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L T I M E R I C E R C H E
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DESCRIZIONE
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La malattia di
Charcot-Marie-Tooth (CMT) di tipo 4B
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NOTIZIA
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Roma,
3 dicembre 2004
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COMUNICATO
STAMPA - RICERCA TELETHON:
ECCO
PERCHÉ LA MALATTIA DÀ AI NERVI
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Ricercatori Telethon chiariscono i meccanismi
molecolari di una forma
della malattia di
Charcot-Marie-Tooth. Ora è più facile pensare a un rimedio
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L’unione fa la forza. E i risultati si
vedono. Ricercatori finanziati da Telethon
hanno capito che cosa scatena la malattia di Charcot-Marie-Tooth (CMT) di
tipo 4B, la forma recessiva
che, insieme alle altre forme della neuropatia, rappresenta la malattia
ereditaria più frequente del sistema nervoso periferico, colpendo circa 1 persona su 2.500. Sui nervi si
deposita troppa mielina, il
nastro isolante che riveste i nervi periferici prodotto dalle cosiddette cellule di Schwann: queste si
allineano lungo i bracci delle cellule del sistema nervoso periferico e li
avvolgono isolandoli per consentire la trasmissione veloce dell’impulso
elettrico. Ma quando la mielina è in eccesso si dispone in modo caotico
facendo diminuire la velocità di conduzione nervosa. La scoperta è stata
pubblicata sul prestigioso The
Journal of Cell Biology*.
Per arrivare a
questa risposta ci sono voluti diversi anni, ma adesso la strada sembra
solo in discesa. Nel 1989 alcuni
ricercatori avevano intuito che cosa non andava nella malattia, ma solo
oggi, a 15 anni di
distanza, Alessandra Bolino,
ricercatore dell’Istituto Telethon
Dulbecco che lavora al Dibit-Istituto
San Raffaele di Milano, in stretta collaborazione con Lawrence Wrabetz presso lo stesso
Istituto, hanno chiarito il meccanismo molecolare alla base della malattia.
Anche i topolini si possono ammalare di CMT4B e questo ha
consentito ai ricercatori di vedere da vicino quali sono gli effetti della
malattia nelle cellule, nei tessuti e negli organi danneggiati. Alessandra
Bolino, sotto l’egida di Telethon, ha scoperto quattro anni fa che il
difetto all’origine della malattia risiede in Mtmr2, un gene per
una fosfatasi, un enzima che sottrae dei gruppi chimici (fosfati) da alcune
proteine per controllarne l’attività. I topolini sono più fortunati
dell’uomo, perché la malattia è meno grave e ciò ha permesso di guardare
nel modello animale quello che succede ai nervi malati. E i risultati non
si sono fatti attendere, primo tra tutti il ruolo di Mtmr2 nel difetto a carico della mielina, ma
non solo: si è visto per la prima volta nelle cellule di Schwann che la
proteina prodotta da Mtmr2 interagisce con
una “collega” chiamata Dlg1, una proteina
che aiuta la cellula a orientarsi nello spazio; senza Mtmr2 e quindi senza il contributo di Dlg1, le cellule sono disorientate, come se
stessero a testa in giù, e la mielina si dispone in modo disordinato. E
ancora, l’assenza del gene responsabile causa difetti nella spermatogenesi,
il processo che genera spermatozoi, come avviene anche nell’uomo.
Commenta la Bolino: “Il
difetto alla base della neuropatia sta in un enzima e questo faciliterà
l’approccio terapeutico; grazie a questo modello di neuropatia siamo
riusciti a capire la biologia della malattia, le molecole coinvolte e
quello che succede ai nervi malati”.
Il progetto ha usufruito anche di
finanziamenti da parte della
Compagnia di San Paolo e di SMA
supermercati, ed è un esempio di ricerca che porta un contributo
decisivo alla comprensione di una malattia genetica. Nonostante i notevoli
risultati già raggiunti, il lavoro continua col massimo impegno: prossima
tappa capire come l’eccesso di mielina intorno ai nervi ne impedisce il
funzionamento.
