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Late-onset TaySachs disease presenting as a

childhood stutter
B E Shapiro and M R Natowicz

J. Neurol. Neurosurg. Psychiatry 2009;80;94-95

doi:10.1136/jnnp.2008.147645

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PostScript
LETTERS
Psychogenic aphonia: spectacular
recovery after motor cortex
transcranial magnetic stimulation
Psychogenic aphonia is a disabling conver-
sion disorder with no standard psychother-
apeutic1 or speech-therapeutic treatment.2
We present here a case report describing a
promising new treatment for this disorder
based on repetitive transcranial magnetic
stimulation (rTMS).
A left-handed 18-year-old woman devel-
oped a sudden total loss of normal speech
production which was preceded by hoarse-
ness. Coughing and syllabic ‘‘trillo’’ phona-
tion were normal, indicating normal
articulatory ability. An otolaryngological
examination noted a normal larynx with no
sign of lesion or vocal cord palsy, and
videostroboscopic examination showed no
vocal-cord adduction except during coughing.
Neurological examination and brain MRI
were normal. The patient reported moderate
familial conflict and academic problems.
Psychological evaluation revealed chronic
anxiety. Thirty sessions of speech therapy
produce no improvement. The conversion
disorder persisted for 20 months. As a final
treatment, two rTMS sessions of 150 s
duration (50 stimuli delivered at 0.33 Hz,
and maximal intensity of 2.5 Tesla) were
attempted with a circular coil (P/N 9784-00).
The first magnetic stimulation was applied to
the left prefrontal cortex with no effect. One
week later, a second rTMS session was
applied to the right motor cortex with a
dramatic and immediate improvement, lead-
ing to a normal speech within a few days, and
still normal at 6 months’ follow-up. We
attributed the clinical improvement to the
rTMS, and not to a placebo effect (lack of
effect with prefrontal cortex rTMS), or the
natural course of the illness.
Functional MRI studies have demon-
strated a reversible decreased activation of
contralateral primary motor3 or somatosen-
sory cortex4 in conversion disorder patients,
with motor and sensory symptoms respec-
tively. An abnormal activation of the orbi-
tofrontal and anterior cingulate cortex has
also been observed.5 The physiopathology of
conversion symptoms could be explained by
an active inhibition of these two prefrontal
areas on primary motor areas.5 6
The modulation of cortical excitability by
rTMS could be a powerful new therapy for
conversion disorders. In the past, patients
with non-organic limb paralysis have been
treated with 15 Hz rTMS sessions of motor
cortex for 5–12 weeks,7 with variable bene-
fits. Here, we hypothesise that they have
activated the depressed motor cortex with
excitatory high-frequency rTMS. On the
contrary, in our aphonic patient, recovery
was total with only one session of
low-frequency rTMS. We have possibly
94
blocked the active inhibition of the motor
cortex with inhibitory low-frequency rTMS.
This spectacular effect could also be
explained by an important laryngeal mus-
cular activation produced by the motor
cortex stimulation and not by the prefrontal
cortex stimulation.
Motor cortex rTMS could be a therapeutic
option for psychogenic aphonia, and perhaps
for other motor conversion disorders. To our
knowledge, this is the first description of
psychogenic aphonia rTMS treatment. The
potential benefit of such treatment should
be evaluated in a randomised controlled trial
versus placebo.
N Chastan,1 D Parain,1 E Vérin,2 J Weber,1 M A Faure,3
J-P Marie4
1
Department of Neurophysiology, Rouen University Hospital,
University of Rouen, France; 2 Department of Physiology,
Rouen University Hospital & UPRES-EA 3830-GRHV,
University of Rouen, France; 3 Phonatrician, Paris, France;
4
Department of Otolaryngology, Rouen University Hospital, &
UPRES-EA 3830-GRHV, University of Rouen, France
Correspondence to: Professor J-P Marie, CHU de Rouen,
Service d’ORL, Dévé 1er étage, 1 rue de Germont, 76031
Rouen cedex, France; jean-paul.marie@chu-rouen.fr
Competing interests: None.
See Editorial Commentary, p 4
Received 20 May 2008
Revised 18 September 2008
Accepted 22 September 2008
J Neurol Neurosurg Psychiatry 2009;80:94.
doi:10.1136/jnnp.2008.154302
REFERENCES
1. Butcher P. Psychological processes in psychogenic
voice disorder. Eur J Disord Commun 1995;30:467–74.
