autosomal dominant congenital fibre type disproportion: a - brain
TRANSCRIPT
doi:10.1093/brain/awh511 Brain (2005), 128, 1716–1727
Autosomal dominant congenital fibre typedisproportion: a clinicopathological andimaging study of a large family
M. J. Sobrido,1,4 J. M. Fernandez,2 E. Fontoira,3 C. Perez-Sousa,5 A. Cabello,6 M. Castro,7 S. Teijeira,1
S. Alvarez,1 S. Mederer,7 E. Rivas,1 M. Seijo-Martınez7 and C. Navarro1
1Department of Pathology and Neuropathology, Hospital do Meixoeiro, Departments of 2Neurophysiology and 3Radiology,Complexo Hospitalario Xeral-Cıes, Vigo, 4Fundacion Publica Galega de Medicina Xenomica, Santiago de Compostela,5Neurology Unit, Complexo Hospitalario Arquitecto Marcide, Ferrol, 6Department of Neuropathology, Hospital 12Octubre, Madrid and 7Department of Neurology, Complexo Hospitalario de Pontevedra, Pontevedra, Spain
Correspondence to: Dr Carmen Navarro, Department of Pathology and Neuropathology, Hospital do Meixoeiro,Vigo 36 200, SpainE-mail: [email protected]
Congenital fibre type disproportion (CFTD) is considered a non-progressive or slowly progressive muscledisease with relative smallness of type 1 fibres on pathological examination. Although generally benign,CFTD has a variable natural course and severe progression has been observed in some patients. The patho-genesis of the disorder is unknown and many authors consider CFTD a syndrome with multiple aetiologiesrather than a separate clinical entity. A positive family history has been reported in about 40% of cases, but theinheritance pattern is not clear. Both autosomal recessive and dominant modes of inheritance have beensuggested. The present paper describes a large, multigenerational kindred that has an inherited myopathyfulfilling the histological criteria of CFTD, with autosomal dominant transmission and high penetrance. Theclinical picture, remarkably similar in all affected familymembers, started in early infancywithmild limbmuscleweakness. There was slow progression of symptoms into adulthood, withmoderate to severe, mainly proximal,muscle weakness without loss of ambulation. Muscle biopsy from two affected individuals demonstrated pre-dominance of small type 1 muscle fibres without other significant findings. Nerve conduction studies werenormal and needle electromyography showed a myopathic pattern. MRI examination performed on threepatients from successive generations showed involvement of proximal limb and paraspinal muscles. The clinicaland pathological homogeneity in the present family, together with the lack of additional histological abnor-malities after decades of disease progression in two affected individuals, supports this being a distinctmyopathywith fibre type disproportion. Whether the disease in this family can be regarded as a form of the congenitalmyopathy known as CFTD or rather a unique condition sharing histological features with CFTD needs furtherinvestigation. This is, to our knowledge, the largest kindred with muscle fibre type disproportion reported todate. Our data confirm autosomal dominant inheritance, and this is the first MRI document of this disorder.
Keywords: congenital fibre type disproportion; congenital myopathy; muscle MRI; autosomal dominant
Abbreviations: CFTD = congenital fibre type disproportion; DTR = deep tendon reflex
Received July 30, 2004. Revised February 14, 2005. Accepted March 17, 2005. Advance Access publication April 27, 2005
IntroductionIn 1973 Brooke coined the term ‘congenital fibre type dis-
proportion’ (CFTD) to describe a disorder of skeletal muscle
with weakness and hypotonia present at birth or shortly
thereafter, generally slow or absent progression of motor
symptoms and frequent skeletal abnormalities, including
congenital hip dislocation, joint contractures, foot deformit-
ies and kyphoscoliosis (Brooke, 1973). The characteristic
histochemical pattern on muscle biopsy consists of a predom-
inance of type 1 fibres, which are at least 12% smaller
than type 2 fibres, the latter being normal or hypertrophic
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(Brooke, 1973; Fardeau et al., 1975; Cavanagh et al., 1979).