******************
*Bolino A et al. J. Cell Biol. Nov 2004; 167:711-21
Per informazioni Dott.ssa
Alessandra Bolino: Tel 348/7117598.
E-mail: bolino.alessandra@hsr.it
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DESCRIZIONE
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Neuropatia
periferica nei pazienti trattati con Leflunomide
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NOTIZIA
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Martedì 21 Settembre 2004, 10:05
Tratto
da Farmacovigilanza.net
La Leflunomide (Arava) è un farmaco impiegato nel trattamento
dell’artrite reumatoide.
Ricercatori del CDER / Drug Safety dell’FDA negli Usa, hanno analizzato le
caratteristiche cliniche, il decorso e l’outcome (esito) della neuropatia
periferica di nuova insorgenza dopo trattamento con Leflunomide.
All’FDA sono giunte 80 segnalazioni. Di queste, il 61% riguardava le donne. L’età media dei pazienti
era di 62 anni.
I sintomi della neuropatia periferica sono insorti in media dopo 6 mesi di impiego della Leflunomide (range: 3 giorni - 3 anni ).
Dal test elettrodiagnostico compiuto su 37 pazienti è emersa una polineuropatia sensorio
motoria, o sensoria, o assonale distale.
I pazienti che hanno interrotto l’assunzione di Leflunomide entro 30 giorni dell’insorgenza dei sintomi della neuropatia
hanno presentato una maggiore probabilità di miglioramento o di guarigione
rispetto a coloro che invece hanno continuato ad assumere la Leflunomide
per più lunghi periodi ( p < 0,001 ).
Secondo i ricercatori dell’FDA la Leflunomide è associata in alcuni casi a
neuropatia periferica.
Fonte: Clin Pharmacol Ther
Per
ulteriori informazioni visita Xagena.it
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DESCRIZIONE
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La chirurgia dell’obesità può causare
neuropatia periferica
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NOTIZIA
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Lunedì 18 Ottobre 2004, 12:52
Tratto da
MedicinaOnline.org
Un significativo numero di persone che si sottopongono a chirurgia
dell’obesità possono andare incontro a grave neuropatia periferica.
Lo studio, compiuto presso la Mayo Clinic di Rochester negli Usa, ha preso
in esame 435 pazienti che si
erano sottoposti a chirurgia dell’obesità.
Il 16% ( n = 71 ) di questi pazienti ha sviluppato
neuropatia periferica.
La causa alla base dello sviluppo della neuropatia è ritenuta essere la
malnutrizione, probabilmente una deficienza di vitamina B12. I pazienti che sono andati incontro a
neuropatia periferica sono stati quelli che hanno perso più peso corporeo,
ed in tempi più rapidi.
Inoltre i pazienti che sviluppano sintomi neurologici, tendono ad avere una
maggiore incidenza di nausea, diarrea, e di rapido svuotamento gastrico.
La neuropatia in alcuni casi può condurre a disabilità permanente.
Fonte: Neurology
Per ulteriori informazioni visita Xagena.it
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DESCRIZIONE
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Studi istologici
sulla malattia di Charcot-Marie-Tooth tipo I con un test non invasivo
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TESTO ORIGINALE
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Preliminary Study of Large and Small Peripheral Nerve Fibers in
Charcot-Marie-Tooth Disease, Type I
Hanson P, Deltombe - Am J Phys Med Rehabil 1998; 77(1):45-8
Histologic studies of Charcot-Marie-Tooth disease, type I, show a contrast
between the lesions of myelinated fibers and the normality of unmyelinated
fibers. Conventional electrophysiologic tests only demonstrate the
alteration of myelinated fibers but do not study unmyelinated fiber
function. We present routine clinical tests that are easily available and
effective for the evaluation of small unmyelinated fibers: thermal
threshold testing for warmth to evaluate small C unmyelinated somatic
fibers and sympathetic skin responses to evaluate small C unmyelinated
sympathetic fibers. Five unrelated patients with a diagnosis of
Charcot-Marie-Tooth disease, type I, confirmed by biopsy were investigated.
