Develop. Med. Child Neurol. 1969, 11,485492

The Sanfilippo Syndrome: An Unusual Disorder of Mucopolysaccharide Metabolism

Neil Gordon* D. Thursby-Pelhamt

Introduction There are a number of syndromes

associated with disorders of muco- polysaccharide metabolism. McKusick (1966) describes six; Hurler, Hunter, Sanfilippo, Morquio, Scheie and Maro- teaux-Lamy syndromes. All have an auto- soma1 recessive mode of inheritance except Hunter’s syndrome when it is sex- linked recessive. The first two show an excess of chondroitin sulphate B and heparitin sulphate in the urine, in the Sanfilippo syndrome heparitin sulphate alone is excreted in excess and in the Scheie and Maroteaux-Lamy syndromes only chondroitin sulphate B. In Morquio’s syndrome keratosulphate may be found. in large amounts in the urine (Robins et a1 1963) and sometimes an excess of chon- droitin sulphate B (Durand et al. 1967), although the urinary excretion pattern in this particular syndrome is still sub judice. Recently, Ockerman (1967) has recorded a patient with symptoms and signs similar to those seen in Hunter’s syndrome. At autopsy the liver contained a greatly increased amount of a mannose- containing substance which must be different from the mucopolysaccharides characterising these other syndromes.

The appearance of children with Hurler’s and Hunter’s syndromes are similar. The head is large, the bridge of the nose flattened and the tip broad with wide nostrils, and the lips and tongue are large with the mouth often held open. Growth is stunted and, in addition, there is shortening of the neck, deformity of the thorax and protuberance of the abdomen. The hands are broad and the fingers shortened. Genu valgum is commonly seen and there may be marked stiffness of the joints. Mental retardation becomes increasingly manifest and the liver and spleen gradually enlarge. In Hunter’s syndrome deterioration may not be so rapid and the clouding of the cornea, the lumber gibbus and the cardiovascular complications so typical of Hurler’s syn- drome do not occur. Also deafness is commoner in Hunter’s syndrome and nodular skin lesions may be present (McKusick 1966). Abnormalities on X-ray examination include long and shallow sella turcica, wedge-shaped deformities of the bodies of the vertebrae with anterior beaking, and shortening and deformity of the phalangeal bones.

In the Sanfilippo syndrome (Sanfilippo et al. 1963) the intellect deteriorates fairly

* Royal Manchester Children’s Hospital, Pendelbury, Lancs. t North Staffordshire Hospital Centre.

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rapidly and deafness is common; but the patient’s height may be normal and there is no clouding of the cornea; although retinitis pigmentosa may lead to blindness. The liver and spleen only enlarge slightly and there are fewer X-ray changes except for thickening of the vault of the skull. Also cardiovascular complications are un- likely to occur.

McKusick (1966) does not consider that the existence of a separate syndrome, described under the name of Morquio- Ullrich, has been proven, and suggests that all those children with skeletal changes, as described by Morquio and Brailsford, will develop somatic changes if they survive long enough. These children are very dwarfed and the facies are characterised by a broad mouth, prominent lips and short nose. Corneal clouding is late in appearance and intelligence is normal or only slightly affected. Flat vertebrae and abnormalities of the femoral heads on X-ray examination are a characteristic feature.

Those with Scheie’s syndrome (Scheie et al. 1962) are of normal intelligence but have stiff joints, excessive body hair and corneal clouding. They are not dwarfs but the mouth is broad. Aortic valve disease appears to be a feature of the condition (McKusick 1966). The Maroteaux-Lamy syndrome (Maroteaux and Lamy 1965) is also compatible with normal intelligence, but bone changes are marked, particularly a hatchet-shaped upper end of the humerus and fragmentation of the head of the femur. The carpal and tarsal bones are under- developed and the vertebrae and ribs flattened. The nose is enlarged and the lips are thick. There is dwarfing with kyphosis, and the liver and spleen are enlarged. The patient described by Ockerman (1967) had a facial appearance suggestive of gargoylism and was mentally retarded. The vertebrae were abnormal with a gibbus. However, the stature was tall and the liver and spleen were only slightly enlarged. There were

lenticular opacities but no corneal clouding.

Clinical Material The following two patients with the

Sanfilippo syndrome illustrate one of the rarer disorders of mucopolysaccharide metabolism.

