FIRST MONTHS OF DRUG THERAPY
IN A CRI-DU-CHAT CASE
Renato COCCHI,
a neurologist and a medical psychologist.
Abstract
It
is reported a case of Cri-du-chat syndrome in a male child aged 4 years and 6
months at first consultation, with chromosomal diagnosis as 46, XY, ish del
(5), t (3:5) (p. 25.3; p.14.3) mat. Among other symptoms, he showed mental
retardation and language retardation, being only able to utter wordless sounds.
Having found several symtoms linked to some brain neurotrasmitters, namely
GABA, glutamate, serotonin, acetylcholine, noradrenalin, a drug therapy acting
on them has been attempted. This is first three months report where some
improvements were noted
Key
words: Stress; chromosome 5; Cri-du-chat syndrome; mental
retardation; drug therapy.
Chromosomal
anomalies
Mental
retardation
Drug modulation of stress reactions
Home Page
We use
the operative definition of stress set on the index page of this WEB site. Then
the following report cannot surprise anybody, because it is the logical
consequence of it.
I wrote
there: We term stress a set of relations linking external or internal stressors
of physical, chemical, biological / metabolic, and psychological / social
origin to nonspecific reactions of a living organism. These reactions come out
from the homeostasis' modification elicited by the stressor or stressors, and
act as a common final pathway.
Among the
consequences of this assumption I pointed out:
1. Any
internal biological / metabolic modification capable to disrupting homeostasis
can cause stress reactions.
2. Every
illness can have symptoms of stress reactions as accompanying symptoms besides
its direct symptoms.
3. The
modulation of stress responses can give some relief to every illness, even to
genetic-chromosomal diseases. (Cocchi R. Pre-menstrual syndrome as the paradigm
of an internal biochemical stress. 2nd World Congress on Stress, Melbourne
1998)
Drug
therapy in Down syndrome was the aim of many research I reported in this WEB
site (see: Home page /Down syndrome). The same I did for a case of
Bourneville's Tuberous Sclerosis. Now I want to refer about the first months of
drug therapy in a Cri-du-chat syndrome, an abnormality of the fifth chromosome.
Case history.
05 May
2001 - Male aged 4 years and 6 months at first consultation, suffers from the
syndrome of Cri-du-chat, with chromosomal diagnosis as 46, XY, ish del (5), t
(3:5) (p. 25.3; p.14.3) mat. He presents mental retardation and language
retardation, being only able to utter wordless sounds. His mood is fairly
serene, with some anger outbursts without any (apparent) reason.
Following
an inter-atrium malformation, he had open heart surgery. From his early months
he caught recurrent bronchitis, and a ab ingestis pneumonia when he was 3
months. Even now he has upper respiratory tract infections' easiness with more
than 4 antibiotic therapies within last 12 months. His face is rosy.
Soon
after he awake, he needs eating, and differently than in past, now he eats
enough, but he is poorly chewing. He likes tasty /salted foods with scarce
greediness for sweet things; He tastes meat bullion, but no information about
cube bullion because the mother did never propose it to him by caution. He uses
to bring everything to his mouth.
The child
has not regular bowel function, with spastic constipation.
Falling
asleep in the evening is always difficult, even between his mother's arms.
During the whole night he is awaking several times. There is drooling when he
is sleeping. Hyperkinesis is evident motor behaviour. If supported by one
adult's hand, he can walk. He recognizes the persons of his family.
This was
the drug regimen prescribed (daily doses):
amantadine 100mg;
glutamine 125mg;
pyridoxine 75mg;
carbamazepine
50mg;
diazepam
1mg.
I
expected the first checkup after one-month therapy, to evaluate if drugs were
adequate, and possible side effects.
02 June
2001 - No side effects of the drugs were reported. He is more quiet, perhaps
with fewer anger outbursts. During last month he caught laryngitis and
bronchitis treated by antibiotics. Now he does not have difficulties in falling
asleep, but he has some awakenings during the night, as it happens previously.
Night drooling decreased.
His
attention increased, and now he uses his voice more. He uses to bring
everything to his mouth as he did before starting drugs. His chewing does not
go better. Spastic constipation did not change. He recognizes more persons and
is more affectionate.
Regimen
variation (daily doses):
glutamine
250mg;
carbamazepine
100mg.
I scheduled
the next checkup after two months.