All of these patients showed marked reduction or absence of motor and
sensory conduction velocities and severe denervation at needle examination.
By contrast, thermal threshold testing for warmth and sympathetic skin
responses were normal, confirming the normality of small C unmyelinated
somatic and sympathetic fibers. We conclude that these noninvasive tests
are helpful in the diagnosis of Charcot-Marie-Tooth disease, type I.
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DESCRIZIONE
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ELETTROMIOGRAFIA
LARINGEALE
Nel tipo II C della
malattia di Charcot-Marie-Tooth, di tipo assonale, presenta debolezza del diaframma
e paralisi del cavo vocale. E’ stata usata l'elettromiografia laringeale
per studiare un paziente con questo disordine. Questa tecnica è utile nella
diagnosi del tipo II di malattia del Charcot-Marie-Tooth.
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TESTO ORIGINALE
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Laryngeal Electromyographic Findings in Charcot-Marie-Tooth Disease
Type II - .Dray TG, Robinson LR, Hillel AD - Arch Neurol 1999; 56(7):863-5
Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy
that exhibits progressive muscular atrophy in the limbs, beginning with the
lower extremities. It is now understood to be a heterogeneous group of
disorders that can be differentiated both clinically and genetically. In
Charcot-Marie-Tooth disease type II C, axonal neuropathy, diaphragm
weakness, and vocal cord paralysis are described within kindreds. We used
laryngeal electromyography to study a patient with this disorder. This
technique has potential in the diagnosis of Charcot-Marie-Tooth disease
type II.
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DESCRIZIONE
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Neuropatia
ereditaria: i vari geni responsabili e loro suddivisione in tipi e
sottotipi
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TESTO ORIGINALE
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Inherited Neuropathies: From Gene to Disease - Keller MP, Chance PF
Brain Pathol 1999; 9(2):327-41
Inherited disorders of peripheral nerves represent a common group of
neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is
a genetically heterogeneous group of chronic demyelinating polyneuropathies
with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B)
and to another unknown autosome (CMT1C).
CMT1A is
most often associated with a tandem 1.5-megabase
(Mb) duplication in chromosome 17p11.2-12, or
in rare patients may result from a point mutation in the peripheral myelin
protein-22 (PMP22) gene. CMT1B is
associated with point mutations in the myelin protein zero (P0 or MPZ) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth
neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is
an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A), another to chromosome 3p (CMT2B)
and another to 7p
(CMT2D).
Dejerine-Sottas disease (DSD), also called hereditary motor and sensory
neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating
polyneuropathy syndrome that may be associated with point mutations in
either the PMP22 gene
or the P0 gene
and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to
pressure palsies (HNPP) is an autosomal dominant disorder that results in a
recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and
HNPP are reciprocal duplication/deletion syndromes originating from unequal
crossover during germ cell meiosis. Other rare forms of demyelinating
peripheral neuropathies map to chromosome 8q, 10q and
11q.
Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an
autosomal dominant disorder causing painful, recurrent brachial
plexopathies and maps to chromosome 17q25.
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DESCRIZIONE
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Caso clinico di una
frattura patologica della tibia nella CMT – siamo a rischio maggiore nelle
fratture
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TESTO ORIGINALE
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Quintart
C, Baillon JM, Libotte M - Acta Orthop Belg 1999; 65(1):105-8
The authors report a case of pathologic
fracture of the distal tibia associated with Charcot-Marie-Tooth disease.
