Identification of Sandhoff disease in a Thai family: clinical and biochemical characterization.
ABSTRACT Sandhoff disease is a GM2 gangliosidosis that is rare in Thailand. The authors report a Thai family with two children known to have infantile form of Sandhoff disease. The index case exhibited mitral valve prolapse with mitral regurgitation as an early sign, which is a rare presentation in Sandhoff disease. Thereafter the patient had developmental regression, startle reaction, and cherry red spots. The diagnosis was confirmed by biochemical analysis.
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ABSTRACT: The hydrolysis of GM2-ganglioside is unusual in its requirements for the correct synthesis, processing, and ultimate combination of three gene products. Whereas two of these proteins are the alpha- (HEXA gene) and beta- (HEXB) subunits of beta-hexosaminidase A, the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific co-factor for the enzyme. A deficiency of any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells, and one of the three forms of GM2-gangliosidosis, Tay-Sachs disease, Sandhoff disease or the AB-variant form. Studies of the biochemical impact of naturally occurring mutations associated with the GM2 gangliosidoses on mRNA splicing and stability, and on the intracellular transport and stability of the affected protein have provided some general insights into these complex cellular mechanisms. However, such studies have revealed little in the way of structure-function information on the proteins. It appears that the detrimental effect of most mutations is not specifically on functional elements of the protein, but rather on the proteins' overall folding and/or intracellular transport. The few exceptions to this generalization are missense mutations at two codons in HEXA, causing the unique biochemical phenotype known as the B1-variant, and one codon in both the HEXB and GM2A genes. Biochemical characterization of these mutations has led to the localization of functional residues and/or domains within each of the encoded proteins.Biochimica et Biophysica Acta 11/1999; 1455(2-3):105-38. · 4.66 Impact Factor
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ABSTRACT: Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal beta-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, beta-hexosaminidase enzyme activity, and mutation analysis was collected. In our cohort of patients, the mean (+/-SD) age of onset of symptoms was 5.3 +/- 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 +/- 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 +/- 5.5 years. The mean age of onset of speech problems was 7.0 +/- 5.6 years, with a mean time of progression to anarthria of 5.6 +/- 5.3 years. Muscle wasting (10.6 +/- 7.4 years), proximal weakness (11.1 +/- 7.7 years), and incontinence of sphincters (14.6 +/- 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course. Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sachs variant and Sandhoff variant groups. Among patients with the Tay-Sachs variant, the HEXA genotype showed a significant correlation with the clinical course.PEDIATRICS 12/2006; 118(5):e1550-62. · 4.47 Impact Factor
Article: A case refort of Sandhoff disease.[Show abstract] [Hide abstract]
ABSTRACT: Sandhoff disease is a rare autosomal recessive metabolic disease presenting bilateral optic atrophy and a cherry red spot in the macula. This case report presents the characteristics of a patient with Sandhoff disease as assessed by ophthalmic, neuroimaging, and laboratory procedures. Ophthalmologic examination revealed that the patient could not fixate her eyes on objects nor follow moving targets. A pale optic disc and a cherry red spot in the macula were seen in both eyes. Low signal intensity at the thalamus and high signal intensity at the cerebral white matter were noted in a T2-weighted brain MR image. A lysosomal enzyme assay using fibroblasts showed the marked reduction of both total beta-hexosaminidases, A and B. Based on the above clinical manifestations and laboratory findings, we diagnosed the patient as having Sandhoff disease.Korean Journal of Ophthalmology 04/2005; 19(1):68-72.
1088 J Med Assoc Thai Vol. 93 No. 9 2010
Sakpichaisakul K, Department of Pediatrics, Maharat Nakhon
Ratchasima Hospital, Chang Phuak Road, Muang, Nakhon
Ratchasima 30000, Thailand.
Phone: 044-246-389, Fax: 044-235-166
Identification of Sandhoff Disease in a Thai Family:
Clinical and Biochemical Characterization
Kullasate Sakpichaisakul MD*, Pairat Taeranawich MD*,
Achara Nitiapinyasakul MD**, Todsaporn Sirisopikun MD*
* Department of Pediatrics, Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand
** Department of Ophthalmology, Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand
Sandhoff disease is a GM2 gangliosidosis that is rare in Thailand. The authors report a Thai family with two
children known to have infantile form of Sandhoff disease. The index case exhibited mitral valve prolapse with mitral
regurgitation as an early sign, which is a rare presentation in Sandhoff disease. Thereafter, the patient had developmental
regression, startle reaction, and cherry red spots. The diagnosis was confirmed by biochemical analysis.
