LETTER TO THE EDITOR

Genetic screening for familial amyloid polyneuropathy inpatients with idiopathic carpal tunnel syndrome

Dear Editor,It is well known that patients with transthyretin

familial amyloid polyneuropathy (TTR-FAP) type II mayhave carpal tunnel syndrome (CTS) as the only clinicalfeature for many years before developing a slowly pro-gressive generalized polyneuropathy with autonomicand cardiac involvement (Plante-Bordeneuve et al.,1998). This clinical course has been associated withdifferent transthyretin (TTR) mutations (Murakami etal., 1994; Ferlini et al., 1996). In addition, because ofthe variable penetrance and the frequent late onset,familial amyloid polyneuropathy (FAP) II patients pres-ent as ‘sporadic’ cases (Plante-Bordeneuve et al.,2007). Because CTS is the most frequent entrapmentneuropathy with an annual incidence rate between0.5 and 5.1 per 1,000 (Roquelaure et al., 2008), weevaluated the prevalence of TTR gene mutations in alarge sample of patients with CTS without clinical evi-dence of other diseases.

Between June 2005 and June 2007, 750 patientswithCTS confirmed by electrodiagnostic study (AmericanAssociation of Electrodiagnostic Medicine, Americanof Neurology, American Academy of Physical Medi-cine and Rehabilitation, 1993) were studied in ourlaboratory. Only cases of apparently idiopathic CTSwithout evidence of connective tissue disease, diabe-tes mellitus, thyroid disease, concurrent subclinicalpolyneuropathy, pregnancy, or cardiologic or auto-nomic involvement were prospectively included. Among415 subjects eligible for our study, 282 gave theirinformed consent to undergo DNA analysis.

Using the salting out method, total DNA wasextracted from leucocytes of the patients. The codingregions of the TTR gene were first amplified by poly-merase chain reaction (PCR) using primers flanking theintron-exon boundaries. PCR products were analyzedby denaturing high performance liquid chromatography(Wave-System Transgenomic). The fragment showing

heteroduplex was sequenced by BigDye TerminatorCycle Sequencing Ready Reaction Kit (Applied Bio-systems) on the ABI PRISM 3130 � l genetic analyzer(Applied Biosystems).

Two hundred eighty-two patients were studied: 75men and 207 women (ratio of 2.7 females to 1 male).The mean age was 52.5 years for men (range 20–83)and 51.2 years for women (range 21–81). The meaninterval between clinical onset and electrophysiologicaldiagnosis of CTS was 3.1 years for men (range 0–11)and 3.9 years for women (range 0–17) (SD 40 months).Bilateral CTS was present in about 50% of cases.A positive family history of CTS was reported in 26 of75 males (35%) and 61 of 207 females (29%). DNAanalysis for TTR gene mutations was negative in allpatients.

Although FAP is an autosomal dominant neuro-pathy, it can present as apparently sporadic cases(Plante-Bordeneuve et al., 2007). Recently, Plante-Bordeneuve et al. (2007) reviewed clinical data of90 patients who presented as non-familial cases in acohort of 300 patients with genetic diagnosis of TTR-FAP. Because of negative biopsy findings and falseimmunolabeling of amyloid deposits, the authors sug-gested that DNA analysis for TTR mutations was themost reliable test for diagnosis of FAP in patients witha progressive axonal polyneuropathy, especially whenassociated with autonomic dysfunction.

In our study, all subjects with idiopathic CTS werenegative for TTR gene mutations, suggesting that idio-pathic CTS and FAP II are distinct diseases. In agree-ment with previous reports (Nora et al., 2004; Elstneret al., 2006), our findings show that idiopathic CTSwas much more common among middle-agedwomen, with a female to male ratio of 3 : 1. A higherprevalence of CTS in women has also been reportedin families with autosomal dominant CTS, indicatingthat a sex-related susceptibility exists in both sporadicand familial CTS (Elstner et al., 2006). By contrast,FAP II affects males more than females with a highmale to female ratio (Plante-Bordeneuve et al., 2007).This different sex-related susceptibility between spo-radic CTS and FAP II makes our findings that patients