Sporadic and familial cases—consistent with both autosomal
dominant and recessive inheritance—have been reported
(Brooke, 1973; Kinoshita et al., 1975; Curless and Nelson,
1977; Eisler and Wilson, 1978; Jaffe et al., 1988). However,
the diagnostic criteria, histopathological features and clinical
course of the disease are still insufficiently defined. Further-
more, the existence of CFTD as a separate disorder has
remained controversial, since type 1 fibre hypotrophy can
also be encountered in other neuromuscular conditions. In
a recent review, Clarke and North (2003) identified 67 cases in
the literature, supporting the retention of CFTD as a distinct
nosological entity. Mutations in the a-skeletal actin (ACTA1)
gene have been identified recently in severe cases of CFTD, but
the molecular mechanisms leading to disproportion in fibre
size are unknown (Laing et al., 2004). Whether ACTA1 muta-
tions can also lead to milder cases of CFTD needs to be
investigated.
In the present paper we describe a multigenerational non-
consanguineous family with a dominantly transmitted neur-
omuscular disease in which 25 members were available to us
for clinical evaluation. Pathological examination of muscle
performed in two affected individuals showed predominance
of small type 1 fibres and an increase in diameter of type 2
fibres without any other remarkable changes. In addition,
detailed electrophysiological and muscle MRI studies were
undertaken in several individuals. To our knowledge, this
is the largest CFTD kindred reported to date.
MethodsPatientsThe kindred reported here (Fig. 1) was first identified when the index
case was referred to the neurology outpatient clinic for evaluation of
muscle weakness. A thorough description of the pedigree and per-
sonal and clinical data on deceased or absent individuals were ob-
tained by a series of clinical interviews. Twenty-five family members
were personally interviewed and examined by one of us. Laboratory
workup, chest X-ray, electrocardiogram and echocardiogram
were performed in the propositus and two additional patients.
An individual was considered affected if muscle weakness was pre-
sent, with or without atrophy.
Electrophysiological studiesDetailed electrophysiological investigations were performed in five
patients. Motor and sensory nerve conduction and late responses
were evaluated using standard procedures (Kimura, 1989). Concent-
ric needle electromyography, including turns/amplitude (T/A) and
multi-motor unit potential analyses were performed in proximal and
distal limb muscles (Stalberg et al., 1983; Bischoff et al., 1994). In
addition, single-fibre EMG was performed in at least one muscle
from each patient (Stalberg and Trontelj, 1994).
MRI studiesThree patients underwent MRI evaluation of muscle. These studies
were performed with a 1.5 T field strength magnet (GE Signa
Horizon LX 9.2) using T1-weighted and Short tau inversion recovery
(STIR) sequences in the axial plane. Scans of the scapular girdles and
arms, pelvic girdle and thighs were obtained for each individual. Scan
parameters for T1-weighted images were: repetition time 400 ms;
echo time 18 ms; matrix 512 · 224; one acquisition; section thickness
10 mm; intersection gap 1 mm; field of view 400–480 mm. STIR
sequences were performed as follows: repetition time 11250 ms for
shoulder and pelvic girdle studies and 3500–6500 ms for thigh stud-
ies; echo time 37.7 ms, inversion time 150 ms; matrix 256 · 256; one
acquisition; section thickness 10-mm; intersection gap 1 mm; field of
view 400–420 mm.
Muscle biopsiesOpen deltoid muscle biopsies were performed on patients V-14 and
VI-1 at the ages of 43 and 25 years, respectively. Specimens were
oriented and each was divided into two pieces, one for histochem-
istry and another for electron microscopy. The first piece was snap-
frozen in liquid nitrogen-cooled isopentane and transverse 7 mm
cryosections were stained with haematoxylin–eosin, periodic acid
Schiff, oil red O, modified Gomori trichrome, nicotinamide adenine
dinucleotide phosphate tetrazolium reductase, succinate dehydro-
genase and myofibrillar adenosine triphosphatase (ATPase) after
preincubation at pH 4.35, 4.63 and 9.4. Tiny rectangular pieces for
electron microscopy were fixed in 2.5% glutaraldehyde, postfixed in
osmium tetroxide and embedded in Epon after routine dehydration.
Semithin sections were stained with toluidine blue and ultrathin
Fig. 1 Genealogy of the family. Generations are labelled with Roman numerals and the individual members with Arabic numbers. Eachmember examined is indicated with an asterisk. Black = affected; white = unaffected; dark grey = probably affected by history; light grey =probably unaffected; question mark = affectation status unknown.
