Dr. Faraneh Vargha-Khadem, Dr. Anthony Monaco and the SPCH1 Gene

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Dr Faraneh Vargha-Khadem MA PhD is Reader in Developmental Cognitive Neuroscience and Head of the Cognitive Neurosciences Unit at the Institute of Child Health, London

Her work on the development of language in infants came to the attention of the autism community when she published a paper with Dr. Anthony Monaco and Dr. Simon E. Fisher of Wellcome Trust Centre for Human Genetics at The University of Oxford ) and others:

Localisation of a gene implicated in a severe speech and language disorder.
Fisher, S.E., Vargha-Khadem, F., Watkins, K.E., Monaco, A.P. and Pembrey, M.E.
Nature Genetics 17 (1998) 168-170.
[Abstracts here and here ]

Drs. Vargha-Khadem and Monaco were mentioned and quoted in a short article in New Scientist's Talking Point (31-Jan-98) that suggests that the gene that shapes the development of human language (provisionally named SPCH1) may also either be one of the genes responsible for autism or may be nearby:

Vargha-Khadem and her colleagues collaborated with Monaco's team to locate the defective gene. They analysed different chromosome segments, reasoning that afflicted individuals should share the grandmother's version of the regions. Two closely spaced segments of chromosome 7 showed a perfect match: they were present in 15 linguistically impaired relatives, but absent in 12 healthy ones.

This means that SPCH1 has to lie very close by, says Monaco. His team also notes in research yet to be published that the same region on chromosome 7 also plays a part in autism, another condition where language is impaired. "This suggests we are going to be helped a lot by knowing how this gene works, and what role it plays in other disorders," says Vargha-Khadem.

A lot of hope is pinned, in the autism community, on finding the genes responsible for autism spectrum disorder subtypes, because then those could then be identified and the individual matched more speedily with appropriate interventions (whether educational or medical) as they become available.

Here are some other references to Dr. Faraneh Vargha-Khadem's work:

Development of intelligence and memory in children with hemiplegic cerebral palsy the deleterious consequences of early seizures.
Vargha-Khadem F, Isaacs E, van der Werf S, Robb S, Wilson J.
Brain. 1992;115:315-329.

Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder.
Vargha-Khadem, F.; Watkins, K.; Alcock, K.; Fletcher, P. & Passingham, R. (1995)
Procedures of the National Academy of Science USA 92, 930-3.

Cerebral Asymmetry in Infants
F. Vargha-Khadem and M. Corballis,
Brain and Language, vol. 8, pp. 1-9, 1979.

Differential effects of early hippocampal pathology on episodic and semantic memory.
Vargha-Khadem, F., Gadian, D.G., Watkins, K.E., Connelly, A., Van Paesschen, W., and Mishkin, M.
Science 277: 376-380, 1997.

Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.
Christie D, Battin M, Leiper AD, Chessells J, Vargha-Khadem F, Neville BG.
Arch Dis Child. 1994;70:275-80.

Speech and language defects.
Vargha-Khadem, Faraneh & Passingham, R.E. (1990)
Nature 346, 226.

A review of cognitive outcome after hemidecortication in humans.
Vargha-Khadem, F. & Polkey, C. E. (1992)
In F. D. Rose & D. A. Johnson (ed.) Recovery from Brain Damage. New York: Plenum Press, 137-51.

Aphasia and handedness in relation to hemispheric side, age at injury and severity of cerebral lesion during childhood.
Vargha-Khadem, Faraneh; O'Gorman, A.M. & Watters, G.V. (1985)
Brain 108, 677-96.

Development of language in six hemispherectomized patients.
Vargha-Khadem, Faraneh; Isaacs, Elizabeth B.; Papaleloudi, Helen; Polkey, Charles & Wilson, John (1991)
Brain 114, 473-95.

Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder.
Vargha-Khadem, F.; Watkins, K.; Alcock, K.; Fletcher, P. & Passingham, R. (1995)
Procedures of the National Academy of Science USA 92, 930-3.

Functional mapping of human primary cortex with a clinical MR imaging system.
Connelly A, Jackson GD, Frackowiak RSJ, Belliveau JW, Vargha-Khadem F, Gadian DG
Radiology 188:125130, 1993.