Pathologic fracture was visible four weeks after initial pain. Treatment
consisted in a short leg walking cast for six weeks. Charcot-Marie-Tooth
disease is a slowly progressive neurogenic muscular atrophy affecting the
distal parts of the lower limbs. The muscular atrophy is responsible for
radiographic bony changes including narrowing of the shaft with thinning of
the cortex, rarefaction at the end of the long bones and relative widening
of the medullary cavity. Pathologic fractures in neuromuscular disease are
rare; a few cases have been reported following application of very small
forces. The authors draw attention to the increased risk of pathologic
fractures in patients with neuromuscular disease. Ambulatory treatment of
fractures should be used whenever possible; prolonged immobilization could
result in further loss of function
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DESCRIZIONE
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Correlazione tra
apatia e stanchezza cronica nelle neuropatie
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TESTO ORIGINALE
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Apathy and Hypersomnia Are Common Features of Myotonic Dystrophy -
Rubinsztein JS, Rubinsztein DC, Goodburn S, Holland AJ - J Neurol
Neurosurg Psychiatry 1998; 64(4):510-5
Objectives: Myotonic dystrophy is a disease characterised by myotonia and
muscle weakness. Psychiatric disorder and sleep problems have also been
considered important features of the illness. This study investigated the
extent to which apathy, major depression, and hypersomnolence were present.
The objective was to clarify if the apathy reported anecdotally was a
feature of CNS involvement or if this was attributable to major depression,
hypersomnolence, or a consequence of chronic muscle weakness.
Methods: These features were studied in 36 adults with non-congenital myotonic dystrophy
and 13
patients with Charcot-Marie-Tooth disease. By using patients with
Charcot-Marie-Tooth disease as a comparison group the aim was to control
for the disabling effects of having an inherited chronic neurological
disease causing muscle weakness. Standardised assessment instruments were
used wherever possible to facilitate comparison with other groups reported
in the medical literature.
Results: There was no excess of major depression on cross sectional
analysis in these patients with mild myotonic dystrophy. However, apathy
was a prominent feature of myotonic dystrophy in comparison with a
similarly disabled group of patients with Charcot-Marie-Tooth disease
(clinician rated score; Mann Whitney U test, p=0.0005). Rates of hypersomnolence were greater
in the myotonic dystrophy group, occurring in 39% of myotonic dystrophy patients, but there was
no correlation with apathy.
Conclusion: These data suggest that apathy and hypersomnia are independent
and common features of myotonic dystrophy. Apathy cannot be accounted for
by clinical depression or peripheral muscle weakness and is therefore
likely to reflect CNS involvement. These features of the disease impair
quality of life and may be treatable.
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DESCRIZIONE
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Analisi sulla
tossicità del farmaco Vincristine per i CMT – si tratta di un farmaco usato
nelle neoplasie tumorali
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TESTO INTEGRALE
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Charcot-Marie-Tooth Disease Type I Diagnosed in a 5-Year-Old Boy After Vincristine Neurotoxicity,
Resulting in Maternal Diagnosis - Olek MJ, Bordeaux B, Leshner RT
J Am Osteopath Assoc 1999; 99(3):165-7
Charcot-Marie-Tooth disease type 1,
also known as hereditary motor sensory neuropathy type 1, is an uncommon autosomal dominant disease that
causes destruction of peripheral nerves with a varied clinical course, but
often leads to muscle weakness. If the peroneal muscle is involved, the
patient may develop a characteristic slapping gait. The dose-limiting side
effect of the chemotherapeutic agent vincristine is usually its
neurotoxicity. We report the case of a 5-year-old patient with leukemia who developed an
acute polyneuropathy after treatment with vincristine. Charcot-Marie-Tooth
disease type 1 was
diagnosed in the patient and, subsequently, in his mother only after
vincristine toxicity was observed.
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DESCRIZIONE
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Indagine e studi
ortopedici sulla patologia
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TESTO ORIGINALE
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The Charcot Joint
Zwipp H, Rammelt S, Dahlen C, Reichmann H - Orthopade 1999; 28(6):550-8
Charcot foot in its original sense is equivalent to stage 4 of hereditary motor and sensory neuropathy
(HMSN) which is known as Charcot-Marie-Tooth disease since 1886. This entity, which can be subdivided into 3 groups including subgroups, predominantly
begins during childhood and progresses slowly. The first symptom, often
unnoticed by the patient for a long period, is weakness of the intrinsic foot
muscles with consecutive hammer-toe formation and mobile pes cavus.
