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caso clinico tay sachs

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Late-onset Tay–Sachs disease
Andrew W Barritt,1,2 Stuart J Anderson,1 P Nigel Leigh,1,3 Basil H Ridha1
Department of Neurology,
Hurstwood Park Neurosciences
Centre, Haywards Heath, UK
Clinical Imaging Sciences Centre,
Brighton and Sussex Medical
School, Falmer, UK
Trafford Centre for Biomedical
Research, Brighton and Sussex
Medical School, University of
Sussex, Falmer, UK
Correspondence to
Dr Andrew W Barritt, Department
of Neurology, Hurstwood Park
Neurosciences Centre, Haywards
Heath, West Sussex, RH16 4EX,
UK; [email protected]
Accepted 27 May 2017
To cite: Barritt AW, J
Anderson S, Leigh PN, et al.
Pract Neurol 2017;0:1–4.
We discuss the assessment and differential
diagnoses of a young adult Hungarian man with
a 1-year history of a progressive and symmetric
amyotrophic lateral sclerosis-like syndrome, along
with irregular action tremor and stimulussensitive myoclonus of the arms. MR scan of the
brain showed isolated cerebellar atrophy and
formal neuropsychometric testing identified
significant subclinical deficits in attention,
processing speed and memory. We suspected a
form of GM2 gangliosidosis, and white cell
enzyme analysis showed markedly reduced
enzymatic activity of b-hexosaminidase A.
Genetic testing subsequently revealed two
heterozygous pathogenic mutations in the HEXA
gene (c.1499delT p.(Leu500fs) and c.805G>A p.
(Gly269Ser)), confirming the very rare diagnosis
of adult-onset Tay–Sachs disease.
A 35-year-old right-handed Hungarian
man presented with 1-year history of
progressive weakness in all four limbs
and tremor of the arms. He had particular difficulties walking, climbing stairs
and lifting objects above the head, and
his writing had deteriorated considerably
owing to the tremor. He had also developed recent slurring of speech when
tired. After sustaining several falls, he had
used a stick when walking outdoors for 6
months, and had lost 3 st in weight over
6 months, despite preserved appetite,
with a noticeable loss of muscle bulk.
There was no pain, sensory or sphincter
disturbance, difficulty swallowing or
breathing and he had normal mood and
subjective cognition.
When aged 14, a neurologist had
assessed him regarding difficulty with
vertical jumping and unsteadiness during
sports, along with a subtle bilateral hand
tremor. There was no specific diagnosis
and the symptoms remained static over
the next 20 years, although his tremor
prevented him from training as an electrician. He completed A-level education in
the UK before enrolling on a business
degree in the USA, which was not
completed due to funding issues. He
returned to the UK aged 23 and worked
as a carer but had recently stopped due
to his deteriorating condition.
He had been previously well with no
relevant family history. There was no
parental consanguinity and no known
Jewish ancestry. His 55-year-old mother
lived in Latvia but his father died young
in a road traffic crash. His alcohol
consumption had always been minimal
and he had never smoked.
On examination, there was mild bilateral upper motor neurone pattern facial
weakness and positive pout reflexes.
Neck flexion and extension were normal.
The upper limbs showed generalised loss
of muscle bulk, most markedly of triceps
bilaterally, with florid fasciculations most
visible in pectoralis and deltoid muscles.
There was a coarse, irregular tremor on
posture and action throughout the
outstretched upper limbs with symmetrically slowed alternating movements
without past pointing. Stimulus-sensitive
myoclonus could be elicited on touching
the right hand. Muscle tone was normal
but with disproportionate elbow extension weakness (2/5), along with
symmetrical weakness of shoulder abduction and external rotation, elbow flexion
and the first dorsal interossei (4/5). In the
lower limbs, tone was normal but there
was symmetrical weakness of hip flexion
(2/5), knee flexion (3/5) and knee extension (2/5), but with fully preserved hip
extension. Flexion of the great toes and
ankle inversion was 4/5 bilaterally with
all other muscle groups having full
power. Reflexes were symmetrically brisk
and plantar responses were extensor but
with no ankle clonus. Sensory examination was normal. To rise from a seated
position he pushed up with his arms to
lock his knees in extension before
walking with a slow, wide-based and
waddling gait (figure 1; for examination
Barritt AW, et al. Pract Neurol 2017;0:1–4. doi:10.1136/practneurol-2017-001665
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retrieval rather than encoding, while prominent deficits in attention and processing speed suggested a
predominantly subcortical pattern of impairment.