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sections were contrasted with uranyl acetate and lead citrate and
mounted in copper grids. Ultrathin sections were examined with
a Philips CM100 electron microscope. Random fields of muscle
sections stained with ATPase at pH 9.4 were examined for fibre
type identification and histometric analysis. The same procedure
was followed at pH 4.63 and 4.35 for type 2 fibre subgroup charac-
terization. The computer program Leica IM 1000 Image Manager
V1.2, Leica Microsystems AG, Switzerland was used to record the
measures, and a histogram of both muscle biopsies was constructed
measuring the lesser fibre diameter (maximum diameter across the
lesser aspect of the muscle fibre) of 300 fibres in each case. The mean
fibre diameter, standard deviation and percentage of each fibre type
were also calculated.
Molecular genetic analysisDNA from two affected members and one unaffected family member
was purified from peripheral blood leucocytes using standard pro-
cedures. We performed PCR amplification followed by bidirectional
sequencing of all ACTA1 coding exons. Previously published primers
and conditions were used for exons 2 and 4–7 (Nowak et al., 1999;
Ilkovski et al., 2001). Exon 3 was amplified with the primer pair E3F,
50-AGACACAATGTGCGACGAAG-30; E3R, 50-GCGGGAGA-
GAGTGAGTGG-30. Fifty nanograms of genomic DNA was mixed
with 0.4 mM of each primer, 200 mM of each deoxynucleotide,
1.5 mM Cl2Mg, 4% DMSO and 0.15 U of Taq polymerase
in a final reaction volume of 25 ml. PCR conditions were: 94� for
3 min, followed by five cycles of 30 s at 94�, 30 s at 66�C and 45 s
at 72�C, after which 34 additional cycles were performed, of 30 s at
94�C, 30 s at 64�C and 45 s at 72�C, followed by a final 4 min
extension at 72�C.
ResultsPedigree analysisThe family pedigree is shown in Fig. 1. The first ancestor
known to be affected by this condition was II-1, who had
been born in Galicia (northwestern Spain). Interviewed family
members believed the disease had been transmitted by indi-
vidual I-2, who was also of Galician origin. There was no
knowledge of consanguinity in the family. Analysis of the
inheritance pattern throughout the pedigree suggested an
autosomal dominant gene with high penetrance. There was no
excess of affected individuals of either sex (13 affected
women and 11affectedmen).Male-to-male, female-to-female,
male-to-female and female-to-male disease transmission were
all present. There was no instance of disease transmission
from unaffected parents.
Case reportsOut of 25 individuals available to us for examination (indic-
ated with an asterisk in Fig. 1), seven showed signs of
myopathy. The clinical findings of affected subjects are
summarized in Table 1.
Case V-14 (index case)The propositus, a 54-year-old woman, was the only child of
non-consanguineous parents. Her mother, who had a previ-
ous miscarriage, had muscle weakness from infancy (case IV-
10 described below). Her father died at age 54 without having
shown neuromuscular symptoms. The patient was born after
a full-term pregnancy and normal delivery. Intrauterine
movements were recalled by her mother as normal. She
was a somewhat floppy infant but had otherwise no respir-
atory or feeding difficulties and no significant motor mile-
stone delay. She could stand at about 8 months and walk at
around 12 months. However, from her early childhood she
had a clumsy gait and difficulty getting up from the floor.
