A number sign (#) is used with this entry because myotonic dystrophy-1 (DM1) is

caused by a heterozygous trinucleotide repeat expansion (CTG)n in the 3-prime

untranslated region of the dystrophia myotonica protein kinase gene (DMPK; 605377)
on chromosome 19q13.

A repeat length exceeding 50 CTG repeats is pathogenic (Musova et al., 2009).

(Un signo de nmero (#) se utiliza con esta entrada, porque la

distrofia-1 miotnica (DM1) es causado por una expansin heterocigotos
de repeticiones de trinucletidos (CTG) n en la regin no traducida 3-
Prime del gen de protena dystrophia miotnica quinasa (DMPK; 605,377)
en 19q13 genoma.

Una longitud de repeticin superior a 50 repeticiones CTG es patgeno

(Musova et al., 2009).

Myotonic dystrophy is an autosomal dominant disorder characterized mainly by

myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG
changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the
3-prime untranslated region of a protein kinase gene. Disease severity varies with the
number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons
have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those
with congenital onset can have more than 2,000 repeats. The disorder shows genetic
anticipation, with expansion of the repeat number dependent on the sex of the
transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted
by males, whereas only alleles longer than 80 repeats tend to expand in maternal
transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (Musova et al.,
2009).
Genetic Heterogeneity of Myotonic Dystrophy
See also myotonic dystrophy-2 (DM2; 602668), which is caused by mutation in the
ZNF9 gene (116955) on chromosome 3q.
(La distrofia miotnica es un trastorno autosmico dominante
caracterizado principalmente por miotona, distrofia muscular,
cataratas, hipogonadismo, calvicie frontal, y cambios en el ECG. El
defecto gentico en DM1 resulta de una repeticin de trinucletidos
amplificado en la regin no traducida 3-Prime de un gen de la protena
quinasa. gravedad de la enfermedad vara con el nmero de
repeticiones: Los individuos normales tienen de 5 a 37 repeticiones,
ligeramente personas afectadas tienen 50 a 150 repeticiones, los
pacientes con clsico DM tienen de 100 a 1000 repeticiones, y aquellos
con inicio congnita puede tener ms de 2.000 repeticiones. El
trastorno muestra anticipacin gentica, con la expansin del nmero
de repeticin depende del sexo del padre transmisor. Alelos de 40 a 80
repeticiones por lo general se expanden cuando se transmiten por los
hombres, mientras que slo los alelos ms de 80 repeticiones tienden a
expandirse en las transmisiones maternales. eventos de contraccin de
la repeticin se producen 4.2 a 6.4% de las veces (Musova et al.,
2009).

La heterogeneidad gentica de la distrofia miotnica

Ver tambin la distrofia miotnica-2 (DM2; 602668), que es causada por
una mutacin en el ZNF9 Gen (116,955) en el genoma 3q)

ADULT-ONSET MYOTONIC DYSTROPHY

In adult-onset DM1, symptoms typically become evident in middle life, but signs can be
detectable in the second decade. Bundey et al. (1970) found that the most useful method
for identifying subclinical cases is slit-lamp examination for lens changes, followed by
electromyography for myotonic discharges, and then by measurement of
immunoglobulins.

Harper (1989) provided a monograph on myotonic dystrophy that has been updated
regularly.

Unlike the other muscular dystrophies, DM initially involves the distal muscles of the
extremities and only later affects the proximal musculature. In addition, there is early
involvement of the muscles of the head and neck. Involvement of the extraocular
muscles produces ptosis, weakness of eyelid closure, and limitation of extraocular
movements. Atrophy of masseters, sternocleidomastoids, and the temporalis muscle
produces a characteristic haggard appearance. Bosma and Brodie (1969) demonstrated
both myotonia and weakness in patients with swallowing and speech disability.
Myotonia, delayed muscular relaxation following contraction, is most frequently
apparent in the tongue, forearm, and hand. Myotonia is rarely as severe as in myotonia
congenita and tends to be less apparent as weakness progresses.

Many of the muscle biopsy changes are nonspecific. Most commonly there are central
nuclei and ring fibers. Necrosis, regeneration, and increase of collagen are never as
severe as in Duchenne muscular dystrophy. In 70% of patients there is hypotrophy of
type I muscle fibers; less commonly there are markedly atrophic fibers (Casanova and
Jerusalem, 1979). In many cases there are target fibers, suggesting neurogenic
dysfunction, but intramuscular nerves appear histologically normal (Drachman and
Fambrough, 1976). Ultrastructural studies show dilatation of T tubules or sarcoplasmic
reticulum, whose contents may be unusually dense (Milhaud et al., 1964). In some cases
the surface membrane may be irregular, with reduplication of basal lamina.