Keywords: Infantile sandhoff disease, Cherry red spot, Mitral valve prolapse
Gangliosides are components of plasma
membranes, which comprise sphingosine, fatty
acids, hexose, hexosamine, and neuraminic acid.
Gangliosides degraded in cellular lysosomal compart-
ment(1). Normally, the hydrolysis of gangliosides is
accomplished by the action of two structurally related
lysosomal enzymes, hexosaminidase A (Hex A) and
hexosaminidase B (Hex B), and the GM2 activator
protein(2). Hex A is composed of two subunits, α and β
(αβ), whereas Hex B has only β subunits (ββ). In the
degradation of GM2 gangliosides mediated by Hex A,
GM2 activator protein is crucial for the phenomenon.
The subunits of hexosaminidase, α and β are encoded
by two main genes, HEXA (15q23-q24) and HEXB (5q13)
respectively(2-4). Particularly, mutation of any one of
these genes can result in autosomal recessive GM2
gangliosidosis which then results in intralysosomal
accumulation of GM2 gangliosides and a few related
glycolipids in neurons of the brain, and to a much
lesser extent in other organs(2). Theoretically, there are
three diseases sharing similar clinical phenotypes,
i.e., Tay-Sachs (α-defects), Sandhoff (β-defects), the
AB-variant (activator defects), most of them cannot be
distinguished by clinical manifestations(3).
Sandhoff disease has three subtypes, which
are infantile, juvenile, and adult onset(4,5). The infantile
form is characterized by early onset of symptoms, which
usually occur in the first 6 to 18 months of life. An
abnormal acousticomotor reaction, psychomotor
deterioration, together with axial hypotonia and
bilateral pyramidal signs, and cortical blindness with
macular cherry red spots are clinical hallmarks of this
disease. This form usually presents as a stereotypical
progression of disease, leading to death before the
age of 4(4,5).
In the juvenile form with mid-childhood
onset, initial manifestations include clumsiness due to
ataxia, subsequent spasticity, athetosis, loss of
languages and seizures(6). The adult patients with
Sandhoff disease present later in adulthood and the
disease progresses more slowly. The juvenile and adult
forms differ from each other primarily by the impact of
disease on intelligence, which is minimal through
much of the course of adulthood(4,6). The cherry red
spot in the macula is less frequently detected in this
In the present report, the authors present a
Thai family with two children affected by Sandhoff
disease and a healthy carrier child. Relevant physical
findings and biochemical analysis of hexosamindase
assay are described.
J Med Assoc Thai 2010; 93 (9): 1088-92
Full text. e-Journal: http://www.mat.or.th/journal
J Med Assoc Thai Vol. 93 No. 9 20101089
A 1-year-5-month Thai boy, previously
diagnosed with cerebral palsy, was hospitalized due to
uncontrolled generalized tonic clonic and myoclonic
seizures aggravated by loud noises. He was born
full-term by vaginal delivery with normal birth weight.
At 9 months of age, he was incidentally found to
have asymptomatic heart murmur from which
echocardiogram revealed mitral valve prolapse with
moderate mitral regurgitation of unclear etiology.
Coincidentally, at that time, his mother also mentioned
a developmental regression of her child as being unable
to sit without support. Thereafter, the generalized tonic
clonic and myoclonic seizures following the exposure
to loud noise began to develop most notably from
15 months of age. Neurologic examination revealed
generalized hypotonia with hyperreflexia, while
other physical findings appeared to be normal. Brain
ultrasound at 10 months showed no significant
abnormalities. Brain CT/MRI was not performed.
The patient was the third child of a healthy,
non-consanguineous couple who came from the same
district in Northeastern Thailand. As for the other two
sons, the oldest died at 3 years of age and was
described to have similar progressive neurological
disorder as the patient, while the second child, now
6 years old, has normal development.