Reading with one hemisphere.
Patterson, K., Vargha-Khadem, F., & Polkey, C.E. (1989).
Brain, 112:39-63.

The Relationship Between Memory Function and Temporal Lobe Pathology in Children.
S.J. Wood, A. Connelly, F. Vargha-Khadem, E.B. Isaacs, J.H. Cross, C.L. Johnson and D.G. Gadian. University College London Medical School, London, UK.
[at International Society for Magnetic Resonance in Medicine Fifth Annual Meeting]

Differential course of development of spatial and verbal memory span: A normative study
Isaacs, E. B.; & Vargha Khadem, F.; 1989
British Journal of Developmental Psychology, 7(4) , Nov, 377-380

Onset of speech after left hemispherectomy in a nine-year-old boy.
Vargha-Khadem, F., Carr, L.J., Isaacs, E., Brett, E., Adams, C., and Mishkin, M.
Brain 119:101-124, 1997.
+ ???
Onset of speech after left hemispherectomy in a nine-year old boy.
Vargha-Khadem, F., Carr, L.J., Isaacs, E., Brett, E., Adams, C., & Mishkin, (1997).
Brain, 120, 159-182.

Hierarchical organization of cognitive memory.
Mishkin, M., Suzuki, W., Gadian, D.G., and Vargha-Khadem, F.
Phil.Trans. R. Soc. Lond. B 352: 1461-1467, 1997.

Amnesia and the organization of the hippocampal system.
Mishkin, M., Vargha-Khadem, F. , and Gadian, D.G.
Hippocampus 8: 212-216, 1998.

Neural basis of an inherited speech and language disorder.
Vargha-Khadem, F., Watkins, K.E., Price, C.J., Ashburner, J., Alcock, K.J., Connelly, A., Frackowiak, R.S.J., Friston, K.J., Pembrey, M.E., Mishkin, M., Gadian, D.G., and Passingham, R.E.
Proc. Natl. Acad. Sci. USA 95: 12695-12700, 1998.

Cognitive deficits associated with frontal lobe infarction in children with sickle cell disease.
Watkins KE, Hewes DKM, Connelly A, Kendall BE, Kingsley DPE, Evans JEP, Gadian DG, Vargha-Khadem F and Kirkham FJ (1998).
Dev Med Child Neurol 40:536-543.

Possible blindsight in infants lacking one cerebral hemisphere
O Braddick, J Atkinson, B Hood, W Harkness, G Jackson, F Vargha- Khadem.
Nature, 360: 461-463 (1992)

Childhood acute lymphoblastic leukaemia: psychometric study
S Richards, J Halsey, F Vargha-Khadem (Great Ormond Street), B Gibson (Glasgow)
Section 99.22 of Imperial Cancer Research Fund: SCIENTIFIC REPORT 1996: Scientific Report to the Council by the Director-General for the year 1st August 1995 to July 1996: Extramural Units: 99. Cancer Studies Unit (Oxford): Richard Peto (ICRF/MRC/BHF Clinical Trial Service Unit and Epidemiological Studies Unit):
Abstract: CNS treatment of children with ALL is an important part of therapy. With improved survival there is increasing concern about the consequent risk of neuropsychological and educational deficits. As three very different CNS treatments will be used in UKALL XI, it will permit the comparison of long term effects of these treatments by a prospective psychometric study. This study started in November 1992 and will continue for five years.

[Full details not found]
Vargha-Khadem (& others?)
Hippocampus, 1998, 8: 198-216

Global Anterograde Amnesia After Early Hippocampal Pathology.
F. Vargha-Khadem, D.G. Gadian, K.E. Watkins, A. Connelly, W. Van Paesschen and M. Mishkin. University College London Medical School, London, UK; National Institutes of Health, Bethesda, MD.
[at International Society for Magnetic Resonance in Medicine Fifth Annual Meeting (Epilepsy Imaging)]

