Am J Hum Genet 31:1-18, 1979 Sialidosis: A Review of Human Neuraminidase Deficiency J. A. LOWDEN' AND J. S. O'BRIEN INTRODUCTION Defects in neuraminidase activity (N-acetylneuraminic acid hydrolase E. C. 3.2.1.18) have recently been described in several clinical disorders. Cantz et al. [1] and Spranger et al. [2] demonstrated a profound deficiency of acid neuraminidase in a patient who had been previously classified as having mucolipidosis I [3, 4]. The patient had a neurodegenerative disorder with Hurleroid features, skeletal dysplasia, and cherry-red spots in the macula. Signs of the illness developed in the first year of life. In addition to the neuraminidase defect, these patients accumulated sialic acid-containing material in fibroblasts. Parents had activities of neuraminidase which were intermediate between patients and controls, implicating the deficiency as a primary defect. Durand et al. [5], O'Brien [6], Thomas et al. [7], and Rapin et al. [8] have described a group of young adults with neuraminidase deficiency who presented with decreasing visual acuity, cherry-red spots in the macula, myoclonus, and sialyloligosaccharides in the urine. Their phenotype differs from that of mucolipidosis I patients in that intelli- gence is normal, somatic and bony abnormalities are absent, and their survival is longer. Family studies indicate that patients with the "cherry-red spot-myoclonus" syndrome are homozygous for a recessive autosomal mutation affecting acid neuraminidase [6, 7]. An infant with Hurleroid features but normal mental development and acid neuraminidase deficiency has been described by Kelly and Graetz [9]. In addition to these two groups of patients another dysmorphic group of young adults, who were previously thought to have a primary defect in 18-galactosidase activity, has now been included in the clinical spectrum of patients with neuraminidase deficiency [10, 11]. Although these patients are normal at birth and throughout early childhood, dysmorphic features, psychomotor degenerative changes, myoclonus, and frequently a cherry-red spot develop at around 10 years of age. It is timely then to review the clinical phenotype of primary human neuraminidase deficiency. We employ the term "sialidosis" here to describe patients with primary neuraminidase deficiency and believe it should be reserved exclusively for this condition. We also discuss the clinical genetics of sialidosis, the chemistry of the compounds stored, the molecular genetics of acid neuraminidase, the secondary neuraminidase deficiencies in other disorders, the secondary deficiency of f3- galactosidase in some patients with sialidosis, and laboratory methods for diagnosis. Received July 12, 1978: revised September 10, 1978. This research was supported by grants NS08682 and GM 17702 from the National Institutes of Health. I Both authors: Department of Neurosciences, M-008, University of California, San Diego, La Jolla, California 92093. © 1979 by the American-Society of Human Genetics. 0002-9297/79/3101-0002$01.45 1 2 LOWDEN AND O'BRIEN CLINICAL PHENOTYPES The 37 patients with proven or probable primary acid neuraminidase deficiency known to us are listed in table 1. To our knowledge table 1 contains no duplications. Two distinct groups are readily identified: (1) sialidosis type 1-a group with normal physical appearance and body proportions, cherry-red spots, myoclonus, and usually normal levels of /-galactosidase in body tissues and fluids; and (2) sialidosis type 2-a dysmorphic group with short stature, bony abnormalities, and often deficient f3- galactosidase in body tissues and fluids. A summary of the pertinent clinical findings in each type is given in table 2. We tabulated all major phenotypic features of the 37 patients in order to subclassify sialidosis type 2 into the infantile and juvenile subgroups; further attempts at subclassification were not productive. TABLE 1 CONFIRMED OR PROBABLE CASES OF SIALIDOSIS Authors Year Reference No. Cases Diagnosis Confirmed* Type 1 -Normosomatic Group: Wynburn-Mason ............. 1943 [12] 1 ... Symonds .............. 1954 [13] 1 ... Glasgow .............. 1957 [14] 1 ... ... Anderson et al . .............. 1958 [15] 2 Tittarellietal .............. 1966 [16] 1 ... Hambert and Peterson ......... 1970 [17] 1 ... Gauzzietal .............. 1973 [18] 2 ... Goldsteinetal .............. 1974 [19] 1 + Justice et al .............. 1976 [20] 1 + Durandetal .............. 1977 [5] 2 + Rapinetal . .............. 1978 [8] 3 + Thomas et al .............. 1978 [7] 2 + Type 2-Dysmorphic Group: Juvenile onset ... Goldbergetal . .......... 1971 [21] 3 Oriietai .......... 1972 [22] 1 Loonenetal . .......... 1974 [23] 1 + ... Kuriyama et al . .......... 1975 [24] 1 Fukunagaetal . 1976 [25] 2 + ... Suzukietal . .......... 