04 August
2001 - This checkup took room three months after the child started drug
therapy. He is doing better. His attention increased with longer time. When one
person is spoking him, he is paying his attention till the end, and soon after
he nods a sensible yes or not.
Anger
outbursts decreased, being shorter but stronger. He uses to hit himself in his
temples or to attack other people and to bite. Parents also noted some head
banging, and mansturbation by rubbing his sex. He is spiteful, and uses to
challenge by doing what he was not allowed to do.
Parents
cannot say if the child has her face modified, as it seems to me. During last
two months he caught only a light sore throat that did not need any antibiotic
therapy.
As for
verbal language, the articulation of throat sounds began. When other people are
speaking to him, he is very attentive to their mouth movements, and try to
imitate them. He increased his voice emission.
Except
his mother (??), he is more affectionate to every person. He does not stand his
mother showing any interest for him, when she is speaking with other persons.
As for his bowel, he always has goat-like stools.
Falling
asleep is earlier, but he uses to awake during the night, then he plays or goes
into the parents' bed. Sleep drooling stopped. During his sleeping, he has
starts, mainly in first hours of sleep. As the parents reported, they seem
similar to Moro type startle reflexes. Before falling asleep, he need to rub
his head against the pillow, perhaps only right part of his head. Sometimes he
falls asleep only on his mother's arms. Hyperkinesis evidently decreased.
Now he
can stand up when he finds something to hang on and to bring up himself, then
he can walk by holding on the furniture. The fire attracted him. Sometimes he
is showing clear rocking behaviour. He gives things and perhaps he understood
the ideas of giving and of getting.
Regimen
variation (daily doses):
diazepam
2mg.
Discussion.
Cri du
chat syndrome is associated with a deletion on the short arm of chromosome 5.
It has an incidence of 1/50,000 in newborn infants. A de novo deletion is
present in 85% of the patients. Ten to 15% are familial cases with more than
90% due to a parental translocation and 5% due to an inversion of chromosome 5.
(Van Buggenhout et al, 2000).
Most
characteristic is the anatomical abnormality of the larynx resulting in a
cat-like cry (Brislin, Stayer and Schwartz 1995). The origin of this has
recently been localised to 5p15.3 and is separate from the remaining clinical
features of the syndrome, which have been localised to 5p15.2 (Cornish et al.,
1999).
Posteriorly
rotated ears, short palpebral fissures with an upward slant, a wide nasal
bridge, a thin upper lip, and a short neck and in addition, complex congenital
heart diseases are also reported (Hutcheon, Mallik and Shaham, 1998).
The
behavioural profile of children with cri du chat syndrome incorporates self
injurious behaviour, repetitive movements, hypersensitivity to sound, clumsiness,
and obsessive attachments to objects. (Cornish and Pigram, 1996). Hyperactivity
was the most significant and frequent problem (Dykens and Clarke, 1997).
There is
a high phenotype variability (Church et al., 1995) and there was no correlation
between the size of the deletion and the level of developmental delay. Patients
with cri-du-chat syndrome can be highly different also in the level of
developmental achievement (Marinescu et al., 1999).
A
hypothesis suggests a separate region in p15.3 for the speech delay (Mainardi
et al., 2001). Using finely tuned measures of cognition, a clear discrepancy in
the pattern of language functioning was often found with better receptive than
expressive language skills (Cornish et al, 1999).
The
verbal language can show that the referential and expressive functions are
relatively good but with a poor adaptation to the interlocutors. The disparity
between the cognitive-semantic, the syntactic and the nonlinguistic cognitive
functions is negligible. Only the pragmatic function of the child remains
weaker than that achieved for the other facets of his language. (Pierart and
Remacle, 1996).
Some
exceptions exist: Cognitive performance can indicate good verbal skills with
specific strengths on those tasks that require the ability to store and
retrieve verbal information in comparison to poor non-verbal, spatial skills
and weaknesses on those tasks that require multi-step manipulation of spatial
stimuli and the ability to form whole percepts from fragmentary parts (Cornish,
1996).
I did not
find any specific report about therapy other than some generic indications to
infant-stimulation programs (Van Buggenhout et al, 2000).
In the
case here reported the incentive to attempt a drug therapy was the presence of
many symptoms linked to stress reactions. In other terms, the presence of
symptoms that are not specific of the Cri-du-chat syndrome. We can find them in
other mental illnesses, not necessarily genetic or chromosomic ones.