Physical examination at 1 year and 5 months
of age showed that he could not follow objects
and had neither visual attention nor eye contact.
Ophthalmological examination revealed inability to
fixate his eyes on objects and not follow moving
targets. Pale optic discs and cherry red spots in the
macula were detected (Fig. 1).
As a result, Tay-Sachs disease was suspected
and peripheral blood samples were taken from the
patient and his living brother for biochemical analysis
at Genetic Laboratory, Department of Pediatrics,
Faculty of Medicine, Ramathibodi Hospital, Mahidol
University. Plasma hexosaminidase A and B activity
was assayed by using spectrophotometric method and
glucopyranoside as tested substrate. The analysis
showed a marked reduction of both total Hex A and B
(5-6% of normal control), and Hex B (9% of normal
control) activities in the patient’s specimen, whereas
Hex A activity was normal (70% of normal control).
These results were consistent with Sandhoff disease
(Table 1). In his brother’s specimen, the result showed
moderately reduced activities of total Hex A and B,
and Hex B, suggesting carrier status of the disease.
Genetic counseling was provided to the parents. Due
to the lack of effective treatment for Sandhoff disease,
the patient’s condition deteriorated and eventually
died of respiratory complication at 2 years of age.
In the present report, a Thai boy who suffered
from the infantile form of Sandhoff disease is described.
The important clues pointing to the diagnosis in the
present case are degenerative brain disorder, startle
reaction, and macula cherry red spots. With all clinical
evidences, GM2 gangliosidosis, i.e. Sandhoff and
Tay-Sachs disease was suspected. Nevertheless, these
two disorders cannot be distinguished by clinical
phenotypes alone since both share almost identical
clinical pictures. Only a few evidences are helpful in
clinical diagnosis; organomegaly and occasional bone
Fig. 1Ocular fundus photographs. Left eye shows a cherry
red spot in the macula (white arrow). Right eye
shows a cherry red spot in the macula (white arrow)
and a pale optic disc (black arrow)
Individual Total Hex A and B
Hex B activity
Hex A activity
(% total activity)
Table 1. Enzyme activities of total hexosaminidase A and B, hexosaminidase A and hexosaminidase B
1090 J Med Assoc Thai Vol. 93 No. 9 2010
deformity can be found in some Sandhoff-affected
individuals, but not in Tay-Sachs disease(3,4,7). The
present patient did not have organomegaly or bone
involvement but showed cardiac abnormality. It
follows therefore that the laboratory analysis of Hex
profiles are necessary for definite diagnosis(7).
A lysosomal enzyme assay from peripheral
blood of the presented patient showed a marked
reduction of both total Hex A and B isoenzymes in
the serum, being a hallmark for Sandhoff disease(8).
The relatively higher percentage of Hex A activity
compared to that of Hex B activity in Sandhoff disease
can be explained by the excess α subunits due to the
fact that fewer β subunits are produced(3,5). The
patient’s brother had moderate reduction of total
Hex A and B, and Hex B isoenzymes, which
characterized him as a carrier of Sandhoff disease(5,7-9).
Unfortunately, parental specimens were not available
for biochemical analysis.
In general, Tay-Sachs disease is rare, but
with a higher prevalence than Sandhoff disease.
The prevalence of Tay-Sachs disease is estimated 1
in 201,000 live births, while Sandhoff disease is
described at 1 in 384,000 live births(4). Tay-Sachs disease
is more prevalent in Jewish populations with an
incidence of 1 in 3,900 live births, whereas the incidence
of Sandhoff disease is 1 in 1,000,000(1,7). The Tay-Sachs
carrier frequency is much higher in the Ashkenazi
Jews (1 in 30) and eastern Quebec French Canadian
(1 in 14) populations compared to that in the general
population (1 in 300)(1,4,7). The Sandhoff carrier
frequency in non-Jewish populations (36 in 10,000)
is slightly higher than Jewish populations (20 in
10,000)(10). In Thailand, only one single case of
Sandhoff disease (infantile form) was previously
reported(11). The case was confirmed by enzyme
analysis in skin fibroblast culture(11).
Macular cherry-red spot is an ophthalmic sign
of lysosomal storage disease and can be used as a
diagnostic clue even though it is not pathognomonic(12).