1977 [26] 4 Okadaetal .......... 1977 [27] 1 + Soggetal .......... 1977 [28] 1 + Infantile onset Sprangeretal .......... 1968 [2] 1 + Berardetal . .......... 1968 [29] 1 + Sprangeretal .......... 1977 [3] 1 + Kelly and Graetz .......... 1977 [9] 1 + Lowdenetal . .......... 1978 [30] 1 + * Diagnosis was confirmed by enzyme assay for neuraminidase or demonstration of sialyloligosaccharides in urine (see table 3). Probable causes are listed based upon their phenotypic similarity to others in the same category. Recently, G. H. Thomas (American Society of Human Genetics annual meeting, Vancouver, 1978) has demonstrated neuramini- dase deficiency in a patient of Goldberg et al. [21]. SIALIDOSIS: NEURAMINIDASE DEFICIENCY 3 TABLE 2 CLINICAL FEATURES OF SIALIDOSIS TYPE I TYPE 2 Juvenile Infantile Age onset .................. 12.4 + 4.7 yrs 10.4 + 5.3 yrs 0- 10 mos Sex .......... 8 Male/10 Female 8 Male/6 Female 2 Male/3 Female Race/ethnic origin ............ 7/10 Italian 10/14 Japanese 5/5 Caucasian Seizures .................... 6/13 5/13 4/5 Myoclonus .................. 16/18 10/13 4/5 Ataxia ..................... 3/12 9/12 3/5 Pyramidal tract signs.......... 0/18 4/13 3/5 Mental retardation ............ 2/18 8/14 ... Cherry-red spots ............. 17/17 12/12 4/5 Corneal clouding/lens opacity 3/17 10/12 4/5 Loss visual acuity ............ 10/10 11/11 1/1 Hearing loss ................ 0/14 6/10 3/4 Coarse facies ................ 0/14 14/14 5/5 Vertebral changes ............ 0/14 13/13 5/5 Growth disturbance ........... 0/14 12/12 4/5 Visceromegaly .............. 1/14 0/12 5/5 Foam cells .................. 4/8 10/11 5/5 EEG abnormal ............... 6/11 4/7 3/4 NOTE. -All details were not available for all cases, thus the denominator in each figure = no. times this clinical feature was mentioned in case reports. Sialidosis Type -Normosomatic Group The clinical findings have been well described by Rapin et al. [8]. Patients present at 8-15 yrs with decreasing visual acuity, myoclonus, or both. Examination reveals normal features, normal growth, and usually normal intellect. Cherry-red spots are seen in the macular region of the fundus. The cornea and lens are usually clear, but occasionally punctuate lens opacities are noted [5]. Visual acuity gradually decreases during the course of the disorder. In one patient [8], the cherry-red spots faded in her 20th year. The myoclonus begins in the limbs and is gradually progressive. It is an action-type myoclonus induced by stimulation, movement, or emotion that usually decreases or abates during sleep. As the disease progresses, it may prevent the patient from walking, sitting, and eventually eating. The massive spasms are poorly controlled with anticonvulsants, diazepam, haloperidol, levodopa, conjugated estrogens, ketogenic diet, or magnesium [8, 17]. In association with the progression of the myoclonus, tendon stretch reflexes increase, but as in Fabry disease, several patients complained of burning pain in their extremities which was exacerbated by hot weather [8]. Because of the severity of the myoclonus, the assessment of intellectual capacity is sometimes difficult. Nevertheless, it appears that intelligence is either not impaired or minimally impaired. Grand mal seizures followed by loss of consciousness were seen in six cases but not in seven others. They were often initiated by a massive myoclonic spasm. Electrophysiologic abnormalities were examined extensively in, two patients by Engel et al. [31 ]. They found low voltage fast activity in the EEG. Similar observations were recorded in other cases [8, 17, 19]. 4 LOWDEN AND O'BRIEN One patient had an enlarged liver [5], but all other physical findings were normal in this group. Of tle 10 type 1 patients whose ethnic origins were listed, seven were of Italian ancestry. Two of the eight patients have died; at 21 and 28 years respectively. The oldest living patients are, however, over 30 years [7, 8]. In nine patients, blood smears and/or bone marrow preparations were examined; vacuolated lymphocytes or foam cells were noted in two [5, 19]. Vacuolation was described in the liver of one patient who died with diabetes [18]. Cytoplasmic inclusions and membrane-bound vacuoles were reported in liver biopsies from two patients, one of whom also had foamy histiocytes in the bone marrow [5]. The other had normal bone marrow [8], but a cerebral biopsy revealed cortical thinning and "neuronal lipidosis" with membrano-vesicular and lysosome-like bodies in neurons [32]. Although many cerebral vacuoles appeared empty or slightly filled with amorphous granular material, lipofuscin bodies were also prominent. In frozen sections of liver, the vacuoles stained with Alcian-blue and the periodic-acid Schiff (PAS) reagent, indicating