TREATMENT WITH
ANTISTRESS DRUGS OF A GM1 GANGLIOSIDOSIS,
OF PROBABLE INTERMEDIATE
JUVENILE-ADULT TYPE. (Updated on Sept, 2003)
Renato COCCHI, neurologist and medical
psychologis
Summary.
The case history of a 10;2 years-old
girl, suffering from GM1 gangliosidosis inherited from heterozygotic parents
with reduction of the beta-galactosidase enzyme, is reported.
The NMR of the brain seems to have very
little if null gangliosidosis storage and the US scan of visceral organs did
not reveal any mucopolysaccharides storage. For the age onset and the current
situation this GM1 gangliosidosis appears an intermediate case between a
juvenile form ( type II ) and a chronic adult form ( type III ).
An antistress and antihyperkinetic drug
therapy, three months later, seems has given some results on the balance,
hyperkinesis, the speaking, the sleep and the feeding.
Key words: GM1 gangliosidosis,
juvenile-adult type, stress, hyperkinesis, drug therapy.
Drug modulation of stress reactions.
Other genetic and chromosomic anomalies.
Mental retardation
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Introduction.
The GM1 gangliosidosis syndrome is an
autosomal recessive disorder caused by a deficiency of beta-galactosidase which
results in a reduced action of it. This anomaly drives to accumulation of the
ganglioside GM1 in the brain, and of large amounts of keratosulfate-like
mucopolysaccharide in the visceral organs. The affected infants could appear
normal at birth. There are three clinical variants, with progressively lower
severity, as it follows:
i. Infantile (type 1): The typical infantile
subtype combines the features of some neurolipidosis (ie, neurodegeneration,
macular cherry-red spots) with those of a mucopolysaccharidosis (ie,
visceromegaly, dysostosis multiplex, coarsened facial features). This form of
GM1 gangliosidosis most frequently presents in early infancy and may be evident
at birth.
ii. Juvenile (type 2): The juvenile subtype
is marked by a slightly later age of onset and clinical variability in the
physical features as typical of the previous form.
iii. Adult (type 3): The adult subtype
features normal early neurologic development with no physical specific signs
and subsequent development of a slowly progressive dementia with parkinsonian
features, extrapyramidal disease, and dystonia.
In the type I, the deposition of GM1
gangliosides is extensive, but in the Type II is less extensive, while in the
type III, it occurs primarily in the basal ganglia. The storage of substances
in the peripheral tissues decreases from type I to type III.
Chronic forms of GM1 (type III)
gangliosidosis are variable and there have been fewer cases to study (Suzuki,
1992). Cortical atrophy is found in insignificant amounts while the basal
ganglia (caudate, putamen, and globus pallidus) show a notable decrease in
size.
In particular, type III (Adult Form) shows a
late onset (teens), lack of visceral involvement while CNS manifestations are
gait disturbances (ataxia), dysarthria, spasticity, slowly progressive dystonia
affecting the face and limbs, mild mental impairment.
Morbidity and mortality.
The infantile form (type 1) typically
presents between birth and age six months with progressive organomegaly,
dysostosis multiplex, facial coarsening, and rapid neurologic deterioration
within the first year of life. Death usually occurs during the second year of
life because of infection (usually due to pneumonia that results from recurrent
aspiration) and cardiopulmonary failure.
The juvenile form (type 2) typically
presents at age 1-2 years with progressive psychomotor retardation. Little
visceromegaly and milder skeletal disease are present compared to the infantile
form. Death usually occurs before the second decade of life.
The adult form (type 3) typically presents
during childhood or adolescence as a slowly progressive dementia with prominent
parkinsonian features and extrapyramidal disease, particularly dystonia. Marked
phenotypic variability may occur. Age at death may vary greatly, from after 20
years of age up to 4th decade.
Epidemiology:
The incidence of this genetic anomaly is
rare and estimated 1 out of 100000-320000 live births.
As for the age of onset, it ranges from
infancy (Type I) to adulthood (Type III).
The risk factor is familial - autosomal
recessive chrom. no: 3p21.33, with beta-galactosidase A as the gene involved.
There is not any gender difference. GM1
gangliosidosis has been found in all races,
Medical approach:
Currently, no effective medical treatment is
available for GM1 gangliosidosis.
