Infantile sandhoff's disease.
A 13-month-old Canadian aboriginal boy presented with global developmental delay and loss of developmental milestones. He was born at 38 weeks to nonconsanguinous parents after an uncomplicated pregnancy. He experienced normal development until the age of 3 months, at which time-delayed motor skills, followed by episodes of myoclonic myoclonic
pertaining to myoclonus.
a generalized seizure consisting of a jerk of most muscles in the body. jerks, were observed. Verbal and social development was normal until approximately 6 months of age.
Physical examination was remarkable for increased head circumference increased head circumference Macrocephaly, see there relative to weight, with frontal bossing and hypotonic hypotonic /hy·po·ton·ic/ (-ton´ik)
1. denoting decreased tone or tension.
2. denoting a solution having less osmotic pressure than one with which it is compared. , nondysmorphic facies. No organomegaly was present. Neurological examination revealed central hypotonia hypotonia /hy·po·to·nia/ (-ton´e-ah) diminished tone of the skeletal muscles.
1. Reduced tension or pressure, as of the intraocular fluid in the eyeball.
2. with head lag and symmetric spasticity involving all four limbs. Deep tendon reflexes were normal, with the exception of ankle clonus clonus /clo·nus/ (klo´nus)
1. alternate involuntary muscular contraction and relaxation in rapid succession.
2. and upgoing plantar reflexes. Bilateral macular macular adjective Related to 1. A macule 2. The macula cherry red spots were visualised, and visual evoked responses were absent. Further investigations including routine bloodwork and metabolic studies were normal. An EEG EEG: see electroencephalography. showed excessive slowing of delta frequencies associated with drowsiness. Plasma hexosaminidase levels were significantly decreased.
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The diagnosis was infantile onset Sandhoff 's disease.
Radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use. findings
Bilateral, diffuse, T1 hyper-, T2 (Figs 1 and 2) and FLAIR hypointense (not shown) thalami were seen. Hyperintense, speckledappearing putamina on T2W images containing punctate punctate /punc·tate/ (punk´tat) spotted; marked with points or punctures.
Having tiny spots, points, or depressions. T2 and FLAIR hypointense foci are demonstrated in Fig. 1. Additional MRI 1. (application) MRI - Magnetic Resonance Imaging.
2. MRI - Measurement Requirements and Interface. findings include a delayed myelination pattern for age, with no visible areas of diffusion restriction.
Single voxel stimulated echo acquisition mode (STEAM) acquisition of the right lentiform nucleus for magnetic resonance spectroscopy revealed diminished N-acetylaspartate (NAA NAA
Nomina Anatomica Avium. ), suggestive of neuronal loss/dysfunction (Fig. 4). Multivoxel acquisition through deep grey matter structures revealed diffusely diminished NAA, most notable within the thalami (not shown). Choline choline: see vitamin.
Organic compound related to vitamins in its activity. It is important in metabolism as a component of the lipids that make up cell membranes and of acetylcholine. levels were found to be elevated which, while a nonspecific finding, may relate to dysmyelination. A few, small, nonspecific lactate peaks were also seen.
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Sandhoff 's disease is a rare autosomal recessive disorder of sphingolipid metabolism, with an incidence of 1 in 384 000 live births, (1) related to a genetic deficiency of the enzyme [beta]-hexosaminidase. Two catalytically active forms of this enzyme exist: [beta]-hexosaminidase A, composed of one [alpha] and one [beta] subunit, and [beta]-hexosaminidase B, which contains two [beta] subunits. (2) The gene HEXA encodes the [alpha] subunit, and mutations affecting this gene result in a deficiency of [beta]-hexosaminidase A, clinically known as Tay-Sachs disease. (1) In Sandhoff 's disease, both [beta]-hexosaminidase A and B have been found to be deficient secondary to mutations within the HEXB gene which encodes the common [beta] subunit. (1-3) Clinically, these two genetic disorders are indistinguishable from each other. (1,4)
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[beta]-hexosaminidase is a lysosomal lysosomal
pertaining to or emanating from lysosomes.
enzymes located in the lysosomes.
lysosomal phospholipidosis enzyme responsible for degrading the ganglioside ganglioside /gan·glio·side/ (gang´gle-o-sid) any of a group of glycosphingolipids found in the central nervous system tissues and having the basic composition ceramide-glucose-galactose-N -acetylneuraminic acid. [GM.sub.2] to [GM.sub.3] by removing the [beta]-N-acetylgalactosamine residue from the nonreducing terminal of the [GM.sub.2] ganglioside. (1,5) In Sandhoff's disease, total hexosaminidase activity is reduced to less than 2 - 3% of normal, unlike Tay Sachs, where total hexosaminidase activity is preserved due to functional [beta]-hexosaminidase B activity. (5) However, the B isoenzyme isoenzyme /iso·en·zyme/ (-en´zim) isozyme.
i is unable to hydrolyse Verb 1. hydrolyse - undergo hydrolysis; decompose by reacting with water
change - undergo a change; become different in essence; losing one's or its original nature; "She changed completely as she grew older"; "The weather changed last night" the [GM.sub.2] ganglioside, which accumulates in the brain (5) and also within the liver, spleen, and kidneys, which may become enlarged. (4,5,14)
Gangliosides have been found to be present primarily within grey matter nuclei and, to a lesser degree, within myelin sheaths of the white matter. (6) [GM.sub.2] ganglioside accumulation within lysosomes lysosomes
n the self-contained organelles found inside most cells, which contain hydrolytic enzymes that aid in intracellular digestion. of cortical neurons results in distension dis·ten·tion also dis·ten·sion
The act of distending or the state of being distended.