During her school years she was a slow runner and jumped
clumsily. She had no language or learning disability. Muscle
strength decayed slowly in the subsequent decades, with step-
wise progression during her three pregnancies. By her fifties
she was able to walk with difficulty, especially when carrying
weights. She occasionally used a cane and had frequent falls on
uneven floor. She could not stand up from a sitting position
or climb stairs without support. She also noticed moderate
weakness in the upper limbs. She had no respiratory difficult-
ies, dysphagia or visual complaints. She reported no muscle
pain, cramps, paraesthesiae or other sensory symptoms. She
had three full-term, uneventful pregnancies and one miscar-
riage. On clinical examination she had normal stature and
mild hyperlordosis, but no scoliosis. Muscle wasting mainly
Table 1 Summary of clinical findings in seven affected members of the family
Case Sex/age Finger Wrist Forearm Arm Toe Foot Leg Hip Hip DTR DTR DTR Proximal Gaitabd/add ext flex/ext abd dorsif dorsif flex/ext flex abd/add elbow knee ankle wasting
IV-10 F/80 4+ 4+ 5/4 3 4+ 4– 4+/4 4– 4–/4+ 0 0 1 ++ WaddlingIV-26 F/80 4 4� 4+/4� 3 2 3 4–/3 3 3/4– 0 0 2 +++ Severe waddlingV-2 M/57 5 5 5/5 5 4+ 4+ 5/4+ 4+ 4+/4+ 2 1 3 –/+ Mild steppageV-14 F/54 5 4+ 5/4 4 4+ 4 5/4– 4 4/4+ 1 0 3 ++ WaddlingVI-1 M/27 5 5 5/4+ 4+ 5 4 5/5 4+ 4+/4+ 0–1 0 3 + Mild waddlingVI-15 F/29 5 5 4+/4+ 4– 5 4+ 5/4+ 4 4/4+ 0 2 3 ++ Mild waddlingVI-16 M/28 5 5 4+/4+ 4+ 4+ 4 5/4+ 4+ 4+/4+ 0 1 2 + Mild waddling
M = male; F = female; abd = abduction; add = adduction; flex = flexion; ext = extension; dorsif = dorsiflexion; DTR = deep tendon reflexes.Muscle strength was graded using the Medical Research Council scale. Muscle groups not included in the table were normal in all individuals.Deep tendon reflexes are classified as absent (0), hypoactive (1–2) or normal (3). Muscle wasting was graded from absent (–) tosevere (+++).
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affected the deltoid and triceps muscles in the upper limbs, as
well as the quadriceps muscles in the lower limbs (Fig. 2A,
upper panel). She had moderate weakness of hip flexor and
extensor muscles, quadriceps, foot and toe dorsiflexors,
deltoid, triceps and extensor carpi muscles. Her gait was wad-
dling and steppage. Extraocular, facial and neck muscles
showed normal strength. Her speech was normal. There
was no joint hyperlaxity, myotonia, fasciculations or pyram-
idal signs. She had no high-arched palate, pes cavus or other
dysmorphic features. Deep tendon reflexes (DTRs) were
hypoactive in the upper limbs, absent at the knee and pre-
served at the ankle. Fundoscopic examination, cerebellar and
sensory systems as well as language and other cognitive func-
tions were normal. Laboratory results were within normal
limits, including thyroid function, pyruvate, lactate, liver en-
zymes, serum aldolase, lactate dehydrogenase and creatine
kinase. Chest X-ray, echocardiogram and ECG were unre-
markable. Nerve conduction studies were normal, thus ruling
out a peripheral neuropathy. Concentric needle EMG showed
myopathic changes. Results are summarized in Table 2. A
muscle biopsy taken from her right deltoid and MRI studies
are described below in detail.
Case IV-26 (Fig. 3)No prenatal data were available on this currently 80-year-old
patient. As far as she knew, her mother’s pregnancy and
delivery had been unremarkable. Muscle weakness was first
noted in early childhood, with clumsiness on getting up,
running and climbing stairs. Weakness had been slowly pro-
gressive and affected lower and upper limbs, without ocular,
face or bulbar muscle involvement. At the time of examina-
tion she was severely disabled. She needed a walker to get
around her house and could not climb stairs. Although
with great difficulty, she was still able to get up from a
chair by herself, alternately using nearby furniture and her
own thighs as support. On examination she had severe weak-
ness and atrophy affecting the proximal lower limbs (mainly
gluteus, psoas, hamstring, quadriceps and tibialis muscles)
and upper limbs (most severely the arm elevator and rotators,
deltoid, biceps and triceps muscles), with mild involvement of
more distal muscles, such as the extensor carpi and lumbri-
calis. Her speech was normal, as were the cranial nerves,
sensory and cerebellar functions. DTRs were all absent except
for the ankle jerk. She had hyperlordosis and mild dorsal
kyphosis, but otherwise no dysmorphic features and no
joint hyperlaxity could be disclosed.
Case VI-1This 27-year-old male was born at term following an uncom-
plicated gestation. No problems were detected in the newborn
period, he was not noticed to be hypotonic, and his crying and
sucking were good. His motor milestones were slightly
delayed, he frequently slipped when sitting, he had difficulty
crawling and he was able to cruise at 18 months. He had
frequent falls in early childhood and at school he was a
poor runner and clumsy at sports. He had difficulty getting
up from the floor, which he achieved with a brisk impulse.