Case 1 (Figs 1 and 2) A girl aged 133 years, born by Caesarian

section after a labour lasting five days, the presentation being breech with extended legs. The pregnancy had been normal. The birthweight was 6 Ib. 1 02. The patient was not ill at birthand had no feeding difficulties in infancy. She sat up, unaided, at 5 months and walked at 20 months. Speech was late in developing but, after the age of two, a few words were being said quite clearly. She attcnded a nursery school in her third year and, at this time, the question of hypothyroidism was raised and treatment

Figs. 1 and 2. Case 1 . Patient, aged 134, with Sanfilippo’s syndrome.

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with thyroxine was given for a while. The patient’s condition remained much

the same until the age of 7 years, when the tonsils were removed. She was then speaking in short sentences, could do simple errands and had been attending a normal school. After the operation there was a marked deterioration. Speech and her considerable powers of miming gradually disappeared. Her balance, never very good, became worse, until eventually she was almost confined to bed and unable to feed herself. At the same time, she became increasingly liable to bouts of agitation in spite of treatment with a variety of tranquillizers, although no seizures of any kind occurred. Her breathingwasinco-ordinated and laboured.

Fig. 2.

At the age of l l + years her thyroid function was again investigated with negative results and gargoylism was con- sidered, but this diagnosis was not confirmed either. A year later, she was admitted to hospital for further investi- gation. No other past history was obtained, except for a liability to upper respiratory infections. There were no sibs and the family history was negative. On examin- ation, the patient’s height was 139.6 cm. and her weight was 35.1 kg. her facies were coarse, with thickened nose and lips, and certainly suggested the possibility of gargoylism. However, there was no apparent clouding of the cornea and no palpable enlargement of the liver and spleen. The heart was of normal size and there were no murmurs. The optic fundi were normal and the pupils reacted normally to light. All movements were inco-ordinate and walking was impossible without assistance. There was slight limitation of extension at the elbows. The right leg was thinner than the left. The tendon reflexes were brisk and equal and the plantar reflexes were flexor. There was no speech.

On X-ray examination the metacarpals and phalanges were tubular, the central part of the shafts being only slightly narrower than the ends, and there was slight bowing of the shafts of the radius and ulnar bones. The vertebral bodies were biconvex and the bones of the skull vault were abnormally thick and dense with prominent diploic venous markings. The bones of the thorax had rather dense trabeculations.

The ECG was normal and the EEG showed only a slight increase in the amount of slow-wave activity for the patient’s age. Chromosome studies showed a normal female karyotype. The CSF protein was slightly raised to 45 mg. per 100 ml. and the Pandy test was faintly positive. The amino-acid chromatogram was normal

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except for an excess of 8-amino-isobutyric acid.

The bovine albumen test was negative but the toluidine blue test showed a spot equivalent to 50 mg.-per cent of chon- droitin sulphate. The peripheral blood and cultures of epidermal cells were examined in the Department of Medical Genetics, Manchester University. Sixty-eight per cent of the lymphocytes showed the metachromatic granules found in disorders of mucopolysaccharide metabolism (Fig. 3). Skin cultures have been taken from this patient but, so far, no granules have been

Fig. 3. Case 1 . Lymphocyte from the peripheral blood showing metachromatic granules.

found in the cells grown. The excretion of mucopolysaccharide in the urine was estimated by Dr. G. Manley of the Nuffield Department of Clinical Bio- chemistry, Radcliffe Infirmary, Oxford, and an excess of heparitin sulphate was found, confirming the diagnosis of the San- filippo syndrome. On electrophoretic separation, the total mucopolysaccharides consisted of 37.2 per cent of chondroitin sulphate, 50-2 per cent of heparitin sulphate I and 11, and 12.6 per cent of mucoprotein. The mucopolysaccharide : creatine ratio was 43 compared with the

normal range in children of 6 to 25. The patient has been on treatment with

vitamin A, 150,000 i.u. a day, and her mental state appears calmer and her breathing is no longer abnormal. Occasion- ally in the evenings she extends her neck and stares upwards and it is difficult to stop her doing this. Her parents think that her condition has stopped deteriorating. She was not able to tolerate a vitamin C-free diet.

Case 2 A girl aged 11 years, born by normal

delivery at full term, after an uneventful pregnancy. She walked at a year old and was fairly quick to develop motor skills. She used single words her in second year, but there has since been no further development of speech. Her behaviour became increasingly restless, but she started at primary school when 5 years old. A year later, having made little progress, she was transferred to a training centre but continued to have home tuition for a while. Bladder control was established before the age of 2 years, but she still tends to suffer from faecal incontinence. Over the years, the child has become increasingly difficult to manage and there is no doubt, from the parents’ account, that her condition has deteriorated. She has lost interest in many of her toys and no longer dresses and undresses her doll. She seems to be relatively insensitive to pain. Occasionally, when tired, her eyes become fixed in an upward direction.

