February 11, 2010 — Researchers at the National Institutes of Health (NIH) have found an association between susceptibility to stuttering and variants of genes encoding enzymes in a single metabolic pathway associated with mucolipidosis types II and III — rare lysosomal storage disorders. It appears that the type of mutation — missense in most stuttering patients, but protein truncation or deletion in mucolipidosis II/III — may determine the resultant pathology.
Published online February 10 in the New England Journal of Medicine, the study was spearheaded by the National Institute on Deafness and Other Communication Disorders at the NIH, with collaboration from the University of the Punjab, Lahore, Pakistan.
GNPTAB and GNPTG, 2 of the genes now implicated in stuttering susceptibility, encode subunits of N-acetylglucosamine-1-phosphate transferase, an enzyme that catalyzes the "tagging" of other enzymes destined for lysosomal functions. NAGPA, the third implicated gene, encodes an enzyme that removes a unit from the tagged molecules, exposing a targeting signal that enables them to move through the Golgi apparatus and into the lysosome. Although GNPTAB and GNPTG mutations are known to cause mucolipidosis II/III, NAGPA mutations have not been reported.
"Lysosomal storage disorders, as diseases, tend to be very rare, but they're extremely well-studied by the medical genetics community and very well understood at the biochemical level and at the level of cell biology," said senior author Dennis Drayna, PhD, chief of the Section on Systems Biology of Communication Disorders, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland, in a telephone interview with Medscape Pathology. "So in that sense it was fortunate that our genetic findings put us into this well-understood area of medical genetics."
The fundamental causes of stuttering are unknown, but among the strongest genetic associations is a locus on chromosome 12. The investigators analyzed a 10-megabase pair region centered on this locus in
a large Pakistani family with 44 of 86 members affected (multigenerational pedigree);
unrelated stuttering individuals from other affected Pakistani families (n = 46);
unrelated affected Pakistani individuals (n = 77); and
270 unrelated affected individuals from England and North America.
Control subjects were unaffected individuals from each culture (Pakistani, n = 96; Western, n = 276).
GNPTAB Most Strongly Associated
The variant most strongly cosegregated with stuttering in the large Pakistani family was a mutation causing a single amino acid substitution in the enzyme encoded by GNPTAB. "With three exceptions, the affected persons [in this family] carried one or two copies of this variant," the study reported. In contrast, 3 affected family members did not carry this GNPTAB variant, and 11 family members (2 homozygous and 9 heterozygous for this mutation) do not stutter.
The same GNPTAB mutation was also found in affected individuals from 3 other Pakistani families, 1 North American of Asian Indian ancestry, 2 unrelated Pakistanis, and 1 Pakistani control participant. Several other GNPTG mutations were identified in 4 affected unrelated individuals, but not in Pakistani or North American control participants. NAGPA mutations were detected in 6 affected unrelated North American/British individuals, but not in North American or Pakistani control participants.
Recognizing the role of these genes in lysosomal storage diseases, the investigators performed clinical exams on several affected individuals with GNPTAB or NAGPA mutations. Apart from their stuttering, all results were normal, with no indication of lysosomal dysfunction.
Despite the apparent lack of penetrance of some GNPTAB mutations, mutations in GNPTG and NAGPA were not found in any unaffected individuals. The 3 genes function in a "single well-defined metabolic pathway," and — most interesting in the present context — individuals with mucolipidosis II/III frequently exhibit expressive speech problems previously considered secondary to their developmental delay.
In explaining how mutations in GNPTAB or GNPTG could lead to either mucolipidosis or stuttering, the authors note that mucolipidosis II and III are autosomal recessive, only affecting homozygotes. All but 2 of the unrelated affected individuals in this study were heterozygotes. In addition, with one exception, this study identified missense mutations rather than mutations involving protein truncation or deletion, as in mucolipidosis II/III. Mutations had not been previously reported in NAGPA, so persistent developmental stuttering may be the primary effect of NAGPA variation.
"[A] number of lysosomal storage disorders...are successfully treated with enzyme replacement therapy, in which the normal enzyme is just infused into [patients], just administered intravenously," said Dr. Drayna, when asked about clinical effects of the study. "So I think the possibility of enzyme replacement therapy is far more likely than gene therapy." He noted, however, that enzyme replacement therapy has been extremely promising for treating symptoms outside the brain, but "these enzymes, to date, haven't shown much of a propensity to get inside the brain.
"So while enzyme replacement therapy for lysosomal storage disorders has very successfully treated many of the different symptoms of these disorders, it has not been very successful at treating the central nervous system symptoms, which is where we assume stuttering has its origins," said Dr. Drayna, adding, "I should mention, though that this is a very active area of research."
"[T]he researchers were able to come up with a surprising candidate pathway for involvement in stuttering, one that probably would have remained elusive using other approaches," noted Simon E. Fisher, DPhil, author of a related editorial in the New England Journal of Medicine and reader in molecular neuroscience, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom, in an email to Medscape Pathology. "In this way, genetics can give us unique insights into biological mechanisms, which may increase understanding and point to novel treatment possibilities."
Dr. Fisher said he thinks the big question now is to understand how disruption of a fundamental process, important for most body cells, could cause such selective impairment in neural control of speech. "Just how wide an impact [do] these metabolic pathways have amongst people who stutter?" he wondered.
"The new study notes that some reports of patients with mucolipidosis II/III have documented speech problems. I think it would be worth a systematic assessment of how prevalent these are," suggested Dr. Fisher, "and whether they have valid similarities with the classic symptoms of stuttering (as opposed to other forms of speech impairment)."
Dr. Drayna and Dr. Fisher have disclosed no relevant financial relationships.
N Engl J Med. Published online February 10, 2010.
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Cite this: First Gene Variants Associated With Stuttering - Medscape - Feb 11, 2010.