Speech development and intelligence were normal. Progres-
sion of muscle weakness in recent years had been unremark-
able. On clinical evaluation he had an independent walk, with
mild waddling and bilateral foot drop. He could stand up
from a sitting position with his arms crossed, although
with some instability. He was able to climb up and down
A B
Fig. 2 (A) Atrophy of the quadriceps is evident in patients V-14 (upper panel) and VI-16 (lower panel). (B) Weakness in foot and toedorsiflexion but not in standing on tiptoes is shown in patient V-2.
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the stairs without support but he could not run down the
stairs. There was mild proximal upper limb weakness, mainly
affecting arm elevator and triceps muscles. Bicipital, tricipital
and knee DTRs were absent. The styloradialis reflex was
hypoactive but present bilaterally and ankle jerks were
normal. He had numerous scars from a juvenile acne con-
globata but otherwise no skin or joint abnormalities were
detected. He had normal height, a poor general muscle
development, mild hyperlordosis, and his face was somewhat
long and thin. However, the face and neck muscles had
normal strength. The extraocular muscles and cranial nerves
were normal, as were the sensory and cerebellar systems. La-
boratory tests, including glucose, urea, creatinine, uric acid,
liver enzymes, total serum protein, albumin, cholesterol,
triglycerides, Na, K, Ca, P, alkaline phosphatase, lactate
dehydrogenase, creatine kinase, aldolase, thyroid function,
lactate and pyruvate, were all normal. Electrocardiogram
results were also normal. Nerve conduction studies were
Table 2 Electromyographic findings of four affected individuals
Case Muscleexamined
Fibrillation/PSWs Multi-MUP analysis Polyphasia Turns/amplitude Fibre density
Amplitude mv(REL SD)
Duration ms(REL SD)
V-2 Biceps � 441 (0.5) 9.5 (–0.3) � N �Tibialis anterior ++ 1019 (2.2) 8.2 (–2.6) ++ N 1.8
V-14 Biceps ++ 505 (1.1) 6.9 (–2.1) + Myopathic 1.6Tibialis anterior ++ 508 (–0.4) 7.4 (–3.2) + Myopathic 1.7
VI-15 Biceps ++ 302 (–1.9) 8.3 (–1.6) � Myopathic 1.7Tibialis anterior + 398 (–1.3) 9.3 (–1.7) ++ Myopathic �
VI-16 Biceps ++ 359 (–0.3) 6.8 (–2.1) � Myopathic 1.8Tibialis anterior ++ 694 (0.8) 7.4 (–3.2) ++ Myopathic �
PSW = positive sharp wave; MUP = motor unit potential; REL SD = relative standard deviation; + = discrete; ++ = moderate; +++ = abundant.
Fig. 3 Photographs of individuals IV-26 and IV-24. The 80-year-old patient (IV-26, arrow) has pronounced proximal muscle atrophycompared with her 82-year-old unaffected sister.
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normal and needle EMG (tibialis anterior muscle bilaterally,
right biceps, deltoid, right vastus medialis) disclosed a
myopathic pattern without spontaneous activity. A muscle
biopsy was obtained from his left deltoid.
Additional family membersSignificant findings on clinical examination of other affected
family members are summarized in Table 1. Case IV-10, the
80-year-old mother of the propositus, showed no problems in
the newborn period and could stand and walk at the appro-
priate age. However, she had difficulty running and going up
and down stairs since early childhood. Her gait had always
been ‘peculiar’. She subsequently developed a slowly progress-
ive muscle weakness, including moderate upper limb weak-
ness and difficulty carrying weights. At the time of
examination she was unable to stand up from a chair without
help. Her gait was waddling. She could take a few independent
steps but generally used a cane and had frequent falls. She had
no dysphagia or problems with language or respiration. Mod-
erate weakness and wasting of the proximal limb muscles was
evident. Facial and extraocular muscles, sensory and cerebel-
lar function were normal.
Individual V-2, the 57-year-old father of VI-1, was born
after an uncomplicated pregnancy with normal intrauterine
movements. He was not regarded as a floppy child, could
breathe and suck normally, and early developmental mile-
stones were unremarkable. In his early school years, however,
he was slower and clumsier than other children. He had no
progression of weakness until his fifties, when he started to
notice some worsening of muscle strength. With time his
walking and running had become clumsier and his ability
to lift weighs was somewhat poorer than expected for his
age. Upon clinical examination he showed mild proximal
limb weakness and difficulty with foot and toe dorsiflexion
(Fig. 2B). However, he could get up from a low seat and could
climb up and down stairs without support. He was tall, had
mild hyperlordosis and a long, thin face with no dysmorphic
features. Facial and neck muscle strength was normal, as were
his intelligence, speech, cranial nerves, sensory and cerebellar
tests. Routine laboratory workup, including creatine kinase,
was normal.