Hippocampal Volume and Everyday Memory in Adolescents Born Preterm,
E.B. Isaacs, A. Lucas, W.K. Chong, S.J. Wood, C.L. Johnson, C. Marshall, F. Vargha-Khadem and D.G. Gadian, University College London Medical School and Great Ormond Street Hospital for Children NHS Trust, London, UK.
[at The 7th Scientific Meeting & Exhibition of the International Society for Magnetic Resonance in Medicine, Philadelphia, PA, USA, 24-28 May 1999 (CLINICAL FOCUS SESSION: Neonatal CNS Imaging)]

Profound Impairment of Episodic Memory after Early Hypoxic-Ischaemic Injury,
D.G. Gadian, J. Aicardi, K.E. Watkins, D.A. Porter, M. Mishkin and F. Vargha-Khadem, University College London Medical School, London, UK and National Institute of Mental Health, Bethesda, MD, USA.
[at The 7th Scientific Meeting & Exhibition of the International Society for Magnetic Resonance in Medicine, Philadelphia, PA, USA, 24-28 May 1999 (CLINICAL FOCUS SESSION: Neonatal CNS Imaging)]

Effects of unilateral versus bilateral pathology on the development of speech and language functions
F. Vargha-Khadem (The Wolfson Center, U.K.)
[at Rodin Remediation Academy 1999 in Japan: Brain Mechanisms and Disorders in Language Comprehension, April 6 - 8, 1999

Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex.
Christie D; Leiper AD; Chessells JM; Vargha-Khadem F [Neurosciences Unit, University of London].
Arch Dis Child 1995;73(2):136-40
Abstract: Cognitive outcome, as measured by verbal and performance IQs, was compared in 35 girls and 47 boys who were in first remission for acute lymphoblastic leukaemia. All children had received presymptoma- tic cranial radiotherapy and intrathecal methotrexate. The mean age at diagnosis was 4.2 years and the mean elapsed time from initial diagnosis to intellectual assessment was 7.1 years. Results showed that children irradiated before the age of 4 years were impaired in certain aspects of non-verbal ability, as well as in measures of short term memory and attention, calculated by factor scores derived from selected subtests of the IQ test. Subtests requiring verbal and non-verbal reasoning showed the greatest impairment after early diagnosis and treatment. In addition girls were selectively impaired in verbal IQ and other aspects of verbal ability, with the degree of impairment exacerbated by early treatment. No relationship was found between degree of impairment and either time since treatment or number of methotrexate injections. It is concluded that early age at irradiation increases the risk of impaired intellectual outcome, particularly in girls.

Chromosome 7 Puts Words in Your Mouth: Genes for Speaking and Grammar
[THIS WEEK ON SCIENCE, January 30, 1998: Hour One, second half]

First Gene Responsible For Speech Located
London: Scientists in Britain have located a gene that may play a crucial role in speech and language disorders.
Nature Genetics, January 26, 1998. [Fisher, Vargha-Khadem and Monaco mentioned]

Children with amnesia cast new light on memory and learning
[Associated Press, Indian Express Newspapers (Bombay) Ltd]

Fact Memory Spared Despite Hippocampal Damage
http://www.nimh.nih.gov/events/prmemory.htm
http://www.nih.gov/news/pr/jul97/nimh-17.htm
http://gopher.nimh.nih.gov/events/prmemory.htm
http://pslgroup.com/dg/3077e.htm

Dr. Anthony Monaco (with Dr. Simon E. Bailey) of the Wellcome Trust Centre for Human Genetics at the University of Oxford was a recipient of Medical Research Council Awards December 1998 for his work on "An international collaborative molecular genetic study of autism and milder phenotypes". Below are some further references to his work:

A full genome screen for autism with evidence for linkage to a region on chromosome 7q.
Bailey, A., Hervas, A., Matthews, N., Palferman, S., Wallace, S., Aubin, A., Michelotti, J., Wainhouse, C., Papanikolaou, K., Rutter, M., Maestrini, E., Marlow, A., Weeks, D.E., Lamb, J., Francks, C., Kearsley, G., Scudder, P., Monaco, A.P., Baird, G., Cox, A., Cockerill, H., Le Couteur, A., Berney, T., Cooper, H., Kelly, T., Green, J., Whittaker, J., Gilchrist, A., Bolton, P., Schonewald, A., Daker, M., Ogilvie, C., Docherty, Z., Deans, Z., Bolton, B., Packer, R., Poustka, F., Ruhl, D., Bolte, S., Klauck, S.M., Spieler, A., Poustka, A., Van Engeland, H., Kemmer, C., De Jonge, M., den Hartog, I., Lord, C., Cook, E., Leventhal, B., Volkmar, F., Pauls, D., Klin, A., Smalley, S., Fombonne, E., Roge, B., Tauber, M., Arti-Vartayan, E., Fremolle-Kruck, J., Pederson, L., Haracopos, D., Brodum-Nielsen, K. and Cotterill, R.
Hum.Mol.Genet. 7 (1998) 571-578.

A sequence-ready physical map of a region of 12q24.1.
Renault, B., Hovnanian, A., Bryce, S., Chang, J.J., Lau, S., Sakuntabhai, A., Monk, S., Carter, S., Ross, C.J.D., Pang, J., Twells, R., Chamberlain, S., Monaco, A.P., Strachan, T. and Kucherlapati, R.
Genomics 45 (1997) 271-278.

Chorea-acanthocytosis: Genetic linkage to chromosome 9q21.
Rubio, J.P., Danek, A., Stone, C., Chalmers, R., Wood, N., Verellen, C., Ferrer, X., Malandrini, A., Fabrizi, G.M., Manfredi, M., Vance, J., Pericak-Vance, M., Brown, R., Rudolf, G., Picard, F., Alonso, E., Brin, M., Nemeth, A.H., Farrall, M. and Monaco, A.P.:
Am.J Hum.Genet. 61 (1997) 899-908.

Familial infantile convulsions and paroxysmal choreoathetosis: A new neurological syndrome linked to the pericentromeric region of human chromosome 16.
Szepetowski, P., Rochette, J., Berquin, P., Piussan, C., Lathrop, G.M. and Monaco, A.P.
Am.J Hum.Genet. 61 (1997) 889-898.

Assignment of genes encoding GABAA Receptor Subunits alpha1, alpha6, beta2, and gamma2 to a YAC Contig of 5q33.
Kostrzewa, M., Kohler, ,A., Eppelt, K., Hellam, L., Fairweather, N.D., Levy, E.R., Monaco, A.P. and Muller, U.
Eur.J Hum.Genet. 4 (1996) 199-204.

A molecular defect in loricrin, the major component of the cornified cell envelope, underlies vohwinkel's syndrome.
Maestrini, E., Monaco, A.P., McGrath, J.A., Ishida-Yamamoto, A., Camisa, C., Hovnanian, A., Weeks, D.E., Lathrop, M., Uitto, J. and Christiano, A.M.
Nat.Genet. 13 (1996) 70-77.

A high-resolution interval map of the q21 region of the human x chromosome.
Philippe, C., Arnould, C., Sloan, F., van Bokhoven, H., van der Velde- Visser, S.D., Chery, M., Ropers, H.H., Gilgenkrantz, S., Monaco, A.P. and Cremers, F.P.M.
Genomics 27 (1995) 539-543.

Yeast artificial chromosome cloning of the xq13.3-q21.31 region and fine mapping of a deletion associated with choroideremia and nonspecific mental retardation.
van der Maarel, S.M., Scholten, I.H.J.M., Maat-Kievit, J.A., Huber, I., de Kok, Y.J.M., de Wijs, I., van de Pol, T.J.R., van Bokhoven, H., den Dunnen, J.T., Van Ommen, G.J.B., Philippe, C., Monaco, A.P., Smeets, H.J.M., Ropers, H.H. and Cremers, F.P.M.
Eur.J Hum.Genet. 3 (1995) 207-218.

X-linked mixed deafness (DFN3): cloning and characterization of the critical region allows the identification of novel microdeletions.
Huber, I., Bitnerglindzicz, M., Dekok, Y.J.M., Vandermaarel, S.M., Ishikawabrush, Y., Monaco, A.P., Robinson, D., Malcolm, S., Pembrey, M., Brunner, H.G., Cremers, F.P.M. and Ropers, H.H.
Hum.Mol.Genet. 3 (1994) 1151- 1154.


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