Neurologic Features

From a series of neurophysiologic investigations of 24 patients with myotonic

dystrophy, Jamal et al. (1986) concluded that there was unequivocal evidence of
widespread nervous system dysfunction. In many patients there was significant
involvement of peripheral large diameter motor and sensory fibers and of small
diameter sensory fibers peripherally and/or centrally. The authors stated that 'the
concept of myotonic dystrophy as a pure myopathy can no longer be sustained.' This
conclusion is supported by the findings in the family reported by Spaans et al. (1986).
Thirteen members of a large family presented with a hereditary motor and sensory
neuropathy in a dominant pedigree pattern. The mean motor conduction velocities for
the median and peroneal nerves in the affected individuals were 62% and 56%,
respectively, of those of the unaffected relatives. Eight of the 13 affected members also
showed more or less prominent signs of myotonic dystrophy. There was no case of
myotonic dystrophy alone.

Turnpenny et al. (1994) found that IQ in myotonic dystrophy declined as the age of
onset of signs and symptoms decreased and as the size of the CTG expansion increased.
The correlation appeared to be more linear with age of onset. Censori et al. (1994)
carried out a prospective case-control study of 25 patients with myotonic dystrophy
using magnetic resonance imaging (MRI) of the brain. They found that 84% of
myotonic dystrophy patients showed white matter hyperintense lesions, compared with
16% of controls. Most of these lesions involved all cerebral lobes without hemispheric
prevalence, but 28% of the myotonic dystrophy patients also showed particular white
matter hyperintense lesions at their temporal poles. Myotonic patients also showed
significantly more cortical atrophy than did controls. However, there was no
relationship between atrophy or white matter hyperintense lesions and age, disease
duration, or neuropsychologic impairment. Damian et al. (1994) found that
amplification of the CTG repeat in leukocytes strongly correlated with cognitive test
deficits when the expansion length exceeded over 1,000 trinucleotides. MRI lesions
were associated with impaired psychometric performance, but the MRI findings of
subcortical white matter lesions correlated only very weakly with the molecular
findings.

Miaux et al. (1997) found that 9 (70%) of 13 patients with a mild form of adult
myotonic dystrophy had T2-weighted signal abnormalities on brain MRI. Four patients
(30%) had lesions greater than 1 cm in diameter. Lesions were symmetric, occurred in
the subcortical white matter, and showed a predilection for the temporal lobe. There was
some evidence of cerebral atrophy in the patients overall but no difference in IQ
between patients and controls. There was no correlation between number of pathologic
CTG repeats and white matter lesions, and there was no correlation between intellectual
impairment and white matter lesions, except in 1 patient who had a difficult birth and
temporal lobe epilepsy. Three patients had marked thickening of the skull, which was
associated with ossification of the falx in 2.

Donahue et al. (2009) reported a 56-year-old woman with a 10-year history of myotonic
dystrophy who presented with progressive lower extremity weakness. Brain MRI
showed multiple discrete and confluent areas of abnormal signal intensity throughout
the subcortical white matter with predominant involvement of the frontal and anterior
temporal lobes. There was also diffuse thickening of the skull with ossification of the
falx. Donahue et al. (2009) noted the similarity of the white matter findings with those
observed in CADASIL (125310), but noted that skull abnormalities are not seen in
CADASIL.

In a study of 21 patients with myotonic dystrophy, Akiguchi et al. (1999) found that
MRI results indicated progressive brain atrophy. Magnetic resonance spectroscopy
demonstrated a significant reduction of the neuronal marker N-acetylaspartate, even in
young patients in whom imaging studies were still equivocal.
Delaporte (1998) found that 15 DM patients with no or minimal muscle weakness
demonstrated a homogeneous personality profile characterized by avoidant, obsessive-
compulsive, passive-aggressive, and schizotypic traits. Fourteen healthy control
individuals and 12 patients with a mild form of muscle disease did not show the same
trait homogeneity. Delaporte (1998) concluded that the personality disorders were not
attributable to the adjustment to a disabling condition, but rather were primary
manifestations of the genetic mutation.

Modoni et al. (2004) performed detailed neuropsychologic testing of 70 patients with

DM1, including 10 with congenital onset and 60 with juvenile-adult onset, who were
subdivided into 4 genotypic subgroups according to number of repeat expansion.
Patients with congenital onset (CTG repeats greater than 1,000) obtained the lowest
scores in verbal attainment, frontal and executive functions, and general intelligence,
consistent with mental retardation. Patients with 50 to 150 repeats showed age-
dependent impairment in memory, frontal lobe, and temporal lobe function. Patients
with 151 to 1,000 repeats showed defects only in frontal and executive tasks. Although
there was a correlation between number of repeats and degree of muscle involvement
for all patients, there was not a significant correlation between number of repeats and
cognitive impairment, except for the congenital group.

Sergeant et al. (2001) stated that neurofibrillary tangles (NFT), as described in patients
with Alzheimer disease (AD; 104300), had been described in the neocortex and
subcortical regions of patients with DM1. NFTs derive from pathologic aggregation of
hyperphosphorylated tau (MAPT; 157140) proteins. By neuropathologic examination,
Sergeant et al. (2001) identified hippocampal NFTs in 4 of 5 patients with DM1 ranging
in age from 42 to 64 years. Three patients had clinical evidence of cognitive impairment
or mental retardation. In some of the patients, other brain regions also had NFTs.
Biochemical characterization showed overexpression of tau protein isoforms lacking
exons 2 and 3, suggesting that the DMPK mutation disrupts normal MAPT isoform
expression and alters the maturation of MAPT pre-mRNA. Maurage et al. (2005)
identified biochemically similar NFTs in multiple brain regions of a patient with DM2;
however, the patient with DM2 was mentally normal, demonstrated no cognitive
decline, and died at age 71 years from a bilateral renal thrombosis.

