Joseph M. Berg

Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the β‐amyloid precursor protein gene

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimers disease (FAD) associated with a mutation (G→A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.

Down syndrome before down: A retrospect

We have attempted to identify published descriptions and reports of skeletal remains, figurines and paintings of suggested or supposed instances of Down syndrome predating John Langdon Haydon Downs initial account of the condition in 1866. A review of the ascertained material in each of these categories has not provided, in our opinion, convincing evidence of presence of the syndrome, although that possibility is not excluded. In the interests of historical authenticity readers are invited to point out perceived errors or omissions in this presentation.

Down syndrome before down: A postscript

in Papers on Paleopathology presented at 3rd European Members Meeting of the Paleopathology Association, Caen, France, Sept. 1980. p C6. Down JLH. 1866. Observations on an ethnic classification of idiots. London Hospital Reports 3:259–262. [Paper reproduced in Berg JM, Korossy M. 2001]. Eiken M. 1989. X-ray examination of the mummies from Quilakitsoq. Meddelelser om Grønland; Man & Society 12:58–68. Hart Hansen JP. 1989. The mummies from Quilaktisoq—paleopathological aspects. Meddelelser om Grønland; Man & Society 12:69–82. Hart Hansen JP, Gulløv HC. 1989. The mummies from Quilakitsoq— eskimos in the 15th century. Meddelelser om Grønland; Man & Society 12:1–196. Hart Hansen JP, Meldgaard J, Nordqvist J. 1991. The Greenland mummies. London: British Museum Publications. Kaufmann HJ, Taillard WF. 1961. Pelvic abnormalities in mongols. Brit Med J 1:948–949. Walker PL, Cook DC, Ward R, Braunstein E, Davee M. 1991. A Down syndrome-like congenital disorder in a prehistoric California Indian. Abstract of Paper presented at 60th Annual Meeting of the American Association of Physical Anthropologists, Milwaukee, WI, April 1991. Am J Phys Anthrop 12(Suppl):179. Joseph M. Berg* University of Toronto and Surrey Place Centre Toronto, Ontario Canada 98 Berg

Re: Atypical antipsychotic use in treating adolescents and young adults with developmental disabilities.

In our clinical practice, we have also observed that some persons with DD at times experience a “dramatic and longlasting response to low-dose atypical neuroleptics” but that “this population, however, seems particularly sensitive to neuroleptic-induced movement disorders (NIMDs), hence caution and close monitoring are required” (1). What we feel deserves greater emphasis for practitioners less familiar with this etiologically and symptomatically diverse population with different types and degrees of DD is that the diagnostic complexities involved are substantial. Even establishing a diagnosis of schizophrenia or autism–pervasive developmental disorder (PDD) can be challenging; differentiating symptoms of psychosis from symptoms of anxiety in persons with autism–PDD can be still more problematic. Friedlander and others did not comment on these challenges in their paper, nor did they attempt to tease apart whether outcome was due to the atypical antipsychotic medication per se or whether and to what extent associated interventions with other medications or nonpharmacologic therapies may have contributed (a difficult thing to establish in a small sample). To identify those for whom atypical antipsychotics are effective, and in what context, further research on larger series is warranted. Friedlander and others note that, even with their clinic’s conservative prescription practices, one-half the individuals in the sample were taking atypical antipsychotics—even when psychotic symptoms were not documented. We agree with the authors that, in the absence of clearly identified psychiatric disorders for which these medications are indicated, the practice of using either typical or atypical antipsychotics to treat behaviour disturbances is no longer tenable. We urge psychiatrists to identify and carefully monitor, in both their research and clinical practice, the target symptoms that the antipsychotic is intended to address, particularly when the symptoms are not psychotic (as may have been the case for many of the individuals with autism–PDD in the present sample). Proceeding in this way helps to ensure that the old practice of overprescribing neuroleptics, noted by Friedlander and others, does not transfer into overprescribing newer antipsychotic medications, particularly in situations where the prescribing physician does not have access to a comprehensive multidisciplinary evaluation process.