MPS 3A Sanfilippo-Syndrom 
Author Message
 MPS 3A Sanfilippo-Syndrom

Dear Ulrich:

Sorry for the delay in responding to your inquiry of 3/28/95.
Unfortunately, I know nothing about Sanfilippo syndrome or its causes.
I was able to perform a Medline search on the topic, and retrieved the
following information.  It appears that the least is known regarding the
type A syndrome.

I'm sorry that this is all I have to offer.  All the best to you.

Ken Brady

1.      Emmanouil NE, Kerameos FC. Developmental malformations of human
tongue and associated syndromes (review). Bull Group Int Rech Sci
Stomatol Odontol 1992;35(1-2):5-12.:The development of the tongue begins
as known, in the floor of the primitive {*filter*}cavity, when the human
embryo is four weeks old. More specifically, the tongue develops from
the region of the first three or four branchial arches during the period
that the external face develops. Malformations of the tongue, are
structural defects, present at birth and happening during embryogenesis.
The most common malformations are: 1. Aglossia 2. Microglossia, which is
always combined with other defects and syndromes, like Moebius syndrome
3. Macroglossia, which is commonly associated with cretinism, Down's
syndrome, Hunter's syndrome, Sanfilippo syndrome and other types of
mental retardation 4. Accessory tongue 5. Long tongue 6. Cleft or Bifid
tongue, condition very usual in patients with the orodigito{*filter*}
syndrome 7. Glossitis Rhombica Mediana, a developmental malformation? 8.
Lingual thyroid. Malformations are extensively analysed and discussed.

2.      Siciliano L, Fiumara A, Pavone L, et al. Sanfilippo syndrome
type D in two adolescent sisters. J Med Genet 1991;28(6):402-5.:We
report on two adolescent sisters with Sanfilippo syndrome type D with
some clinical features different from other cases previously described.
They are the oldest cases reported to date and provide new clues about
the course of the disease. Enzymatic and immunological characterisation
of the patients' fibroblasts indicated deficiency of
N-acetylglucosamine-6-sulphate sulphatase (GlcNAc-6S sulphatase).
However, Northern blot analysis showed apparently normal mRNA encoding
GlcNAc-6S sulphatase. These findings suggest that abnormal translation
or premature degradation may be responsible for the enzyme defect in
these cases of Sanfilippo syndrome type D.

3.      Freeman C, Hopwood JJ. Sanfilippo D syndrome: correction of
glucosamine-6-sulphatase deficiency following fibroblast culture in
Chang's media. Prenat Diagn 1991;11(9):711-7.:The de-O-sulphation of
alpha-linked glucosamine-6-sulphate residues in heparan sulphate
requires a specific sulphatase, glucosamine-6-sulphatase, which has been
shown to be deficient in tissues of Sanfilippo D, or
mucopolysaccharidosis type IIID (MPS IIID), patients. MPS IIID
fibroblasts cultured in Basal Eagle's medium supplemented with either
fetal calf serum or heat-inactivated fetal calf serum, MDCB or Ultraserg
media had residual glucosamine-6-sulphatase activities towards a
heparin-derived trisaccharide substrate,
O-(alpha-N-acetylglucosamine-6-sulphate)-(1----4)-L-O-(alpha- iduronic
acid-2-sulphate)-(1----4)-D-O-2,5-anhydro[1-3H]mannitol-6- sulphate,
GlcNAc6S-IdoA2S-anM6S, which were less than 1 per cent of the normal
range for fibroblasts cultured in Basal Eagle's medium supplemented with
fetal calf serum. However, the glucosamine-6-sulphatase activities of
MPS IIID fibroblasts grown in Chang's medium were similar to the
activities in normal control fibroblasts which were cultured in Basal
Eagle's medium. These results indicate that caution is required for
prenatal diagnosis of MPS IIID patients using chorionic villi or
amniotic cells cultured in Chang's medium.

