Shriberg

Genetic and Diagnostic Marker Research
in Childhood Apraxia of Speech
Lawrence D. Shriberg
Waisman Center
University of Wisconsin-Madison
Program Committee Session:
Link Between Theory and Practice
American Speech-Language-Hearing Association
National Convention, San Diego, CA
November 18, 2011
Acknowledgments
Waisman Center Phonology Project
University of Wisconsin-Madison
Collaborators
Marios Fourakis
Jane McSweeny
Leonard Abbeduto
Kathy Jakielski
Sheryl Hall
Alison Scheer-Cohen
Kirrie Ballard
Barbara Lewis
Heather Karlsson
Sonja Tatro
Adriane Baylis
Christopher Moore
Joan Kwiatkowski
Christie Tilkens
Stephen Camarata
Rhea Paul
Heather Lohmeier
David Wilson
Thomas Campbell
Nancy Potter
Kathy Chapman
Sharynne McCleod
Biostatistics and Genomics
Peter Flipsen, Jr.
Angela Morgan
Roger Brown
Gordana Raca
Morton Gernsbacher
Edythe Strand
David Dimmock
Gregory Rice
Hill Goldsmith
Bruce Tomblin
Craig Jackson
Shelley Smith
Jordan Green
Erin Wilson
Jennifer Laffin
Elizabeth Worthey
This research is supported by the National Institute on Deafness and Other Communication Disorders [DC00496], an
American Recovery and Reinvestment Act Supplement Grant, and a core grant to the Waisman Center from the National
Institute of Child Health and Development [HD03352].
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings in Speech Delay
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
Diagnosis: Childhood Apraxia of Speech
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings in Speech Delay
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
Speech Disorders Classification System (SDCS)
Genetic and Environmental
Risk and Protective Factors
I. Etiological Processes
(Distal Causes)
Neurodevelopmental Substrates
II. Speech Processes
(Proximal Causes)
Encoding/Memory
*Transcoding
**Execution
(Representational)
(Planning/Programming)
(Neuromotor)
III. Clinical Typology
Speech Errors
(SE)
Speech Delay
(SD)
Speech
DelayGenetic
(SD-GEN)
**Motor Speech
(SE-/r/)
*Motor Speech
DisorderApraxia
Of Speech
(MSD-AOS)
(MSD-DYS)
Motor Speech
DisorderNot Otherwise
Specified
(MSD-NOS)
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
-- -- -- -- ------
Speech DelayDevelopmental
Psychosocial
Involvement
(SD-DPI)
Speech Errors /s/
Speech Errors /r/
(SE-/s/)
--- --- --- --- ---
-- -- -- -- ------
--- --- --- --- ---
-- -- -- -- ------
Speech DelayOtits Media
With Effusion
(SD-OME)
Motor Speech Disorder
(MSD)
DisorderDysarthria
IV. Diagnostic Markers
--- --- --- --- ---
V. Phenotypes
--- --- --- --- ---
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings in Speech Delay
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
Regions of Interest
and Candidate Genes for Speech Delaya
Chromosome
Candidate Gene
Group
1
1p34-36
DYX8
Pennington
3
3p12-q13
ROBO1 (DYX5)
Lewis
6
6p22-p21
DCDC2, KIAA0319
Pennington;
Rice
15q21
DYX1C1 (EKN1)
Pennington
15
aBased
ROI
on genetic research in verbal trait disorders (speech, language, reading)
Recent Genetic Findings for
Speech Sound Disorders (SSD)a,b
Chromosome
Gene
3
ROBO2
11
BDNF
15
DYX1C1
a
Endophenotype c
Nonsense
Multisyllabic
Words
Words
X
X
Phenotype
SSD
X
X
X
X
X
Lewis et al. (2011)
Speech Sound Disorders (SSD) includes Speech Delay (SD) and possible motor speech disorders
c
X = Significant p value
b
Summary of Molecular Genetic Findings
in Speech Sound Disorders

To date, Regions of Interest (ROIs) and/or
candidate genes for Speech Sound Disorders
have been reported for 5 of the 22 autosomes:
1, 3, 6, 11,15.

