Clinical Genetics 1978: 13: 241-250

Sanfilippo A syndrome in the fetus ROBERTS. GREENWOOD, RICHARDE. HILLMAN, HILDAALCALA AND WILLIAM S. SLY

Departments of Pediatrics, Neurology and Pathology, Washington University School of Medicine; Divisions of Neurology and Medical Genetics, St. Louis Children’s Hospital, St. Louis, Missouri; and Department of Pathology, Texas Children’s Hospital, Houston, Texas, U.S.A. A family is reported in which Sanfilippo A syndrome affected three siblings: the proband

and twin premature infants. The feasibility of intrauterine diagnosis of rnucopolysaccharidoses (MPS) Type IIIA, was demonstrated by the excessive accumulation of S5SO4mucopolysaccharides in fibroblasts cultnred from amniotic fluid obtained by amniocentesis. Cross-correction studies and enzymatic analysis of cultured skin fibroblasts from the proband and the infants revealed the absence of the MPS IIIA correction factor, heparan sulfate sulfatase. However, when the premature infants expired shortly after birth, no central nervous system histopathology or ultrastructural abnormalities were found. From these observations it would appear that the third trimester fetus with MPS type IIIA has little CNS involvement. Received 22 September, accepted for publication 27 October 1977

The discovery and characterization of factors which prevent mucopolysaccharide accumulation in fibroblasts from patients with mucopol ysaccharidoses (MPS) have furthered our understanding of the pathogenesis of MPS and suggested a means for treatment (Frantantoni et al. 1968a,b, HorsCayla et al. 1968). Thus, enzymes administered intravenously might be pinocytosed, enter the lysosomes of affected cells, and degrade accumulating acid glycosaminoglycans (DeDuve 1964). Since only a fraction of the normal intracellular enzymatic activity may be required for mucopolysaccharide degradation, treatment might be effective even though enzyme replacement produced considerably less than normal enzyme levels (O’Brien et al. 1973). Enzyme replacement has been attempted in MPS types I, 11, 111, and VII using whole blood,

plasma, platelet and leukocyte infusions or fibroblast transplantation (DiFerrante et al. 1971, Knudson et al. 1971, Dekaban et al. 1972, Erickson et al. 1972, Booth & Nadler 1973, Dean et al. 1973, Sly et al. 1974, Lasser et al. 1975). The results of such therapy initially appeared promising, but additional experience and more objective evaluation methods have raised serious doubts as to whether successful therapy could be achieved using these means (Desnick et al. 1976). Effective enzyme replacement wili probably require a continuous supply of large quantities of more stable, active, nonimmunogenic enzyme which can gain access to the target organs. In cases of MPS I, 11, 111, and VIT this may require that intravenously administered enzymes cross the bloodbrain barrier o r that the enzyme be given by a route allowing direct access to the

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brain. Moreover, since storage material may accumulate in utero in the case of some lysosomal diseases (Desnick et al. 1973), the temporal sequence of biochemical and pathologic events will have to be established in order to time treatment initiation, frequency and duration properly. The purpose of the present communication is to report the pathologic and biochemical features of Sanfilippo A syndrome (MPS IIIA) in third trimester twins who were born prematurely. This report supports the contentions of Harper et al. (1974) that MPS IIIA can be reliably diagnosed irt utero and that the third trimester fetus with MPS IllA has no central nervous system histopathology. Case Reports