This fundus appearance also accompanies other
neuronal lipid-storage disorders including Sandhoff
disease (GM2 type II), gangliosidosis GM2 type III
and GM1 type I, Niemann-Pick disease, sialidosis
types I and II, Farber disease, mucolipidosis III, and
metachromatic leukodystrophy(13,14). The cherry red
spot in the macula is due to the accumulation of
sphingolipid in retinal ganglion cells. As the disease
progresses, optic atrophy can be present(13).
Mitral valve prolapse (MVP) has been
described a common disorder, with prevalence
estimates generally ranging from 5 to 15 percent in
previously reports(15). The larger study of the
prevalence of MVP in the general population from
the Framingham investigators, they reported overall
prevalence of 2.4% the same as the Theal et al study
reporting a prevalence of MVP was 2.7%(15,16). The
prevalence did not differ significantly between
ethnic groups. To date, the largest study of the
echocardiographic prevalence of MVP was 0.6%,
which was substantially lower than that previously
reported. The knowledge pertaining to MVP is mainly
based on that studied in adults. However, MVP is
not an uncommon finding in children younger than
13 years of age. Most of the children with MVP are
asymptomatic(17). MVP has been documented to be
more prevalent in patients with Marfan syndrome,
Ehlers-Danlos syndrome, osteogenesis imperfecta
and other collagen related disorders(18). The patient
described had MVP with moderate mitral regurgitation,
which in fact, could represent an extremely rare
manifestation of Sandhoff disease. Similar cardiac
findings have been previously reported in a single
patient with infantile Sandhoff disease(19). To the
authors knowledge, there is no correlation of MVP
and hexosaminidase, thus MVP may be an incidental
Neuroimaging of GM2 gangliosidosis have
already been published in a few reports(20). The abnormal
lesions on bilateral thalamic and basal ganglia region
on CT/MRI were associated with GM2 gangliosidosis,
which could be a clue for specific diagnosis(20). In the
presented patient, CT/MRI scans were not performed
because the diagnosis was confirmed by plasma
Treatment for Sandhoff disease generally
involves symptomatic and supportive care, i.e.
management of the seizures and interventional
programs for motor and mental retardation. Genetic
counseling and prenatal diagnosis for future pregnancy
should be offered to the affected families.
In conclusion, the authors described a patient
with classic infantile form of Sandhoff disease who
had a rare cardiac manifestation as an early sign.
Although uncommon association, this is an important
sign to recognize. Further studies are needed to
determine the correlation between hexosaminidase
The authors thank for Dr. Daungrudee
Wattanasirichaigoon for help with the biochemical
J Med Assoc Thai Vol. 93 No. 9 20101091
analysis, critical advice and editing the manuscript,
and to Dr. Objoon Trachoo and Dr. Mahippathorn
Chinnapa for revision of the manuscript and English
1. Menkes JH, Wilcox WR. Inherited metabolic
diseases of the nervous system. In: Menkes JH,
Sarnat HB, Maria BL, editors. Child neurology. 7th
ed. Philadelphia: Lippincott Williams & Wilkins;
2. Lyon G, Kolodny EH, Pastores GM. Early infantile
progressive genetic encephalopathies: clinical
problems and diagnostic considerations. In: Lyon
G, Kolodny EH, Pastores GM, editors. Neurology
of hereditary metabolic diseases of children. 3rd
ed. New York: McGraw-Hill; 2006: 78-85.
3. Mahuran DJ. Biochemical consequences of
mutations causing the GM2 gangliosidoses.
Biochim Biophys Acta 1999; 1455: 105-38.
4. Maegawa GH, Stockley T, Tropak M, Banwell B,
Blaser S, Kok F, et al. The natural history of
juvenile or subacute GM2 gangliosidosis: 21 new
cases and literature review of 134 previously
reported. Pediatrics 2006; 118: e1550-62.
5. Yun YM, Lee SN. A case refort of Sandhoff disease.
Korean J Ophthalmol 2005; 19: 68-72.
6. Hendriksz CJ, Corry PC, Wraith JE, Besley GT,
Cooper A, Ferrie CD. Juvenile Sandhoff disease—
nine new cases and a review of the literature. J
Inherit Metab Dis 2004; 27: 241-9.
