Mucolipidosis and Stuttering via the GNPTAB Gene

Mucolipidosis II (ML II) (OMIM 252500), also called inclusion-cell or I-cell disease, is part of the lysosomal storage disease family. The disease manifests at birth, and patients typically do not survive past the first 1-2 years. Phenotypic characteristics include thickening of the skin, coarse facial features, hypertrophic gingival, thoracic deformities, clubfoot, kyphosis, hip dislocations, dysostosis multiplex, and cardiac involvements. Death usually occurs due to respiratory insufficiency from stiffening of the thoracic cage (Leroy et al. GeneReviews, 2012, www.genetests.org). ML II can be differentiated from mucolipidosis III alpha/beta (ML III α/β) (OMIM 252600) by earlier clinical onset and more severe phenotypic characteristics.

ML III α/β, also called pseudo-Hurler polydystrophy, manifests clinically at approximately 3 years of age. Phenotypic characteristics include slow growth rate, moderate dysostosis multiplex, joint stiffness, mild coarsening of facial features, mild cognitive impairment. Cardiorespiratory complications are the common cause of death (Leroy et al. GeneReviews, 2012, www.genetests.org).

Stuttering (also called stammering) is speech that is characterized by frequent repetition or prolongation of sounds, syllables, or words or by frequent hesitations or pauses that disrupt the rhythmic flow of speech. Stuttering affects ~1% of the population and has a mean onset around 30 months of age (Yairi et al. J Speech Hear Res 35:782-788, 1992). Stuttering often resolves spontaneously before adulthood, particularly in females. In rare cases stuttering can occur in adulthood as a result of brain injury (Fawcett. CNS Spectrums 10:94-95, 2005) or drug use (Krishnakanth et al. Prim Care Companion J Clin Psychiatry 10:333-334, 2008). Secondary behaviors, such as eye blinking or other involuntary head movements, are not uncommon (Prasee and Kikano. Am Fam Physician 77:1271-1276, 2008).

Mucolipidosis II and III α/β (ML II and ML IIIα/β) are inherited in an autosomal recessive manner and are caused by variants in GNPTAB, which encodes the enzyme alpha/beta GlcNAc-1-phosphotransferase. ML II variants mostly result in premature translational termination (or nonsense mediated decay) (Tiede et al. Nat Med 11:1109-1112, 2005; Kudo et al. Am J Hum Genet 78:451-463, 2006; Tappino et al. Mol Genet Metab 93:129-133, 2008; Tappino et al. Hum Mutat 30:E956-973, 2009). Nonsense, frameshift, and splicing variants are also common in ML IIIα/β, but missense variants are more common than in ML II and are mostly localized to the protein recognition domain, leaving the catalytic domain with some residual activity (Bargal et al. Mol Genet Metab 88:359-363, 2006). Variants in GNPTAB have also been associated with stuttering (Kang et al. N Engl J Med 362:677-685, 2010). GNPTAB encodes the α and β subunits of GlcNAc-phosphotransferase, a protein involved in the lysosomal enzyme-targeting pathway. Four GNPTAB missense variants were reported in stuttering patients. Most patients were heterozygous for the variants, although a few were homozygous. Penetrance of the variants does not appear to be complete. Variants in the GNPTG and NAGPA genes, also involved in the lysosomal enzyme-targeting pathway, were similarly reported in stuttering patients.

The sensitivity for the GNPTAB sequencing test is >95% for both ML II and ML III α/β. Kang et al. 2010 reported that 25 of 393 stuttering patients (6%) had variants in one of the three genes (GNPTAB, GNPTG, and NAGPA). About half of the 25 patients had variants in GNPTAB.

This test provides full coverage of all coding exons of the GNPTAB gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.