(DISTROFA MYOTNICA DE ADULTOS

En el DM1 de inicio en el adulto, los sntomas suelen ser evidentes en la

vida media, pero los signos pueden ser detectables en la segunda dcada.
Bundey et al. (1970) encontraron que el mtodo ms til para identificar
casos subclnicos es el examen con lmpara de hendidura para los cambios
de lente, seguido por la electromiografa para descargas miotnicas y luego
por medicin de inmunoglobulinas.

Harper (1989) proporcion una monografa sobre la distrofia miotnica que

se ha actualizado regularmente.

A diferencia de las otras distrofias musculares, la DM inicialmente implica

los msculos distales de las extremidades y slo afecta ms tarde a la
musculatura proximal. Adems, hay una participacin temprana de los
msculos de la cabeza y el cuello. La participacin de los msculos
extraoculares produce ptosis, debilidad del cierre del prpado y limitacin
de los movimientos extraoculares. La atrofia de los masseteres, los
esternocleidomastoides y el msculo temporal produce una apariencia
caracterstica. Bosma y Brodie (1969) demostraron miotona y debilidad en
pacientes con deglucin y discapacidad del habla. La miotona, retraso de la
relajacin muscular despus de la contraccin, es ms frecuente en la
lengua, el antebrazo y la mano. La miotona rara vez es tan grave como en
la miotona congnita y tiende a ser menos evidente a medida que la
debilidad progresa.

Muchos de los cambios en la biopsia muscular son inespecficos. Ms

comnmente hay ncleos centrales y fibras de anillo. La necrosis, la
regeneracin y el aumento de colgeno nunca son tan severos como en la
distrofia muscular de Duchenne. En el 70% de los pacientes hay hipotrofia
de las fibras musculares tipo I; Menos comnmente hay fibras
marcadamente atrficas (Casanova y Jerusalem, 1979). En muchos casos
hay fibras diana, lo que sugiere una disfuncin neurognica, pero los nervios
intramusculares parecen histolgicamente normales (Drachman y
Fambrough, 1976). Estudios ultraestructurales muestran dilatacin de los
tbulos T o del retculo sarcoplasmtico, cuyo contenido puede ser
inusualmente denso (Milhaud et al., 1964). En algunos casos la membrana
superficial puede ser irregular, con reduplicacin de la lmina basal.

Caractersticas neurolgicas

De una serie de investigaciones neurofisiolgicas de 24 pacientes con

distrofia miotnica, Jamal et al. (1986) concluyeron que haba evidencia
inequvoca de disfuncin generalizada del sistema nervioso. En muchos
pacientes hubo una afectacin significativa de fibras perifricas sensoriales
y de motor de gran dimetro y de fibras sensoriales de pequeo dimetro
perifrica y / o centralmente. Los autores afirmaron que "el concepto de
distrofia miotnica como miopata pura ya no puede sostenerse". Esta
conclusin es apoyada por los hallazgos en la familia reportados por Spaans
et al. (1986). Trece miembros de una familia numerosa presentaron una
neuropata motora y sensorial hereditaria en un patrn de pedigr
dominante. Las velocidades medias de conduccin motora de los nervios
mediano y peroneo en los individuos afectados fueron 62% y 56%,
respectivamente, de los de los familiares no afectados. Ocho de los 13
miembros afectados tambin mostraron signos ms o menos prominentes
de distrofia miotnica. No hubo ningn caso de distrofia miotnica sola.

Turnpenny et al. (1994) encontraron que el CI en la distrofia miotnica

disminuy a medida que la edad de inicio de los signos y sntomas
disminuy y como el tamao de la expansin del CTG aument. La
correlacin pareca ser ms lineal con la edad de inicio. Censori et al. (1994)
realizaron un estudio prospectivo de casos y controles de 25 pacientes con
distrofia miotnica utilizando la resonancia magntica (MRI) del cerebro.
Encontraron que el 84% de los pacientes con distrofia miotnica mostraban
lesiones hiperintensas de la materia blanca, en comparacin con el 16% de
los controles. La mayora de estas lesiones implicaron todos los lbulos
cerebrales sin prevalencia hemisfrica, pero el 28% de los pacientes con
distrofia miotnica tambin mostraron lesiones hiperintense de la materia
blanca particular en sus polos temporales. Los pacientes miotnicos
tambin mostraron una atrofia cortical significativamente mayor que los
controles. Sin embargo, no hubo relacin entre atrofia o lesiones
hiperintensas de la materia blanca y edad, duracin de la enfermedad o
deterioro neuropsicolgico. Damian et al. (1994) encontraron que la
amplificacin de la repeticin de CTG en leucocitos se correlacionaba
fuertemente con los dficits de prueba cognitiva cuando la longitud de
expansin superaba los 1.000 trinucletidos. Las lesiones por RM se
asociaron con deterioro del rendimiento psicomtrico, pero los hallazgos de
RM de lesiones subcorticales de la sustancia blanca se correlacionaron muy
dbilmente con los hallazgos moleculares.

