Original Article 259 Serial MR Imaging and 1H-MR Spectroscopy in Monozygotic Twins with Tay-Sachs Disease Authors A. Imamura1, 2, H. Miyajima1, R. Ito1, K. O. Orii1 Affiliations 1 Key words ▶ Tay-Sachs disease ● ▶ MR imaging ● ▶ MR spectroscopy ● ▶ N-acetylaspartate ● ▶ myoinositol ● ▶ lactate ● Abstract & received accepted 2 31.08.2008 15.01.2009 Bibliography DOI 10.1055/s-0029-1202285 Neuropediatrics 2008; 39: 259–263 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0174-304X Correspondence A. Imamura, MD Department of Pediatrics Gifu Prefectural General Medical Center 4-6-1, Noishiki Gifu 500-8717 Japan Tel.: + 81/58/246 11 11 Fax: + 81/58/248 38 05 aimamura30@hotmail.com Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan Four-year-old monozygotic female twins with early onset Tay-Sachs disease are described. The sisters showed similar slowly progressive clinical symptoms and deterioration, however the younger sister also demonstrated intractable myoclonus in the right leg. The serial MR images and 1H-MR spectroscopy of the brain were obtained in both twins. MR images showed high intensity on T2-weighted image in the bilateral white matter, however there were no signal changes in the basal ganglia and thalamus during any of the phases. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was decreased in the both white matter lesions and the corpus striatum, and that of myoinositol (mI)/Cr was increased in the damaged white matter on MR spectroscopy. The elevation of the lactate peak was clearly demonstrated in the left basal ganglia of the younger sister; however it was not shown in cerebral lesions of the elder sister. Changes in metabolites on MR spectroscopy were closely linked to the respective clinical features of each twin. Follow-up examination by 1H-MR spectroscopy is useful for the evaluation of neuronal changes in children with Tay-Sachs disease. Introduction & Case Report & Tay-Sachs disease is an autosomal recessive neurodegenerative disorder of ganglioside metabolism with a deficiency of hexosaminidase A. The deficiency of hexosaminidase A, an enzyme involved in the metabolism of gangliosides, causes an accumulation of GM2 ganglioside in neurons and impairment of neuronal function. Typical features of the commonest form, infantile type, show normal or delayed development until around 6 months followed by regression, exaggerated startle response, myoclonic seizures, visual loss, macrocephaly, and bilateral retinal cherry red spots. However, the clinical course ranges from mild to severe according to the activity of hexosaminidase A [4]. Neuroradiological findings including cranial CT and MRI have been described, but there have been few reported MR spectroscopy findings in Tay-Sachs disease [2, 10]. We have performed serial MR imaging and 1HMR spectroscopy in monozygotic siblings with early onset Tay-Sachs disease manifesting a mild phenotype, and discuss the evaluation of neuronal damage in these two cases. Four-year-old monozygotic female twins with progressive deterioration were the first children of non-consanguineous parent. Pregnancy was uneventful, however delivery was scheduled by Cesarean section at 34 weeks of gestation. The birth weights of the elder and younger sister were 1 536 g and 1 986 g, respectively. There was asphyxia and neonatal jaundice in both twins. Motor development slowly progressed to walking with support at 18 months. However, neurological deterioration was noted thereafter. Therefore, the twins were admitted to Gifu Prefectural General Medical Center for evaluation and diagnosis. Head circumference was not enlarged. There was no evidence of hepatosplenomegaly. Physical examination showed generalized hypotonia and the ophthalmological examination demonstrated bilateral cherry red spot macular funds of the eye in both children. Biochemical measurements of lysosomal enzyme activity with leukocytes showed decreased hexosaminidase A; 26.9 nmol/mg p/h in the elder sister, and 25.0 nmol/mg p/h in the younger sister (normal range: 251.1 − 607.4 nmol/mg p/h). Imamura A et al. Serial MR Imaging and 1H-MR Spectroscopy … Neuropediatrics 2008; 39: 259–263 260 Original Article Fig. 1 Serial MR image with T1- (a − d, i − l) and T2- (e − h, m − p) weighted image of the patients at 2 years and 3 years of age (a, e and b, f: elder sister at 2 years; c, g and d, h: elder sister at 3 years; i, m and j, n: younger sister at 2 years; k, o and l, p: younger sister at 3 years, respectively.) There was high signal intensity on T2-weighted image of the bilateral occipital white matter, centrum semiovale and the region showed spreading from 2 years to 3 years of age in both children. Brain atrophy and dilatation of the lateral ventricles had also spread from 2 years to 3 years of age in both children. There was no signal change in the bilateral corpus striatum in either child. Therefore, they were