Genetic Conditions, Psychiatric Symptoms and Mechanism of Action

Dr Brian Boettcher
Consultant Psychiatrist
Shelton Hospital,
Shrewsbury, UK

Correspondance to: Dr Brian Boettcher, Shropshire's Community and Mental Health Services NHS Trust,Shelton
Hospital, Bicton Heath, Shrewsbury  SY3 8DN.,UK.

Occasional genetic syndromes are often not recognised. Unless one
keeps the possibility in mind they will be missed. The relevance to a
forensic patient, or, for that matter any patient, is obvious, from a
clinical, treatment, and a legal point of view. One such Syndrome was
discussed recently at Reaside Forensic Psychiatric Unit in
Birmingham, UK. The bottom line was that if you suspect such a
syndrome, obtain the opinion of a geneticist as this is a highly
specialised area and investigation needs expert advice.

There can be variations on these syndromes with incomplete penetrance
or other genetic mixtures. Scrambler et al described “the wide range
of phenotypes associated with hemizygosity for 22q11, a pattern which
can be found within the family as well as between individuals”[1] .
The abnormalities found in-patients with monosomy 22q11, including
Velocardiofacial Syndromes (VCF), are consistent with a defect within
the mesenchephalic and cardiac neural crest. The anomalies may occur
alone rather than as part of a syndrome and it is anticipated that a
proportion of patients with isolated features of DiGeorge (DGS) and
Velocardiofacial Syndromes have a deletion gene mutation at 22q11.”
[2] Most patients with VCFS/DGS have a similar 3-Mb deletion, whereas
some have a nested distal deletion endpoint resulting in a 1.5-Mb
deletion, and a few rare patients have unique deletions.[3]  A cohort
of 250 patients was described in 1999 whose clinical findings help to
define the extremely variable phenotype associated with the 22q11.2
deletion and may assist clinicians in providing genetic counseling
and guidelines for clinical management based on these findings.[4]

 Such conditions can throw new light on the chemistry of disorders as
described below.

Velocardiofacial Syndrome has the following features:

Mouth Cardiac Facies Eyes Nose
Cleft palate
Velopharyngeal insufficiency
Small open mouth
Pharyngeal hypotonia
Congenital heart septal defect
Ventricular Septal Defect
Tetralogy of Fallot

Medial Displacement of internal carotid arteries

Myopathic Facies
Pierre Robin syndrome
Narrow Palpebral fissure
  Almond-shaped palpebral fissures
  Small optic discs
  Tortuous retinal vessels
  Posterior embryotoxon
  Decreased Nasophayngeal Lymphoid tissue
  Prominent tubular nose
  Deficient nasal alae
 Bulbous nasal tip  Nasal voice
Neuropsychiatric Head Somatic GU Lab
Learning disability
  Blunt or inappropriate affect
  Mental retardation
  Psychotic illness
Microcephaly Minor Auricular anomalies Slender hands and digits

Short stature

Overlapping features of DiGeorge Syndrome

  Neonatal Hypocalcemia
  T-lymphocyte dysfunction
  Monosomy for a 22q11 region

The Inheritance is autosomal dominant and there is often deletion of chromosome 22q11  [5]

For completion's sake the following is the description of DiGeorge Syndrome, which is not especially relevant to psychiatry. Individuals with the DiGeorge syndrome often have cardiac defects,  immune system deficiencies and can be moderately retarded. The cause of the DiGeorge syndrome is a defect in chromosome 22, where one of
the bands in the long arm has been deleted. The deletion can be suspected by looking at the karyotype and can be confirmed by FISH.

..\Bigframe_links/kdig.htmlThis image shows the karyotype of an
individual with the DiGeorge syndrome. By looking carefully at the
pair of 22's, you can see that there is a light band missing in the
chromosome to the right. It might be easier to see the defect in the
composite karyotype of chromosome 22 from the same individual. 

..\Bigframe_links/dig.htmlThis image shows a FISH, where the probe
has been used to locate the defect associated with the Digeorge
syndrome. [6]

The Catechol-O-methyl transferase (COMT) gene has been previously
mapped to 22q11.

COMPT metabolises catecholamines, such as noradrenaline, adrenaline,
and dopamine in soluble and membrane-bound forms but is found
predominantly in the cyctoplasm. Low COMPT activity has been
associated with in women with primary affective disorder [7].

It is conceivable that individuals hemizygous for COMT and carrying a
low metabolising alle on their non-deleted chromosome would be
predisposed to the development of the psychotic features of VCF. This
event could occur via decreased inactivation of catecholamines in the
brain, increased placental transfer of catecholamines, or both. . 23%
of a randomly selected population were classified as low
metabolisers [8], so the frequency of the low activity alle(s)
would a considerable proportion of the VCF syndrome group. [9]


[1] Wilson DI, Cross JA, et al. DiGeorge Sequence, isolated aortic
coarctation and isolated ventricular septal defect in three sibs with
a 22q11 deletion of maternal origin Br. Heart J 1991;66:308-12

[2] Scrambler PJ, Kelly D, Lindsay E, Williamson R, Goldberg R,
Shprintzen R, Wilson DI, Goodship JA, Cross IE, Burn J, Lancet
1992,339; May 9 1138-1139

[3] McDonald-McGinn DM, Kirschner R, Goldmuntz E, Sullivan K, Eicher
P, Gerdes M, Moss E, Solot C, Wang P, Jacobs I, Handler S, Knightly
C, Heher K, Wilson M,Ming JE, Grace K, Driscoll D, Pasquariello P,
Randall P, Larossa D, Emanuel BS,Zackai EH. Am J Hum Genet 1999 Mar;64

[4] Funke B, Edelmann L, McCain N, Pandita RK, Ferreira J, Merscher
S, Zohouri M, Cannizzaro L, Shanske A, Morrow BE. Genet Couns 1999;10

[5] This information was obtained from NIH  at


[7]] Cohn CK,Dunner DL,Azelrod J. Reduced Catechol-O-
methyltransferase activity in red blood cells of women with primary
affective disorder. Science 1070;170:1323-24

[8] Weinshilboum RM, Raymond FA. Inheritance of low erythrocyte
catecho-O-methyltransferase activity in men AM J Med Genet

[9]Dunhan I J, Collins J, Wadey R, Scambler P. Lancet 1992; 340 Nov
28, 1361-1362


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