Miaux et al. (1997) encontraron que 9 (70%) de 13 pacientes con una forma
leve de distrofia miotnica de adultos presentaron anomalas de la seal
ponderada en T2 en la resonancia magntica cerebral. Cuatro pacientes
(30%) tenan lesiones mayores de 1 cm de dimetro. Las lesiones fueron
simtricas, se produjeron en la sustancia blanca subcortical, y mostraron
una predileccin por el lbulo temporal. Hubo alguna evidencia de atrofia
cerebral en los pacientes en general, pero no hubo diferencias en el CI entre
los pacientes y los controles. No hubo correlacin entre el nmero de
repeticiones patolgicas CTG y lesiones de la sustancia blanca, y no hubo
correlacin entre el deterioro intelectual y Lesiones de la sustancia blanca,
excepto en 1 paciente que tuvo un parto difcil y epilepsia del lbulo
temporal. Tres pacientes presentaron marcado engrosamiento del crneo,
que se asoci con la osificacin de la falda en 2.Donahue et al. (2009)
inform de una mujer de 56 aos con una historia de 10 aos de distrofia
miotnica que present debilidad progresiva de las extremidades inferiores.
La resonancia magntica cerebral mostr mltiples reas discretas y
confluentes de intensidad de seal anormal en toda la sustancia blanca
subcortical, con predominio de los lbulos temporal frontal y anterior.
Tambin hubo espesamiento difuso del crneo con osificacin de la falda.
Donahue et al. (2009) seal la similitud de los hallazgos de la sustancia
blanca con los observados en CADASIL (125310), pero seal que las
anomalas craneales no se observan en CADASIL. En un estudio de 21
pacientes con distrofia miotnica, Akiguchi et al. (1999) encontraron que los
resultados de la RM indicaron una atrofia cerebral progresiva. La
espectroscopia de resonancia magntica demostr una reduccin
significativa del marcador neuronal N-acetilaspartato, incluso en pacientes
jvenes en los que los estudios de imagen eran an equvocos. Deselaporte
(1998) encontr que 15 pacientes con DM sin debilidad muscular mnima
demostraron un perfil de personalidad homogneo caracterizado por
evitacin , Obsesivo-compulsivo, pasivo-agresivo, y rasgos esquizotipicos.
Catorce individuos de control sanos y 12 pacientes con una forma leve de
enfermedad muscular no mostraron la misma homogeneidad de rasgo.
Delaporte (1998) concluy que los trastornos de la personalidad no eran
atribuibles al ajuste a una condicin incapacitante, sino que eran
manifestaciones primarias de la mutacin gentica.Modoni et al. (2004)
realizaron pruebas neuropsicolgicas detalladas de 70 pacientes con DM1,
incluyendo 10 con inicio congnito y 60 con inicio juvenil-adulto, que se
subdividieron en 4 subgrupos genotpicos segn el nmero de expansiones
repetidas. Los pacientes con aparicin congnita (CTG repite ms de 1.000)
obtuvieron las puntuaciones ms bajas en logros verbales, funciones
frontales y ejecutivas e inteligencia general, consistente con retraso mental.
Los pacientes con 50 a 150 repeticiones mostraron deterioro dependiente
de la edad en la memoria, el lbulo frontal y la funcin del lbulo temporal.
Los pacientes con 151 a 1.000 repeticiones mostraron defectos slo en
tareas frontales y ejecutivas. Aunque hubo una correlacin entre el nmero
de repeticiones y el grado de compromiso muscular para todos los
pacientes, no hubo una correlacin significativa entre el nmero de
repeticiones y el deterioro cognitivo, excepto para el grupo
congnito.Sergeant et al. (2001) indic que los enredos neurofibrilares
(NFT), descritos en pacientes con enfermedad de Alzheimer (AD, 104300),
se haban descrito en las regiones neocrtex y subcorticales de pacientes
con DM1. Las NFT derivan de la agregacin patolgica de protenas tau
hiperfosforiladas (MAPT; 157140). Por examen neuropatolgico, Sergeant et
al. (2001) identificaron NFT hipocampales en 4 de 5 pacientes con DM1 con
edades entre 42 y 64 aos. Tres pacientes tenan evidencia clnica de
deterioro cognitivo o retraso mental. En algunos de los pacientes, otras
regiones del cerebro tambin tenan NFT. La caracterizacin bioqumica
mostr sobreexpresin de las isoformas de protenas tau carentes de los
exones 2 y 3, lo que sugiere que la mutacin DMPK altera la expresin
normal de la isoforma MAPT y altera la maduracin del MAPR pre-mRNA.
Maurage et al. (2005) identificaron NFTs bioqumicamente similares en
mltiples regiones del cerebro de un paciente con DM2; Sin embargo, el
paciente con DM2 era mentalmente normal, no demostr deterioro
cognitivo, y muri a los 71 aos de una trombosis renal bilateral.)