Two of the five genes have been associated
with a binary phenotype (Speech Sound
Disorders) that includes both Speech Delay
and possibly motor speech disorder.
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings in Speech Delay
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
Complex Neurodevelopmental Disorders
Reporting ‘Significant’ Speech Delay/CAS










Autism
Chromosome Translocations
Down syndrome (Trisomy 21)
Rolandic Epilepsy
Fragile X syndrome (FMR1)
Joubert syndrome (CEP290; AHI1)
Galactosemia
Rett syndrome (MeCP2)
Russell-Silver syndrome (FOXP2)
Velocardiofacial syndrome (22q11.2 deletion)
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
III.
Collaborative Genetics Research
The Iconic Pedigree
FOXP2: KE Family Studiesa
Genotype:
Half the family members in each generation have a
point mutation in FOXP2 (7q31)
Biomarker:
None to date
Endophenotype: Affected members had low scores on a nonword
repetition task
Phenotype:
Affected members received services for a severe
speech sound disorder consistent with CAS
Affected members had low scores on a task
assessing oral motor movements
Other:
a
Many affected members had low verbal and performance IQs,
language impairments, other involvements
Over two decades of continuous research. Detailed summaries of findings available
in many sources.
FOXP2 and CAS in Four Other Families

MacDermot et al. (2005) reported that of 49 probands in
Europe, Australia, or the United States with reported apraxia
of speech who were screened for FOXP2 mutations, 1
proband (i.e., approximately 2% attributable risk), his affected
sister and their mother had a heterozygous nonsense
mutation in FOXP2.
 The
4-year-old boy had a developmental delay in speech,
language, and social skills. He communicated mainly using
single words and was unable to repeat multisyllabic words.
 His
20-month-old sister had a history of motor and
oropharyngeal dyspraxia, was unable to speak any words,
could not identify objects, and had poor vocalization.
 His
mother reported a history of speech delay in childhood
and showed severe problems in communication, with poor
speech clarity and simple grammatical constructions.
FOXP2 and CAS in Four Other Families

Zeesman et al. (2006) reported a 5-year-old girl with an
interstitial deletion of paternally-derived chromosome
7q31.2-q32.2 encompassing the FOXP2 gene.
 This girl has a severe communication disorder with
evidence of oromotor dyspraxia and mild developmental
delay. She was unable to cough, sneeze, or laugh
spontaneously.
 This child also has dysmorphic features, including
microcephaly, brachycephaly, small nose, long philtrum,
and down-turned corners of the mouth. These features
are similar to those for the child described in Sarda et
al. (1988) and the child “CS” reported in Lai et al. (2000)
who had a translocation disrupting FOXP2.
FOXP2 and CAS in Four Other Families

Shriberg et al. (2006) reported a de novo balanced 7;13
translocation in a 50-year old mother and her 19-year-old
daughter
 Mother and daughter have been treated for apraxia of speech
since early childhood
 Mother and daughter have a broad range of mild cognitive
impairments and severe speech and language deficits similar
to those reported for affected members of the KE family
 Mother and daughter have speech profiles consistent with both
apraxia and spastic dysarthria.
FOXP2 and CAS in Four Other Families

Rice et al. (in press) report a de novo deletion of
FOXP2 in a 24-year-old mother and her 4-year-old son.
 Mother and son treated for apraxia of speech since early
childhood
 Mother and son have cognitive impairments and severe
speech and language deficits similar to those reported
for affected members of the KE family and to those
reported for a mother and daughter with a de novo
balanced 7;13 translocation affecting FOXP2
(Shriberg et al., 2006)
 Mother’s speech profile is consistent with both
apraxia and spastic dysarthria; son severe apraxia
 Son does not cough or laugh spontaneously
Genetic Research in CAS
 FOXP2
 Studies reporting Speech Delay (Zhao et al., 2010)
 Studies of downstream genes (Roll et al., 2010)
 Studies with animal models (birds, mammals)
 FOXP1
 Carr et al. (2010); Hamdan et al. (2010)
 Horn et al. (2010); Pariani (2009)
 FOXG1
 Brunetti-Pierri et al. (2011)
 ELP4
 Pal et al. (2010)
 RAI1
 Kogan et al. (2009)
 Some recent literature reviews:
 Bishop (2009); Fisher & Scharff (2009); Grigorenko (2009);
Ramus & Fisher (2009); Vernes & Fisher (2009); Lewis (2010);
Newbury & Monaco (2010); Newbury, Fisher, & Monaco (2010);
Shriberg (2010)
Topics
I.
Speech Sound Disorders (SSD)
A. Multicausal Perspective
B. Genetic Findings in Speech Delay
II.
Childhood Apraxia of Speech (CAS)
A. Neurogenetic Perspective
B. Genetic Findings
C. Diagnostic Findings
Design
Research in Speech Sound Disorders
Speech Sound Disorders
(SSD)
Clinical
Typology:
Speech
DelayGenetic
(SD-GEN)
Speech
Processes:
Diagnostic
Markers:
Speech Delay
(SD)
Speech DelayOtits Media
With Effusion
(SD-OME)
Speech DelayDevelopmental
Psychosocial
Involvement
(SD-DPI)
Speech Errors
(SE)
Speech Errors /s/
Speech Errors /r/
(SE-/s/)
(SE-/r/)
Motor Speech Disorder
(MSD)
Motor Speech
Disorder
ApraxiaOf Speech
(MSD-AOS)
Motor Speech
DisorderDysarthria
(MSD-DYS)
Encoding/Memory
Transcoding
Execution
(Representational)
(Planning/Programming)
(Neuromotor)
Motor Speech
DisorderNot Otherwise
Specified
(MSD-NOS)
Current Diagnostic Markers and
Classification Criteria for CASa
“For a judgment of the presence of CAS, the child had to exhibit
vowel distortions and at least 3 of the following 10 characteristics
in at least 3 of the tasks:










difficulty achieving initial articulatory configurations or
transitionary movement gestures
equal stress or lexical stress errors
distorted substitutions
syllable segregation
groping
intrusive schwa
voicing errors
slow rate
slow DDK
increased difficulty with multisyllabic words”
a Shriberg,
L.D., Potter, N.L., & Strand, E.A (2011).
Speech Disorders Classification System (SDCS)
Candidate Diagnostic
Markers for Eight
Subtypes of SSDa
Componentsb
Organized
Ten Linguistic Domains Analytics (TLDA)
Competence, Precision, Stability Analytics (CPSA)
Operationalized
Madison Speech Assessment Protocol (MSAP)
Procedures for transcription, prosody-voice analyses,
and acoustic analyses
Standardized
Reference Database (200 typical speakers, 3 to 80
years old)
a
Candidate markers selected from pediatric and adult literature in speech sound
disorders of known and unknown origin.
b
All components processed in the PEPPER software environment.
Ten Linguistic Domains Analytic (TLDA)
for Speech Sound Disorders (SSD)
TLDA
Speech Delay
SD-GEN SD-OME
Segmental
1. Vowels
2. Consonants
3. Vowels and
Consonants
Suprasegmental
Prosody
4. Phrasing
5. Rate
6. Stress
Voice
7. Loudness
8. Pitch
9. Laryngeal
Quality
10. Resonance
Quality
SD-DPI
Motor Speech Disorders
MSD-NOS
MSD-AOS
MSD-DYS
Madison Speech Assessment Protocol:
Three Analytic Constructs
Competence
(Normative;
Mastery)
Precision
Stability
(Spatiotemporal
Accuracy)
(Spatiotemporal
Consistency)
Speech Disorders Classification System (SDCS)
Candidate Diagnostic
Markers for Eight
Subtypes of SSDa
Componentsb
Organized
Ten Linguistic Domains Analytics (TLDA)
Competence, Precision, Stability Analytics (CPSA)
Operationalized
Madison Speech Assessment Protocol (MSAP)
Procedures for transcription, prosody-voice analyses,
and acoustic analyses
Standardized
Reference Database (200 typical speakers, 3 to 80
years old)
a
Candidate markers selected from pediatric and adult literature in speech sound
disorders of known and unknown origin.
b
All components processed in the PEPPER software environment.
Madison Speech Assessment Protocol:
Speech, Prosody, and Voice Tasks
Four age-based protocols:
Preschool, school-aged, adolescent, adult
Each protocol includes 15 tasks; about 1 hour to administer

Articulation Task

DDK Task

Challenging Word Tasks (3)

Phonation Tasks (2)

Challenging Phrase Task

Stress Tasks (2)

Consonant Task

Vowel Tasks (3)