Case I The proband was a 3%-year-old male who first entered SLCH at 2% years of age for evaluation of delayed development. No other relative had been affected by a similar or related illness. The 23-year-old Korean mother’s two previous pregnancies terminated in spontaneous abortions. The birth of this child was uncomplicated. Birth weight was 3000 g. He fed normally and initially developed normally. At 2% years of age, however, the child had not developed any understandable speech and seemed to comprehend only a few words. His appetite and growth were considered normal, although he had always been considered “chubby.” He had not experienced frequent infections, but did have one prolonged episode of otitis media and was hospitalized on one occasion for diarrhea and dehydration. On examination, the child was quite irritable and difficult to examine. Weight was 8.5 kg, height 94.5 cm, and head circumference 51 cm. He had little facial expression, coarse facial features, a depressed nasal bridge and an interpupillary distance of 6 cm. Skin and

subcutaneous tissue were obviously thickened. Neither corneal nor lenticular opacities were present. His teeth, while not widely spaced, were carious and his hair texture was coarse. A Grade I-II/VI systolic ejection murmur was heard along the lower left sternal border, but there was no cardiomegaly. The liver was palpable 6 cm below the right costal margin. Extension of the interphalangeal joints was limited, but the proportions of the hands were normal. Neurologically, the child had relatively normal motor function but very poor verbal development. Laboratory studies included a normal complete blood count, urinalysis, urine amino acids analysis and male karyotype. Radiographs of the skeletal system revealed a large skull size with increased interorbital distance. The vertebral bodies were ovoid, particularly in the lumbar spine where there was an associated 12” gibbus. Bilateral acetabular underdevelopment, tapering of the proximal 2nd to 5th metacarpals and mild flaring of the proximal humeri were also seen. Urine glycosaminoglycan (GAG) excretion was increased (2.9 mg/ 100 ml). Serum iduronidase activity was normal. Psychological test results included scores of 68 on the Vineland Social Maturity Scale, 58 on the Cattell Infant Intelligence Scale, and 35 on the Verbal Language Development Scale. Although Hunter syndrome (MPS 11) was suspected initially, the diagnosis of MPS IIIA was made using cultured fibroblasts as described below. When he was seen at age 3 years 3 months, the only new signs were prominence of the supraorbital ridge, thick eyebrows, flaring of the rib cage and a spleen tip palpable 2 cm below the left costal margin. Repeat psychological testing showed scores of 59 on the Vineland Social Maturity Scale, 23 on the Verbal Language Development Scale, and 46 on the Stanford-Binet Intelligence Scale.

SANFlLlPPO A SYNDROME

2 and 3 These infants were siblings of the proband. During this pregnancy, the mother’s fourth, there was frequent vaginal spotting which was treated by iron injection. The parents agreed to amniocentesis for prenatal diagnosis, although they had decided in advance against therapeutic abortion. Amniocentesis was performed in the fifth month of pregnancy after sonography. Although this proved to be a twin pregnancy, twin pregnancy was not recognized at the time of sonography. Fluid from this amniocentesis was sent to St. Louis Children’s Hospital for analysis. Two weeks after amniocentesis the mother went into spontaneous labor and delivered male twins. Examination of the placentae revealed two chorions. The first twin (twin A) was born without complications. Birth weight was 1470g. Shortly after birth the child developed respiratory distress and was transferred to St. Louis Children’s Hospital. Delivery of the second twin (twin B) was complicated by a prolapsed cord and double footling breech presentation requiring version extraction. This child, weighing only 965 g, was severely depressed at birth and died 1 h after birth. At St. Louis Children’s Hospital, twin A was found to be in moderate respiratory distress with retractions, grunting, and tachypnea. He had no dysmorphic features. His gestational age was estimated to be 28 weeks. His weight, length (30 cm), and head circumference (23 cm) were less than the 3rd percentile for a fetus of 28 weeks gestation. Chest radiographs obtained at admission revealed moderate hyaline membrane disease. The child initially required supplemental oxygen and 1 day after admission was placed on a respirator when he began having frequent episodes of apnea and cyanosis. On the third day of life, intermittent episodes of hyperextension of the infant’s body and extremities were noted. Cuses

