Advertisement
Research Article

CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

  • Seval Türkmen equal contributor,

    equal contributor Contributed equally to this work with: Seval Türkmen, Gao Guo

    Affiliation: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

    X
  • Gao Guo equal contributor,

    equal contributor Contributed equally to this work with: Seval Türkmen, Gao Guo

    Affiliation: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

    X
  • Masoud Garshasbi,

    Affiliations: Max Planck Institute for Molecular Genetics, Berlin, Germany, Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    X
  • Katrin Hoffmann,

    Affiliation: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

    X
  • Amjad J. Alshalah,

    Affiliation: University of Babylon, Babylon, Iraq

    X
  • Claudia Mischung,

    Affiliation: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

    X
  • Andreas Kuss,

    Affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany

    X
  • Nicholas Humphrey,

    Affiliation: Centre for Philosophy of Natural and Social Science, London School of Economics, London, United Kingdom

    X
  • Stefan Mundlos,

    Affiliations: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany, Max Planck Institute for Molecular Genetics, Berlin, Germany, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany

    X
  • Peter N. Robinson mail

    peter.robinson@charite.de

    Affiliations: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany

    X
  • Published: May 22, 2009
  • DOI: 10.1371/journal.pgen.1000487

Reader Comments (2)

Post a new comment on this article

This is not a Novel Syndrome – This is a New Variant of Uner Tan Syndrome

Posted by Uner-Tan on 09 Jul 2010 at 06:38 GMT

The authors of this paper claim they have discovered a novel syndrome characterized by habitual quadrupedal locomotion, mental retardation, and congenital ataxia. However, the same syndrome had already been described in 2005, and was called Uner Tan syndrome (UTS) [1, 2]. This is not even mentioned in the article, and no comparison between UTS and the “novel syndrome” is put forward. It should be clarified why the so-called novel syndrome is different from UTS, which showed a genetic heterogeneity [3]. A novel mutation in an already described syndrome does not mean it is a novel syndrome. Dissimilar mutations may indeed lead to the same phenotype [3], and “similar genetic lesions can have entirely different phenotypes” [4]. Further, CA8 mutations may be involved in many disorders, affecting almost the whole motor system including the brain, spinal cord, and skeletal muscles. The modulation of calcium channels is involved in numerous neural processes all over the central and peripheral nervous system, with consequent implications in many disease states, such as Huntington’s and Alzheimer’s disease, in addition to the spinocerebellar ataxias [5].
The article seems to be incomplete in many respects. For instance, the quadrupedal locomotion is not fully described. In fact, the affected individuals with UTS exhibit diagonal-sequence quadrupedal locomotion like our ancestors and all other primates [1, 2, 6, 7]. This is important with regard to evolution, since the neural networks for the quadrupedal locomotion have been reserved for 400 million years [8].
The authors do not study the brain lesions using any radiological examination such as MRI and/or PET scans, although they suggest a cerebrocerebellar dysfunction to explain the so-called novel syndrome, especially with regard to quadrupedal locomotion. Brain MRI and PET scans of the UTS patients showed cerebellar hypoplasia with mild gyral simplifications in the brain [9], except one case who had an entirely normal brain MRI scan [10]. In addition, an adult male with a paralyzed leg due to infantile poliomyelitis exhibited habitual quadrupedal locomotion to walk and run around. This man was a bright person with an entirely normal brain [11]. So, the author’s speculation, “perhaps it is only when congenital ataxia is coupled to a certain kind of malfunction of the cerebral cortex that individuals are likely to remain walking on all fours” does not seem to be plausible, and the human quadrupedalism may not be accounted for by a cerebral lesion or malfunction, contrary to the authors’ opinion.
Moreover, the authors suggest that ataxia associated with mental retardation, generally not seen in other types of ataxias, may be associated with cerebral dysfunction, which, in turn might be closely related to the emergence of human quadrupedalism. This speculation is also not tenable, since, first of all, there are individuals with entirely normal brains and intelligence who still prefer quadrupedal locomotion (see above). On the other hand, mental retardation may not only be associated with cerebral dysfunction, it may also be related to cerebellar dysfunction, since the role of the cerebellum in psychomotor development and cognition is