There is no other past history of sig- nificance and the family history is negative except that one sibling died from a cerebral tumour. There are two twin brothers who are both in good health. The patient’s family live near that of the first patient, but there is no evidence that they are related.

On examination, the patient’s height is 126.9 cm. and her weight is 49.35 kg. Her

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facies are suggestive of gargoylism. The bridge of her nose is flattened, her nostrils are wide and her lips large. Her hair is coarse and her eye-brows heavy. There is no corneal clouding (Fig. 4). Response to sounds appear to be normal. The liver and spleen are not enlarged and there are no herniae. Development is now very retarded and there is no intelligible speech. There is a slight restriction of extension at the elbow-joints.

Fig. 4. Case 2. Patient, aged 1 1 , with Sanfilippo’s syndrome.

X-rays of the skull showed thickening of the vault in the occipital region but X-rays of the spine showed only a moderate scoliosis. The EEG was disturbed by muscle and movement artefact but revealed no evidence of any disorder of cerebral function. The buccal smear was chromatin- positive with 18 per cent of the cells show- ing a single Barr body. The urinary amino-acid chromatogram was normal. The result of the toluidine blue test on the urine was a mucopolysaccharide excretion equivalent to 20 mg. per 100 ml. expressed as chondroitin sulphate. Dr. Manley reported that on electrophoretic separation of the mucopolysaccharides in the urine there was 40 per cent of chondroitin

sulphate, 45 per cent of heparitin sulphate I and 11, and 15 per cent ofmucoprotein-a pattern typical of the Sanfilippo syndrome. The mucopolysaccaride: creatine ratio was 133, compared with the normal range in children of 6 to 25.

This patient’s mental state also became less agitated on treatment with vitamin A, 150,000 i.u. a day. She seemed happier, although still showing hyperkinetic be- haviour. A vitamin C-free diet had to be stopped after a few weeks because of a definite deterioration in the patient’s condition.

Discussion The diagnosis of disorders of muco-

polysaccharide metabolism will be sug- gested by the patient’s appearance, cretinism being the only other condition bearing any particular resemblance. A history of progressive mental deterioration, and the presence of other sibs similarly affected, will increase the probability of such a disorder of metabolism. Supportive evidence may be given by X-ray examin- ation, particularly of the spine in Hurler’s syndrome if this shows beaking of the vertebrae, but the diagnosis will only be confirmed by the demonstration of excess of mucopolysaccharides in the urine. Chondroitin sulphate Aand Band heparitin sulphate are excreted normally in the urine. An excessive excretion in the urine may be demonstrated by the bovine albumen test (Denny and Dutton 1962), but the toluidine blue test appears to be more reliable (Berry and Spinnager 1960). Meta- chromatic granules may be demonstrated in the circulating polymorphonuclear leucocytes (Reilly 1941) but more often in the circulating lymphocytes (Muir et al. 1963, McKusick et al. 1965). Mucopoly- saccharide granules may be demonstrated in bone-marrow cells (Pearson and Lorincz 1964) and in cultured fibroblasts from the skin of affected patients (Danes

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and Bearn 1966~). It is sometimes necessary to carry out more detailed studies of the mucopolysaccharides in the urine, and it may be possible in future to estimate the plasma levels of acid muco- polysaccarides (Sanfilippo and Good 1 964).

No definite cause of these syndromes is known, although McKusick (1966) sug- gests various possibilities. There may be a defect in the binding protein or a change in the amino-acid sequence making its binding properties less effective. Muco- polysaccharides may be produced in excess of the normal capacity of the binding protein. Also, there may be a deficiency of an enzyme responsible for linking muco- polysaccharides to the binding protein.

The mental deterioration that occurs in these syndromes is particularly marked in the Sanfilippo variety. As in other neuronal storage diseases, the cause of this must be related to the distention of nerve cells which is usually conspicuous. There is evidence that the material stored by the neurones differs from the substances present in the liver and other organs (Blackwood et al. 1958). The latter are mucopolysaccharides but the former are partly a soluble lipid compound, probably ganglioside.