4.      Thompson JN, Jones MZ, Dawson G, Huffman PS. N-acetylglucosamine
6-sulphatase deficiency in a Nubian goat: a model of Sanfilippo syndrome
type D (mucopolysaccharidosis IIID). J Inherit Metab Dis
1992;15(5):760-8.:A male Nubian goat (SD-1) presented at birth with
neurological manifestations consistent with a lysosomal storage disease.
Histological studies of tissue obtained at autopsy suggested
glycosaminoglycan storage. Total urinary glycosaminoglycan levels, as
measured by the uronic acid method, were elevated but overlapped with
levels in a younger control goat. However, N-sulphate content was
increased 2- to 5-fold, suggestive of heparan sulphate excretion, and
this elevation was confirmed by cellulose acetate electrophoresis.
Further, urinary levels of free N-acetylglucosamine 6-sulphate were
increased 6-fold over controls, SD-1 cultured skin fibroblasts, labelled
with [35S]sulphate from the incorporated twice as much radioactivity
into macromolecular material as did normal fibroblasts. Forty-eight
hours after removal of [35S]sulphate from the medium the SD-1
fibroblasts retained 58% of the label, whereas in control fibroblasts it
had declined to 20%, indicative of [35S]proteoglycan storage in SD-1.
The assay of fibroblast extracts revealed a profound deficiency of
N-acetylglucosamine 6-sulphatase whereas eight other activities
including beta-mannosidase, arylsulphatase B, iduronate 2-sulphatase,
N-acetylgalactosamine 6-sulphatase, and heparin sulphamidase were
normal. Mixing of SD-1 sonicates with normal sonicates showed no
evidence of an inhibitor, and mixing of SD-1 sonicates with Sanfilippo D
cell sonicates yielded no activity. These data ruled out multiple
sulphatase deficiency and suggested the first example of the human
Sanfilippo syndrome, type D (N-acetylglucosamine 6-sulphatase
deficiency) in goats.

5.      Pande H, Chester A, Lie H, Thorsby E, Stormorken H. Concomitant
occurrence of mucopolysaccharidosis IIIB and Glanzmann's thrombasthenia.
Further evidence of a hyperactive
alpha-N-acetylglucosaminidase-producing allele. Clin Genet
1992;41(5):243-7.:A daughter of first cousins had two extremely rare,
recessive disorders: thrombasthenia (Glanzmann's disease, glycoprotein
IIb/IIIa deficiency) and mucopolysaccharidosis IIIB, (Sanfilippo B
syndrome, alpha-N-acetylglucosaminidase (NAG) deficiency). Normal
alpha-N-acetylglucosaminidase activity was observed in two obligate
heterozygotes (the proband's father and her maternal grandmother),
suggesting that in addition to the normal and defective alleles, a
third, hyperactive allele is also present in this family. Such a
hyperactive allele seems to be quite prevalent in our area, and makes
the biochemical identification of heterozygotes impossible if no
extensive family surveys provide additional clues. There was no linkage
between the two diseases, nor between any of them and several
{*filter*}-groups and HLA-antigens tested for.

6.      Ozand PT, Devol EB, Gascon GG. Neurometabolic diseases at a
national referral center: five years experience at the King Faisal
Specialist Hospital and Research Centre. J Child Neurol 1992;7(1):11.:Of
910 children under the age of 12 years referred to the national center,
we were able to assign an etiology to 473 (52%). This group consisted of
lysosomal storage diseases (32%), amino acid disorders (14%), organic
acid disorders (16%), various chromosome abnormalities and syndromes
with dysmorphia or brain dysgenesis (26%), and various other metabolic
diseases (12%). While such amino acidemias as branched-chain amino
acidemia (MSUD) in classic and intermediate forms (44%) and
hyperphenylalaninemia (PKU) due to 6-pyruvoyltetrahydropterin synthase
deficiency (6PTSD) (19%) were common, classic PKU was rare (16%).
Methylmalonic acidemia (31%), 3-hydroxy-3-methylglutaryl-coenzyme A
lyase deficiency (16%), and propionic acidemia (12%) were encountered
more frequently than other types of organic acidemias. When compared to
the number of referred Down's syndrome patients, the results suggested
the birth of at least one infant with neurometabolic disease per 50
births. Five tribes of Saudi Arabia constituted 26% of the diagnosable
neurometabolic diseases. Diseases such as MSUD, 6 PTSD, Sanfilippo
syndrome type B, methylmalonic acidemia, homocystinuria, GM2
gangliosidosis Sandhoff variant, infantile central nervous system spongy
degeneration (Canavan disease), and neuraminidase deficiency showed
definite tribal occurrence. In addition, 32% to 42% of the definitely
diagnosed, and 25% to 87% of patients with probable neurometabolic
disease but without a definable etiology, had more than one sibling
affected. It is concluded that the many rare autosomal diseases of Saudi
Arabia are due to "founder effect" created by marriages occurring within
tribal and extended family boundaries.

