pair mutation as the Navajo
Possible MLD Connection of
Yupik and Navajo
• ARSA mutation in central Asia
• Admixture of Athabascan and Yupik in Alaska in
the past
• New equilibrium of gene frequencyin western
navajo after long walk as MLD not seen in other
Athabascan populations
• Founder effect for MLD in Yupiks
Everyone has 6-8 deleterious
autosomal recessive genes...
“Where are the other diseases?”
Anonymous but highly respected Southwest Geneticist
Diseases of the Founder Effect in the
Navajo
•
•
•
•
•
•
•
Metachromatic Leukodystrophy
Severe Combined Immunodeficiency Syndrome
Navajo Neurohepatopathy
Microvillous Inclusion Disease
Athabascan Brainstem Dysgenesis
Oculocutaneous Albinism Type 2
Navajo Poikiloderma
Severe Combined Immunodeficiency
(SCID)
•
•
•
•
•
T and B cell dysfunction
Low lymphocyte counts (ALC < 2,000)
Low mixed lymphocytic culture stimulation
Markedly low IgA, IgG and IgM
Absent thymus
SCID – Absent Thymus
The “Boy in the Bubble”
SCID clinical presentation
•
•
•
•
•
•
Mouth and genital ulcers in child< 6mos of age
Recurrent/refractory thrush
Chronic diarrhea
Failure to thrive
Recurrent or disseminated infection
Fatal before age one year if untreated
Oral and Genital Ulcers
Arch Dermatol. 1999;135(8):927-931 Cowan et al
SCID-A
• now known to also occur in 4 Apache tribes in the
Southwest
• unique single base pair change (A to C) in exon 8
of Artemis gene on chromosome 10p
• Unique base pair mutation in all Athabascan
patients consistent with a founder effect
Athabascan SCID Incidence
• Overall SCID worldwide incidence 1/100,000
• Initially, iIncidence in Navajo felt to be 1/10,000
births (Jones et al in 1991
• Data from 1985 to present suggests about 1/2,000
live births (Dr. Diana Hu, very personal communication)
• Is rate increasing? Detection better?
Navajo Infant Mortality Rates
100
80
60
Navajo
40
US white
20
Calendar Year
19
99
19
94
19
89
19
85
19
81
19
77
19
73
0
19
54
Rae per 1,000 live births
Infant Mortality Rate
Microvillous Inclusion Disease
Microvillous Inclusion Disease
•
•
•
•
Intractable Secretory Diarrhea
Intestinal Villus Atrophy
Microvilli as intracytoplasmic inclusions
Unique shared single base pair mutation of
MYO5B in all Navajo children
Microvillous Inclusion Disease
• Mutations in myosin Vb found in 10 patients with MVID
• Five Navajo patients all homozygous for a single base
pair mutation in exon 16 causing substitution of leucine
for proline
• Parents all heterozygote for this mutation
• Speculation that is area is critical for folding of protein
AJMG: 146A, 2008
Microvillous Inclusion Disease
• First case on Navajo diagnosed in 1990
• Likely prior cases died and signed out as neonatal
sepsis or severe diarrhea and dehydration
• Worldwide incidence of 1/1,000,000
• Western Navajo incidence of 1/2,000
Navajo Infant Mortality Rates
100
80
60
Navajo
40
US white
20
Calendar Year
19
99
19
94
19
89
19
85
19
81
19
77
19
73
0
19
54
Rae per 1,000 live births
Infant Mortality Rate
Navajo Neurohepatopathy (NNH)
• First described in 1967 by Appenzeller and
Snyder
• Found in Navajo on the western Reservation
• Initial controversy as to etiology: uranium and
heavy metal exposure vs heritable illness
NNH Diagnostic Criteria
• Clinical presentation
–
–
–
–
–
–
Sensory Neuropathy
Motor Neuropathy
Corneal Anesthesia
Liver Disease
Metabolic or infectious disease derangement
CNS demyelination on radiologic imaging
• 4/6 or 3/6 and sibling with NN
Corneal Ulceration secondary to
loss of sensation
Claw Hand Deformity secondary to
motor neuropathy
Liver Disease in NNH
•
•
•
•
•
neonatal hepatitis
fulminant liver failure in childhood
cirrhosis
hepatocellular carcinoma