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A lumbar puncture revealed grossly bloody spinal fluid. A short time later the infant expired. Autopsy. - At autopsy, twin A had bilateral intra-alveolar hemorrhage, subarachnoid hemorrhage and intraventricular hemorrhage on gross examination. Microscopically, organ development was compatible with prematurity. l n addition, evidence of hyaline membrane disease and acute eosinophilic necrosis of neurons was seen. Twin B had bilateral collapsed lungs, hemorrhagic ascites, and cystic degeneration of the adrenal cortices. Organ development again was consistent with prematurity. Samples taken from the myocardium, lungs, intestines, liver, spleen, lymphatic system, pancreas and kidneys of both twins were fixed in Zenker’s formalin or in absolute alcohol, and were stained with PAS, PAS with diastase, Alcian blue (pH 2.53) and toluidine blue (pH 4). Samples of these same tissues from an infant that died shortly after birth were used as controls. No samples from either twin had abnormal mucopolysaccharide storage by light microscopy. Sections from formalin-fixed frontal, parietal, temporal and occipital cortex, basal ganglia, midbrain, medulla, cerebellum, spinal cord, peripheral nerves and dorsal root ganglia were stained with hematoxylin-eosin and Luxol fast blue-PAS. In addition, frozen sections from the cerebral cortex and spinal cord were stained with PAS, oil Red-0 and Sudan black B. No abnormal accumulation of lipids or mucopolysaccharide was found in these sections from the twins’ nervous systems. Materials and Methods for Special Studies

Amniotic fluid cells were cultured according to standard techniques and S5S04-labeled mucopolysaccharide uptake was measured (Fratantoni et al. 1969).

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G R E E N W O O D , H I L L M A N , ALCALA A N D SLY Table 1

Cross correction studies in mixed fibroblast cu Itures % Abnormal (uncorrected) "'SO4 accumulation by mixed fibroblasts when known strain was:

Proband Twin A Twin 6 MPS Type 111 A

MPS Type I1 66 %' 54 ?h 46 % 65 %

MSP Type I l l A 97 % 90 % 98 % -

The percent was calculated by dividing the cpmlmg accumulated by the mixed culture by the average of the two cultures grown individually (unmixed).

Fibroblasts were cultured from skin biopsies from the proband and both twins. Cross-correction studies were performed on these fibroblast cultures using the methods of Neufeld & Cantz (1971). Costal and iliac cartilage samples from twin A were fixed, sectioned and stained for electron microscopy according to methods previously described (Silberberg et al. 1972). Tissues from frontal cortex, thalamus and liver were sampled at the time of autopsy, which was carried out % h post mortem. The samples were cut in sections 2-3 mm

Flg. 1. Hepatocyte from twin A. This cell contains many unit membrane bound vacuoles seen as round clear cytoplasmic inclusions. Giuteraldehyde-osmium tetroxide fixation: lead citrate staining ( X 16.770).

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SANFILIPPO A SYNDROME Fig. 2. Hepatic vacuoles at high magnification. The vacuoles shown here contain sparse filamentous and granular material. Gluteraldehydeosmium tetroxide fixation: lead citrate staining ( x 48,000).

thick and fixed in 4 % gluteraldehyde in 0.1 M sodium cocodylate buffer, pH 7.3 at 4°C. Tissues were washed overnight in 0.1 M sodium cocodylate buffer, pH 7.3. Postfixation was done in 1 % osmium tetroxide in the same buffer. Tissues were dehydrated and then embedded in Epon resin and cured overnight in a 70" oven. Samples of the liver from a 24-week-old fetus with a normal liver were sampled and prepared in a similar way for controls. Thin sections 0.1 pm were cut with a diamond knife in an LKB-Huxley microtome, stained with lead citrate, and examined with a Phillips 300 electron microscope.