2. Maniecka-Aleksandrowicz B, Domeracka-Kolodziej
A, Rozak-Komorowska A, et al. Management and
therapy in functional aphonia: analysis of 500 cases.
Otolaryngol Pol 2006;60:191–7.
3. Burgmer M, Konrad C, Jansen A, et al. Abnormal
brain activation during movement observation in
patients with conversion paralysis. Neuroimage
2006;29:1336–43.
4. Ghaffar O, Staines WR, Feinstein A. Unexplained
neurologic symptoms: an fMRI study of sensory
conversion disorder. Neurology 2006;67:2036–8.
5. Marshall JC, Halligan PW, Fink GR, et al. The
functional anatomy of a hysterical paralysis. Cognition
1997;64:B1–8.
6. Hurwitz TA, Prichard JW. Conversion disorder and
fMRI. Neurology 2006;67:1914–15.
7. Schonfeldt-Lecuona C, Connemann BJ, Viviani R, et
al. Transcranial magnetic stimulation in motor
conversion disorder: a short case series. J Clin
Neurophysiol 2006;23:472–5.
Late-onset Tay–Sachs disease
presenting as a childhood stutter
Late-onset Tay–Sachs disease (LOTS) is a
rare lysosomal storage disorder caused by
deficient beta-hexosaminidase A (HEXA)
activity. Toxicity results from the accumu-
lation of gangliosides in the central nervous
system. In juvenile-onset forms, patients
present in childhood with progres-
sive incoordination and/or developmental
regression; in the ‘‘chronic’’ or ‘‘adult-onset’’
forms, patients present from childhood
J Neurol Neurosurg Psychiatry January 2009 Vol 80 No 1
through early adulthood with weakness,
ataxia, dysarthria, spasticity, dystonia, tre-
mor or psychosis. While stutter is reported
accompanying other symptoms of LOTS,1 it
is not reported as the sole initial manifesta-
tion. We report three patients who pre-
sented in childhood with developmental
stutter, years before developing other neu-
rological manifestations.
Patient 1: This 6-year-old girl, born to
non-consanguineous parents of Ashkenazi
Jewish and non-Jewish European back-
ground, was the product of an uncompli-
cated pregnancy and delivery. She spoke her
first words at 10 months, sat independently
and crawled at 7 months, and walked
independently at 12.5 months. She devel-
oped a marked stutter at 3 years, fine motor
delays at 4 years, and subsequent deteriora-
tion of gross and fine motor skills, social
regression, cognitive decline and reduced
speech output.
Neurological exam at age 6 showed poor
attention, difficulty following one-step com-
mands, sparse and dysarthric speech, tongue
weakness, limb rigidity and toe walking.
Diagnostic testing revealed leucocyte HEXA
activity of 4% (normal: 63–75%) and serum
HEXA activity of 2% (normal: 56–80%),
consistent with Tay–Sachs disease.
Mutation analysis of the HEXA gene revealed
compound heterozygosity for the
+TATC1278–1281 and c.1496G.A p.R499H
mutations. A paternal uncle had a develop-
mental stutter.
Patient 2: This 33-year-old right-handed
man, born to non-consanguineous parents of
non-Jewish European and Russian heritage,
was the product of an uncomplicated preg-
nancy, labour and delivery. He had one febrile
seizure at 9 months. Early developmental
milestones were normal. At 8 years, he
developed an intermittent stutter. At age 14,
he noted proximal weakness. Slowly progres-
sive weakness and unsteadiness ensued. In his
late teens, he had the first of several acute
psychotic episodes. In his late twenties, he
developed progressive dysarthria and dyspha-
gia. Diagnostic testing revealed leucocyte
HEXA activity of 5% (normal: 63–75%).
Mutation analysis revealed c.805G.A
p.G269S and c.1510C.T p.R504C mutations.
An older brother has LOTS.
Neurological examination at age 33
showed an apathetic, inattentive male with
dysarthria, weakness of triceps, finger exten-
sors, hip flexors, and left quadriceps, quad-
riceps fasciculations, pathologically brisk
patellar reflexes and extensor plantar
responses. There was limb dysmetria, ataxia,
dysdiadochokinesis, a postural tremor of
both upper extremities and a wide-based,
spastic gait.