Address correspondence to: Prof. Aldo Quattrone, Full Professor ofNeurology, Cattedra ed U.O. di Neurologia, Universita degli Studi‘‘Magna Græcia’’, Campus Universitario Germaneto, Viale Europa, 88100Catanzaro, Italy. Tel: þ39-0961-3647011; Fax: þ39-0961-3647177;E-mail: a.quattrone@isn.cnr.it

Journal of the Peripheral Nervous System 13:151–152 (2008)

ª 2008 Peripheral Nerve Society 151 Blackwell Publishing

with sporadic CTS did not carry TTR mutations notsurprising.

Most CTS patients have a first-degree relative withthe same disease. Indeed, about 30% of all ‘apparentlysporadic’ CTS patients have cases of CTS in their fam-ilies (Elstner et al., 2006). In our series, no patientwith a family history of CTS had mutations in the TTRgene, suggesting that family history of CTS does notincrease a patient’s chance of having TTR mutations.

In conclusion, although CTS can be an early findingin FAP type II, on the basis of our findings we cannotrecommend genetic screening in patients with CTSwithout other manifestations suggestive of FAP.

Sincerely,Paola Valentino, Domenico Pirritano, Francesco

Bono, and Aldo QuattroneInstitute of Neurology, University Magna Græcia,

Catanzaro, Italy

Maria Muglia, Rita Nistico, Maria Liguori, LuigiCitrigno, and Aldo Quattrone

Institute of Neurological Sciences, National ResearchCouncil, Cosenza, Italy

Umberto Aguglia and Damiano BrancaRegional Epilepsy Center, Azienda Ospedaliera

Bianchi-Melacrino-Morelli, Ospedali Riuniti, ReggioCalabria, Italy

Umberto AgugliaSchool of Medicine, University Magna Græcia,

Catanzaro, Italy

ReferencesAmerican Association of Electrodiagnostic Medicine, American

of Neurology, American Academy of Physical Medicine andRehabilitation (1993). Practice parameter for electrodiag-

nostic studies in carpal tunnel syndrome: summary state-ment. Muscle Nerve 16:1390–1391.

Elstner M, Bettecken T, Wasner M, Anneser F, Dichgans M,Meitinger T, Gasser T, Klopstock T (2006). Familial carpal

tunnel syndrome: further evidence for a genetic contribu-tion. Clin Genet 69:179–182.

Ferlini A, Salvi F, Uncini A, el-Chami J, Winter P, Altland K,Repetto M, Littardi M, Campoleoni A, Vezzoni P, Patrosso MC

(1996). Homozygosity and heterozygosity for the trans-thyretin Leu64 mutation: clinical, biochemical and molecular

findings. Clin Genet 49:10–14.Murakami T, Tachibana S, Endo Y, Kawai R, Hara M, Tanase

S, Ando M (1994). Familial carpal tunnel syndrome due toamyloidogenic transthyretin His 114 variant. Neurology 44:

315–318.Nora DB, Becker J, Ehlers JA, Gomes I (2004). Clinical

features of 1039 patients with neurophysiological diagno-

sis of carpal tunnel syndrome. Clin Neurol Neurosurg 107:64–69.

Plante-Bordeneuve V, Lalu T, Misrahi M, Reilly MM, Adams D,Lacroix C, Said G (1998). Genotypic-phenotypic variations in

a series of 65 patients with familial amyloid polyneuro-pathy. Neurology 51:708–714.

Plante-Bordeneuve V, Ferriera A, Lalu T, Zaros C, Lacroix C,Adams D, Said G (2007). Diagnostic pitfalls in sporadic trans-

thyretin familial amyloid polyneuropathy (TTR-FAP). Neurology69:693–698.

Roquelaure Y, Ha C, Pelier-Cady MC, Nicolas G, Descatha A,Leclerc A, Raimbeau G, Goldberg M, Imbernon E (2008).

Work increases the incidence of carpal tunnel syndrome inthe general population. Muscle Nerve 37:477–482.

Letter to the Editor Journal of the Peripheral Nervous System 13:151–152 (2008)

152