Results

The 3~S0,-mucopolysaccharideaccumulation by cultured amniotic fluid cells was 420 % of the control value. Skin fibroblasts from the proband and the twins also accumulated excessive amounts of 35S0,-labeled mucopolysaccharides. This excessive accumulation was reduced when the skin fibroblasts were grown with fibroblasts from a patient with Hunter syndrome (MPS 11) but not with Sanfilippo Type A syndrome (Table 1). These results suggested that the defect in mucopolysaccharide metabolism in this family was that common to Sanfilippo Type A patients: a deficiency of heparan sulfate

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GREENWOOD, HILLMAN, ALCALA AND SLY Flg. 3. Hepatocyte vacuoles at high magnification. These vacuoles contain, in addition to scattered filamentous and granular material, dense osmophilic structures and conglomerates of dense linear and granular material. Gluteraldehyde-osmium tetroxide fixation; lead citrate staining ( x 48.000).

sulfatase. T h e deficiency of heparan sulfate sulfatase in extracts of cultured fibroblasts from the proband and twin B was confirmed enzymatically in the laboratory of Elizabeth Neufeld. Normal levels of Nacetyl-a-D-glucosaminidase, the Sanfilippo type B factor, were demonstrated in the proband’s skin fibroblasts. Electron microscopic examination of chondrocytes showed a basically normal architecture. Cellular organelles were of the usual type and structure. N o n e of the lipid inclusions or vacuoles seen in older patients with Sanfilippo syndrome were found. There

were, however, some features suggestive of decreased cartilage viability. Some chondrocytes contained an unusual number of lysosome-like bodies o r vacuoles, apparently derived from degenerative organelles. Increased lipid inclusions free in the cytoplasm in chondrocyteq from both twins, likewise, were consistent with decreased viability. Sections from frontal cortex and thalamus showed normal neurons and glial cells. Organelles within neurons were unremarkable and there was no evidence of intracytoplasmic inclusions. Hepatocytes from the liver of twin A showed abundant

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positivity after amylase digestion, suggesting that the vacuoles contain some glycogen (Konyar et al. 1972). The discovery that cultured fibroblasts show excessive sulfated mucopolysaccharide accumulation and slow turnover correctable by addition of “corrective factors” formed the basis of in vitro complementation tests which led to reclassification of the mucopolysaccharidoses. Thus, Type 111 MPS, Sanfilippo syndrome, was found to consist of two biochemically separable groups: Type A in which the abnormal sulfated mucopolysaccharide accumulation in fibroblasts from such patients is prevented by addition of heparan sulfate sulfatase; and Type B in which the accumulation is prevented by addition of N-acetyl-alpha D glucosaminidase Discussion (Kresse et al. 1971, Kresse & Neufeld 1972, O’Brien 1972, Von Figura & Kresse 1972). The diagnosis of type IIIA MPS, involving The intrauterine diagnosis of other forms three members of this family, seems well established. The clinical features of the dis- of MPS by means of amniocentesis has order in the proband, the exaggerated 35S04 been reported. In general, two methods of mucopolysaccharide accumulation in cells amniotic fluid analysis have been used to cultured from the proband and the twin diagnose mucopolysaccharidosis: demonstrasiblings, the cross-correction studies showing tion of increased GAG in the amniotic failure of cross-correction by MPS IIIA fluid and evidence of 35S04-labeledmucocells, and demonstration of heparan sulfa- polysaccharide accumulation in cultured tase deficiency in fibroblasts from the pro- amniotic fluid cells (Fratantoni et al. 1969, band and one sibling, all support this dia- Matalon et al. 1970). While the latter test has been considered reliable, false negative gnosis in these three patients. results have been reported using the former Uitrastructural findings in the liver of twin A are similar to those reported in other method. Intrauterine diagnosis of MPS children with mucopolysaccharidoses (van IIIA has been reported in at least one Hoof & Hers 1964, Dodion et al. 1966, other fetus. Harper et al. (1974) described increased levels of heparan sulfate in amniHaust 1968). These cytoplasmic inclusions otic fluid and fetal liver, cytoplasmic inare believed to be of lysosomal origin (Wallace et al. 1966, Konyar et al. 1972). clusion in fetal fibroblasts and liver, and The histochemical ultrastructural studies of abnormal 3 5 S 0 4 accumulation in cultured Haust & Landing (1961) and Konyar et al. fetal cells. Fibroblasts from this fetus dem(1972) suggest that the material contained onstrated a deficiency in heparan sulfate within the vacuoles may represent sulfated sulfatase. The report of Harper et al. (1974) mucopolysaccharide, as demonstrated by its and the present study indicate that intrautaffinity for toluidine blue, alcian blue, col- erine diagnosis of type IIIA MPS is posloidal iron and silver nitrate. These inves- sible. tigators also noted a slight increase in PAS The infants described in this report had intracytoplasmic membrane-bound vacuoles of variable size (Fig. 1). Most of these vacuoles measuring 0.2-0.5 pm were partially filled with finely granular or filamentous electron dense material. The abundance of this material within a vacuole appeared greatest when the vacuole was small. Other vacuoles contained, in addition, centrally placed, electron dense, osmiophilic, solid, round or multilamellar, concentric structures (Fig. 3). Lipid droplets were also present. In general, the remaining organelles were normal, both in number and morphology. Hepatocytes of the normal control liver did not contain vacuoles like those seen in twin A’s hepatocytes.