diagnosed as having infantile Tay-Sachs disease. Cranial MR images demonstrated bilateral hyperintense signal changes in the periventricular white matter on T2weighted and FLAIR weighted images. However, there was no ▶ Fig. 1). Myosignal change in the basal ganglia in either twin (● clonic seizure was seen predominantly in the right leg at 2 years of age. In the elder sister, seizures disappeared rapidly after administration of valproic acid; however it became intractable in the younger sister despite administration of valproic acid and clobazam. The electroencephalogram (EEG) showed generalized slowing background rhythm without any paroxysmal discharges. Imamura A et al. Serial MR Imaging and 1H-MR Spectroscopy … Neuropediatrics 2008; 39: 259–263 Original Article 261 Fig. 2 Proton MR spectroscopy localized on the bilateral corpus striatum at 2 years of age (a and b: right and left corpus striatum of the elder sister, c and d: those of the younger sister, respectively.) NAA/Cr was decreased in the bilateral corpus striatum, however Cho/Cr and mI/Cr showed an almost normal range in both children. The lactate peak was seen in the left corpus striatum in younger sister. Serial 1H-MR spectroscopy was performed twice, at 2 and 3 years of age, respectively. Localization of a 15 × 15 × 15 mm region of interest (ROI) was achieved using short TE (30 ms) point-resolved spectroscopy (PRESS) sequences. Proton MR spectra from different ROIs were acquired within measuring times of 5 min each (TR 2000 ms, 128 accumulations). The ROI was positioned over the bilateral basal ganglia and included the occipital cortex and white matter. MR spectroscopy demonstrated a significantly decreased low Nacetylaspartate (NAA)/creatine (Cr) ratio (normal at 5 to 15 years, 1.80 ± 0.17 [6–9, 11, 12]) in the bilateral basal ganglia and included the surrounding white matter. In addition, an elevated myoinositol (mI)/Cr ratio (normal at 5–15 years, 0.66 ± 0.07 [6– 9, 11, 12]) was shown in the bilateral involved white matter of ▶ Fig. 2). The lactate peak was seen in the the younger sister (● left basal ganglia in the younger sister. Serial MR spectroscopy showed a greater decrease of NAA/Cr in the involved white matter and corpus striatum at 3 years old than at 2 years old in each twin, and a greater increase of mI/Cr in the involved white matter at 3 years old compared to that at 2 years old in the younger sister. There was still a clearly defined lactate peak in the left basal gan▶ Table 1). The cliniglia in the younger sister at 3 years of age (● cal course of the twins showed a mild phenotype with the disease, however the hypertonia gradually progressed, and they were bed-ridden at 30 months. They could not take oral nutri- tion, therefore they had been put on nasal tube feeding from 3 years of age. Now they sometimes have a cold, however they need neither tracheotomy nor hospitalization. They had a putative Gln390Pro mutation, however another mutation had not been identified in HexA gene. Discussion & GM2 gangliosidosis is a rare disorder characterized by the intralysosomal accumulation of GM2 ganglioside due to a deficiency in beta-hexosaminidase A (HexA), which has an alpha-beta dimeric structure, or its cofactor (the GM2 activator protein). Three forms of GM2 gangliosidosis have been described on the basis of the type of enzymatic deficit. First, the beta-HexA alphasubunit deficiency leads to a beta-Hex A deficiency (variant B, Tay-Sachs disease). Second, beta-HexA beta-subunit deficiency leads to a beta-HexA and B deficiency (variant 0, Sandhoff disease). GM2 activator is a non-enzymatic protein, which mediates the interaction between the water-soluble enzyme beta-HexA and its membrane-embedded substrate, GM2-ganglioside, at the lipid-water interface. In the final form, GM2 activator deficiency leads to normal beta-HexA activity (variant AB). The classic infantile form of Tay-Sachs disease shows a rapidly progressive neuronal degeneration leading to death in the first few years of life [4]. In the pathological aspect, storage of mem- Imamura A et al. Serial MR Imaging and 1H-MR Spectroscopy … Neuropediatrics 2008; 39: 259–263 262 Original Article Table 1 Serial data of proton MR spectroscopy localized on the bilateral corpus striatum and occipital white matter at 2 and 3 years of age in both children. Patient 1 (elder sister) Corpus striatum (right/left) White matter (right/left) NAA/Cr Cho/Cr mI/Cr lactate NAA/Cr Cho/Cr mI/Cr lactate Patient 2 (younger sister) 2 years 3 years 2 years 3 years 1.36/1.36 0.78/0.84 0.54/0.55 −/− 1.25/1.40 0.73/0.79 0.77/0.81 −/− 1.05↓/1.15↓ 0.86/0.83 0.58/0.63 −/− 0.85↓/0.97↓ 0.89/0.89 0.73/0.75 −/− 1.26/1.41 0.82/0.83 0.57/0.65 −/+ 1.42/1.36 0.82/1.04 0.78/0.81 −/− 1.07↓/0.98↓ 0.95/0.91 0.68/0.63 −/+ 1.15↓/1.17↓ 1.05/0.79 0.88↑/0.90↑ −/− brane cytoplasmatic bodies in neurons was caused by an accumulation of GM2-ganglioside