Most of these disorders are progressive and in the absence of a known cause there is no definite treatment. Long-term corti- costeroid therapy has been tried, with some clinical improvement, on the basis of an interference with the deposition of muco- polysaccharides in the tissues, or an in- hibition of the incorporation of sulphate into acid mucopolysaccharide produced within the liver (Renuart 1967). Anabolic steroids have also been given and improve- ment recorded (Nanivadekar and Nani- vadekar 1966). Patients with Hurler’s syn- drome on this treatment showed clearing of the corneal clouding. It is maintained that, as anabolic steroids increase the up- take of sulphate by mucopolysaccharides

in the bones, this process may be defective in children with gargoylism. It has recently been suggested that a vitamin C-free diet may affect the course of gargoylism. Schafer et al. (1966) found that cell cultures from patients with Hurler’s syndrome contained more chondroitin sulphate By or dermatan sulphate, than controls and that the amount of chon- droitin sulphate increased still further when vitamin C was added to the medium in which the cells were grown. An infant with Hurler’s syndrome was given a diet con- taining no ascorbic acid. Mucopoly- saccharides continued to be excreted in the urine, but growth and development so far seemed normal. Moreover, there is no evidence of scurvy, which suggests that the patient may have some method of syn- thesising ascorbic acid and that this may be related to the metabolic disorder.

A patient with Hurler’s syndrome, admitted to the Royal Manchester Child- ren’s Hospital under the care of Dr. R. I. Mackay, has been given a vitamin C-free diet over the past nine months. The clinical condition was advanced at the time this diet was started, so, as might be expected, there has been no definite change in the symptoms and signs. However, there has also been no evidence of scurvy. On the other hand, the two patients with the Sanfilippo syndrome who were given this diet soon showed a deterioration in their general health and an increase in their ataxia. Saturation tests confirmed a lack of vitamin C, and on the resumption of a normal diet the children’s conditions quickly returned to their previous state. These findings raise the possibility that the different response to the vitamin C-free diet may be related to the metabolic differences between the Hurler and Sanfilippo syndromes.

Danes and Bearn (1 9666) reported that vitamin A reduced the total mucopoly- saccharide content of skin fibroblast

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cultures from normals and patients with Hurler’s syndrome. They also found that vitamin A increased the urinary excretion of mucopolysaccharides, which suggests that this substance may have a therapeutic effect in disorders of mucopolysaccharides metabolism (Danes and Bearn 1967), although the excess excretion may only be an overflow mechanism (Walker 1967).

Both the patients with the Sanfilippo syndrome have been on treatment with vitamin A, 150,000 i.u. a day, and the parents feel that this has improved the children’s condition, but it is too soon to make any objective assessment.

The results of treatment may so far be inconclusive, but they emphasise the need for the early diagnosis of these syndromes so that further knowledge may be gained on methods ofcontrolling their progressive course.

Acknowledgements: We wish to thank Dr. A. E. H. Emery, Dr. J. Timson and Miss P. Todd, Department of Medical Genetics, University of Manchester, and Dr. E. C. Butterworth, Bio- chemistry Department, North Staffordshire Royal Infirmary, for their help in the investigation of these patients, and we are particularly grateful to Dr. G. Manley of the Nuffield Department of Clinical Biochemistry, Radcliffe Infirmary, Oxford for estimating the excretion of mucopolysaccharides in the urine.

SUMMARY The clinical, genetic, and biochemical features of seven varieties of disordered muco-

polysaccharide metabolism are described. Two examples of the Sanfilippo syndrome are recorded. Aids to the diagnosis of the syndromes are reviewed and theories of causation and therapy are discussed.

R&SUMI? Le syndrome de Sanflippo: un trouble inhabituel du mktabolisme des mucopolysaccharides

Les caractkristiques cliniques, gknktiques et biochimiques de sept variktks de troubles du mktabolisme des mucopolysaccharides sont dkcrits. Deux exemples du syndrome de Sanfilippo sont rapportks, une revue est faite des klkments de diagnostic du syndrome, on discute les diffkrentes thkories sur les causes de syndrome ainsi que son traitement.

ZUSAMMENFASSUNG Das Sanfilippo-Syndrom: Eine seltene Storung des Mukopolysaccharid-Stoflwechsels

Die klinischen, genetischen und biochemischen Faktoren bei sieben Mukopolysaccharid- stoffwechsel-Storungen werden beschrieben. Zwei Faille mit einem Sanfilippo-Syndrom werden dargestellt. Hinweise zur Diagnose der Syndrome sowie Theorien ihrer Entstehung und Therapie werden diskutiert.

RESUMEN El sindrome de Sanfilippo: un dislurbio poco com rin del metabolismo mucopolisactirido Se describen las caracteristicas clinicas, genkticas y bioquimicas de siete tipos de trastorno

del metabolismo mucopolisachrido. Se dan detalles de dos casos de sindrome de Sanfilippo. Se comentan 10s signos diagnbsticos de 10s sindromes, y se discuten teorias de etiolbgicas y terapkuticas.

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