[Middle English distensioun, from Old French, from Latin of neuronal cell bodies and nucleus displacement. (5,7,8) Over time, this cellular enlargement results in neuronal dysfunction and severe neurodegeneration from eventual neuronal loss. (5,8-10) Neuronal deterioration and death results in cortical atrophy with widened sulci, narrowed gyri gyri /gy·ri/ (ji´ri) plural of gyrus. , dilated ventricles and atrophy of the optic nerves and cerebellum. (9) Ganglioside storage has been found to induce degeneration of white matter. (5,10) Pathologically, there is evidence for demyelination demyelination /de·my·elin·a·tion/ (de-mi?e-li-na´shun) destruction, removal, or loss of the myelin sheath of a nerve or nerves. Called also myelinolysis. (11,12) as well as delayed myelination, (11) which is believed to be secondary to the grey matter disease. (13) At autopsy, lipid storage and oedema have been found within the white matter. (14)
While the biochemical basis of Sandhoff 's disease is well understood, the exact aetiology resulting in neuronal death and cerebral atrophy is yet to be elucidated. (15) Animal models have suggested that neurons distorted by accumulated sphingolipids directly activate inflammatory pathways and cause eventual apoptosis. (14,15) Sphingolipid accumulation is also thought to incite reactive gliosis, resulting in a progressive increase of head circumference by 1 1/2 to 2 years of age. (12,15-17)
The clinical expression of Sandhoff 's disease is variable. The classic infantile form is characterised by an onset between 3 and 9 months of age, (1,16,18) following initial normal development. Clinical manifestations are variable and may include initiation of a pronounced startle response after 3 or 4 months of age. (17,19) Previously acquired developmental milestones decline, and severe muscular hypotonia, followed by spastic quadraparesis and seizures, are additional features. (16,18) Macular cherry red spots are occasionally observed, (17,19) though this finding is nonspecific and also seen in several other lysosomal storage disorders. Disease progression is rapid, resulting in death by 3 to 5 years of age. Currently, there is no curative treatment and therapy remains supportive. (18)
The juvenile/subacute variant often presents with ataxia between 2 and 5 years of age, (19) and has a slowly progressive course and more favourable prognosis. (1,2) The adult/chronic subtype generally presents in the second or third decade of life, with a variable clinical picture of either spinocerebellar degeneration or motor neurone disease The motor neurone diseases (or motor neuron diseases) (MND) are a group of progressive neurological disorders that destroy motor neurones, the cells that control voluntary muscle activity such as speaking, walking, breathing, and swallowing. (19) and typically has a fair survival rate. (1,2,19)
Although Sandhoff 's disease has been traditionally considered to be a grey matter disease, neuroimaging studies have characterised abnormalities within both the white and grey matter of Sandhoff patients. Despite extensive variability in findings among studied patients, bilateral symmetric thalamic thalamic /tha·lam·ic/ (thah-lam´ik) pertaining to the thalamus. changes have been found to be an early, predictable finding that is probably specific to the [GM.sub.2] gangliosidoses, such as Sandhoff 's disease, and may be useful in determining whether to perform more specific investigations in infants suspected of having a neurodegenerative disease. (5,17) The thalami are usually homogeneously hyperdense on computed tomography (CT) (5,16,17,20) and T2 hypointense (11,12,20) and T1 hyperintense (12,20) on magnetic resonance imaging magnetic resonance imaging (MRI), noninvasive diagnostic technique that uses nuclear magnetic resonance to produce cross-sectional images of organs and other internal body structures. (MRI). MR findings have been found to be particularly variable within the caudate nucleus, globus pallidus, and putamen putamen /pu·ta·men/ (pu-ta´men) the larger and more lateral part of the lentiform nucleus.
n. , though these structures have been shown to be T2-hyperintense. (17)
Currently, there are several theories as to how the stored sphingolipids affect neuroimaging. Abnormal accumulation of macromolecules Macromolecules
A large molecule composed of thousands of atoms.
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macromolecules or lipids increases tissue viscosity and shortens T2 relaxation time, manifesting as a decreased T2 signal, explaining the MR findings among Sandhoff patients. (8) Dystrophic calcification involving the thalami is thought to be responsible for the hyperdense CT appearance. (7,8,17) However, it is generally thought that the neuroimaging features are the end result of intralysosomal storage and gliosis owing to axonal and myelin loss in the central cortical neurons. (8,16,17)
The white matter changes in Sandhoff 's disease are best appreciated with MRI. During the early, asymptomatic disease stage, normal neurological development (20,21) and MRI neuroimaging (6) presume normal myelination. (20) Later imaging of cerebral white matter has demonstrated homogeneous or patchy T2 hyperintensity within frontal, (18) temporal and occipital occipital /oc·cip·i·tal/ (ok-sip´i-t'l) pertaining to the occiput; located near the occipital bone.