Progredient atrophy of the peroneal, extensor, tibialis posterior and
finally triceps surae muscles leads to fixed pes cavus varus excavatus with
severe varus deformity of the hindfoot, secondary varus position of the
talus at the ankle level and subsequent arthrosis of the medial
compartment. Permanent varus deformity of the ankle almost invariably leads
to stress fractures of the malleoli because of repetitive microtrauma
(stage 5 of
HMSN). Early detection of the disease with nerve conduction studies at
clinical suspicion allows tibialis posterior transfer, correctional
osteotomy of the hindfoot or arthrodesis of Chopart's or Lisfranc's joint
and can postpone or prevent the otherwise inevitable triple arthrodesis
which has a less favorable long-term prognosis. At stage 4 (manifest Charcot foot) and stage 5 (neuropathic fracture of the ankle) a
reorientating ankle arthrodesis is advocated, with additional subtalar
pathology correctional double arthrodesis becomes necessary. In diabetic
arthropathy of the ankle (Type IV according to Sanders and Frykberg), which
is often referred to as "Charcot Ankle", tibiocalcanear
arthrodesis is indicated. In case of supervening infection or extensive necrosis
a modified Pirogoff amputation is carried out as a salvage procedure.
Doubled periods of non weight-bearing, immobilization and brace protection
of the ankle help to reduce the frequently observed implant failure in both
forms of osteoarthropathy. In addition to stable implants retrograde
calcaneotalotibial transfixation with a Steinmann pin may help to protect
the achieved result despite prolonged bone consolidation.
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DESCRIZIONE
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Particolare tipo di
anestesia per il parto in una donna di 25 anni, con insufficienza
respiratoria e CMT
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TESTO ORIGINALE
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Anaesthesia for Caesarean Section in a Patient With
Charcot-Marie-Tooth Disease
Reah G, Lyons GR, Wilson RC - Anaesthesia 1998; 53(6):586-8
We describe the management of a 25-year-old
primigravida with severe respiratory insufficiency secondary to
Charcot-Marie-Tooth disease type I scheduled for Caesarean section.
Incremental subarachnoid anaesthesia via a microcatheter was utilised.
Mother and baby made an uneventful recovery and were discharged home on the
tenth postoperative day.
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DESCRIZIONE
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Indagine sulla
relazione che esiste tra forza muscolare ed abilità funzionali
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TESTO ORIGINALE
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Quadriceps Strength and Timed Motor Performances in Myotonic
Dystrophy, Charcot-Marie-Tooth Disease, and Healthy Subjects
Lindeman E, Leffers P, Reulen J, et al. - Clin Rehabil 1998; 12(2):127-35
Background And Purpose: The leading hypothesis was that a relation exists
between muscular strength and functional abilities. Therefore a study was
undertaken to quantify such a relationship in a population of subjects with
different muscular strengths. This population consisted of healthy subjects
and subjects with slowly progressive neuromuscular disorders.
Methods: The study included 33
patients with myotonic dystrophy, 29
patients with Charcot-Marie-Tooth disease and 20 healthy subjects. Isokinetic and isometric knee
torques were measured on an isokinetic dynamometer at various velocities.
The following activities were timed: descending and ascending stairs,
rising from a chair, rising from supine, walking at natural speed and
walking at maximum speed.
Results: The population covered a wide range of the variables: whereas the
healthy subjects performed best (i.e. had the highest knee torques and
performed the activities most quickly), the myotonic dystrophy group
included the subjects with the lowest knee torques. The natural logarithms
(In) of isokinetic extension torque at the highest velocity (120 degrees/s) and those of the time taken to
perform the described activities showed the highest levels of correlation.
It was found that after correction for age and weight, 56% (walking at natural speed) to 73% (descending stairs) of the variance in the In
of the time taken could be attributed to the variance in the In of the
torques.