7.      Sasaki T, Sukegawa K, Masue M, Fukuda S, Tomatsu S, Orii T.
Purification and partial characterization of
alpha-N-acetylglucosaminidase from human liver. J Biochem (Tokyo)
1991;110(5):842-6.:A deficiency in alpha-N-acetylglucosaminidase is
known as mucopolysaccharidosis IIIB or Sanfilippo B syndrome. We
purified this enzyme almost 39,000-fold from liver to homogeneity with
3% recovery. Use of concanavalin A (Con A)-Sepharose and
heparin-Sepharose resulted in 13.4-fold and 11.6-fold purifications of
the enzymatic activity, respectively. The molecular mass was estimated
to be 300 kDa by gel filtration and 80 kDa by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The
isoelectric point was 5.1, optimal pH was 4.5, and the Km for
p-nitrophenyl alpha-N-acetylglucosamine was 0.13-0.20 mM. The purified
enzyme was stable at 50 degrees C for 1 h and within the pH range of
6.5-8.5. Anti-serum against the purified enzyme raised in BALB/c mice
inhibited the activities of alpha-N-acetylglucosaminidase.

8.      Freeman C, Hopwood JJ. Human glucosamine-6-sulphatase
deficiency. Diagnostic enzymology towards heparin-derived trisaccharide
substrates. Biochem J 1992;.:Glucosamine-6-sulphatase (6S) activity
towards a series of radiolabelled heparin-derived trisaccharide
substrates was determined in cultured human skin fibroblast and
leucocyte homogenates, and in urine supernatants of normal individuals
and patients affected with 6S deficiency [Sanfilippo D syndrome;
mucopolysaccharidosis (MPS) type IIID]. The N-sulphated and N-acetylated
derivatives of the trisaccharide substrate O-(alpha-glucosamine
6-sulphate)-(1----4)-L-O-(alpha-iduronic acid
2-sulphate)-(1----4)-D-O-2,5-anhydro[1-3H]mannitol 6-sulphate
(GlcNH6S-IdoA2S-anM6S) were prepared by enzymic digestion of a
pentasulphated tetrasaccharide isolated following the HNO2 deamination
of heparin. Purified lysosomal enzymes and MPS-patient skin fibroblasts
were used along with chemical degradation to confirm the structure of
each of the substrates that were utilized to study the interaction of
the enzyme activities required to degrade the highly sulphated regions
of heparan sulphate. Human liver, skin fibroblast and urine 6S
activities were separated by chromatofocusing into at least four and
possibly up to six individual activities. 6S activities present in each
of the tissues generally had similar catalytic properties, including Km
values, pH optima and inhibition with NaCl, Na2SO4 and NaH2PO4.
Leucocyte and skin fibroblast 6S activities towards
GlcNAc6S-IdoA2S-anM6S were maximal at pH 4.1 and 3.9 respectively, with
Km values of 2.8 microM and 0.9-1.7 microM respectively. Urine 6S
activity towards GlcNAc6S-IdoA2S-anM6S was stimulated 30-fold by BSA at
pH 3.9, which shifted the pH optimum from 5.1 to 4.2 and decreased the
Km value at pH 4.2 from 4.0 microM to 0.5 microM. Residual 6S activity
present in the skin fibroblast homogenates from MPS IIID patients was
characterized for activity towards GlcNAc6S-IdoA2S-anM6S and observed to
have similar pH optima and Km values to normal skin fibroblast 6S
activities, although the residual 6S activity was less than 1% of the
normal control range.

9.      Cossu F, Cannas C, Medda C. [Propofol and fentanyl in Sanfilippo
disease. Surgical intervention with adenotonsillectomy]. Minerva
Anestesiol 1992;58(5):319-21.:An intravenous anesthesia with propofol
and fentanyl was used for adenotonsillectomy in a child affected by
mucopolysaccharidosis. This technique proved to be safe and convenient
without peri- and postoperative complications.