Figure 1 Still images from examination video (available online)
showing a coarse tremor on posture and action (A), shoulder
abduction (B) and hip flexion weakness with visible bilateral
wasting of the quadriceps muscles (C) and an extensor left
plantar response (D).
see online supplementary video). Cardiorespiratory,
abdominal, skin, lymph node and testicular examinations were normal and there was no gynaecomastia.
Serum creatine kinase was 603 units/L (0–190).
Normal or negative blood investigations included full
blood count, renal profile, liver and thyroid function
tests, serum C reactive protein, erythrocyte sedimentation rate, antinuclear antibody, extractible nuclear
antigen, serum immunoglobulins, serum protein electrophoresis, antineuronal antibodies, antiganglioside
antibodies, HIV, syphilis, Lyme disease and hepatitis
A–C serology.
Neurophysiological assessment showed normal
peripheral motor and sensory studies apart from
slightly reduced sural sensory action potentials bilaterally. Needle electromyography found widespread
chronic denervation, including the tongue.
MR scan of brain and whole spine showed disproportionate cerebellar atrophy but was otherwise
normal (figure 2); cerebrospinal fluid was normal.
ECG showed normal sinus rhythm. CT scan with
contrast of chest, abdomen and pelvis was normal.
Formal neuropsychological assessment was limited
by his writing difficulties. Out of 14 subcomponent
domains, he scored within the mildly impaired range
in three (visual attention/working memory and
delayed verbal recall; 21.4%), mild-to-moderate range
in six (auditory attention/working memory, delayed
visual recall, immediate verbal recall, semantic word
fluency and verbal recognition memory; 42.8%) and
moderate-to severe range in two (processing speed
and immediate visual recall; 14.2%). In contrast, he
performed in the normal range on tests of visual
perception, confrontational naming and intellectual
ability/non-verbal reasoning (21.4%). His relatively
preserved recognition memory suggested difficulty of
This patient’s progressive upper and lower motor
neuronopathy without sensory involvement raised
the possibility of amyotrophic lateral sclerosis.
However, there were atypical features including the
teenage onset of tremor and sporting difficulties,
the predominantly proximal pattern of muscle
weakness, disproportionate wasting and weakness of
triceps muscles, the jerky upper limb tremor and
myoclonus and disproportionate cerebellar atrophy.
Beyond cervical myeloradiculopathy, mimics of
amyotrophic lateral sclerosis with upper and lower
motor neurone involvement are rare.1 2 Repeat
expansions of the C9orf72 gene, causing of a spectrum of phenotypes including amyotrophic lateral
sclerosis and frontotemporal dementia, can be associated with regional cerebellar atrophy. However, its
penetrance is unusual under 35 years of age and
also he had no features of frontotemporal
dementia.3 4 Cerebellar atrophy raised the possibility of a complex form of autosomal dominant
spinocerebellar ataxia, such as spinocerebellar
atrophy type 3 (Machado–Joseph disease), in which
there may be pyramidal signs and anterior horn cell
disease. However, the absence of extraocular movement abnormalities and extrapyramidal signs were
against this. Although normal appearing white
matter on brain MRI would not exclude an adultonset adrenoleukodystrophy, the cerebellar involvement, lack of sphincter disturbance or sensory signs
and subsequently, normal very-long-chain fatty acid
levels made this and polyglucosan body disease
unlikely. Adult-onset Niemann–Pick disease type C
Figure 2 MR brain imaging showing diffuse cerebellar atrophy
on sagittal T1 (A), axial T2 (B) and coronal T1 (C) sequences
with prominent cerebellar folia and widening of the fissures
Barritt AW, et al. Pract Neurol 2017;0:1–4. doi:10.1136/practneurol-2017-001665
Downloaded from on July 27, 2017 - Published by
may present with a myriad of features, including
cerebellar ataxia and movement disorders, but our
patient did not have the characteristic vertical
supranuclear gaze palsy. Nevertheless, as cerebellar
atrophy is a recognised feature in this and other
GM2 gangliosidoses, we undertook a white cell
enzyme analysis; this showed normal total hexosaminidase activity at 1210 nmol/hour/mg (885–5965
and includes hexosaminidase B activity) but a
markedly low white cell b-hexosaminidase A functioning at 10 nmol/hour/mg (134–700), representing
only 15% normal hexosaminidase A activity (usually
62%–79%). Genetic testing identified compound
heterogeneous pathogenic mutations with both
1499T deletion and the 805G>A substitution in
the HEXA gene. We therefore made a definitive
diagnosis of late-onset Tay–Sachs disease.