common feature - elevated GGT
Ratio of Mitochondrial/Nuclear DNA
Hepatology (2001)34(1)119
MtDNA Depletion Syndromes
and MPV 17
• Sequenced genes associated with Mt DNA
depletion Syndromes
• Mitochondrial inner membrane protein
• Found in chromosome 2p21-23
• Absence or malfunction causes OXPHOS failure
and mitochondrial depletion
• Mutations found in 3 families (Italy, Canada and
Morocco) with hepatocerebral mtDNA depletion
syndromes clinically similar to NNH
Spinazzola NatGenet 2April2006
Navajo Neurohepatopathy is caused by a
mutation in the MPV17 Gene
•
•
•
•
Homozygosity mapping linked to 2p24
Focused on MPV17 gene
Homozygous Exon 2 R50Q mutation
Same missense mutation found in all 6 NNH
patients confirming disease is likely due to
founder effect
Karadimas AJHG:79:2006
Athabascan Brainstem Dysgenesis
Homeobox A1 Deficiency
•
•
•
•
•
•
Horizontal Gaze Palsy
Central Hypoventilation
Sensorineural Deafness
Developmental Delay
Seizure Disorder
Cardiac Outflow Tract Anomalies
Horizontal Gaze Palsy
Horizontal Gaze Palsy
Athabascan Brainstem Dysgenesis
• Similar syndrome reported in Turkish and Saudi
children
• First non-lethal homeobox protein mutation found
in humans
• All Navajo patients share a unique single base
pair mutation c/w founder effect
• Different base pair mutation found in Saudi and
Turkish children
Oculocutaneous Albinism
Oculocutaneous Albinism Type 2
• skin and hair hypopigmentation
• visual impairment
• 122.5 kb deletion in the p gene unique to Navajos
OCA 2 and the Founder Effect
• No benefit to albinism in the sunny west
• No known heterozygote benefit
• Temporary increase in gene frequency due to a
founder effect
Navajo Poikiloderma
Navajo Poikiloderma
•
•
•
•
Immune Deficient
Cyclical neutropenia
Decreased neutrophil killing power
Recurrent sinusitis, pneumonia and eventually
bronchiectasis
• Develops hypo and hyperpigmented areas and
telangiectasisas
Heritable Diseases- Incidence
MLD
SCID-A
Western Navajo U.S.
1:3000
1:40,000
1:2000
1:100,000
MVID
OCA-2
Nav Neuropathy
Brainstem Dys
Nav Poikilo
1:2000
1:2000
1:1600
1:2600
?
1:1,000,000
1:36,000
-------------
Genetic Bottlenecks
• Bottleneck in migration to Southwest associated
with SCID and Hox A1 and Navajo Poikiloderma
These illnesses are seen in Navajo and Apache
• Bottleneck of Long walk associated with OCA-2,
MLD, NNH and MVID. These illnesses are seen
only in the Navajo and especially on the western
side of the Navajo Nation
WHO Criteria Screening
•
•
•
•
•
Condition an important health problem
Cost of case finding reasonable
Recognizable in latent phase
Effective treatment available
Acceptable to population tested
Genetic Screening in the Navajo
• SCID-A
– Early identification clearly changes outcome
– culturally acceptable- Navajo IRB approved newborn
screening study
– technologically possible
– T cell receptor excision circles (TREC) on dried blood
spots; absent TREC suggests T-cell dysfunction
– Affordable
Single Gene Examples of the Founder
Effect
• Cystic Fibrosis in the Zuni
• Congenital Adrenal Hyperplasia in the Yupik
Eskimo
• Glutaric aciduria type I in the Cree
• Scleroderma in the Oklahoma Chocktaw
Founder Effects in Global Health
• As infant mortality falls in low resource countries
it is likely that other rare heritable illnesses may
become more noticeable
• WHO screening criteria can be applied to
determine what interventions, if any, should be
put in place
Thanks to…
•
•
•
•
•
•
•
Morton Cowan/Lanying Li- UCSF
Anthony Hayward/Ron Sokol- Univ. of Colo.
David Wenger- Thomas Jefferson Univ.
Russ Snyder/Otto Appenzeller/Carol Clericuzio-UNM
Irwin Arias- Tufts/NIH
Tuan Vu- Cornell
Chris Cunniff/Bob Erickson- Univ. of Az.