10.     Vellodi A, Young E, New M, Pot MC, Hugh JK. Bone marrow
transplantation for Sanfilippo disease type B. J Inherit Metab Dis
1992;15(6):911-8.:Allogeneic bone marrow transplantation was performed
on twins with Sanfilippo B disease. They were the first two patients
with this disorder to undergo the procedure. There was definite evidence
of engraftment as shown by conversion to donor {*filter*} group antigen and
tissue type, and increased leukocyte alpha-glucosaminidase activity.
Nine years post transplant, neither twin is as handicapped as her
untreated brothers were at the same age, although in one twin
hyperactivity and behavioural problems, characteristic of the disorder,
are present. Details of the twins' intellectual development and growth,
their alpha-glucosaminidase activity and urinary glycosaminoglycan
excretion are reported.

11.     Di NP. Sanfilippo B disease: a re-examination of a particular
sibship after 12 years. J Inherit Metab Dis 1991;14(1):23-8.:A
particular sibship, with mild and severe types of Sanfilippo B disease
within the same family, was re-examined after 12 years. The phenotypes
of the mild and of the severe patients were maintained, specifically the
mental retardation. Cultures of lymphoblasts from the mild patient were
established and proteins were electrophoresed in native conditions and
then immunoblotted with specific antibody. Two bands of 182,000 and
131,000 Da were found, comigrating with the enzyme from normal
lymphoblasts and the enzyme from normal urine. The data are discussed in
relationship to the molecular defect underlying
alpha-N-acetylglucosaminidase deficiency and to the ability of the
antiserum to react with normal, mutant, monomeric and multimeric forms
of the enzyme.

12.     Zaremba J, Kleijer WJ, Huijmans JG, Poorthuis B, Fidzianska E,
Glogowska I. Chromosomes 14 and 21 as possible candidates for mapping
the gene for Sanfilippo disease type IIIC. J Med Genet 1992;29(7).

13.     Sewell AC, Wern C, Pontz BF. Brachyolmia: a skeletal dysplasia
with an altered mucopolysaccharide excretion. Clin Genet
1991;40(4):312-7.:A 15-year-old girl is described with brachyolmia. She
presented with short-trunked dwarfism, hypolordosis of the lower spine
and radiological features of the disease. She was initially considered
to have a mucopolysaccharidosis (type III Sanfilippo) on account of a
pathological urinary glycosaminoglycan excretion pattern. The amount of
urinary glycosaminoglycans was normal, but we found an increased amount
of an undersulphated chondroitin sulphate molecule. Our finding of an
undersulphated glycosaminoglycan points to a disturbance in chondroitin
sulphate synthesis, and it is rare that a defect in glycosaminoglycan
synthesis leads to a skeletal dysplasia. To our knowledge, this is the
second case of brachyolmia with a possible defect in chondroitin

14.     Beck M. [Mucopolysaccharidosis. Nosology--clinical
aspects--therapeutic approaches]. Monatsschr Kinderheilkd
1991;139(3):120-7.:The mucopolysaccharidoses represent a group of
lysosomal storage disorders characterized by coarse facies, skeletal
deformities, and often mental deterioration. Recent clinical and
biochemical studies have revealed a broad genetic heterogeneity of these
metabolic diseases: An identical enzyme defect may lead to a mild form
with normal {*filter*} height and normal life expectancy or to a severe
hydrops fetalis that does not survive the first days of life.
Conversely, Sanfilippo disease is an example that identical phenotypes
may result from mutations of different genes. From clinical observations
it became clear, that not only the skin, brain and skeletal system are
involved in the storage process, but also the lungs and the
cardiovascular system. Until recently, no more than palliative treatment
could be offered. This consists of corneal transplantation, cervical
fusion to prevent atlantoaxial subluxation, especially in Morquio's
disease, and shunt operation to relieve hydrocephalus. In the last
decade bone marrow transplantation became available; this may have
beneficial effects in selected cases, especially in
mucopolysaccharidosis I. Since the genes of several lysosomal enzymes
have been identified, many efforts to introduce the normal gene into the
affected cells were done. This method was successfully applied in an
animal model. But many efforts in several laboratories are still
necessary until this therapeutic regimen will become available for
patients with mucopolysaccharidosis.

Mon, 13 Oct 1997 03:00:00 GMT
 [ 1 post ] 

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