7. Ozkara HA, Topcu M, Renda Y. Sandhoff
disease in the Turkish population. Brain Dev
1997; 19: 469-72.
8. Wendeler M, Sandhoff K. Hexosaminidase assays.
Glycoconj J 2009; 26: 945-52.
9. Lowden JA, Ives EJ, Keene DL, Burton AL,
Skomorowski MA, Howard F. Carrier detection in
Sandhoff disease. Am J Hum Genet 1978; 30: 38-45.
10. Cantor RM, Roy C, Lim JS, Kaback MM. Sandhoff
disease heterozygote detection: a component of
population screening for Tay-Sachs disease
carriers. II. Sandhoff disease gene frequencies in
American Jewish and non-Jewish populations.
Am J Hum Genet 1987; 41: 16-26.
11. Wasant P, Wattanaweeradej S, Raksadawan N,
Kolodny EH. Lysosomal storage disorders in
Thailand: the Siriraj experience. Southeast Asian J
Trop Med Public Health 1995; 26(Suppl 1): 54-8.
12. Sango K, Yamanaka S, Ajiki K, Arai N, Takano M.
Involvement of retinal neurons and pigment
epithelial cells in a murine model of sandhoff
disease. Ophthalmic Res 2008; 40: 241-8.
13. Fenichel GM. Psychomotor retardation and
regression. In: Fenichel GM, editor. Clinical
pediatric neurology: a signs ad symptoms
approach. 5th ed. Philadelphia: Elsevier; 2005:
14. Ospina LH, Lyons CJ, McCormick AQ. “Cherry-
red spot” or “perifoveal white patch”? Can J
Ophthalmol 2005; 40: 609-10.
15. Freed LA, Levy D, Levine RA, Larson MG,
Evans JC, Fuller DL, et al. Prevalence and clinical
outcome of mitral-valve prolapse. N Engl J Med
1999; 341: 1-7.
16. Theal M, Sleik K, Anand S, Yi Q, Yusuf S, Lonn E.
Prevalence of mitral valve prolapse in ethnic
groups. Can J Cardiol 2004; 20: 511-5.
17. Van Der Ham DP, De Vries JK, Van Der Merwe PL.
Mitral valve prolapse: a study of 45 children.
Cardiovasc J S Afr 2003; 14: 191-4.
18. Grau JB, Pirelli L, Yu PJ, Galloway AC, Ostrer H.
The genetics of mitral valve prolapse. Clin Genet
2007; 72: 288-95.
19. Venugopalan P, Joshi SN. Cardiac involvement in
infantile Sandhoff disease. J Paediatr Child Health
2002; 38: 98-100.
20. Yuksel A, Yalcinkaya C, Islak C, Gunduz E, Seven
M. Neuroimaging findings of four patients with
Sandhoff disease. Pediatr Neurol 1999; 21: 562-5.
1092J Med Assoc Thai Vol. 93 No. 9 2010
Sandhoff disease รายงานผู้ป่วยในครอบครัวไทย: อาการแสดงทางคลินิก และผลปฏิบัติการ
กุลเสฏฐ ศักดิ์พิชัยสกุล, ไพรัตน์ เตรนาวิทย์, อัจฉรา นิธิอภิญญาสกุล, ทศพร ศิริโสภิตกุล
Sandhoff disease เป็นโรคในกลุ่ม GM2 gangliosidosis ซึ่งพบน้อยมากในประเทศไทย ผู้นิพนธ์
รายงานผู้ป่วย 2 รายเป็นพี่น้องกันเป็นโรค Sandhoff disease ที่มีอาการแรกเริ่ม ในช่วงทารก ผู้ป่วย 1 ราย
มาพบแพทย์ด้วยอาการทางหัวใจ ได้แก่ mitral value prolapse และ mitral regurgitation โดยเป็นอาการนำ
ที่พบน้อยมากใน Sandhoff disease หลังจากนั้นผู้ป่วยเริ่มมีพัฒนาการถดถอย ร่วมกับ startle reaction และ
ตรวจพบ cherry red spots การวินิจฉัยผู้ป่วยรายนี้ยืนยันโดยผลปฏิบัติการทางชีวเคมี