Patient VI-15 is the oldest daughter of the index case. She
did not show any complications during early infancy and
could cruise at 9 months. Motor difficulties were first noticed
by age 4 years when getting up from the floor, jumping or
running. She was clumsier at sports than her schoolmates. She
currently needed support to walk up stairs. Her gait was
mildly waddling and she had difficulty in walking on her
heels. Coordination, cranial nerves and sensory examination
were normal.
Patient VI-16 was born at term after normal pregnancy and
delivery. Intrauterine movements were recalled as normal by
his mother. His first months and early motor milestones were
unremarkable. He could walk at 16 months. Motor clumsiness
was first noticed by age 2 years. By that time he had difficulty
getting up from the floor or from a kneeling position and was
a clumsy runner. Although reading was delayed, speech and
mental development were otherwise normal. On examination
at age 28 he showed proximal limb wasting (Fig. 2A, lower
panel) and had difficulty climbing up stairs while holding
moderate weights. He had no muscle pain or limb numbness.
Cranial nerves and facial and neck muscle strength were nor-
mal. He had mild hyperlordosis, waddling gait and difficulty
with heel walking. Neurophysiological examination was per-
formed in patients V-2, VI-15 and VI-16; results are shown in
Table 2.
All other evaluated family members showed no abnormal-
ity upon neurological examination. Individual VI-19 had a
somewhat clumsy gait, but no weakness or muscle atrophy
was noticed. She could jump, squeak and run up and down
the stairs without difficulty. Non-examined, probably affected
individuals were identified by report of other family members
as having an abnormal walk and poor muscle performance
from infancy. The disease could be traced back two genera-
tions before the oldest living individuals. The first family
member known to be affected (II-1) had shown progressive
gait problems and clumsiness most of her life. Her father was
thought to suffer from similar symptoms, but this could not
be confirmed by currently living relatives.
Electrophysiological studiesNerve conduction and electromyographic studies were per-
formed in patients V-2, V-14, VI-1, VI-15 and VI-16. Nerve
conduction studies, including F waves and distal latencies,
were normal. Concentric needle EMG showed scattered fib-
rillations and positive wave potentials at rest. Mild voluntary
effort easily recruited short-duration, low-amplitude motor
unit potentials, pointing to a primary muscle disorder. This
was further documented by multi-motor unit potential ana-
lysis. Single fibre density was normal in all cases. Table 2
summarizes the electromyographic findings of cases V-2,
V-14, VI-15 and VI-16.
MRI studiesAffected individuals from three generations were available for
MRI of muscle. MRI study of patients IV-10, V-14 and VI-16
at 80, 54 and 28 years of age, respectively, demonstrated
bilateral and symmetrical muscular involvement. At the
shoulder girdles and upper thorax, VI-16 showed moderate
loss of volume and fatty infiltration of paraspinal muscles,
and discrete loss of volume without fatty infiltration of rotator
cuff muscles in both shoulders. A more advanced disease stage
could be seen in V-14 as an increase of intramuscular fat and
atrophy, especially in the paraspinal muscles, and a decrease
of muscle volume in the shoulder girdles and chest wall. In
late stages, as seen in IV-10, there was generalized atrophy
affecting all muscles.