Cardiac Features

Hawley et al. (1983) suggested that the tendency to have heart block or arrhythmia with
myotonic dystrophy is a familial characteristic. The implication was that there may be 2
forms of myotonic dystrophy. They studied 18 families and found heart block in 4.

In a single large kindred, Tokgozoglu et al. (1995) compared the cardiac findings in 25
patients with myotonic dystrophy with age-matched normal family members. They
found that the patients were more likely to have conduction abnormality (52% vs 9%),
mitral valve prolapse (32% vs 9%), and wall motion abnormality (25% vs 0%). Left
ventricular ejection fractions and stroke volume were reduced compared with normals.
Using multivariate analysis, the number of CTG repeats (range, 69 to 1367; normal, less
than 38) was the strongest predictor of abnormalities in wall motion and EKG
conduction. Patients with more extensive neurologic findings had a higher incidence of
wall motion and/or EKG conduction abnormalities. The authors also found that the
relation of mitral valve prolapse to the size of the CTG repeat was of borderline
significance.
Cardiac involvement is well described in adults with myotonic dystrophy. Bu'Lock et al.
(1999) undertook detailed cardiac assessment in 12 children and young adults with
congenital myotonic dystrophy using control data from 137 healthy children and young
adults. All patients were in sinus rhythm with a normal P wave axis. Three had first-
degree heart block and 4 had a borderline P-R interval (200 ms). Four others had more
complex conduction abnormalities. Three patients had mitral valve prolapse. Eleven of
the 12 patients had abnormalities of 1 or more parameter of left ventricular diastolic
filling. None of these patients were symptomatic. The authors commented that the
prognostic implications of these findings were unclear; however, they concluded that
echocardiographic assessment of left ventricular diastolic function may be a useful
adjunct to electrocardiographic monitoring of patients with congenital myotonic
dystrophy.

Antonini et al. (2000) performed a prospective study of 50 DM1 patients without known
cardiac disease at the time of enrollment. Nineteen patients developed major cardiac
abnormalities during the 56-month study. No correlation was found between CTG
length and frequency of EKG abnormality or type of arrhythmia. CTG length was
inversely correlated with age at onset of EKG abnormality.

Bassez et al. (2004) reported 11 DM1 patients under the age of 18 years who had severe
cardiac involvement. Two patients died suddenly, 1 patient had cardiac arrest with
successful resuscitation, and 1 asymptomatic 13-year-old girl presented with recurrent
presyncope. Rhythm disturbances included atrial flutter in 4, ventricular tachycardia in
4, and atrial fibrillation in 1. Five patients had atrioventricular block necessitating
pacemaker implantation. Six of 11 patients (55%) experienced arrhythmic events with
vigorous exercise. Genetic analysis detected between 235 and 1,200 CTG repeats in all
patients. No cardiac involvement was detected before age 10 years. Bassez et al. (2004)
concluded that patients with congenital or childhood forms of DM1 may present with
cardiac abnormalities and that exercise testing is a necessary evaluation in these
patients.

Groh et al. (2008) found that 96 of 406 patients with genetically confirmed DM1 had
severe ECG abnormalities, and that these patients were older, had more CTG repeats,
and had more severe muscular impairment compared to those without ECG
abnormalities. After a mean follow-up period of 5.7 years, 69 patients who did not have
ECG abnormalities at the start of the study had developed ECG abnormalities and 81
patients died. There were 27 sudden deaths, 32 deaths from progressive neuromuscular
respiratory failure, 5 nonsudden deaths from cardiac causes, and 17 deaths from other
causes. The major cause of death in the cohort was respiratory failure associated with
progressive muscular weakness. A severe ECG abnormality and a clinical diagnosis of
atrial tachyarrhythmia conferred relative risks for sudden death of 3.30 and 5.18,
respectively.
(Caractersticas cardacas

Hawley et al. (1983) sugirieron que la tendencia a tener bloqueo cardaco o

arritmia con distrofia miotnica es una caracterstica familiar. La implicacin
fue que puede haber 2 formas de distrofia miotnica. Ellos estudiaron a 18
familias y encontraron bloqueo cardaco en 4.

En un nico ncleo grande, Tokgozoglu et al. (1995) compararon los

hallazgos cardacos en 25 pacientes con distrofia miotnica con miembros
normales de la familia de edad. Ellos encontraron que los pacientes tenan
ms probabilidades de tener anormalidad de conduccin (52% vs 9%),
prolapso de la vlvula mitral (32% vs 9%) y anormalidad en el movimiento
de la pared (25% vs 0%). Las fracciones de eyeccin del ventrculo izquierdo
y el volumen sistlico se redujeron en comparacin con los normales.
Utilizando el anlisis multivariado, el nmero de repeticiones CTG (rango, 69
a 1367, normal, menos de 38) fue el predictor ms fuerte de las anomalas
en el movimiento de la pared y la conduccin de EKG. Los pacientes con
hallazgos neurolgicos ms extensos tuvieron una mayor incidencia de
movimiento de la pared y / o anomalas de conduccin de EKG. Los autores
tambin encontraron que la relacin del prolapso de la vlvula mitral con el
tamao de la repeticin CTG fue de importancia lmite.

