J Neurol (2015) 262:226–227 DOI 10.1007/s00415-014-7597-z
LETTER TO THE EDITORS
Small fiber neuropathy in a woman with fragile X-associated tremor/ataxia syndrome (FXTAS) Jean-Baptiste Chanson • Nelly Boehm • Brigitte Samama • Andoni Echaniz-Laguna Mathieu Anheim
•
Received: 17 September 2014 / Revised: 22 November 2014 / Accepted: 24 November 2014 / Published online: 9 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG repeat disorder in the FMR1 gene. The full mutation (above 200 CGG repeats) leads to Fragile X syndrome (FXS, clinically dominated by mental retardation) whereas the premutation (between 55 and 200 CGG repeats) causes FXTAS which is an adult-onset neurodegenerative-inherited disorder. FXTAS clinically corresponds to intention tremor and gait ataxia appearing in the 6th decade, in addition to optional cognitive dysfunction, parkinsonism and neuropathy of the large fibers [1, 3]. No isolated small fiber neuropathy (SFN) was reported in FXTAS up to now. A 62-year-old woman was already known as FMR1 premutation carrier (88 CGG) because she had a daughter previously diagnosed with FXS. The patient gradually developed severe dysesthesia and allodynia of the distal J.-B. Chanson (&) A. Echaniz-Laguna M. Anheim De´partement de Neurologie, Hoˆpitaux Universitaires de Strasbourg, 1 avenue Molie`re, 67098 Strasbourg, France e-mail: [email protected] N. Boehm B. Samama Institut d’Histologie Service Central de Microscopie Electronique, Universite´ de Strasbourg, 4 rue Kirschleger, 67000 Strasbourg, France N. Boehm B. Samama M. Anheim Fe´de´ration de Me´decine Translationnelle de Strasbourg (FMTS), Universite´ de Strasbourg, 4 rue Kirschleger, 67000 Strasbourg, France M. Anheim Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Universite´ de Strasbourg, 1 Rue Laurent Fries, 67400 Illkirch-Graffenstaden, France
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extremities of the lower limbs for 6 years. Clinical examination only revealed a very mild cerebellar syndrome. Brain MRI showed mild cerebellar atrophy and hyperintensity of corpus callosum splenium. Taken together, these abnormalities were consistent with the diagnosis of probable FXTAS [1]. The nerve conduction studies showed no abnormality of the large nerve fibers but we found an abolition of the sympathetic skin reflexes in the lower limbs and an increased latency in the upper limbs. A 4-mm punch biopsy was, therefore, performed in distal and proximal lower limb and immunostained with anti-protein gene product 9.5 antibody using immunohistochemistry. The distal intraepidermal nerve fiber density (IENFD) was estimated at 3 fibers/mm and the proximal IENFD at 12.5 fibers/mm (Fig. 1). The distal value was under the 5th percentile (3.3 for this age and gender category) [5]. We then concluded to a length-dependant small fiber neuropathy (SFN). It was attributed to FXTAS since the patient had no other relevant disease, no history of toxic exposure and normal biological analyses including measurement of fasting plasma glucose level (\6.1 mmol/l), glycated hemoglobin (\6 %), urea, creatinine, CRP, folic acid, vitamin B12, thyroid-stimulating hormone and antinuclear antibodies. Blood cell count, protein electrophoresis test and Lyme disease, HIV and HCV serology were also normal. We report, for the first time to our knowledge, the case of a histologically confirmed length-dependant SFN in a woman with FXTAS. Neuropathy was frequently associated with FXTAS but the published data have focused on features associated with large fiber neuropathy such as decreased reflexes, impaired vibration sense and ataxia as well as abnormal nerve conduction studies. In a study including 22 FXTAS patients (18 men and 4 women), a loss of vibration sense at ankle was noted in 50 % of them
J Neurol (2015) 262:226–227
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Fig. 1 Loss of small nerve fibers in distal leg. Skin biopsy specimen sections from the thigh (a) and distal leg (b), immunostained with protein gene product 9.5, showing a marked decrease of the density of intraepidermal nerve fibers (arrows) in the distal biopsy
and abolished Achilles reflexes in the same percentage while no patient complained of neuropathic pain [1]. However, other data suggest that involvement of small fibers may be not uncommon. Jacquemont et al. [4] reported that 35 % of 20 male FXTAS patients suffer from numbness and/or neuropathic pain such as burning, cramping or paresthesias in the lower extremities. A case of severe autonomic dysfunction (postprandial hypotension) in a FXTAS patient was described [6]. These studies did not include sympathetic skin reflex, laser-evoked potentials or IENFD [1, 4, 7]. Only one article provided the histological analysis of nerves in an autopsied FXTAS male patient without clinically significant neuropathy. A global analysis of sural and sciatic nerve only showed mild loss of both small and large myelinated fibers without specific changes. No analysis of IENFD was performed [2]. It is of interest for the clinical practice to keep in mind that SFN may be the first sign of FXTAS and that FXTAS should be considered in case of SFN of unknown etiology. In our case, SFN was responsible for the most disabling signs of FXTAS. This presentation could be not uncommon in women who often have less typical signs of FXTAS [1, 3]. Further studies are needed to explore the frequency of this association and the potential mechanisms accounting for the sensitivity of small fibers in FXTAS. Acknowledgments Conflicts of interest
The patient is acknowledged. None.