Symptomatic treatment for some neurologic
followings is available but does not
alter the clinical course significantly.
Currently, drug therapy is not a component
of the standard of care for this illness.
Diet:
No specific diet variation showed any
significant alteration of the clinical course.
Since occurred to visit a girl suffering
from GM1 gangliosidosis, I tried an antistress drug therapy. What follows is
the report of the first month of therapy.
The case history.
F, 8;2-years old at first consultation.
Recently, in a Tuscan University Unit, she had first, and confirmed, the
diagnosis of GM1 gangliosidosis. The parents became aware that something
doesn't go when the child had about two years and half, because a regression of
speaking.
Genetics: Cariotype 46, XX.
Beta-galactosidase = 13 nmol/mg prot. (normal range: 100-200);
alpha-neuraminidase 0.86 nmol/m/h (normal range: 2-7.2).
Diagnosis: GM1 Gangliosidosis.
Parents: beta-galactosidase, mother = 42
nmol/mg prot.; father = 65 nmol/mg prot. (Both heterozygotic parents for the
beta-galactosidase enzyme).
Brain NMR (performed in 2002 ): Modest
increase of the liquoral spaces without any parenchimal lesion.
Fundus oculi: Normal with regular maculas.
Superior abdomen US scan (June 200): Normal
dimensions, (conformation, and structures, when visible) of liver, biliar
pathways and portal veins, gall bladder, pancreas, spleen, kidneys, renal
pelvises and ureters, suprarenal glands.
07 June 2003: Currently, she shows a
regression of the rough motility, which is worsening for the ataxy, a
regressive delay of speaking and mental retardation. She always had difficulty
in fine motility.
Born to term from a regular pregnancy, with
normal length of the delivery, she had modest cyanosis and birthweight of 4300
grams. In her first year of life she ate and slept normally, without any
illnesses from cooling, with coloured face, and a little constipated bowel. She
was crying much without any apparent reason.
Walking came out at 12 months, the two-words
sentence at 24 months.
At night she sleeps well, but often in the
mornings is irritable since her awakening. She has often night bruxism or she
sucks her tongue. Some time talks during her sleep, and she had some episodes
of night terror.
She is inclined to do the opposite, but this
doesn't happen for the lexical choice of the speech.
She would not eat anything till the ten of
the mornings, while in the afternoon eats very much. Poor greediness for sweet
things, except the ice cream, of which is not greedy in particular degree.
Liking for the meat broth is normal. She has always refused the milk, and many
dairy products. She has much drooling and difficulty to bear new environments.
She stands badly the heat, has paresthesias
to the nape and so she doesn't want to be combing. Regular bowel function or a
little atonic constipated, but not diarrheas. She does not suffer from
illnesses from cooling, so not therapies with antibiotics. Surely a
hyperkinetic girl.
Starting therapy (by the oral via, daily
doses): Glutamine 125mg; amantadine 50mg, pyridoxine 75mg, diazepam 1.4mg.
05 July 2003. No problems occurred for the
drug taking, and she is accustomed to taking them. Perhaps she has a little
more balance, and is more sure when going upstairs. By the sea she was worse.
She has done nothing that going down the gangway of the swimming pool, jumping
over or diving. She seemed not have any rest. Now, she drinks more.
The speaking improved; she uses it more, and
with new words, but still at the two-words sentence. The fine motility did not
change. The sleep is improved. When she sleeps too much, she becomes irritable.
When she awakes late, she does opposite things (The Contrary Mary?).
Altogether, she shows less opposition, and perhaps less intolerant of new
environments.
She refuses less to have breakfast in a due
time and in the afternoon eats less. She stood better the heat, which this year
was much sultry. The nap paresthesias did not improve. Less bruxism, even if
she sucks more the tongue. The bowel function works as first. In this therapy
month she never talked during her sleep, and did not show any episode of night
terror. She seems be more attentive, but hyperkinesis runs as usual. Less
drooling occurred and she holds more the closed mouth. More affectionate and
more serene.
Therapeutic variation (daily dose, by the
oral via): Glutamine 250mg; amantadine 100mg.
06.09.2003: Her father says that she did not
show any improvement. The mother instead reports that daughter is more calm,
less hyperkinetic. Her motility seems not improved (no new acquisition).