La afectacin cardaca est bien descrita en adultos con distrofia miotnica.

Bu'Lock et al. (1999) realiz una evaluacin cardiaca detallada en 12 nios y
adultos jvenes con distrofia miotnica congnita utilizando datos de control
de 137 nios y adultos jvenes sanos. Todos los pacientes estaban en ritmo
sinusal con un eje de onda P normal. Tres tenan bloqueo cardaco de primer
grado y 4 tenan un intervalo P-R limtrofe (200 ms). Otros cuatro tenan
anormalidades de conduccin ms complejas. Tres pacientes presentaron
prolapso de la vlvula mitral. Once de los 12 pacientes presentaron
anomalas de 1 o ms parmetros de llenado diastlico del ventrculo
izquierdo. Ninguno de estos pacientes fue sintomtico. Los autores
comentaron que las implicaciones pronsticas de estos hallazgos no estaban
claras; Sin embargo, concluyeron que la evaluacin ecocardiogrfica de la
funcin diastlica del ventrculo izquierdo puede ser un complemento til
para el monitoreo electrocardiogrfico de pacientes con distrofia miotnica
congnita.

Antonini et al. (2000) realizaron un estudio prospectivo de 50 pacientes con

DM1 sin enfermedad cardiaca conocida en el momento de la inscripcin.
Diecinueve pacientes desarrollaron anomalas cardiacas mayores durante el
estudio de 56 meses. No se encontr correlacin entre la longitud CTG y la
frecuencia de la anormalidad de EKG o el tipo de arritmia. La longitud de
CTG se correlacion inversamente con la edad al inicio de la anomala de
ECG.

Bassez et al. (2004) inform de 11 pacientes con DM1 menores de 18 aos

con afectacin cardaca grave. Dos pacientes fallecieron repentinamente, un
paciente tuvo paro cardiaco con reanimacin exitosa y una nia
asintomtica de 13 aos present presincopia recurrente. Las alteraciones
del ritmo incluyeron flutter auricular en 4, taquicardia ventricular en 4 y
fibrilacin auricular en 1. Cinco pacientes tenan bloqueo auriculoventricular
que necesitaba implante de marcapasos. Seis de 11 pacientes (55%)
experimentaron episodios arrtmicos con ejercicio vigoroso. El anlisis
gentico detect entre 235 y 1.200 repeticiones CTG en todos los pacientes.
No se detect compromiso cardaco antes de los 10 aos de edad. Bassez et
al. (2004) concluyeron que los pacientes con formas congnitas o infantiles
de DM1 pueden presentar anomalas cardiacas y que la prueba de esfuerzo
es una evaluacin necesaria en estos pacientes.

Groh et al. (2008) encontraron que 96 de 406 pacientes con DM1

genticamente confirmada presentaban anomalas graves en el ECG, y que
estos pacientes eran mayores, tenan ms repeticiones CTG y tenan un
deterioro muscular ms severo en comparacin con aquellos sin anomalas
ECG. Despus de un perodo medio de seguimiento de 5,7 aos, 69
pacientes que no presentaban anomalas ECG al inicio del estudio haban
desarrollado anomalas en ECG y 81 pacientes fallecieron. Hubo 27 muertes
repentinas, 32 muertes por insuficiencia respiratoria neuromuscular
progresiva, 5 muertes sin causa por causas cardiacas y 17 muertes por
otras causas. La principal causa de muerte en la cohorte fue insuficiencia
respiratoria asociada con debilidad muscular progresiva. Una anomala
grave del ECG y un diagnstico clnico de taquiarritmia auricular confieren
un riesgo relativo de muerte sbita de 3,30 y 5,18, respectivamente.)

CONGENITAL MYOTONIC DYSTROPHY

Harper (1975) observed that in a small proportion of cases, myotonic dystrophy may be
congenital with neonatal hypotonia, motor and mental retardation, and facial diplegia.
With rare exception, it is the mother who transmits the disease. Diagnosis can be
difficult if the family history is not known because muscle wasting may not be apparent,
and cataracts and clinical myotonia are absent, although the latter is sometimes
detectable by electromyography. Fried et al. (1975) observed that infants with neonatal
myotonic dystrophy (almost always the mother is affected) have thin ribs. Talipes at
birth, together with hydramnios and reduced fetal movements during pregnancy, is
frequent. Respiratory difficulties are frequent and are often fatal. Those that survive the
neonatal period initially follow a static course, eventually learning to walk but with
significant mental retardation in 60 to 70% of cases. By age 10 they develop myotonia
and in adulthood develop the additional complications described for the adult-onset
disease. Roig et al. (1994) reported long-term follow-up of 18 patients diagnosed with
congenital myotonic dystrophy. Three of the 18 had died, and 5 were lost to follow-up.
The remaining 10 had IQs of less than 65. Universal findings were language delay,
hypotonia, and delayed motor development. There was no difficulty with routine
immunizations nor were there anesthetic complications observed in any of the 7 patients
who underwent surgery.

