The enzyme performs a crucial step in the breakdown of the glycosaminoglycan heparan sulfate which is found in the extra-cellular matrix and on cell surface glycoproteins. Although undegraded heparan sulfate is the primary stored substrate, glycolipids such as gangliosides are also stored despite no genetic defect in the enzymes associated with their breakdown.

MPS-III A has an incidence of approximately 1 in 115 000 live births. Higher rates are found in certain populations such as the Ashkenazi jews. It is a rare disease.

Natural History and Diagnosis

It should be noted that MPS-III A, B, C and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.

The disease manifests in young children. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuitism and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. The child often develops normally initially. Acquisition of speech is often slow and incomplete. The disease then progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to carers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. Death eventually results from inanition. The life-span of an affected child does not usually extend beyond late teens to early twenties.

Although the clinical features of the disease are mainly neurological, patients may also develop diarrhoea, carious teeth, and an enlarged liver and spleen. There is a broad range of clinical severity. The disease may very rarely present later in life as a psychotic episode.

The diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.

Treatment

Treatment remains largely supportive. The behavioural disturbances of MPS-III respond poorly to medication. If an early diagnsosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood-brain barrier and therefore cannot treat the neurological manifestations of the disease.

Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system. Several promising therapies are in development. Gene therapy is under investigation for MPS-III in animal models. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the brain blood-brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

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Estrogens control aggressive behavior in some patients with Sanfilippo syndrome
From Neurological Research, 9/1/99 by Hier, Daniel B

We report two women with Sanfilippo syndrome. Both had characteristic aggressiveness that was refractory to treatment with conventional agents. Both women improved on oral estrogen therapy and showed diminished aggressiveness. [Neurol Res 1999; 21: 611-612]

Keywords: Aggression; estrogens; Sanfilippo syndrome; mental retardation

INTRODUCTION

Sanfilippo syndrome is a rare degenerative disorder (Mucopolysaccharidosis III) with severe intellectual and behavioral consequences. Aggressive and disruptive behaviors often make management of this syndrome difficult1-6. Clinically and biochemically the Sanfilippo syndrome is distinct from other mucopolysaccharidoses. The Sanfilippo syndrome itself is heterogeneous and four biochemically distinct forms have been identified. However, the four forms of the syndrome are not clinically distinguishable. Most surviving patients are institutionalized. Management of aggressive behavior is often unsuccessful despite multiple medication trials5.6. We describe the use of estrogens to successfully control aggressive behavior in two female patients.

CASE 1

This 27-year-old white woman with severe mental retardation and aggressive behavior has been institutionalized since childhood. She had been doing well developmentally until her kindergarten year when she developed learning problems and then gradually deteriorating behavior. After transfer to a facility for the mentally retarded, her care was complicated by extreme aggressiveness so that she required two full-time attendants to avoid destructive behaviors. Lithium, beta-blockers, minor tranquilizers, antidepressants, anticonvulsants or anti-psychotic transquilizers did not mollify her aggressiveness. She was hospitalized in July 1994 in order to control aggressive behavior. On evaluation, she was profoundly retarded. Speech output was minimal. Her cranial nerves were intact. Motor strength and reflexes were normal. She had coarsening of facial features. Her hair was coarse. Examination of the hands and feet revealed somewhat shortened digits. Her behavior was both aggressive and self-destructive. She would scratch herself and strike out at her caregivers. Her urine was positive for heparan sulphate. Her plasma revealed a deficiency of N-acetyl-alphaglucosaminidase suggestive of Sanfilippo syndrome type B (Mucopolysaccharidosis Type IIIB). The patient was started on a progestogen/estrogen combination (0.3 mg norgestrel/0.03 mg ethinyl estradiol) with a significant improvement in mood and decrease in aggressiveness.

CASE 2

This 19-years-old white woman had a history of seizures and mental retardation. Her birth and development were normal until age five years when her school performance started to deteriorate. She was subsequently placed in a class for the developmentally delayed. She later developed seizures and gait problems. There was progressive deterioration in behavior with aggressiveness towards caregivers and self-destructive behaviors. On examination at age 19 years, she was profoundly retarded and able to vocalize only a few words. She was very fidgety and restless. Urine examination showed increased heparan sulphate. Her leukocytes revealed a deficiency of sulfaminidase indicative of Sanfilippo syndrome type A. She was treated serially with carbamazepine, haloperidol, thioridiazine, and benzodiazepines with no improvement in aggressiveness. She was placed on a progestogen/estrogen combination (0.3 mg norgestrel/0.03 mg ethinyl estradiol) with marked improvement in her behavior and a reduction in aggressive episodes.

DISCUSSION

The mucopolysaccharidoses (MPS) are a group of inherited disorders caused by a deficiency of specific lysosomal enzymes. The enzyme deficiency interferes with cellular function because of excessive accumulation in the cells of partially degraded glycosaminoglycans. These glycosaminoglycans are also excreted in the urine. Sanfilippo syndrome is a devastating condition for physicians and parents alike. Marked developmental regression, disordered sleep, hyperactivity, and aggressiveness characterize the syndrome. Many exhibit other distressing and unusual night-time behaviors (staying up all night, chewing the bedclothes, and crying out suddenly). Despite severe cognitive deficits, muscular strength is often normal favoring the possibility of inflicting harm during aggressive episodes. Various drugs have been tried in the management of aggressive patients with Sanfilippo syndrome including neuroleptics, anticonvulsants, benzodiazepines, and stimulants without reproducible success. The relationship between estrogen and aggressive behavior in man is uncertain. Nonetheless, estrogens have been occasionally used to control aggressive behavior with favorable results"s. We found estrogen therapy useful in decreasing aggressive behaviors in two women with Sanfilippo syndrome. Estrogen therapy should be considered in controlling aggressive behavior of post-pubertal woman with aggressive behavior.

REFERENCES

1 Bax MC, Colville GA. Behaviour in mucopolysaccharide disorders. Arch Dis Child 1995; 73: 77-81

2 Colville GA, Waters JP, Yule W, Bax M. Sleep problems in children with Sanfilippo syndrome. Dev Med Child Neurol 1996; 38: 538-544

3 Wraith JE, Danks DM, Rogers JG. Mild Sanfilippo syndrome: A further cause of hyperactivity and behavioural disturbance. Med J

Aust 1987; 147: 450-451

4 Clearly MA, Wraith JE. Management of Mucopolysaccharidosis type Ill. Arch Dis Child 1993; 69: 403-406

5 Kim WJK, Berger P, Bunner S, Carey MP. Behavioural manifestations of genetic disorder. J Am Acad Child Adolesc Psychiatry 1996; 35: 976-977

6 Nidiffer FD, Kelly TE. Developmental and degenerative patterns associated with cognitive, behavioural and motor difficulties in the

Sanfilippo syndrome: An epidemiological study. J Men L)enc Kes 1983; 27:185-203

7 Arnold SE. Estrogen for refractory aggression after traumatic brain injury. Am J Psychiatry 1993;10: 1564-1565

8 Kyomen HH, Nobel KW, Wei JY. The use of estrogen to decrease aggressive physical behavior in elderly men with dementia. J Am Geriatr Soc 1991; 39: 1110-1112

Daniel B. Hier, Sharat Ahluwalie, Michelle Melyn and George E. Hoganson Jr*

Department of Neurology, *Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA

Correspondence and reprint requests to: Daniel B. Hier, MD, Department of Neurology, University of Illinois at Chicago, 912 S. Wood Street, Chicago, IL 60612-7330, USA. Accepted for publication March 1999.

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