Ethical standard On behalf of all the authors, the corresponding author states that we acted in accordance with the ethical standards of the 1964 Declaration of Helsinki.
Informed consent The patient gave her informed consent prior to her inclusion in the study.
References 1. Apartis E, Blancher A, Meissner WG, Guyant-Marechal L, Maltete D, De Broucker T, Legrand AP, Bouzenada H, Thanh HT, Sallansonnet-Froment M, Wang A, Tison F, Roue-Jagot C, Sedel F, Charles P, Whalen S, Heron D, Thobois S, Poisson A, Lesca G, Ouvrard-Hernandez AM, Fraix V, Palfi S, Habert MO, Gaymard B, Dussaule JC, Pollak P, Vidailhet M, Durr A, Barbot JC, Gourlet V, Brice A, Anheim M (2012) FXTAS: new insights and the need for revised diagnostic criteria. Neurology 79:1898–1907 2. Gokden M, Al-Hinti JT, Harik SI (2009) Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology 29:280–284 3. Hagerman R, Hagerman P (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 12:786–798 4. Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, BerryKravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72:869–878 5. Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS (2010) Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 15:202–207 6. Pugliese P, Annesi G, Cutuli N, Arabia G, Nicoletti G, Annesi F, Tarantino P, Gambardella A, Valentino P, Zappia M, Quattrone A (2004) The fragile X premutation presenting as postprandial hypotension. Neurology 63:2188–2189 7. Soontarapornchai K, Maselli R, Fenton-Farrell G, Tassone F, Hagerman PJ, Hessl D, Hagerman RJ (2008) Abnormal nerve conduction features in fragile X premutation carriers. Arch Neurol 65:495–498
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LETTER TO THE EDITORS
Small fiber neuropathy in a woman with fragile X-associated tremor/ataxia syndrome (FXTAS) Jean-Baptiste Chanson • Nelly Boehm • Brigitte Samama • Andoni Echaniz-Laguna Mathieu Anheim
•
Received: 17 September 2014 / Revised: 22 November 2014 / Accepted: 24 November 2014 / Published online: 9 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG repeat disorder in the FMR1 gene. The full mutation (above 200 CGG repeats) leads to Fragile X syndrome (FXS, clinically dominated by mental retardation) whereas the premutation (between 55 and 200 CGG repeats) causes FXTAS which is an adult-onset neurodegenerative-inherited disorder. FXTAS clinically corresponds to intention tremor and gait ataxia appearing in the 6th decade, in addition to optional cognitive dysfunction, parkinsonism and neuropathy of the large fibers [1, 3]. No isolated small fiber neuropathy (SFN) was reported in FXTAS up to now. A 62-year-old woman was already known as FMR1 premutation carrier (88 CGG) because she had a daughter previously diagnosed with FXS. The patient gradually developed severe dysesthesia and allodynia of the distal J.-B. Chanson (&) A. Echaniz-Laguna M. Anheim De´partement de Neurologie, Hoˆpitaux Universitaires de Strasbourg, 1 avenue Molie`re, 67098 Strasbourg, France e-mail: [email protected] N. Boehm B. Samama Institut d’Histologie Service Central de Microscopie Electronique, Universite´ de Strasbourg, 4 rue Kirschleger, 67000 Strasbourg, France N. Boehm B. Samama M. Anheim Fe´de´ration de Me´decine Translationnelle de Strasbourg (FMTS), Universite´ de Strasbourg, 4 rue Kirschleger, 67000 Strasbourg, France M. Anheim Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Universite´ de Strasbourg, 1 Rue Laurent Fries, 67400 Illkirch-Graffenstaden, France
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extremities of the lower limbs for 6 years. Clinical examination only revealed a very mild cerebellar syndrome. Brain MRI showed mild cerebellar atrophy and hyperintensity of corpus callosum splenium. Taken together, these abnormalities were consistent with the diagnosis of probable FXTAS [1]. The nerve conduction studies showed no abnormality of the large nerve fibers but we found an abolition of the sympathetic skin reflexes in the lower limbs and an increased latency in the upper limbs. A 4-mm punch biopsy was, therefore, performed in distal and proximal lower limb and immunostained with anti-protein gene product 9.5 antibody using immunohistochemistry. The distal intraepidermal nerve fiber density (IENFD) was estimated at 3 fibers/mm and the proximal IENFD at 12.5 fibers/mm (Fig. 1). The distal value was under the 5th percentile (3.3 for this age and gender category) [5]. We then concluded