b-Hexosaminidase A is a dimeric lysosomal enzyme
comprising alpha subunits encoded by the HEXA
gene (chromosome 15) and beta subunits coded by
the HEXB gene (chromosome 5). It is the only one
of three isozymes that hydrolyses the ganglioside
GM2 into GM3.5 6 GM2 belongs to the glycosphingolipid
constituents of the lipid bilayer of cell
membranes7—and occurs almost exclusively in the
nervous system, particularly within grey matter.8
Abnormal accumulation of GM2 within lysozymes
usually results from a deficiency of the b-hexosaminidase A enzyme itself, either due to autosomal
recessive gene defects in HEXA (Tay-Sachs disease)
or HEXB (Sandhoff ’s disease). Extremely rarely it
may arise instead from deficiency of its activator
protein encoded by the GM2A gene.9 The severity
of individual clinical presentations probably relates
to the degree of residual enzyme activity.5 Most
commonly, severe homozygous mutations lead to
little or no functional enzyme activity, resulting in
relentless developmental regression and early death
in infancy.6 Less severe enzyme defects can delay
presentation until adolescence or adulthood, with a
rather heterogeneous disease spectrum. However,
even in late-onset Tay-Sachs disease, there is often a
history of subtle motor difficulty in childhood.6 7
There is usually neuromuscular weakness, pyramidal
signs and cerebellar dysfunction, but at least a third
have also neuropsychiatric disturbances (some
initially believed to have schizophrenia), and others
have extrapyramidal syndromes, dystonia, overactive
bladder symptoms and cognitive decline.6 7 A
subgroup of patients with late-onset Tay–Sachs
disease have a clinically manifest sensory
Barritt AW, et al. Pract Neurol 2017;0:1–4. doi:10.1136/practneurol-2017-001665
neuropathy,10 but our patient’s diminished sural
sensory action potentials reflected subclinical
The nature and extent of cognitive involvement in
late-onset Tay-Sachs disease is variable with a reported
incidence ranging from 0% to 50%.7 11–13 Deficits in
executive functioning and memory are the most
common. Computerised testing (NeuroTrax) can identify verbal impairment.11 There is also an association
between the burden of neurological involvement and
degree of cognitive dysfunction.13 Formal neuropsychometric testing in our patient showed a
predominantly subcortical pattern of cognitive
impairment with prominent deficits in attention, processing speed, executive function, working memory
and memory retrieval. This is consistent with the relatively greater neuropathological involvement of the
subcortical structures and cerebellum in late-onset
Tay–Sachs disease.14
Clinicians should be aware of late-onset Tay-Sachs
disease as an extremely rare mimic of amyotrophic
lateral sclerosis associated with tremor and cerebellar
atrophy. Formal psychometric testing may highlight
previously unsuspected deficits. Delineating the extent
of cognitive impairment will influence the multidisciplinary management of the hexosaminidase deficiency
syndromes, which remains supportive in the absence
of any clinically effective disease-modifying treatment.
