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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
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 1864-1868
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 MLDG 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 UlcersArch 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
Infant Mortality Rate
0
20
40
60
80
100
1954
1973
1977
1981
1985
1989
1994
1999
Calendar Year
Ra
e p
er
1,0
00
liv
e b
irth
s
Navajo
US white
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
Infant Mortality Rate
0
20
40
60
80
100
1954
1973
1977
1981
1985
1989
1994
1999
Calendar Year
Ra
e p
er
1,0
00
liv
e b
irth
s
Navajo
US white
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 DysgenesisHomeobox 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- IncidenceWestern Navajo U.S.
MLD 1:3000 1:40,000SCID-A 1:2000 1:100,000
MVID 1:2000 1:1,000,000OCA-2 1:2000 1:36,000Nav Neuropathy 1:1600 -----Brainstem Dys 1:2600 -----Nav Poikilo ? -----
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.
