J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1103 on 1 September 1989. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:1103-1106

Short report Sandhoff disease mimicking adult-onset bulbospinal neuronopathy

P K THOMAS, ELISABETH YOUNG,* R H M KING From the Department ofNeurological Science, Royal Free Hospital School ofMedicine, and the Department of Clinical Biochemistry,* Hospitalfor Sick Children, Great Ormond Street, London, UK suMMARY A 32 year old male is described with an onset ofupper limb postural tremor in adolescence followed by muscle cramps. Progressive proximal amyotrophy and weakness in the limbs developed late in the third decade. Examination disclosed, in addition, bilateral facial weakness and mild dysarthria. studies revealed A and B deficiency, indicating a diagnosis of Sandhoff disease. Intra-axonal membranocytoplasmic bodies were present in a rectal . The presentation, which resembled that of X-linked bulbospinal neuronopathy, widens the clinical spectrum for disorders related to GM2 . Protected by copyright. The GM2 gangliosidoses result from a deficiency either mimicking that of X-linked bulbospinal neuron- of the hexosaminidase enzyme which hydrolyses the opathy."9 terminal N-acetylgalactosamine from the GM2, or of the activator protein for the enzyme. Two Case report major isoenzymes of hexosaminidase are found in human tissues, namely hexosaminidase A and hex- This 32 year old male had a normal early developmental osaminidase B (hex A and hex B). Hex A is composed history. He received speech therapy for a mild articulatory of a and subunits coded for on chromosomes 15 and disturbance ofdyslalic nature during childhood. He was seen ,B by a neurologist at the age of 15 years because of upper limb 5 respectively whereas hex B is composed only of f tremor and a diagnosis of essential tremor was made. This subunits. Thus a mutation at the a locus gives rise to has persisted. He has been prone to muscle cramps for some deficiency of hex A and a mutation at the fl locus to a years. From the age of 28 or 29 years, slowly progressive deficiency of hex A and hex B. proximal lower limb weakness has become evident, accom- Hex A deficiency occurs in Tay-Sachs disease and panied by wasting ofthe thighs. He has noticed no upper limb has also been reported in adult GM2 gangliosidosis.' weakness and has had no symptoms referable to the cranial Hex A and B deficiency occurs in Sandhoff disease. nerves. Bladder, bowel and sexual function has been normal. Sandhoff disease usually presents before the age of 9 He has no children or siblings. His father is neurologically months with mental and motor regression, visual normal. His mother has a mild lower limb sensory abnor- mality related to spinal cord involvement secondary to http://jnnp.bmj.com/ failure with cherry-red spots, and macrocephaly. midthoracic vertebral crush fractures sustained in a car Cases of Sandhoff disease with a later onset and accident. There is no other family history of neurological protracted course have been described, presenting disorder. His parents are both Caucasian and nonconsan- with progressive , spasticity and psychomotor guinous. retardation in late childhood,2"5 as a progressive ataxic Neurological examination revealed normal cranial nerve syndrome in adult life,6 or with spinal muscular function except for mild bilateral facial weakness and slight atrophy that resembles Kugelberg-Welander disease.7 dysarthria. There was no contraction fasciculation of the We report a new presentation in early adult life, face. His tongue was normal. In the upper limbs there was mild bilateral proximal muscle weakness and wasting and a on October 5, 2021 by guest. tremor of the outstretched Address for reprint requests: Prof P K Thomas, Department of postural hands, present during Neurological Science, Royal Free Hospital School of Medicine, movement. In the lower limbs, there was bilateral quadriceps Rowland Hill Street, London NW3 2PF, UK. wasting and moderately severe weakness of hip flexion and abduction, lesser weakness ofquadriceps, and mild weakness Received 23 December 1988 and in revised form 19 March 1989. of the anterolateral muscles in the lower legs. There was no Accepted 28 March 1989 lower limb tremor or ataxia. His tendon reflexes were normal 1103 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1103 on 1 September 1989. Downloaded from