Rudnik-Schoneborn et al. (1998) reviewed the obstetric histories of 26 women with

myotonic dystrophy who had a total of 67 gestations, comparing gestations with
affected and unaffected fetuses. Of the 56 infants carried to term, 29 had or most likely
had inherited the gene for DM from their affected mothers; 18 of the 29 (61%) were
affected by the congenital form of DM. Perinatal loss rate was 11% and associated with
congenital DM. Preterm labor was a major problem in gestations with DM-fetuses (55
vs 20%), as was polyhydramnios (21% vs none). While forceps deliveries or vacuum
extractions were required in 21% of deliveries with DM-fetuses and only 5% of
unaffected fetuses, the frequency of cesarean sections were similar in the 2 groups.
Obstetric problems were inversely correlated with age at onset of maternal DM, while
no effect of age at delivery or birth order on gestational outcome was seen.

Stratton and Patterson (1993) established the molecular diagnosis of myotonic

dystrophy in a fetus shown to have bilateral effusions and scalp and upper torso edema
by ultrasound examination at 30 weeks' gestation. Polyhydramnios was also present.
Thus, nonimmune hydrops fetalis is a manifestation of congenital myotonic dystrophy.
The mother had previously unsuspected myotonic dystrophy, but she did show grasp
myotonia. Her brother had a confirmed diagnosis. The DM gene showed marked
expansion in her fetus. Stratton and Patterson (1993) found reports of 15 other cases of
nonimmune hydrops fetalis associated with congenital myotonic dystrophy. (Robin et al.
(1994) described nonimmune hydrops fetalis in association with severely impaired fetal
movement, giving support to the notion that fetal hypomobility is a cause of this
disorder. The hydropic infant stopped moving 8 weeks before delivery and did not move
postnatally. Autopsy revealed extensive CNS destruction of unknown cause.)

Other Features

Diabetes mellitus occurs in 5% of cases, frequently with hypersecretion of insulin

(Barbosa et al., 1974). There is impaired responsiveness to follicle stimulating hormone
with hypogonadism (Sagel et al., 1975), often impairment of adrenal androgens, and
occasional thyroid dysfunction, but pituitary function is usually intact (Lee and Hughes,
1964). Di Chiro and Caughey (1960) reviewed radiographic findings in the skull in 18
cases. In 17, 'hyperostotic' changes in the vault were found, the sex distribution being
equal. In 8 cases with hypogonadism, the hyperostosis was most advanced.

Excessive catabolism of IgG contributes to low circulating levels of IgG (Wochner et

al., 1966).
(DISTROFIA CONTINENTAL MYOTONIC

Harper (1975) observ que en una pequea proporcin de casos, la distrofia

miotnica puede ser congnita con hipotona neonatal, retraso motor y
mental y dipleja facial. Con raras excepciones, es la madre la que transmite
la enfermedad. El diagnstico puede ser difcil si no se conoce la historia
familiar, ya que el desgaste muscular puede no ser aparente, y las cataratas
y la miotona clnica estn ausentes, aunque esta ltima es a veces
detectable por electromiografa. Fried et al. (1975) observaron que los nios
con distrofia neonatal miotnica (casi siempre la madre est afectada)
tienen costillas delgadas. Talipes en el nacimiento, junto con hydramnios y
movimientos fetales reducidos durante el embarazo, es frecuente. Las
dificultades respiratorias son frecuentes ya menudo son fatales. Los que
sobreviven al perodo neonatal inicialmente siguen un curso esttico,
eventualmente aprendiendo a caminar pero con retraso mental significativo
en 60 a 70% de los casos. A los 10 aos desarrollan miotona y en la edad
adulta desarrollan las complicaciones adicionales descritas para la
enfermedad de inicio en el adulto. Roig et al. (1994) informaron el
seguimiento a largo plazo de 18 pacientes diagnosticados con distrofia
congnita miotnica. Tres de los 18 haban muerto y 5 perdieron el
seguimiento. Los 10 restantes tenan CI de menos de 65. Los hallazgos
universales fueron retardo de lenguaje, hipotona y retraso en el desarrollo
motor. No hubo dificultad con las inmunizaciones de rutina ni hubo
complicaciones anestsicas observadas en ninguno de los 7 pacientes
sometidos a ciruga.

Rudnik-Schoneborn et al. (1998) revisaron las historias obsttricas de 26

mujeres con distrofia miotnica que tuvieron un total de 67 gestaciones,
comparando gestaciones con fetos afectados y no afectados. De los 56
bebs llevados a trmino, 29 tenan o muy probablemente haban heredado
el gen para DM de sus madres afectadas; 18 de los 29 (61%) fueron
afectados por la forma congnita de DM. La tasa de prdida perinatal fue
del 11% y se asoci con DM congnita. El parto prematuro fue un problema
importante en gestaciones con DM-fetos (55 vs 20%), al igual que
polihidramnios (21% vs ninguno). Mientras que en el 21% de los partos con
fetos DM y slo el 5% de los fetos no afectados se requeran partos con
frceps o extracciones al vaco, la frecuencia de cesreas fue similar en los
2 grupos. Los problemas obsttricos se correlacionaron inversamente con la
edad al inicio de la DM materna, mientras que no se observ ningn efecto
de la edad en el parto o el orden de nacimiento en el desenlace gestacional.