Patient 3: This 39-year-old left-handed
man born to non-consanguineous parents
of Ashkenazi Jewish and non-Jewish
German background was the product of
an uncomplicated pregnancy, labour and
delivery. Early developmental milestones
 Downloaded from jnnp.bmj.com on 28 January 2009
were unremarkable. He developed a stutter
at 6 years and progressive clumsiness at age
10. He experienced acute psychotic depres-
sion his first year of college. In his early
thirties, he developed progressive weakness
and dysarthria. Diagnostic testing showed
leucocyte HEXA activity of 0%; mutation
analysis revealed c.805G.A p.G269S and
c.1510C.T p.R504C mutations.
Neurological examination at 39 years
showed ataxic, dysarthric speech, mild
weakness of the left triceps, finger extensors
and bilateral quadriceps, prominent quad-
riceps fasciculations, frontal release signs, a
mild postural tremor, dysdiadochokinesis of
both upper extremities, moderate limb
ataxia of the upper and lower extremities
and a wide-based gait.
COMMENT
Developmental stutter is characterised by
disruptions in speech flow due to involuntary
repetition or prolongation of sounds and
syllables. The neuroanatomic basis is unclear.
Disturbances in auditory, motor, or linguistic
systems are proposed. Positron emission
tomography studies in developmental stut-
terers implicate the right cerebral speech-
motor and left cerebellar hemispheres in
stuttering.2 Foundas et al contend that anom-
alous anatomic configurations of the perisyl-
vian, prefrontal and sensorimotor cortex are a
risk factor for developmental stuttering, based
on morphometric analysis of volumetric MRI
scans of developmental stutterers.3 They
hypothesise that two neural networks coor-
dinate speech production, an outer ‘‘linguis-
tic’’ loop and an inner ‘‘phonatory’’ loop.
Others contend, however, that anomalous
cortical configurations in the brains of devel-
opmental stutterers are likely the result of,
rather than a cause of, developmental stutter-
ing, while still others propose that the basal
ganglia-thalamocortical motor circuits play a
major role in stuttering.
Multiple lines of evidence indicate a
multifactorial genetic basis for idiopathic
developmental stuttering.4 Stutter has also
been reported in some chromosomal dis-
orders and monogenic syndromes, including
Down, Turner and Prader–Willi syndromes.
Stutter is also noted in other genetic
conditions including Fragile X, Tourette,
Sotos and Partington syndromes, sterol
carrier protein X deficiency, hereditary spas-
tic paraplegia type 4, pantothenate kinase-
associated neurodegeneration, neurofibro-
matosis type I and biotin-responsive basal
ganglia disorder.
This report adds new information regard-
ing the diversity of presentations and natural
histories of late-onset forms of Tay–Sachs
disease. These three cases in which stutter
was the initial presentation of LOTS indicate
that childhood stutter can be a harbinger of
LOTS and that stutter may occur more
frequently in LOTS than previously appre-
ciated. The observation that stutter can be the
initial clinical manifestation of LOTS also
J Neurol Neurosurg Psychiatry January 2009 Vol 80 No 1
suggests a biochemical vulnerability of the
neural networks involved in speech produc-
tion to the toxicity of ganglioside accumula-
tion. The few detailed neuropathological
studies of individuals with LOTS and stutter
provide little additional insight into the
aetiology of developmental stutter in LOTS
because of the co-occurrence with other,
severe neurological disabilities in those indi-
viduals.
Other late-onset forms of lysosomal sto-
rage disorders may also present with stutter,
especially GM1 gangliosidosis, metachro-
matic leucodystrophy, Krabbe disease and
Niemann–Pick type C, all of which have
overlapping clinical features with LOTS.5
This, in turn, suggests a common pathoge-
netic process underlying stutter in these
late-onset lysosomal lipid storage disorders.
Other important questions include:
1. In which other genetic conditions is
stutter an important but undescribed or
underappreciated aspect of the clinical
phenotype?
2. Does the neuropathological substrate for
stutter in Tay–Sachs disease differ from
that in idiopathic developmental stutter?
3. Can our knowledge of the pathophy-
siology and neuropathology of some of
the monogenic disorders prove useful in
providing insights regarding the
mechanisms of common, idiopathic
developmental stutter?