1104 Thomas, Young, King Table 1 Hexosaminidase activity in thepatient and hisparents Total hexosaminidase % hexosaminidase A Plasma WBC Skinfibroblasts (pmol/ml/h) (unol/mgptn/h) Plasma WBC Skinfibroblasts Patient 0-02 0 06 0-69 81 94 99 Mother 0 3 0-9 - 86 85 - Father 1-0 1-9 - 55 62 - Normal range 0-52-0 0-7-3-6 24-13-9 52-78 49-70 43-62 n 100 100 24 100 100 24 Sandhoff disease (infantile) 0-004 0-02-020 0-07-009 86-100 85-100 83-100 n 17 17 3 16 14 3 Obligate heterozygotes 03-09 0-41-1 - 71-86 66-84 - Sandhoff disease n 18 22 18 22

apart from sluggish knee jerks. His plantar responses were flexor and there was no sensory loss. Examination of other systems was negative. There was no gynaecomastia. Routine haematological and biochemical studies were normal. There were no vacuolated lymphocytes. His serum creatine kinase activity was slightly increased (219 IU/i; normal < 195 IU/1). Electromyography showed chronic partial denervation in the right deltoid, biceps brachii, first dorsal interosseous, vastus medialis and tibialis anterior muscles. Motor nerve conduction velocity was normal (median 63 m/s; ulnar 55 m/s; peroneal 43 m/s). Median, Protected by copyright. ulnar, radial and sural sensory nerve action potentials were absent. Central motor conduction time was normal (cortex- C8/Tl, magnetic stimulation: right 6-0 ms, left 5-6 ms) as was an electrocardiogram. His karyotype (fibroblast culture) was normal. Fig 1 Semithin section ofrectal biopsy specimen showing Special investigations multiple macrophages containing lipid inclusions (arrows). Lysosomal enzyme studies revealed a profound deficiency of Araldite section, thionin and acridine orange stain, x 550. hexosaminidase activity (table 1) compared with other http://jnnp.bmj.com/ on October 5, 2021 by guest.

Fig 2 Electron micrographfrom rectal biopsy specimen showing an axonfilled with multiple lamellar inclusion bodies. Bar 1 Pn. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1103 on 1 September 1989. Downloaded from

Sandhof disease mimicking adult-onset bulbospinal neuronopathy 1105 Table 2 Clinical spectrum ofGM2 gangliosidoses Cases of hexosaminidase A deficiency of delayed onset have been described in recent years in whom a locus mutations (deficiency ofhex A) lower motor neuron involvement has been a promin- Tay-Sachs disease Juvenile GM2 gangliosidoses with hex A deficiency resembling ent feature. In some of these it has constituted the sole Batten-Spielmeyer-Vogt disease neurological manifestation,'7 "-'s such cases resembling Chronic GM2 gangliosidoses with hex A deficiency Atypical spinocerebellar degeneration juvenile-onset spinal muscular atrophy. Our patient Cases resembling juvenile spinal muscular atrophy (Kugelberg- most closely resembles that of Case 1 of Parnes et al'6 Welander) and amyotrophic lateral sclerosis in whom postural tremor and muscle cramps preceded Normal adults limb muscle weakness but in whom sensory nerve locus mutations (deficiency ofhex A and B) conduction was normal. The three cases ofMitsumoto Sandhofl's disease Juvenile Sandhoffs disease et al'7 has a multisystem degeneration with amyotro- Progressive ataxia ± phy, ataxia, spasticity and mental retardation, one Chronic GM2 gangliosidosis with hex A and B deficiency having an axonal sensorimotor neuropathy. The six Multisystem disorder with ataxia, dementia, pyramidal signs and amyotrophy in varying combinations described by Argov and Navon' also showed a multi- Juvenile onset spinal muscular atrophy system degeneration, as did those reported by Adams Neuromuscular disease resembling X-linked bulbospinal muscular atrophy and Green5 and Harding et al.'8 Normal adults The enzyme studies in our patient