Although low-dose pyrimethamine, a dihydrofolate
reductase inhibitor, induces a small but significant
increase in circulating white cell hexosaminidase A
activity in patients with late-onset Tay-Sachs disease
possessing certain mutations, the effect wanes and
even reverses with long-term exposure; this can
correct to baseline after drug withdrawal.15 In a small
open-label study, three of four patients continued to
deteriorate over 18 months, whereas the other
remained stable despite receiving cyclical low-dose
pyrimethamine with regular monitoring of white cell
enzyme activity.15
Contributors AWB performed a literature search and review and
drafted the article. SJA performed a literature search, review of the
literature and part-drafted the article. PNL and BHR provided
clinical expertise and critical appraisal of the article for submission.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer
reviewed. This paper was reviewed by Robin Lachmann, London,
© Article author(s) (or their employer(s) unless otherwise stated in
the text of the article) 2017. All rights reserved. No commercial use
is permitted unless otherwise expressly granted.
1 Ghasemi M. Amyotrophic lateral sclerosis mimic syndromes.
Iran J Neurol 2016;15:85–91.
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Key points
Clinicians should be aware of late-onset Tay–Sachs disease
as an extremely rare mimic of amyotrophic lateral sclerosis
associated with tremor and cerebellar atrophy; such patients
need white cell enzyme testing, looking particularly for
hexosaminidase A deficiency.
" Patients with late-onset Tay–Sachs disease may have longstanding subtle clumsiness or athletic difficulties dating to
childhood and teenage years.
" There may be subclinical cognitive deficits identified only on
formal neuropsychometric testing and typically reflecting
subcortical dysfunction;
" The only clue from brain imaging may be an isolated cerebellar atrophy.
2 Turner MR, Talbot K. Mimics and chameleons in motor
neurone disease. Pract Neurol 2013;13:153–64.
3 Bocchetta M, Cardoso MJ, Cash DM, et al. Patterns of regional
cerebellar atrophy in genetic frontotemporal dementia.
Neuroimage Clin 2016;11:287–90.
4 Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of
C9ORF72-related disease; genotype/phenotype correlations and
potential modifiers of clinical phenotype. Acta Neuropathol
5 Chen H, Chan AY, Stone DU, et al. Beyond the cherry-red spot:
ocular manifestations of sphingolipid-mediated
neurodegenerative and inflammatory disorders. Surv
Ophthalmol 2014;59:64–76.
6 Neudorfer O, Kolodny EH. Late-onset Tay-Sachs disease. Isr
Med Assoc J 2004;6:107–11.
7 MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric
aspects of the adult variant of Tay-Sachs disease. J
Neuropsychiatry Clin Neurosci 1998;10:10–19.
8 Stryer L. Biosynthesis of Membrane Lipids and Steroids.
Biochemistry. W.H. Freeman & Company, 1995.
9 Neudorfer O, Pastores GM, Zeng BJ, et al. Late-onset Tay-Sachs
disease: phenotypic characterization and genotypic correlations
in 21 affected patients. Genet Med 2005;7:119–23.
10 Shapiro BE, Logigian EL, Kolodny EH, et al. Late-onset TaySachs disease: the spectrum of peripheral neuropathy in 30
affected patients. Muscle Nerve 2008;38:1012–5.
11 Elstein D, Doniger GM, Simon E, et al. Neurocognitive testing
in late-onset Tay-Sachs disease: a pilot study. J Inherit Metab Dis
12 Zaroff CM, Neudorfer O, Morrison C, et al.
Neuropsychological assessment of patients with late onset GM2
gangliosidosis. Neurology 2004;62:2283–6.
13 Frey LC, Ringel SP, Filley CM. The natural history of cognitive
dysfunction in late-onset GM2 gangliosidosis. Arch Neurol
14 Suzuki K. Neuropathology of late onset gangliosidoses. A
review. Dev Neurosci 1991;13:205–10.
15 Osher E, Fattal-Valevski A, Sagie L, et al. Effect of cyclic, low
dose pyrimethamine treatment in patients with late onset Tay
Sachs: an open label, extended pilot study. Orphanet J Rare Dis
Barritt AW, et al. Pract Neurol 2017;0:1–4. doi:10.1136/practneurol-2017-001665
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Late-onset Tay−Sachs disease
Andrew W Barritt, Stuart J Anderson, P Nigel Leigh and Basil H Ridha
Pract Neurol published online July 24, 2017
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