and the nerve cell dysfunction was progressive and secondary Wallerian degeneration and destruction of myelin occurred in the disease [14]. Although a few neuroradiological studies have previously been reported in Tay-Sachs disease, serial neuroradiological findings have not been shown [2, 3, 5, 10, 13, 16]. This is the first report of serial MR image and 1H-MR spectroscopy findings in monozygotic twins with Tay-Sachs disease. In previous studies, involvement of the bilateral basal ganglia, caudate nucleus, and thalamus had been shown as characteristic neuroradiological findings in the early stage of infantile Tay-Sachs disease [3, 5, 13, 16]. In our cases, those findings were not detected, although hyperintensity in the bilateral white matter was shown at an earlier phase and then slowly progressed. Decreased NAA/Cr and elevated mI/Cr ratios were shown in the involved bilateral occipital cortex and white matter on 1H-MR spectroscopy. Serial 1H-MR spectroscopy indicated a greater decrease in NAA/Cr and greater increase in mI/Cr in the same area. NAA is located almost exclusively in the neurons and axon, therefore, decreased NAA is associated with impaired function of neurons and/or axonal injury. Elevation of mI, which is a marker of glial cells, may reflect gliosis. The involvement of the occipital cortex and white matter of our cases may indicate progressive cortical neuronal loss, abnormal myelin production and active demyelination [15]. In our patients, elevated mI/Cr was shown in the occipital cortex and white matter of the younger sister with intractable epilepsy, therefore gliosis of the brain might have been more severe in the younger sister than in the elder sister. On our serial 1H-MR spectroscopy study of the basal ganglia, NAA/Cr was more decreased, however, both Cho/Cr and mI/Cr showed an almost normal range in both siblings. It is suggested that neuronal dysfunction had already occurred in the basal ganglia although MRI had not detected any abnormal signal change. In addition, the lactate peak was shown in the left basal ganglia in the younger sister with intractable myoclonic seizure of the right leg. Basal ganglia involvement with GM2 gangliosidosis contains multiple pathological neuronal changes, such as loss of axon and myelin, gliosis, and accumulation of calcium associated with the intracellular storage of GM2 ganglioside [13]. Characteristic neuroradiological findings in Tay-Sachs disease, are hypointensity on T2-weighted images and hyperintensity on T1-weighted images in the basal ganglia, and these findings are caused by accumulation of calcium in neuronal tissue. In previous studies by 1H-MR spectroscopy in patients with GM2 gangliosidosis, increased lactate peaks were shown in the bilateral basal ganglia of a Sandhoff disease patient, which was suggested to indicate an anaerobic metabolism in the neuronal tissue. In our patients, there was no signal change on MR images of the basal ganglia, however, anaerobic glycolysis might have occurred at a stage prior to calcium accumulation in the left basal ganglia, causing intractable right leg myoclonus in the younger sister [1]. Decreased NAA/Cr and increased mI/Cr in basal ganglia on 1HMR spectroscopy had been reported in the three patients with infantile Tay-Sachs disease [2], however those in the mild phenotype had not been reported. In our study, decreased NAA/Cr was shown both in the corpus striatum and occipital region including cortex and white matter, while increased mI/Cr was shown in the latter. Serial MR images showed progressive mild brain atrophy and hyperintensity on T2-weighted images in the bilateral white matter including the centrum semiovale and optic radiation. These results may suggest that cortical neuronal dysfunction, secondary axonal degeneration and myelin destruction had taken place in the occipital region, while neuronal dysfunction without myelin destruction had occurred in the corpus striatum in our patients [14]. Mutation analysis of the HexA gene was performed in our patients. The nt1169A to C (Gln390Pro) was identified as a new mutation in the HexA gene, however there was no apparent mutation of the other allele. The common mutations in Japanese patients, IVS 5, -1G to T and one base deletion at nt613C were not identified. Patients with these mutations manifest a severe infantile form of the disease, while our patients demonstrated slowly progressive deterioration and a mild clinical course [15]. In this study, we describe the neuroradiological findings of mildly progressive Tay-Sachs disease infantile form in monozygotic twins. Changes in metabolites on 1H-MR spectroscopy were closely linked to the clinical features of the patients. The findings of 1H-MR spectroscopy in our patients indicated the involvement of striatum neurons without signal change on MR images. 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