indicate a Activatorfactor mutations (normal hex A and B activity) deficiency ofhexosaminidase A and B. The case is thus Resembling Tay-Sachs disease, but milder classifiable as an example of delayed onset Sandhoff Siezures, dementia and normal pressure hydrocephalus disease. An asymptomatic individual has been re- Normal adults ported who possessed the homozygous Sandhoff phenotype,'9 but the presence in the rectal biopsy from our patient of intraaxonal membranocytoplasmic lysosmal which had activities within the normal bodies of the type that occur in GM, gangliosidosis ranges, indicating a diagnosis of Sandhoff disease. makes it highly probable that the hexosaminidase Protected by copyright. Hexosaminidase was measured in plasma, leucocytes and cultured skin fibroblasts using the synthetic 4-methylum- deficiency is responsible for his neurological disorder. belliferyl substrate as described previously.'0 Urinary The higher residual activity in his fibroblasts as oligosaccharides were normal. compared with patients with the classical infantile form of Sandhoff disease may explain the later onset Rectal biopsy of symptoms. A case has been described with the Moderate numbers ofmacrophages containing PAS-positive Franceschetti syndrome and a significant reduction in material were present in the lamina propria (fig 1). Small hexosaminidase B in which there was a balanced numbers of neurons related to the muscularis mucosa chromosomal translocation (5:13) (qll:pll).20 The contained rounded sudanophilic eosinophilic inclusions karyotype in the present case was normal. which were PAS-negative but which showed positive staining with Luxol fast blue. The appearances and staining reactions Of the 23 obligate heterozygotes for infantile Sand- were those of a gangliosidosis and consistent with Sandhoff hoff disease that we have tested, 21 had either a total disease (Prof B Lake). Electron microscopy confirmed the hexosaminidase activity or percentage hex A outside presence of multiple concentric lamellar structures within the normal range in either plasma, leucocytes or both. axons (fig 2). The remaining two obligate carriers had both total hexosaminidase activity and percentage hex A in the Discussion overlap range of heterozygotes and normal controls. The mother of our patient had enzyme levels consis- The clinical features in this patient bore a distinct tent with a heterozygote for Sandhoff disease whereas http://jnnp.bmj.com/ resemblance to X-linked bulbospinal neuronopathy the levels in his father were within the normal range. with the early onset of upper limb postural tremor, Although confirmatory serological studies were not followed by muscle cramps, limb girdle and predomin- undertaken, the physical resemblances between father ant proximal limb muscle weakness, mild facial weak- and son were so close as to leave no doubt that the ness and dysarthria. X-linked bulbospinal neuron- stated paternity was correct. opathy was initially considered to represent a "spinal It is possible that the parents possess different muscular atrophy", but sensory nerve action poten- mutations, only one of which is reflected in altered tials are depressed or absent and mild sensory loss may enzyme activity with the synthetic 4-methylum- on October 5, 2021 by guest. be present at times.8 9 Sensory nerve action potentials belliferyl substrate. The patient might therefore be a were lost in the present case, although there was no compound heterozygote. If so, this could be relevant sensory loss. Gynaecomastia is present in approx- to his atypical presentation. imately 50% of patients with X-linked bulbospinal Measurement of the hexosaminidase activity in the neuronopathy but was not shown by our patient. parents against the natural GM, substrate may be more J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1103 on 1 September 1989. 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1106 Thomas, Young, King informative, as may DNA analysis. At present, neuronopathy: a report of 10 cases. J Neurol Neurosurg however, no material from the parents is available for Psychiatry 1982;45:1012-9. 