Conclusion And Discussion: A strong relation between quadriceps strength
and timed motor performances were demonstrated. The impact of strength
reduction on time taken was most obvious in subjects with considerably
decreased strength. Therefore, it is feasible to try to influence muscle
strength in patients with relevant strength reduction in order to achieve
better functional ability.
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DESCRIZIONE
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Un caso
di displasia associate alla neuropatia CMT
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TESTO ORIGINALE
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Charcot-Marie-Tooth Disease Associated With Hip Dysplasia: A Case
Report
Cucuzzella TR, Guille JT, MacEwen GD - Del Med J 1996; 68(6):305-7
A 31-year-old
woman with a known history of hip dysplasia was found to have
Charcot-Marie-Tooth disease following abnormal conduction studies done at
the time of surgery. Physical examination in this patient was otherwise
normal, and the diagnosis of Charcot-Marie-Tooth disease had not been
previously considered. This report demonstrates the importance of keeping
in mind the association between hip dysplasia and Charcot-Marie-Tooth disease.
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DESCRIZIONE
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Dalla
Corea un caso di una famiglia con
sordità associate alla patologia
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TESTO ORIGINALE
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Neuromuscul Disord 2004 May;14(5):325-8 (ISSN: 0960-8966)
Joo IS;
Ki CS; Joo SY; Huh K; Kim JW
Department of Neurology, Ajou University School of Medicine, Suwon, South
Korea.
Charcot-Marie-Tooth
disease with deafness is a clinically distinct entity and is associated with
mutations or deletions in several genes including PMP22 gene. Here, we report a large family showing
characteristic phenotypes of Charcot-Marie-Tooth type 1A along with deafness in an autosomal dominant
fashion. We detected a sequence variation (c.68C>G) co-segregating with the disease phenotype
and leading to a T23R missense mutation
in PMP22.
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DESCRIZIONE
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Studi
radiologici sul nervo craniale
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TESTO ORIGINALE
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Charcot-Marie-Tooth
Disease: Extensive Cranial Nerve Involvement on CT and MR Imaging [In
Process Citation]
AJNR Am J Neuroradiol 2004 Mar;25(3):494-7 (ISSN: 0195-6108)
Aho
TR; Wallace RC; Pitt AM; Sivakumar K
Section of Neuroradiology, St. Joseph's Hospital and Medical Center, Barrow
Neurologic Institute, Phoenix, AZ. Division of Neurology, Neuromuscular
Diseases Section, St. Joseph's Hospital and Medical Center, Barrow
Neurologic Institute, Phoenix, AZ.
Summary: We report a case of
genetically verified Charcot-Marie-Tooth disease in which the
patient had cranial nerve symptoms. CT and MR imaging demonstrated
enlargement of several cranial nerves, as well as their skull-base
foramina, with faint contrast material enhancement identified.
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DESCRIZIONE
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Una
famiglia dell’Aquila (Italia) con lesioni cerebrali e CMT – L’ipotesi è un
meccanismo di auto-immunità
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TESTO ORIGINALE
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Brain
White Matter Lesions in an Italian Family with Charcot-Marie-Tooth
Disease [epub ahead of print] [Record Supplied By Publisher]
Eur Neurol 2004 Apr 1;51(3):168-171 (ISSN: 0014-3022)
Sacco
S; Totaro R; Bastianello S; Marini C; Carolei A
Department of Neurology, University of L'Aquila, L'Aquila, Italy.
Type 1A, the most common form of Charcot-Marie-Tooth
(CMT1A) disease, is
characterized by demyelination of the peripheral nervous system. So far,
only a few cases of the disease with concomitant brain white matter lesions
have been described. We report an Italian family with CMT1A disease, consisting of the proband and 4 affected members, presenting with concomitant
brain white matter lesions at magnetic resonance imaging. The association
is particularly fascinating and might depend on an autoimmune mechanism, not
yet clarified. Copyright 2004 S. Karger AG,
Basel.
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