Stratton y Patterson (1993) establecieron el diagnstico molecular de la

distrofia miotnica en un feto que mostr efusiones bilaterales y cuero
cabelludo y edema del torso superior mediante examen ecogrfico a las 30
semanas de gestacin. Polyhydramnios tambin estaba presente. Por lo
tanto, la hidropsia fetal no inmune es una manifestacin de la distrofia
miotnica congnita. La madre tena una distrofia miotnica previamente
insospechada, pero s mostr miotona. Su hermano tena un diagnstico
confirmado. El gen DM mostr una marcada expansin en su feto. Stratton y
Patterson (1993) encontraron informes de otros 15 casos de hidropesa fetal
no inmune asociada con distrofia miotnica congnita. (Robin et al., 1994)
describieron la hidropsia fetal no inmune en asociacin con un movimiento
fetal severamente daado, dando apoyo a la nocin de que la hipomobilidad
fetal es una causa de este trastorno. El nio hidropico dej de moverse 8
semanas antes del parto y no se movi despus del parto. La autopsia
revel una extensa destruccin del SNC de causa desconocida.)

Otras funciones

La diabetes mellitus ocurre en el 5% de los casos, con frecuencia con

hipersecrecin de insulina (Barbosa et al., 1974). Existe una alteracin de la
capacidad de respuesta a la hormona folculo estimulante con
hipogonadismo (Sagel et al., 1975), a menudo un deterioro de los
andrgenos suprarrenales, y la disfuncin tiroidea ocasional, pero la funcin
pituitaria es usualmente intacta (Lee y Hughes, 1964). Di Chiro y Caughey
(1960) revisaron los hallazgos radiolgicos en el crneo en 18 casos. En 17,
se encontraron cambios "hiperostticos" en la bveda, siendo la distribucin
del sexo igual. En 8 casos con hipogonadismo, la hiperostosis fue la ms
avanzada.

El catabolismo excesivo de IgG contribuye a niveles bajos de IgG circulantes

(Wochner et al., 1966).)

Schwindt et al. (1969) claimed that 25 to 50% of patients have abdominal symptoms
due to cholelithiasis. Brunner et al. (1992) described 4 DM patients with recurrent
intestinal pseudoobstruction. In 1 patient it preceded significant muscle weakness by 15
years. Conservative measures usually were effective. Improved intestinal function was
noted in 1 patient treated with the prokinetic agent cisapride. A partial sigmoid resection
was performed in 3 patients with dolichomegacolon. Two of the patients were sibs.
Brunner et al. (1992) pointed out that there are many reports of familial occurrence of
specific complications of DM: cardiac conduction disturbances, focal myocarditis,
mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus,
and dilatation of the urinary tract. Familial idiopathic intestinal pseudoobstruction
occurs as an intestinal myopathy (155310) or in a neuronal form (243180); it occurs
also in Duchenne muscular dystrophy (310200).

Ciafaloni et al. (2008) found that 17 of 38 patients with DM1 reported excessive
daytime sleepiness. Thirteen of these 17 patients underwent sleep studies, and 7 of them
showed reduced sleep latency, sleep-onset REM, or both. However, CSF levels of
hypocretin (HCRT; 602358), which is implicated in the pathogenesis of narcolepsy
(161400), were normal in all 38 DM1 patients.

(Schwindt et al. (1969) afirm que del 25 al 50% de los pacientes presentan sntomas
abdominales debido a colelitiasis. Brunner et al. (1992) describieron a 4 pacientes de
DM con pseudoobstruccin intestinal recurrente. En 1 paciente precedi a debilidad
muscular significativa por 15 aos. Las medidas conservadoras generalmente eran
efectivas. Se observ mejora de la funcin intestinal en 1 paciente tratado con el agente
procintico cisaprida. Se realiz una reseccin sigmoidal parcial en 3 pacientes con
dolichomegacolon. Dos de los pacientes eran hermanos. Brunner et al. (1992) sealaron
que hay muchos reportes de ocurrencia familiar de complicaciones especficas de DM:
trastornos de la conduccin cardaca, miocarditis focal, prolapso de la vlvula mitral,
pilomatrixomas, polineuropata, hidrocefalia de presin normal y dilatacin del tracto
urinario. La pseudoobstruccin intestinal idioptica familiar ocurre como miopata
intestinal (155310) o en forma neuronal (243180); Ocurre tambin en la distrofia
muscular de Duchenne (310200).

Ciafaloni et al. (2008) encontr que 17 de 38 pacientes con DM1 reportaron

somnolencia diurna excesiva. Trece de estos 17 pacientes se sometieron a estudios de
sueo, y 7 de ellos mostraron menor latencia de sueo, REM de sueo, o ambos. Sin
embargo, los niveles de CSF de hipocretin (HCRT, 602358), que est implicado en la
patognesis de la narcolepsia (161400), fueron normales en todos los 38 pacientes con
DM1.)