9 Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T. X- further study. linked recessive bulbospinal neuronopathy: a clinicopath- This case widens the already extensive spectrum of ological study. Brain 1989;112:209-32. clinical presentations that have been shown to be 10 Brett EM, Ellis RB, Haas L, Ikonne JU, Lake BD, Patrick AD, attributable to GM2 gangliosidoses (table 2).2' Stephens R. Late onset GM2 gangliosidosis; clinical, path- ological and biochemical studies on eight patients. Arch Dis Child 1973;48:775-85. 11 Jellinger K, Anzil AP, Seeman D, Bernheimer H. Adult GM2 We thank Dr Gerald Stern for referring the patient, Dr gangliosidosis masquerading as slowly progressive muscular Nicholas Murray for undertaking some of the elec- atrophy. Motor neuron disease phenotype. Clin Neuropathol trodiagnostic studies, Professor Brian 1982;1:31-44. Lake for 12 Johnson W, Wigger HJ, Karp HR. Juvenile spinal muscular examining the rectal biopsy and the Friedreich's atrophy. A new hexosaminidase deficiency phenotype. Ann Ataxia Group for financial support. Neurol 1982;1:I1-16. 13 Kolodny E, Lyerla T, Raghavan SS, Seashore G, Fogelson H, Pope HG. Significance of hexosaminidase A deficiency in adults. Neurology 1982;32:A81-82. References 14 Dale AJD, Engel AG, Rudd NL. Familial hexosaminidase A deficiency with Kugelberg-Welander phenotype and mental I Argov Z, Navon R. Clinical and genetic variations in the change. Ann Neurol 1983;14:109. syndrome of adult GM2 gangliosidoses resulting from hex- 15 Karni A, Navon R, Sadeh M. Hexosaminidase A deficiency osaminidase A deficiency. Ann Neurol 1984;16:14-20. manifesting as spinal muscular atrophy of late onset. Ann 2 Woods S, MacDougall BG. Juvenile Sandhoff's disease: some Neurol 1988;24:451-3. properties of the residual hexosaminidase in cultured 16 Parnes S, Karpati G, Carpenter S, Ng Ying Kin NMK, Wolfe LS, fibroblasts. Am J Hum Genet 1976;28:489-95. Suranyi L. Hexosaminidase A deficiency presenting as atypical 3 Goldie WD, Holtzman D, Suzuki K. Chronic hexosaminidase A juvenile-onset spinal muscular atrophy. Arch Neurol and B deficiency. Ann Neurol 1977;2:156-8. 1985;42:1 176-80. 4 MacLeod PM, Wood S, Jan JE, Applegarth DA, Dolman C. 17 Mitsumoto H, Sliman RJ, Schafer IA, Sternick ES, Kaufman B, Progressive cerebellar ataxia, spasticity, psychomotor retarda- Wilbourn A, Horwitz SJ. Motor neuron disease and adult Protected by copyright. tion, and hexosaminidase deficiency in a 10 year old child: hexosaminidase A deficiency in two families: evidence for juvenile Sandhoff disease. Neurology 1977;27:571-3. multisystem degeneration. Ann Neurol 1985;17:378-85. 5 Adams C, Green S. Late onset hexosaminidase A and hexosamin- 18 Harding AE, Young EP, Schon F. Adult onset supranuclear idase A and B deficiency: family study and review. Dev Med ophthalmoplegia, cerebellar ataxia, and neurogenic proximal Child Neurol 1986;28:23643. muscle weakness in a brother and sister: another hexosamin- 6 Oonk JG, van de Helm HJ, Martin JJ. Spinocerebellar degenera- idase A deficiency syndrome. J Neurol Neurosurg Psychiatry tion: hexosaminidase A and B deficiency in two adult sisters. 1987;50:687-90. Neurology 1979;29:380-4. 19 Dreyfus JC, Poenaru L, Svennerholm L. Absence of hexosamin- 7 Barbeau A, Plasse L, Cloutier T, Paris S, Roy M. Lysosomal idase A and B in a normal adult. N Engl J Med 1975;292:61-3. enzymes in ataxia: discovery of two cases of late onset hex- 20 Balestrazzi P. Franceschetti syndrome in a child with a de novo osaminidase A and B deficiency (adult Sandhoff disease) in balanced translocation (5:13) (qI 1 I 1) and significant decrease French Canadians. Can J Neurol Sci 1984;11:601-6. of hexosaminidase B. Hum Genet 1983;64:305-8. 8 Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan- 21 Johnson WG. The clinical spectrum ofhexosaminidase deficiency Hughes JA, Ponsford JR. X-linked recessive bulbospinal diseases. Neurology 1981;31:1453-6. http://jnnp.bmj.com/ on October 5, 2021 by guest.