B E Shapiro,1 M R Natowicz2
1
Neuromuscular Division, Department of Neurology,
University Hospitals of Cleveland, Case Western Reserve
University School of Medicine, Cleveland, OH, USA;
2
Institutes of Pathology and Laboratory Medicine, Genetics,
Neuroscience, and Pediatrics, Cleveland Clinic, Cleveland,
OH, USA
Correspondence to: Dr B E Shapiro, Neuromuscular
Research, The Neurological Institute, University Hospitals
Case Medical Center, Case Western Reserve University
School of Medicine, 11100 Euclid Avenue, Cleveland, OH
44106-5098, USA; bes002@aol.com
Competing interests: None.
Received 22 February 2008
Revised 12 September 2008
Accepted 26 September 2008
J Neurol Neurosurg Psychiatry 2009;80:94–95.
doi:10.1136/jnnp.2008.147645
REFERENCES
1. Philippart M, Carrel RE, Landing BH. Tay–Sachs
disease with atypical chronic course and limited brain
storage: Alpha-locus Hexosaminidase genetic
compound. Neurochem Res 1995;20,11:1323–8.
2. Fox PT, Ingham RJ, Ingham JC, et al. Brain correlates
of stuttering and syllable production. A PET
performance-correlation and analysis. Brain
2000;123:1985–2004.
3. Foundas AL, Bollich AM, Feldman J, et al. Aberrant
auditory processing and atypical planum temporale in
developmental stuttering. Neurology 2004;63:1640–6.
4. Suresh R, Ambrose N, Roe C, et al. New complexities
in the genetics of stuttering: significant sex-specific
linkage signals. Am J Hum Genet 2006;78:554–63.
5. Chakraborty S, Rafi MA, Wenger DA. Mutations in
the lysosomal b-galactosidase gene that causes the
adult form of GM1 gangliosidosis. Am J Hum Genet
1994;54:1004–13.
PostScript
Effect of steroid treatment in
cerebellar ataxia associated with
anti-glutamic acid decarboxylase
antibodies
Glutamic acid decarboxylase (GAD) catalyses
the transformation of glutamate into c-
aminobutyric acid (GABA). Anti-GAD auto-
antibodies (GAD-Ab) have been associated
with insulin-dependent diabetes mellitus
(IDDM) and with other possibly immuno-
mediated syndromes affecting the CNS
including stiff-man syndrome (SPS),1 progres-
sive encephalomyelitis with rigidity and
myoclonus (PERM) and cerebellar ataxia,1 2
mostly in association with IDDM. These
findings support the autoimmune origin of
the neurological symptoms, possibly induced
by an anti-GAD-Ab-mediated neuronal dys-
function. Manto et al3 induced cerebellar and
spinal cord symptoms in rats, by intrathecal
injection of IgG from anti-GAD-Ab positive
patients affected by SPS or cerebellar ataxia,
suggesting a pathogenetic mechanisms invol-
ving a change of balance between glutamate
and GABA, causing glutamate excitotoxicity.
High-dose intravenous immunoglobulins
and plasmapheresis have been suggested as
possible therapies, but cerebellar symptoms
have been rarely found to improve. Recently
Lauria et al4 induced clinical improvement in
a patient with anti-GAD-Ab cerebellar
ataxia through high doses of methylpredni-
solone, suggesting that it should be consid-
ered as first-line therapy in these patients.
We describe a 76-year-old man developing
an anti-GAD associated subacute cerebellar
syndrome that improved dramatically after
steroid treatment.
CASE REPORT
A 76-year-old man was admitted to our clinic
in January 2007 for the development, since
June 2006, of a subacute progressive gait
instability and loss of fluency of movement
execution. Within 3 months, he presented
progressive slurred speech, swallowing diffi-
culties and four limbs incoordination. Six
months after the onset of symptoms, his gait
unbalance worsened dramatically, inducing
frequent falls, requiring the use of a walker
and permanent help from a care giver. He was
diagnosed as having IDDM in 2006. The
medical history of his family was unremark-
able for cerebellar ataxia, autoimmune dis-
eases and diabetes mellitus.
The first neurological examination,
performed during hospitalisation, showed
nystagmus, severe dysarthria, bilateral dys-
metria on finger-to-nose and adiadochokin-
esis in a pronation–supination test. He
presented severe difficulty in writing and
in drawing an Archimedes spiral. He also
had trunk and gait ataxia, for which the use
of a walker was necessary, and difficulty in
standing, thus making the Romberg position
impossible. The International Cooperative
95