Early paraspinal lumbar muscle involvement was seen in
VI-16. An oedema-like pattern was present on STIR sequences
as diffuse hyperintensity of muscle bellies with normal
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appearance on T1-weighted images. This oedema-like pattern
was also noticed in case V-14, together with moderate
fatty infiltration and decrease in muscular bulk. Symmetrical
glutei involvement was seen in case VI-16 as patchy areas of
increased signal intensity on STIR images, and discrete
fatty infiltration as linear deposits of intramuscular fat on
T1-weighted images. Progressive and generalized involvement
of the pelvic girdle was seen in V-14 and IV-10 with marked
muscular atrophy. Thigh involvement was also bilateral and
symmetrical, with slow progression of the disease throughout
the generations. In VI-16, patchy areas of hyperintensity were
present on STIR images and there was also a linear pattern of
fat deposition in adductor and hamstring muscles. Subtle
changes in muscle signal intensity could be seen in both quad-
riceps, especially in the vastus lateralis. Interestingly, the
gracilis muscles were spared and the semitendinosus muscles
were less affected than the rest of the hamstring muscle group
(Fig. 4A and B). These changes were more prominent in V-14
(Fig. 4C and D), with marked atrophy and fatty infiltration of
the quadriceps (especially the vastus intermedius and lat-
eralis) and adductor magnus. The posterior compartment
of the thigh was less severely affected than the anterior muscle
group. Gracilis muscles were still spared, and there was also
relative sparing of the rectus femoris, sartorius, adductor
longus and semitendinosus. Diffuse and marked atrophy
could be seen in IV-10 (Fig. 4E), also affecting the gracilis
and hamstring muscles, but to a lesser degree than in the vasti
and adductor magnus.
Muscle pathologyLight microscopy examination revealed similar findings in
both biopsies (Fig. 5). General tissue architecture was
preserved. Although muscle fibres were generally polygonal
in shape, some of the smaller fibres had rounded contours.
Subsarcolemmal nuclei were unremarkable with no internal
nucleation. Connective tissue was not increased and there
was no fatty infiltration. Figures of degeneration, necrosis,
Fig. 4 MRI of muscle in three affected individuals. (A) T1-weighted image showing bilateral and symmetrical involvement of the thighs inpatient VI-16. Linear bands of fat infiltration affect predominantly the medial and anterior muscular compartments. (B) STIR axial image atthe same level showing intramuscular patchy areas of high signal intensity, predominantly in both adductor compartments. In case V-14,T1-weighted and STIR images of the thighs (C and D, respectively) demonstrate a more advanced disease stage compared with A and B.Vastus intermedius, vastus lateralis and the adductor group show moderate atrophy and fatty infiltration (long arrows), while thesemitendinosus muscles are less affected (short arrows) and the gracilis muscles are spared (arrowheads). (E) Axial T1-weighted image ofthe thighs in case IV-10 revealed marked atrophy and fatty infiltration in all muscle groups. Quadriceps and adductor muscles are intenselyatrophic (asterisks), while the semitendinosus (arrows) and gracilis (arrowheads) are moderately affected.
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myophagia or inflammation were not observed. Oxidative
enzymes demonstrated a regular myofibrillar network on
both type 1 and type 2 fibres. Two distinct fibre populations
were identified, randomly distributed among the fascicles.
Histochemical staining revealed that all small fibres were of
type 1 and the largest fibres invariably corresponded to type 2,
most of these being 2A fibres. These findings were consistent
with the diagnosis of congenital fibre type disproportion.
Both histograms (Fig. 6) showed a predominance of type 1
fibres, the smallest belonging to type 1 and the largest to type
2. In the propositus, type 1 fibres accounted for 78.5% of
fibres and had a mean diameter of 24.21 6 5.46 (SD) mm,
whereas type 2 fibres had a mean diameter of 55.23 6 8.18
mm. In patient VI-1, type 1 fibres constituted 84.1% of fibres,
with a mean diameter of 33.30 6 8.21 mm and the mean
diameter of type 2 fibres was 72.32 6 16.04 mm. The diameter
of type 1 fibres was thus 56.17 and 53.96% smaller than the
mean diameter of type 2 fibres in cases V-14 and VI-1,
respectively. Electron microscopic examination was unre-
markable except for fibre size discordance. Myofibrillar struc-
ture and organization were normal in both fibre types, as were
nuclei and mitochondria. The plasma membrane was not
abnormally folded in small fibres, and the basal membrane
was of normal appearance.
Molecular genetic analysisNo mutations were identified in the coding sequence of the
ACTA1 gene in affected subjects from the present kindred.
DiscussionThe clinical features of the family reported here suggest pro-
gressive myopathy of a relatively benign nature. The only
finding on muscle examination of two affected individuals
was a disparity in size between type 1 and 2 muscle fibres, the
characteristic pathological feature of CFTD. The diagnosis of
CFTD requires selective smallness of type 1 muscle fibres, with
a difference greater than 12% between the mean diameters of
type 1 and type 2 fibres (Brooke and Engel, 1969; Brooke,
Fig. 5 Muscle biopsy of case VI-1. ATPase at pH 4.63, showingpredominance and smallness of type 1 fibres (darker fibres). Clearfibres are of type 2. Note that only one of the type 2 fibresbelongs to subtype 2B (asterisk).