Conversational Sample
Madison Speech Assessment Protocol:
Data Reduction
PEPPER Environment
Perceptual
Narrow phonetic transcription
Prosody-Voice Screening Profile
Acoustic
TF32-Active X
Automated; high throughput
Speech Disorders Classification System (SDCS)
Candidate Diagnostic
Markers for Eight
Subtypes of SSDa
Componentsb
Organized
Ten Linguistic Domains Analytics (TLDA)
Competence, Precision, Stability Analytics (CPSA)
Operationalized
Madison Speech Assessment Protocol (MSAP)
Procedures for transcription, prosody-voice analyses,
and acoustic analyses
Standardized
Reference Database (200 typical speakers, 3 to 80
years old)
a
Candidate markers selected from pediatric and adult literature in speech sound
disorders of known and unknown origin.
b
All components processed in the PEPPER software environment.
Procedures to Code Participants as “Positive”
for a Sign Using Reference Databases
 Z-scores
are derived from participants’ raw
scores on each continuous Competence,
Precision, and Stability index using age-gender
subgroups in the reference databases of
typically developing speakers.
 Z-scores
> 1.0 in conceptually designated
direction meet criterion for ‘Positive’ (i.e.,
affected).
Promising Diagnostic Signs for Motor
Speech Disorder – Apraxia of Speech (MSD-AOS)a
Segmental
Precision
Stability
Vowels/Diphthongs
Reduced Vowel Space
Reduced Vowel Substitution
Coefficients
Increased Distorted Vowel
Substitutions
Less Precise Diphthongs
Less Stable F1
Less Stable Vowel Duration
Consonants
Increased % of /j/ Deletions in
Clusters
Less Stable Sibilant Centroids
Reduced SRT Transcoding Scores
Suprasegmental
Phrasing
Increased % of Pauses
Increased % of Inappropriate
Pauses
Rate
Slower Speaking Rate
Slower Articulation Rate
Resonance Quality
Lowered F2: High Vowels
(Nasopharyngeal)
a
Bolded signs use acoustic methods
Less Stable F2: High Vowels
(Nasopharyngeal)
cr
20
10
0
ss
St
ab
D
ur
at
io
n
e
F1
ac
le
Sp
ab
we
l
St
we
l
Vo
Vo
ed
le
uc
ss
of Participants Positive for Marker
90
Le
R
ed
Le
ea
Percentage
In se
ap d
pr P e
op rc
ria en
t e t ag
Pa e
us o f
Sl
es
ow
er
Ar
t ic
ul
at
io
n
R
at
Sl
e
ow
er
Sp
ea
ki
ng
Lo
R
at
we
e
re
d
F2
:H
ig
h
Vo
we
ls
In
Seven Candidate Diagnostic Markers
of Apraxia of Speech
100
AOS (n = 47-53)
SD (n = 22-24)
80
70
60
50
40
30
Per Participant Percentage of Positive Signs (7) of AOS
Participants with Speech Delay Compared to
Participants with Apraxia of Speech
Speech Delay
(n=22; ages 3-6 yrs)
Control Group
CAS_Idiopathic
(n=26; ages 3-19 yrs)
CAS_Neurogenetic
(n=20; ages 5-50 yrs)
Apraxia of Speech
AOS (Neurologic)
(n=7; ages 45-84 yrs)
Per Participant Percentage of Positive Signs (7) of AOS
Participants with Speech Delay Compared to
Participants with Apraxia of Speech
Speech Delay
(n=22; ages 3-6 yrs)
Control Group
CAS_Idiopathic
(n=21; ages 3-19 yrs)
CAS_Neurogenetic
(n=20; ages 5-50 yrs)
Apraxia of Speech
AOS (Neurologic)
(n=7; ages 45-84 yrs)
Per Participant Percentage of Positive Signs (7) of AOS
Participants with Speech Delay Compared to
Participants with Apraxia of Speech
Speech Delay
(n=22; ages 3-6 yrs)
Control Group
CAS_Idiopathic
(n=21; ages 3-19 yrs)
CAS_Neurogenetic
(n=19; ages 5-50 yrs)
Apraxia of Speech
AOS (Neurologic)
(n=7; ages 45-84 yrs)
Per Participant Percentage of Positive Signs (7) of AOS
Participants with Apraxia of Speech
Compared to Participants with Speech Delay
90.5%
Sensitivity
MSD-NOS?
100.0%
Sensitivity
94.7%
Sensitivity
Sensitivity for
Combined AOS
groups = 93.6%
77.3%
Specificity
Speech Delay
(n=22; ages 3-6 yrs)
Control Group
CAS_Idiopathic
(n=21; ages 3-19 yrs)
CAS_Neurogenetic
(n=19; ages 5-50 yrs)
Apraxia of Speech
AOS (Neurologic)
(n=7; ages 45-84 yrs)
Our Most Accurate ‘Checklist’ Criterion
to Date to Phenotype a Speaker as
Positive for Apraxia of Speech

Checklist Criterion:
Positive (affected) on any 4 or more of 7 signs of
apraxia of speech

Findings to date for 69 qualified participants:
22 Speech Delay; 47 apraxia of speech





Sensitivity
Specificity
Positive Likelihood Ratio
Negative Likelihood Ratio
Odds Ratio
93.6%
77.3%
4.1
.08
50.7
Some Information on the Seven Most
Discriminative Signs of MSD-AOS to Date

Signs assess Vowels, Phrasing, Rate, and Resonance

Specificity is the primary challenge because young children
with Speech Delay are also less precise and less stable
than age-matched typical speakers

