Editors' ChoiceGenetics

Persistent Stuttering: Finding the Key to the Riddle

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Science Translational Medicine  24 Feb 2010:
Vol. 2, Issue 20, pp. ec30
DOI: 10.1126/scitranslmed.3000983

Persistent stuttering, which is characterized by repetition, prolongation, and blocks in speech, affects approximately 1% of the population in the United States. A disorder shared by well-known personalities such as Marilyn Monroe and Winston Churchill, stuttering has long been an enigma to the scientific community. Recent work, however, appears to shed light on the biological mechanism that underlies at least a subset of cases. Studying a large, consanguineous Pakistani family affected by stuttering, Kang et al. identified several mutations in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB) on the long arm of chromosome 12, a region that has been linked to persistent stuttering in prior investigations. GNPTAB encodes a key enzyme in the formation of mannose-6-phosphate (M6P), which is a critical factor in the directing of degradation enzymes, known as hydrolases, to the lysosome. As the investigators expanded their analysis to include affected subjects in North America and Britain, they identified in the M6P synthesis pathway two additional genes, GNPTG and NAGPA, that also harbored mutations linked to persistent stuttering. These mutations appeared rare to nonexistent in unaffected control groups, suggesting a pathogenic link to the disease. Although lysosomal disorders have been classically associated with mucolipidoses—severe diseases caused by decreased degradation of cellular components and consequent neurologic and skeletal symptoms—the mutations identified in patients with persistent stuttering appear unique. The results from this study support a potential new molecular mechanism in the development of persistent stuttering, a disease that has evaded scientific understanding for decades. Or as Churchill might say, it is a riddle, wrapped in a mystery, inside an enigma; but perhaps there is a key.

C. Kang et al., Mutations in the lysosomal enzyme–targeting pathway and persistent stuttering. New Engl. J. Med. 22 February 2010 (doi:10.1056/nejmoa0902630). [Full Text]

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