to a length-dependant small fiber neuropathy (SFN). It was attributed to FXTAS since the patient had no other relevant disease, no history of toxic exposure and normal biological analyses including measurement of fasting plasma glucose level (\6.1 mmol/l), glycated hemoglobin (\6 %), urea, creatinine, CRP, folic acid, vitamin B12, thyroid-stimulating hormone and antinuclear antibodies. Blood cell count, protein electrophoresis test and Lyme disease, HIV and HCV serology were also normal. We report, for the first time to our knowledge, the case of a histologically confirmed length-dependant SFN in a woman with FXTAS. Neuropathy was frequently associated with FXTAS but the published data have focused on features associated with large fiber neuropathy such as decreased reflexes, impaired vibration sense and ataxia as well as abnormal nerve conduction studies. In a study including 22 FXTAS patients (18 men and 4 women), a loss of vibration sense at ankle was noted in 50 % of them
J Neurol (2015) 262:226–227
227
Fig. 1 Loss of small nerve fibers in distal leg. Skin biopsy specimen sections from the thigh (a) and distal leg (b), immunostained with protein gene product 9.5, showing a marked decrease of the density of intraepidermal nerve fibers (arrows) in the distal biopsy
and abolished Achilles reflexes in the same percentage while no patient complained of neuropathic pain [1]. However, other data suggest that involvement of small fibers may be not uncommon. Jacquemont et al. [4] reported that 35 % of 20 male FXTAS patients suffer from numbness and/or neuropathic pain such as burning, cramping or paresthesias in the lower extremities. A case of severe autonomic dysfunction (postprandial hypotension) in a FXTAS patient was described [6]. These studies did not include sympathetic skin reflex, laser-evoked potentials or IENFD [1, 4, 7]. Only one article provided the histological analysis of nerves in an autopsied FXTAS male patient without clinically significant neuropathy. A global analysis of sural and sciatic nerve only showed mild loss of both small and large myelinated fibers without specific changes. No analysis of IENFD was performed [2]. It is of interest for the clinical practice to keep in mind that SFN may be the first sign of FXTAS and that FXTAS should be considered in case of SFN of unknown etiology. In our case, SFN was responsible for the most disabling signs of FXTAS. This presentation could be not uncommon in women who often have less typical signs of FXTAS [1, 3]. Further studies are needed to explore the frequency of this association and the potential mechanisms accounting for the sensitivity of small fibers in FXTAS. Acknowledgments Conflicts of interest
The patient is acknowledged. None.
Ethical standard On behalf of all the authors, the corresponding author states that we acted in accordance with the ethical standards of the 1964 Declaration of Helsinki.
Informed consent The patient gave her informed consent prior to her inclusion in the study.
References 1. Apartis E, Blancher A, Meissner WG, Guyant-Marechal L, Maltete D, De Broucker T, Legrand AP, Bouzenada H, Thanh HT, Sallansonnet-Froment M, Wang A, Tison F, Roue-Jagot C, Sedel F, Charles P, Whalen S, Heron D, Thobois S, Poisson A, Lesca G, Ouvrard-Hernandez AM, Fraix V, Palfi S, Habert MO, Gaymard B, Dussaule JC, Pollak P, Vidailhet M, Durr A, Barbot JC, Gourlet V, Brice A, Anheim M (2012) FXTAS: new insights and the need for revised diagnostic criteria. Neurology 79:1898–1907 2. Gokden M, Al-Hinti JT, Harik SI (2009) Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology 29:280–284 3. Hagerman R, Hagerman P (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 12:786–798 4. Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, BerryKravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72:869–878 5. Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS (2010) Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 15:202–207 6. Pugliese P, Annesi G, Cutuli N, Arabia G, Nicoletti G, Annesi F, Tarantino P, Gambardella A, Valentino P, Zappia M, Quattrone A (2004) The fragile X premutation presenting as postprandial hypotension. Neurology 63:2188–2189 7. Soontarapornchai K, Maselli R, Fenton-Farrell G, Tassone F, Hagerman PJ, Hessl D, Hagerman RJ (2008) Abnormal nerve conduction features in fragile X premutation carriers. Arch Neurol 65:495–498
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