Stuttering has a really strong genetic component

0
98

For centuries, people have feared being judged for stuttering, a condition often misunderstood as a psychological problem caused by things like bad parenting or emotional trauma.

But research presented at a science conference on Saturday explores its biological underpinnings: genetics and brain differences.

“By understanding the biology, we’re going to decrease the stigma. We’re going to increase the acceptance,” one of the speakers, Dr. Gerald Maguire, said in a recent interview with The Associated Press. He’s a California psychiatrist who is involved in testing potential medications for stuttering based on the science.

Globally, 70 million people stutter, including President Joe Biden, who has spoken publicly about being mocked by classmates and a nun in Catholic school for his speech impediment. He said overcoming it was one of the hardest things he’s ever done.

After a campaign event in 2020, his struggle came to the fore when he met a New Hampshire teen who also stuttered. Brayden Harrington said after his dad told him about Biden, he wanted to introduce himself and shake hands. They wound up talking for an hour.

Living with a stutter hasn’t been easy, Brayden said, recalling a particularly difficult moment years ago when he got caught on words reciting the Gettysburg address in class, then went home and cried.

“I want to carry on what Joe Biden said to me,” he said. “That this does not define you and that you can be much more than you see yourself as.”

WHY DO PEOPLE STUTTER?

Stuttering has been documented as far back as ancient China, Greece and Rome. But no one really had any idea what caused it until modern genetic science and brain imaging began providing clues.

Researchers identified the first genes strongly linked to stuttering more than a decade ago. Imaging studies peered into the brains of adults and older children, and in the last few years, University of Delaware speech disorder researcher Ho Ming Chow started looking at 3- to 5-year-olds. That’s around the age many kids begin stuttering, with about 80% outgrowing it.

Chow said the imaging shows slight brain differences in young children who keep stuttering, compared with those who recover and those who never stuttered. He discussed his research Saturday at the American Association for the Advancement of Science conference.

For example, Chow and his colleagues found genetic mutations related to stuttering are associated with structural abnormalities in the corpus callosum, a bundle of fibers that connects the two hemispheres of the brain and ensures they can communicate; and the thalamus, a relay station that sorts sensory information to other parts of the brain. Past research has also linked stuttering to the basal ganglia, brain structures involved in the coordination of movement.

“We know stuttering has a really strong genetic component,” Chow said. Though several genes may be involved and the exact genetic causes may vary by child, “they probably affect the brain in a similar way.”

Chow’s colleague Evan Usler stutters, and he likened it to “yips,” or involuntary wrist spasms, during golf. He said the latest evidence shows it’s a disorder of the cognitive control over speech.

Still, many people incorrectly believe people stutter because they are nervous, shy or suffered childhood adversity – and if they just tried harder, they could stop.

“We have a long way to go” to change such beliefs, said University of Maryland researcher Nan Bernstein Ratner. “There’s still a lot of mythology out there.”

MOVING AHEAD, WITH ACCEPTANCE

Speech therapy is the mainstay of stuttering treatment. But the medicines currently being tested could be approved for stuttering in the next few years, first for adults and later for kids, said Maguire, who has stuttered since childhood.

Studies have suggested that stuttering may be related to excess levels of a chemical messenger in the brain called dopamine, and some turn down dopamine activity or block its action in a particular way.

Nover, a speech pathologist active in the National Stuttering Association, said many people will surely be interested in trying stuttering medications – although not her. She is happy with her life as it is and has accepted her stuttering, she said. If Colton were struggling and wanted to try medication as a teen, however, she’d be open to the idea.

Brayden, now 14, wouldn’t be.

Taking medicine is “just taking away a part of you…taking away part of your personality,” he said.

Without his stutter, he said, he wouldn’t have set his sights on being a speech and language pathologist when he grows up. He wouldn’t have written a children’s book to inspire others. And he wouldn’t have overcome the challenges that made him brave.


Speech and language represents an integral component of the human experience; we unite language (what we say) and speech (how we say it)1 to express our thoughts, feelings, and experiences with one another. Successful verbal communication requires coordination among neurological, cognitive, motor, and linguistic systems; dysregulation across or among any of these systems may result in disordered speech and language.2, 3, 4

Developmental stuttering is a common speech disorder with an onset between 2 and 5 years of age characterized by prolongations, blocks, and repetitions of speech sounds.5 Although most studies report a 5% lifetime prevalence of stuttering,2,6, 7, 8, 9 the true prevalence may be higher due to restrictive reporting criteria and poor subject selection,4,10 particularly since onset and recovery can be transient during early childhood.11

Individuals who are affected by the condition either stutter into adulthood (persistent stuttering) or stutter during early childhood but recover with the assistance of therapy, or spontaneously, typically before age 8 years (recovered stuttering). Persistent developmental stuttering afflicts approximately 1% of the adult population,4,12 which equates to more than 2.5 million adults afflicted with developmental stuttering in the United States.13

This common speech condition impacts the quality of life for many. Persistent stuttering has no known cure, and therapy for affected individuals often results in only a modest reduction in severity.14 Moreover, those who stutter frequently require a lifetime of therapy to manage the speech challenges as well as the psycho-social impact.15, 16, 17 Job performance and employability in adults who stutter can be affected, leading to substantial economic impacts.18, 19, 20

Despite extensive research on the psychological and economic consequences of this speech disorder, the etiology of developmental stuttering remains elusive. Current evidence postulates neurological,21 biological,22 and genetic underpinnings for stuttering,23, 24, 25, 26, 27, 28, 29, 30 though few causal associations have been identified to date. Even though multiple studies in the past few decades12,23,30, 31, 32, 33 evince a genetic predisposition for developmental stuttering, its genetic etiology and architecture largely remain evasive.

Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; many individuals who stutter have a family member who also stutters.12 However, heritability estimates of developmental stuttering have varied widely across studies,7,34, 35, 36, 37, 38 with estimates ranging from 0.42 to 0.84 from the two largest twin studies, each comprising a sample size greater than 20,000 individuals. Although heritability estimates performed in twin studies of developmental stuttering point to genetic causes, such estimates also indicate the presence of environmental factors contributing to developmental stuttering. Monozygotic twin concordance rate estimates range from 38%–62% in these two studies.36,37

Nevertheless, many studies of other complex disorders (e.g., type 2 diabetes39,40 [MIM: 125853], serum lipid levels,41 Parkinson disease,42 and Alzheimer disease43,44 [MIM: 104300]) with similar or smaller heritability estimates have discovered genetic risk factors essential to understanding the molecular basis of the trait, suggesting that similar genetic study designs may offer key insights into the etiology of developmental stuttering.

To date, published literature investigating genetic contributions to developmental stuttering has primarily drawn on family-based analyses and studies of population isolates.23, 24, 25, 26, 27,29, 30, 31,33,45 Linkage and other family-based approaches have been successful at identifying rare and private causal variants with large genetic effects in the absence of genetic heterogeneity. For developmental stuttering, identifying the causal gene(s) within and across families has proven challenging. For example, in 2005 Riaz et al.24 performed linkage analyses in 46 consanguineous Pakistani families where stuttering occurred in at least two generations and diagnosis was confirmed independently by two different clinicians; they discovered a region on 12q23.3 linked with developmental stuttering in a single family without pinpointing an exact causal gene.

Five years later in 2010, Kang et al.27 reported the results from a follow-up study of 77 unrelated Pakistani individuals who stutter plus unrelated cases from the same 46 Pakistani families interrogated by Riaz et al. in 2005;24 their investigation pinpointed three causal genes critical for the mannose-6-phosphate lysosomal targeting pathway: GNPTAB (MIM: 607840), GNPTG (MIM: 607838), and NAGPA (MIM: 607985).

In 2018, Kazemi et al.46 performed Sanger sequencing and homozygosity mapping for 25 Iranian families afflicted by developmental stuttering and identified an additional 3 variants in GNPTAB and GNPTG that co-segregated with stuttering. Additional studies have revealed several regions across the genome linked with the trait but only identified three candidate risk genes: DRD231 (MIM: 126450), AP4E133 (MIM: 607244), and CYP17A130 (MIM: 609300).

Lan et al.31 performed an association study focusing specifically on dopaminergic gene haplotypes and allele frequencies among SNPs in the Han Chinese population and identified risk and protective alleles in DRD2. These results were not replicated in 2011 by Kang et al.32 in a case-control cohort from Brazil and western Europe. In 2015, Raza et al.33 used whole-exome sequencing to identify two heterozygous AP4E1 coding variants that co-segregated with persistent developmental stuttering in a large Cameroonian family (the same polygamous family as published in their earlier work from 201347); they also observed these same two variants in unrelated Cameroonians with persistent stuttering.

Although Raza et al.33 also reported 23 additional rare variants (including loss-of-function variants) within AP4E1 among unrelated stuttering individuals from Cameroon, Pakistan, and North America, their findings have yet to be replicated by another group. In 2017, Mohammadi et al.30 performed a case-control study of the Kurdish population aged 3 to 9 years from Western Iran, specifically focusing on the dimorphic nature of stuttering, and identified an allelic polymorphism associated with stuttering susceptibility in CYP17A1, a gene integral for the synthesis of steroid hormones.

As reported by Frigerio Domingues et al.48 in 2019, these results were not replicated in an independent case- and population-matched control association study from the United States, Brazil, Pakistan, and Cameroon. Despite these efforts, the molecular pathophysiology of developmental stuttering in general populations remains obscure, in part due to the dearth of studies exploring common genetic risk factors in unrelated individuals and the lack of consensus across studies.

The International Stuttering Project (ISP) was formed to represent global outbred populations of individuals who stutter, specifically to illuminate genetic etiology and broaden investigations of its diverse and variable phenotype (see Web resources). Given the success of investigations for heritable complex diseases, genome-wide association analyses of developmental stuttering are poised to provide insights into its molecular basis.

Moreover, prior investigations into the genetics underlying developmental stuttering have comprised samples and study designs ill-equipped to detect common variant effects or reconcile genetic heterogeneity. Our study accommodates both. Here, we accrued a global and multiethnic clinically ascertained developmental stuttering case set through the ISP and report genome-wide significant (GWS) findings in a meta-analysis study of developmental stuttering.

reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8756529/

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.