Of or relating to the occipital bone.
n. regions, (6,18) and periventricular white matter, (18) and also within the internal and external capsules. (11) Involvement of brainstem white matter has been found to extend from the internal capsules to the level of the pons, (17) medulla medulla: see brain stem. , (20) and cerebellar white matter, (20) though infratentorial involvement is regarded as secondary to the primary abnormalities of the supratentorial white matter. (17) These late-occurring white matter abnormalities are presumed to be the result of secondary demyelination following cortical neuronal death and axonal deterioration, rather than from primary dysmyelination. (13,20,22) However, a combination of delayed myelination and demyelination (11,17) has also been proposed. Diffuse thinning of the corpus callosum as well as both cerebellar and cerebral cortical atrophy have been demonstrated as abnormal signal intensities on T1--and T2-weighted images that have invariably been attributed to disturbed myelination or calcification. (5,10,11,17,20,23)
A correlation between the degree of thalamic hyperdensity and the presence or severity of white matter disease or atrophy has not yet been demonstrated. (5,11,17)
Proton magnetic resonance Noun 1. proton magnetic resonance - resonance of protons to radiation in a magnetic field
NMR, nuclear magnetic resonance
magnetic resonance - resonance of electrons or atoms or molecules or nuclei to radiation frequencies as a result of space quantization spectroscopy (MRS) has revealed progressive elevation in myoinositol (mI):Cr ratios (12,18) within white matter, grey matter, and the thalamus thalamus (thăl`əməs), mass of nerve cells centrally located in the brain just below the cerebrum and resembling a large egg in size and shape. . (18) As the mI peak signifies glial cell activity, it has been hypothesised that accumulation of [GM.sub.2] gangliosides results in glial cell proliferation, or reactive gliosis. (12)
Demyelination in Sandhoff 's disease is expected as a consequence of neuronal loss although, despite clinical and radiographic deterioration, Cho/Cr ratios have been found to remain normal. (12,18) It is thought that the accumulation of gangliosides within cell membranes results in a relative reduction of Cho precursors, thus minimising MRS evidence of demyelination. (12)
NAA and N-acetylaspartylglutamate (tNAA) are markers of neuroaxonal integrity and have been found to decline with neuronal damage and loss. (12,25,26) Progressive declines in NAA and tNAA, consistent with neuronal loss, have been observed in Sandhoff patients. (12,18)
Sandhoff's disease is characterised by the accumulation of N-acetylhexosamine-containing oligosaccharides oligosaccharides (ol´igōsak´rīdz),
n. , both within glycosphingolipids and as free oligosaccharides, both of which contain N-acetyl moieties. (10,26) Further analysis has revealed that it is the level of stored glycosphingolipids, and not the level of cerebral oligosaccharides, that correlates with disease severity. (10) Both animal and human data have confirmed a new spectrum adjacent to the tNAA resonance with a resonance frequency of approximately 2.07 ppm which has been assigned to the N-acetyl moiety moiety: see clan. of N-acetylhexosamine (NAHex). (10,18,26) Human data have shown this resonance to be most prominent in white matter and the thalamus and, to a lesser degree, within paramedian parietal grey matter, though this was not seen within the basal ganglia. (18) This resonance is believed to relate directly to the pathophysiology of Sandhoff 's disease by suggesting that oligosaccharides containing NAHex accumulate in cortical and subcortical subcortical /sub·cor·ti·cal/ (-kor´ti-k'l) beneath a cortex, such as the cerebral cortex. grey matter as well as in white matter. (18) Animal proton MRS studies have demonstrated consistently higher intensities of Nacetyl resonances than controls, and have also shown a progression of increasing intensity of these resonances from presymptomatic to terminal disease stages. (10,26) This presymptomatic NAHex resonance has yet to be demonstrated within presymptomatic Sandhoff patients. (18)
Knowledge of the existence of the NAHex resonance may be of direct clinical relevance in the future as the use of MRS broadens to include both non-invasive diagnostic and treatment strategies. (10,12) This approach may also be helpful in evaluating potential experimental strategies in the treatment of this and other disorders of lysosomal storage (10,26) as well as in helping to monitor disease progression. (12)
(1.) Maegawa GHB GHB
GHB 1 Gamma-hydroxybutyrate, γ-hydroxy-butyrate See GABA 2 Glycosylated hemoglobin, see there
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Kimberly Sass, MD
Sheldon Wiebe, MD, FRCPC, FAAP
Department of Medical Imaging, Royal University Hospital, Saskatoon, Saskatchewan, Canada
E Lemire, MD, PhD, FRCPC, FCCMG, FACMG
Department of Pediatrics, Division of Medical Genetics, Royal University Hospital, Saskatoon