There currently is no one sign of AOS with sufficient
diagnostic accuracy. As database expansions permit, the
most discriminative signs of AOS are expected to vary by
age, cognitive status, language status, speech severity,
and causal context (i.e., idiopathic, neurogenetic,
neurologic)
Challenges in Diagnostic Assessment
of CAS Using the MSAP

Validity and reliability require a certain level of
knowledge and skills in narrow phonetic
transcription, prosody-voice coding, and acoustic
analyses

Biggest challenge to date is the large amount of
missing data on the speech tasks
 Participants can not or will not do the task
 Participants can do the task, but they make errors on
the non-target elements required for
assessment of targets e.g., for formant
measures of the vowel in a CVC word e.g., ‘bat’
Design
Research in Speech Sound Disorders
Speech Sound Disorders
(SSD)
Clinical
Typology:
Speech
DelayGenetic
(SD-GEN)
Speech
Processes:
Diagnostic
Markers:
Speech Delay
(SD)
Speech DelayOtits Media
With Effusion
(SD-OME)
Speech DelayDevelopmental
Psychosocial
Involvement
(SD-DPI)
Speech Errors
(SE)
Speech Errors /s/
Speech Errors /r/
(SE-/s/)
(SE-/r/)
Motor Speech Disorder
(MSD)
Motor Speech
Disorder
ApraxiaOf Speech
(MSD-AOS)
Motor Speech
DisorderDysarthria
(MSD-DYS)
Encoding/Memory
Transcoding
Execution
(Representational)
(Planning/Programming)
(Neuromotor)
Motor Speech
DisorderNot Otherwise
Specified
(MSD-NOS)
Thanks . . .
http://www.waisman.wisc.edu/phonology/
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Maassen & P. van Lieshout, (Eds.), Speech Motor Control: New Developments in Basic and Applied
Research. Oxford: Oxford University Press.
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prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2.
Journal of Speech, Language, and Hearing Research, 49, 500-525.
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Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2.
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Madison Studies of Complex
Neurodevelopmental Disorders
Neurodevelopmental
Disorder
Completed
Speech Sound Disorders
Speech
Delay (SD)
Speech
Errors (SE)
Motor Speech Disorders
MSD-CAS
MSD-DYS
MSD-NOS
Autism: Verbal
Yes
Yes
No
No
No
Fragile X syndrome
Yes
Yes
No
No
Yes
Galactosemia
Yes
Yes
Yes
Yes
Yes
Joubert syndrome (1)
Yes
Yes
Yes
Yes
──
Madison Studies of Complex
Neurodevelopmental Disorders
Neurodevelopmental
Disorder
In Process
Speech Sound Disorders
Speech
Delay (SD)
Speech
Errors (SE)
Motor Speech Disorders
MSD-CAS
MSD-DYS
MSD-NOS
Autism: Low Verbal
──
──
──
──
──
Down syndrome
──
──
──
──
──
Velocardiofacial syndrome
──
──
──
──
──
Joubert syndrome
──
──
──
──
──
Rolandic Epilepsy
──
──
──
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──
cr
20
10
0
ss
St
ab
D
ur
at
io
n
e
F1
ac
le
Sp
ab
we
l
St
we
l
Vo
Vo
ed
le
uc
ss
of Participants Positive for Marker
90
Le
R
ed
Le
ea
Percentage
In se
ap d
pr P e
op rc
ria en
t e t ag
Pa e
us o f
Sl
es
ow
er
Ar
t ic
ul
at
io
n
R
at
Sl
e
ow
er
Sp
ea
ki
ng
Lo
R
at
we
e
re
d
F2
:H
ig
h
Vo
we
ls
In
Seven Candidate Diagnostic Markers
of Apraxia of Speech
100
AOS (n = 47-53)
SD (n = 22-24)
80
70
60
50
40
30
Method
Group 4: Neurogenetic and Idiopathic CAS
Percentage of
Consonants
Correct (PCC)
Age (yrs)
n
Neurogenetic
Chromosome Region
Deletion or Translocation
M
SD Range
%
Males
M
SD
4 13
3
11-16
25.0
76.3
5.0
Copy Number Variation
2 11
5
8-15
100.0
80.6
7.8
FOXP2
4 24 19
4-50
25.0
77.5
23.5
Galactosemia
8
5-16
75.0
68.2
19.4
Joubert Syndrome
1 11 ─
─
100.0
70.0
─
Prader-Willi Syndrome
1
8 ─
─
0.0
92.2
─
Subtotals
Idiopathic
9
4
20 13 10
4-50
55.0
74.2
16.5
20
4-19
65.0
72.5
12.1
9
4