well-known [12, 13]. Cases for intellectual impairment linked to cerebellar hypoplasia can be found easily in the scientific literature [14]. Despite that, the authors state “…mental retardation, which is not generally a feature of other hereditary ataxias, such a Joubert syndrome…”. This is, however, not true. The Joubert syndrome is indeed associated with mental retardation in addition to vermial hypoplasia, hyperpnea, hypotonus, oculomotor apraxia, and ataxia [15, 16]. Consequently, an hereditary ataxia coupled with mental retardation, as in the Joubert syndrome, does not show a brain impairment; instead, it reflects a cerebellar (or vermial) disorder. Accordingly, the human quadrupedalism, at least in their cases, may not be the result of congenital ataxia coupled with malfunction of the cerebral cortex, as the authors suggest. Furthermore the authors did not perform neuroradiological examinations, such as MRI and PET scans, to support their speculations.
The title of the article, “CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait”, is also misleading since a mutation in a single gene cannot be responsible for a syndrome with all of its symptom complex. As mentioned above, this is not a novel syndrome, it is a new variant of UTS, which shows genetic heterogeneity, and CA8 mutation can be one of the genes associated with UTS. The Uner Tan syndrome should be considered as a developmental disorder, and the origins of the UTS should be associated with brain development. A new case of UTS — with late childhood quadrupedalism — was recently reported [17]. It was suggested in this latter work that human quadrupedalism may be a result of adaptive self-organization, considering the dynamical systems theory, which applies to a system that changes over time. According to this theory, motor behavior emerges from the dynamic interactions of many subsystems, self-organizing to produce a movement, which does not depend upon the prior existence of commands embedded within the brain during development. “Stepping and, ultimately, walking are not innate or prescribed. Rather, they are self-organized and emergent, reflecting an assembly of multiple subsystems within the infant’s history of activity in context” [18]. Thus, the origins of human quadrupedalism should not be restricted to any single factor alone, but may instead be the result of the adaptive self-organization originating from dynamic interaction of contributing subsystems, such as neural networks, genetics, posture, balance, body constraints, muscle strength, extensor and flexor motor systems, perceptual processes, cognition, environment, and motivation.
References
[1] Tan U (2005) Unertan syndrome; quadrupedality, primitive language, and severe mental retardation; a new theory on the evolution of human mind. NeuroQuantology 4: 250-5.
[2] Tan U (2006) A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution. Int J Neurosci 116: 361-9.

[3] Ozcelik T, Akarsu N, Uz E, et al. (2008) Mutations in the very low density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci, USA 105: 4232-6.
[4] Prasun P, Pradhan M, Agarwal S (2007) One gene, many phenotypes. J Postgrad Med 53: 257-61
[5] Foskett JK (2010) Inositol triphosphate receptor Ca2+ release channels in neurological diseases. Pflugers Arch – Eur J Physiol 460: 481-494.
[6] Tan U (2006) Evidence for “Unertan Syndrome” and the evolution of the human mind. Int J Neurosci 116: 763-74.
[7] Shapiro LJ, Raichien DA (2005) Lateral sequence walking in infant papio cynocephalus: implications for the evolution of diagonal sequence walking in primates. Am J Phys Anthropol 126: 205-13.
[8] Reilly SM, McElroy EJ, Odum RA, Hornyak VA. Tuataras and salamanders show that walking and running mechanics are ancient features of tetrapod locomotion. Proc R Soc B 2006; 273: 1563-8.
[9] Tan U, Pence S, Yilmaz M, Ozkur A, et al. (2008) “Unertan Syndrome” in two Turkish families in relation to devolution and emergence of homo erectus: neurological examination, MRI, and PET scans. Int J Neurosci 118: 313-36.
[10] Tan U (2006) Evidence for “Unertan Syndrome” as a human model for reverse evolution. Int J Neurosci 116: 1539-47.

[11] Tan, U (2007) A wrist-walker exhibiting no “Unertan Syndrome”: a theory for possible mechanisms of human devolution toward the atavistic walking patterns. Int J Neurosci 117: 147-56.
[12] Steinlin M, Styger M, Boltshauser E (1999) Cognitive impairments in patients with congenital nonprogressive cerebellar ataxia. Neurol 53: 966-73.
[13] Rapoport M, van Reckum R, Mayberg H (2000) The role of the cerebellum in cognition and behavior: selective review. J Neuropsych Clin Neurosci 12: 193-4.
[14] Margari L, Ventura P, Presicci A, Buttiglino M, Perniola T (2004) Congenital ataxia and mental retardation in three brothers. Ped Neurol 31: 59-63.
[15] Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA (2004) Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Gen 36: 1008-13.
[16] Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztirha L, Gleeson JG (2004) Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Gen 75: 979-87.
[17] Tan M, Karaca S, Tan U (2010) A new case of Uner Tan syndrome – with late childhood quadrupedalism. Mov Dis 25: 652-653.
[18] Thelen E, Ulrich BD (1991) Hidden skills: a dynamic systems analysis of treadmill stepping during the first year. Monogr Soc Res Child Dev 56: 1-98.

No competing interests declared.