The expressive language is more used, with
new words. She pays more attention, understands better what people are saying.
She understands and does well double commands.
Now, her sleep is without problems and less
moving during it. Perhaps she is less sucking her tongue when she is falling
asleep. If she slept too much, to the mornings she is "lunatic", as
the mother said.
Now, she is better even to the mornings. She
did not have other "ununderstandable" temper tantrums.
She became more capricious with more
pretensions as she did previously. Her interest for the videotape of the
Zecchino d'oro (an Italian and international festival of children's songs) is a
less exclusive one. Opposition decreased. When into the car, she now accepts to
fast the seat belt, differently than in past.
The sameness too decreased.
Currently she is having breakfast, and
stopped the need of eating in the afternoon. Nap paresthesias reduced. In the
summer season she became more constipated. She doesn't have even any drooling
and her mouth is less opened. She became taller (> 5cm ). The mother saw her
scratching limbs and legs (It is a new symptom, to be carefully observed and
referred). As for her health, she did well.
She is more affectionate to her mother. All
relatives and neighbours find her more calm and even the music rehabilitative
professional agreed.
Therapeutic variation: carbamazepine 100mg.
Always in September the girl had a checkup
in the same Tuscan university centre, where physicians said that she suffered
from the genetic illness Gangliosidosis GM1, now better defined as
Galactosialidosis. They examined her and found her in a stable condition, with
a light worsening of the ataxy. They prescribed the following therapy, added to
the current regimen, which the parents let it known: piracetam 3g;
acetil-L-carnitine 500mg.
November 2003. She worsened in last 10-15
days. The starting of the carbamazepine in the therapeutic regimen elicited
some troubles (tremors, and some falls for increasing of ataxy). In the evening
she strings of pearls. The music therapist finds that she uses better the wind
instruments but she uses less the left hand. When into the car, she arranges
well the seat belt.
Some days she is more calm but in the
morning she is unsociable and in opposition. Since the afternoon she plays even
by herself and she is more calm. Still capricious, as first, but she is more
affectionate.
Usually she goes at school an hour later.
The classmates keep her excluded. Her attention is good, for what she has
interest in. The verbal language improved as for the vocabulary, while it
worsened as for words' articulation. She can read the sentence, but in an
atonic way. The comprehension is good, and perhaps improved.
Currently, she has less appetite. She is
always constipated and did stop drooling. Her hands are always cool, less the
feet. She does scratch anymore (perhaps she was allergic? Or there was a
tactile hyperaesthesia?). Now she permits to have her hair combed. Her sameness
nearly disappeared.
Therapeutic variation (daily doses, by the
oral via): Carbamazepine 100mg.
April 2004: Worsened since the beginning of
March. In the Tuscan university centre, meanwhile, they had doubled the
piracetam dosing. Even there they did not confirm the galattosialidosis
diagnosis they already made, and proposed again the diagnosis of GM1
galattosidosis.
The falls became less frequent and her
motility improved. If she falls, she uses her hands to reduce the earth impact.
She doesn't understand the danger, but she seems nearly that she searches for
it. She strings pearls, in the evening, she succeeds and likes it. Now she is
more hyperkinetic. Her tongue is less protruded and she sleeps with her mouth
closed.
During Christmas she was more calm.
According to the parents now she cannot be managed and she cries all the day
and he is continuously in opposition. She throws away every object; Otherwise,
she bites her hands, or her shirt or her knees. At school he is a
"disaster". She goes to bang, as if she does not see the obstacles,
or she does it on purpose (?). She needs closing the doors of the school
classrooms. Now, she is more affectionate to her father and less to her mother.
When she is motivated, she pays more attention. To the mirror, she recognizes
herself. She likes to have a body massage.
He sleeps is well, and she doesn't cry any
ore during the sleep. She is falling asleep on about the 10.30 pm and her
mother wakes up her on about the eight am. The night bruxism is now rare. Now
she sleeps in her room, because she wants to be more autonomous.
She uses more the language, no new words,
and old words are articulated in a worse way. At least the two-words sentence
is usual. The comprehension is always good. She acts the double orders and even
triple ones. The verbal language is sometimes substituted with the wailing.
