Stuttering And Tay-sachs

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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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LETTERS

Psychogenic aphonia: spectacular recovery after motor cortex transcranial magnetic stimulation Psychogenic aphonia is a disabling conversion disorder with no standard psychotherapeutic1 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 developed a sudden total loss of normal speech production which was preceded by hoarseness. Coughing and syllabic ‘‘trillo’’ phonation 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, leading 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 demonstrated a reversible decreased activation of contralateral primary motor3 or somatosensory cortex4 in conversion disorder patients, with motor and sensory symptoms respectively. An abnormal activation of the orbitofrontal 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 benefits. 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 muscular 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 Ve´rin,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, De´ve´ 1er ´etage, 1 rue de Germont, 76031 Rouen cedex, France; [email protected] 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. 2.

3.

4.

5.

6. 7.

Butcher P. Psychological processes in psychogenic voice disorder. Eur J Disord Commun 1995;30:467–74. 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. Burgmer M, Konrad C, Jansen A, et al. Abnormal brain activation during movement observation in patients with conversion paralysis. Neuroimage 2006;29:1336–43. Ghaffar O, Staines WR, Feinstein A. Unexplained neurologic symptoms: an fMRI study of sensory conversion disorder. Neurology 2006;67:2036–8. Marshall JC, Halligan PW, Fink GR, et al. The functional anatomy of a hysterical paralysis. Cognition 1997;64:B1–8. Hurwitz TA, Prichard JW. Conversion disorder and fMRI. Neurology 2006;67:1914–15. 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 accumulation of gangliosides in the central nervous system. In juvenile-onset forms, patients present in childhood with progressive incoordination and/or developmental regression; in the ‘‘chronic’’ or ‘‘adult-onset’’ forms, patients present from childhood

through early adulthood with weakness, ataxia, dysarthria, spasticity, dystonia, tremor or psychosis. While stutter is reported accompanying other symptoms of LOTS,1 it is not reported as the sole initial manifestation. We report three patients who presented in childhood with developmental stutter, years before developing other neurological manifestations. Patient 1: This 6-year-old girl, born to non-consanguineous parents of Ashkenazi Jewish and non-Jewish European background, was the product of an uncomplicated 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 developed a marked stutter at 3 years, fine motor delays at 4 years, and subsequent deterioration 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 commands, 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 developmental 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 pregnancy, 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 progressive 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 dysphagia. 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 extensors, hip flexors, and left quadriceps, quadriceps 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 J Neurol Neurosurg Psychiatry January 2009 Vol 80 No 1

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PostScript

were unremarkable. He developed a stutter at 6 years and progressive clumsiness at age 10. He experienced acute psychotic depression 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 quadriceps 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 stutterers implicate the right cerebral speechmotor and left cerebellar hemispheres in stuttering.2 Foundas et al contend that anomalous anatomic configurations of the perisylvian, 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 coordinate speech production, an outer ‘‘linguistic’’ loop and an inner ‘‘phonatory’’ loop. Others contend, however, that anomalous cortical configurations in the brains of developmental stutterers are likely the result of, rather than a cause of, developmental stuttering, 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 disorders 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 spastic paraplegia type 4, pantothenate kinaseassociated neurodegeneration, neurofibromatosis type I and biotin-responsive basal ganglia disorder. This report adds new information regarding 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 appreciated. 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 production to the toxicity of ganglioside accumulation. 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 individuals. Other late-onset forms of lysosomal storage disorders may also present with stutter, especially GM1 gangliosidosis, metachromatic leucodystrophy, Krabbe disease and Niemann–Pick type C, all of which have overlapping clinical features with LOTS.5 This, in turn, suggests a common pathogenetic 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 pathophysiology 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; [email protected] 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.

2.

3.

4.

5.

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. 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. Foundas AL, Bollich AM, Feldman J, et al. Aberrant auditory processing and atypical planum temporale in developmental stuttering. Neurology 2004;63:1640–6. 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. 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.

Effect of steroid treatment in cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies Glutamic acid decarboxylase (GAD) catalyses the transformation of glutamate into caminobutyric acid (GABA). Anti-GAD autoantibodies (GAD-Ab) have been associated with insulin-dependent diabetes mellitus (IDDM) and with other possibly immunomediated syndromes affecting the CNS including stiff-man syndrome (SPS),1 progressive 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 dysfunction. 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 involving 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 methylprednisolone, suggesting that it should be considered 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 difficulties 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 unremarkable for cerebellar ataxia, autoimmune diseases and diabetes mellitus. The first neurological examination, performed during hospitalisation, showed nystagmus, severe dysarthria, bilateral dysmetria on finger-to-nose and adiadochokinesis 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