We list
now several of them, with the possible neurochemical mechanism involved in
brackets:
- mental retardation (GABA - glutamate?);
- speech retardation (GABA - grutamate?)
- anger
outbursts without reason (noradrenaline-adrenaline);
- uper
respiratory tract infections easiness (cortisol - glutamine);
- spastic
constipation (peripheral acetylcholine);
- poor
greediness for sweet things (glutamate - GABA);
-
difficulty in falling asleep (serotonin);
-
recurrent awakenings during the night (GABA - adrenaline);
- night
drooling during sleep (GABA - peripheral acetylcholine);
-
hyperkinesis and attention deficit disorder (dopamine - GABA);
-
"neurotic" mansturbation in childhood (adrenaline).
These are
the symptoms I used for choosing the drug regimen acting on GABA (diazepam,
carbamazepine and pyridoxine), on glutamate and cell-mediated immunity
(glutamine) and on dopamine (amantadine).
It is
possible that the new balance between the type A and the type B GABAergic
inhibition, indirectly improves serotoninergic and cholinergic pathways besides
increasing the stress threshold. Till now, I did not prescribe specific drugs
acting in these two neurotransmitters.
Three
months of drug therapy are surely few, but some improvements do appear clear.
The chromosomal anomaly stays and will stay without any variation, but its
phenotypical frame can be modified. This fact can make the child's and his
parents' life more viable. This, perhaps, is not a little thing.
The
working hypothesis at the basis of this approach found its confirmation in a
case already judged as fully irreducible. The presence of stress reactions, the
amount of which can be modulated by drugs, does allow such positive results.
References
Brislin
RP; Stayer SA; Schwartz RE. Anaesthetic considerations for the patient with cri
du chat syndrome. Paediatr Anaesth 1995, 5: 139-141.
Church
DM; Bengtsson U; Nielsen KV; Wasmuth JJ; Niebuhr E. Molecular definition of
deletions of different segments of distal 5p that result in distinct phenotypic
features. Am J Hum Genet 1995, 56: 1162-1172
Cornish
KM. The neuropsychological profile of cri du chat syndrome without significant
learning disability. Dev Med Child Neurol 1996, 38:941-944.
Cornish
KM; Bramble D; Munir F; Pigram J. Cognitive functioning in children with
typical cri du chat (5p-) syndrome. Dev Med Child Neurol 1999, 41: 263-266.
Cornish
KM; Cross G; Green A; Willatt L; Bradshaw JM. A neuropsychological-genetic
profile of atypical cri du chat syndrome: Implications for prognosis.
J Med
Genet 1999, 36: 567-370.
Cornish
KM;Pigram J. Developmental and behavioural characteristics of cri du chat
syndrome. Arch Dis Child 1996,
75:448-450.
Dykens EM; Clarke DJ. Correlates of
maladaptive behavior in individuals with 5p- (cri du chat) syndrome. Dev Med
Child Neurol 1997, 39:752-756.
Hutcheon RG; Mallik A; Shaham M. Clinical
features and mental development of a child with a prenatally identified
45,XX,der(5)t(5; 18) (p15; q11.2),-18 karyotype. J Med Genet 1998, 35: 865-867.
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Overhauser J; Pierluigi M; Bricarelli FD.
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Genotype-phenotype correlation. J Med Genet 2001, 38: 151-158.
Marinescu RC; Johnson EI; Dykens EM; Hodapp
RM; Overhauser J. No relationship between the size of the deletion and the
level of developmental delay in cri-du-chat syndrome. Am J Med Genet 1999, 86:
66-70.
Pierart B; Remacle M. L'evolution d'un cas
de syndrome du cri du chat: caracteristiques ORL, cognitives et langagieres.
Folia Phoniatr Logop 1996, 48: 223-230.
Van Buggenhout GJ; Pijkels E; Holvoet M;
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patients. Am J Med Genet 2000, 90: 203-215.
Firts published in Internet on November 2001. Copyright by Renato Cocchi, 2001.
Author's address: dr Renato COCCHI, via
Rabbeno, 3
42100 Reggio Emilia (Italy).
renatococchi@libero.it
Chromosomal anomalies
Mental retardation
Drug modulation of stress reactions
Testo in italiano