Among the classmates she is constantly
alone, outside a ritualized help at the moment she is going into the classroom.
She reads lesser.
Now, she returned more pale, with eye
sockets, and to lose much saliva. Her health is going well; she has had only
one cold.
Therapeutic variation: Thinking that
pharmacological interferences occurred, according to parents piracetam and
acetil-levocarnitine stopped.
The current regimen (daily doses, by the
oral via): Glutamine 125mg; s-adenosil-l-methionine 100mg; pyridoxine 75mg;
amantadine 150mg; diazepam 2.2mg; 5-hydroxi-tryptophan 25mg; amitriptyline
2-4mg.
Discussion.
Facing a girl with a genetic anomaly fully
new for me as the GM1 gangliosidosis, for which the parents asked for help, as
the usual need at once we go to see if there are stress symptoms. So, because
they justify the trial of an antistress drug therapy by themselves alone.
Before all it seems that perinatal
suffering, by cyanosis, with some resentments in the first year life (crying
much, and little constipation).
Other symptoms are:
* a tendency to postpone the breakfast;
* afternoon bulimia;
* refusal for the sweet things;
* poor tolerance for the heat;
* nap paresthesias;
* sometimes atonic constipation;
* bruxism.
Not much to begin, with two symptoms of
energy lack (atonic constipation and afternoon bulimia) and the other five from
excess. The refusal of the milk could well have acted as a self-protection
mechanism the body elicited against the galactose the same milk owns.
The form by itself is very unusual. For what
concerns the age of the onset, we can regard it as a juvenile form, for the
current age and condition it may be more related to adult chronic forms. Since
the borders are always conventional facts, nothing forbids us to think that it
is an intermediate juvenile-adult form.
Till now the NMR, does not show gangliosides
storage in the brain, nor mucopolysaccharides storage in the visceral organs.
It is not clear to which this phenotipycal
difference can be attributed, if it follows more subtle genetic and protective
components, if the deficit of neuroaminidase has some protective function, or
if the child has increased answer ability to the internal metabolic stress
induced by the genetic anomaly. We cannot affirm that these three hypotheses
are mutually exclusive.
After three months from the beginning of a
well tolerated anti-hyperkinetic and antistress drug therapy, we may affirm
that this medical approach as fully feasible. Some result came out on the
balance, on hyperkinesis, on the language, on the sleep and on the feeding.
This fact is not an extraordinary one,
because already seen in very much cases of Down syndrome (Down.htm ) and in other
genetic or chromosomal anomalies (Genetics.htm ).
As usual, nobody pretends to correct the
genetic anomaly, but only to give more resistance to the subject's body
References.
Goldman JE, Katz O, Rapur I et al. Chronic
Gm1 gangliosidosis presenting as dystonia: Clinical and pathological features.
Ann Neur, 1981, 9:465-75.
Suzuki K, Kamoshita S. Clinical pathology of
Gm(1)-gangliosidosis (generalized gangliosidosis). J Neuropath Exp Neur, 1969,
28:25-73
Suzuki, K. "Neuropathology of Late
Onset Gangliosidosis." Developmental Neuroscience. 1991;13: 205-10.
Suzuki Y, Sakuraba H, Oshima A, et al:
Clinical and molecular heterogeneity in hereditary beta-galactosidase
deficiency. Dev Neurosci 1991; 13: 299-303.
Suzuki Y, Oshima A, Nanba E: B-Galactosidase
deficiency (B-Galactosidosis): GM1 gangliosidosis and Morquio B disease. In:
Scriver CR, Sly WS, Valle D, et al, eds. The Metabolic and Molecular Bases of
Inherited Disease . 8th ed. McGraw-Hill Professional; 2001: 3775-3810.
Takano, T, Yamanouchi Y: GM1 gangliosidoses.
Human Genetics 1993, 92:403-404.
Tegay D. GM1 gangliosidosis. eMedicine
Journal, May 31 2002, Volume 3, Number 5.
.
Posted in Internet on July 2003. Copyright by Renato Cocchi, 2003.
Author's address: dr Renato COCCHI, via
Rabbeno, 3
42100 Reggio Emilia.
renatococchi@libero.it
Other genetic and chromosomic anomalies.
Mental retardation
Drug modulation of stress reactions.
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