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storage of complex lipids in mucopolysacno histologic or ultrastructural evidence of charide storage disorders may be a seconabnormal storage material in brain, or costal of the primary enzymatic defect. dary effect and iliac cartilage. Twin A and the fetus dePrimary storage product may accumulate to scribed by Harper et al., however, did have concentrations which inhibit other lysosomal hepatocyte cytoplasmic inclusion bodies. Microscopic examination of specimens hydrolases. H e presented evidence for betafrom many regions of the nervous system galactosidase inhibition by dermatin sulfate of the fetus reported by Harper et al. (1974) and suggested that this may explain G M , failed to demonstrate histologic evidence of accumulation in the Hurler syndrome. We abnormal neuronal ganglioside storage. The examined the effects of heparan sulfate, the observations in the infants reported here and MPS 111 storage material, on several hythose reported by Harper et al. (1974) sug- drolases and found inhibition similar to gest that the brain of the third trimester that reported by Kint. Human hexosaminifetus with Type IIIA MPS is spared histo- dase, both total and heat stable, beta-glucupathologically, although the enzymatic de- ronidase, and alpha-mannosidase were all fect characteristic of Type IIIA MPS was inhibited 50-60 % when heparan sulfate (0.2 mg/ml final concentration) was present demonstrable in fetal tissues. The failure to detect neuronal storage in an assay mixture utilizing synthetic 4material implies that the metabolic defects methylumbelliferyl derivatives as substrates leading to the ganglioside accumulation (W. Sly, unpublished observations). These in the child with MPS I11 is either not yet findings agree with those of Avila & Convit present or that insufficient time had elapsed (1975) who analyzed the inhibitory effects for detectable ganglioside accumulation; of glycosaminoglycans on a large number however, the absence of abnormal storage of leukocyte lysosomal hydrolases and may material in the fetal nervous system is con- help explain some of the biochemical absistent with the clinical features of Type I11 normalities found in the previously reported MPS. The appearance of symptoms attri- infant with MPS IIIA (Harper et al. 1974). butable to nervous system dysfunction usu- Harper et al. (1974) found moderate inally occurs after 2 years of age (Danks et al. creases in heparan sulfate and low p-D1972). In other types of MPS the presence glucuronidases activity in brain tissue. Brain or absence of mental retardation seems to N-acetyl-P-D-glucosaminidaseand P-D-gacorrelate best with neuronal ganglioside lactosidase activity were normal. In other accumulation (Wolfe et al. 1964, Haust organs, the activities of these same enzymes 1973). Thus, one might not expect ganglio- were reduced where heparan sulfate was side accumulation to be evident before the greatly increased. These reductions in enzyme activity might have been secondary to age of 2 or 3 years. Biochemical studies of brain tissue from the elevated levels of heparan sulfate demonpatients with MPS 111 reveal only moderate strated in these organs. In fact, lysosomal increases of ganglioside, most of this is ac- levels of heparan sulfate may have been counted for by increased white matter high enough to affect many more hydrolases gangliosides (Suzuki 1972). In the gray in vivo than might be apparent from assays matter, the total ganglioside content is often in homogenates where lysosomes have been normal, but GM, and GM, components can disrupted and the heparan sulfate diluted be increased (Suzuki 1972). Why should in the process. Furthermore, hydrolase acgangliosides be increased in heparan sulfate tivity in assays utilizing artificial substrates deficiency? Kint (1 973) has suggested that may be subjected to less inhibition by glyco-

SANFlLlPPO A SYNDROME

saminoglycans than occurs in v i v o with natural substrates. Regardless of the explanation for the eventual abnormal cerebral lipid accumulation, it is encouraging that t h e neonates reported herein h ad no histologic evidence of abnormal central nervous system ganglioside storage. If t h e missing enzyme could be delivered to the appropriate cells. such treatment instituted after birth might prevent t h e neurological regression which is such a conspicuous part of Sanfilippo A syndrome.

Acknowledgments

This work was supported in part by PHS grants G M 210966, A M 1153, and A M 0080, the Rankin Jordan Tr u s t F u n d and t h e Allen P. and Josephine B. Green Foundation, Mexico, Missouri. We wish to thank Dr. Ruth Silberberg who performed the ultrastructural studies on the cartilage from Cases 2 and 3, Dr. Elizabeth Neufeld in whose laboratory the enzymatic analysis was done, and Betty Cordes f o r secretarial assistance. References

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type B: enzyme replacement and metabolic correction in cultured fibroblasts. Science 181, 753-755. Silberberg, R., D. L. Rimoin, R. E. Rosenthal & M. B. Hasler (1972). Ultrastructure of cartilage in the Hurler and Sanfilippo Fyndromes. Arch. Path. 94, 500-510. Sly, W. S., J . G . Glaser, K. Roozen, F. Brot & P. Stahl (1974). Enzyme replacement studies with 6-glucuronidase deficiency. Enzyme Therapy in Lysotnmal Storage Diseases, ed. J. M. Tager, G . J. M. Hooghwinkel 61 W. T. Daems. Amsterdam, North Holland, pp. 288-291. Suzuki, K. (1972). Neurochemical aspects of mucopolysaccharidoses. Handbook of Neurochemirtry, Vol. 7, ed. A. Lajtha. New York, Plenum Press, pp. 17-32. Van Hoof, F. & H. G. Hers (1964). L’ultrastructure des cellules hkpatiques dans la maladie de Hurler (gargoylisme). C . R . Acad Sci. (Paris) 259, 1281-1283. Von Figura, K. & H. Kresse (1972). The Sanfilippo B corrective factor: A N-acetyl-alphaD-glucosaminidase. Biochem. Biophys. Res. Commun. 48, 262-269. Wallace, B. J., D. Kaplan, M. Adachi, L. Schneck & B. W. Volk (1966). Mucopolysaccharidosis type 111. Marphologic and biochemical studies of two siblings with Sanfilippo syndrome. Arch. Path. (Chic.) 82, 462-473. Wolfe, H. J., J. B. Blennerhasset, G. F. Young & R. B. Cohen (1964). Hurler’s syndrome: A histochemical study. New techniques for localization of very water-soluble mucopolysaccharides. Arner. 1. Path. 45, 1007-1027. Address: Robert S. Greenwood, M . D . Department of Neurology University of North Carolina at Chapel H i l l 751 Clinictrl Science Bldg. 2 2 9 8 Cliupel Hill, NC 27514 U.S.A.

Sanfilippo A syndrome in the fetus.

Clinical Genetics 1978: 13: 241-250 Sanfilippo A syndrome in the fetus ROBERTS. GREENWOOD, RICHARDE. HILLMAN, HILDAALCALA AND WILLIAM S. SLY Departm...
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