10 20 30 40 50 60 70 80 90 100 110
0
25
50
75
100
125
150
Nu
mb
ero
ffi
bre
s
diameter (µm)
1 (78.5%)
2 (21.5%)
Fibre type
A
10 20 30 40 50 60 70 80 90 100 110
diameter (µm)
0
25
50
75
100
Nu
mb
ero
ffi
bre
s
B
1 (84.1%)
2 (15.9%)
Fibre type
Fig. 6 Histograms of the biopsies from patients V-14 (A) and VI-1 (B). In both cases there is a two-peaked curve with a markedpredominance of small type 1 fibres.
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1973). Type 2 fibre hypertrophy has been described in some
cases (Brooke, 1973; Cavanagh et al., 1979; Ter Laak et al.,
1981). Because fibre size disproportion can sometimes be ob-
served in muscle biopsy in addition to other distinctive abnor-
malities, the existence of CFTD as a separate diagnostic
category remains controversial (Martin et al., 1976; Brooke
et al., 1979; Cavanagh et al., 1979). Type 1 fibre predominance
can often be observed in nemaline and centronuclear
myopathies (Karpati et al., 1970; Radu and Ionescu, 1972).
Other congenital myopathies, as well as other neuromuscular
and central nervous system disorders, can also show relative
type 1 fibre hypotrophy and must be ruled out in order to
establish a diagnosis of CFTD (Clarke and North, 2003). A
number of patients initially diagnosed with CFTD were later
shown to have other, distinct neuromuscular disorders
(Cavanagh et al., 1979; Martin et al., 1976; Dehkharghani
et al., 1981; Glick et al., 1984). It has been proposed that, in
order to avoid confusion, a diagnosis of CFTD should be re-
served for those cases with no other histological changes but a
disproportion in size of type 1 and type 2 muscle fibres (Jaffe
et al., 1988). Additional muscle abnormalities are generally not
found in CFTD except for an excess of central nuclei and
occasional rod-like formations (Caille et al., 1971; Brooke,
1973; Cavanagh et al., 1979; North, 2003). Intersample differ-
ences have been emphasized in previous reports (Cavanagh
et al., 1979). In addition, a disproportion in fibre size up to 25%
can be normal at certain ages (Polgar et al., 1973; Banker and
Engel, 1994). Special care with the differential diagnosis must
be taken when biopsy is performed in very young children. In
several instances, fibre size disproportion normalized in suc-
cessive biopsies taken at different ages (Iannaccone et al., 1987).
In the present kindred, the histograms of two available
muscle biopsies showed dissimilarity in size of 56.17 and
53.96%, respectively, between type 1 and type 2 fibres. The
mean degree of fibre size disproportion reported in CFTD was
41% (range 12–74%) (Clarke and North, 2003). Clarke and
North (2003) reviewed the clinical characteristics of CFTD
when either 12 or 25% was used as the minimum degree of
size disproportion required for diagnosis, and found that size
dissimilarity of 25% or greater was associated with a more
severe clinical phenotype and lack of improvement. While the
expected percentage of type 1 fibres in normal human muscle
is about 40% (Johnson et al., 1973), in CFTD there is usually
predominance of type 1 fibres (�55%). In the two biopsies
of the present study, type 1 fibres constituted 78.5 and 84.1%
of the fibres, respectively. In most reported CFTD cases, type
2A fibres are smaller than type 2B fibres, the latter constituting
less than 5% of the fibres or being absent in up to 35% of
the cases (Clarke and North, 2003). In case VI-1 of our
family, type 2B fibres represented 4.5% of the total. No other
histological abnormalities were identified in our patients
upon light microscope and ultrastructural examination. In
the present family the homogeneity of pathological findings
in muscle samples from two affected individuals showing a
disproportion in fibre size without additional abnormalities
well into adulthood (25 and 43 years of age, respectively, at the
time of biopsy) allows the exclusion of other conditions and
suggests this is a distinct nosological entity.
The disorder in our patients fulfils the histopathological
criteria accepted for CFTD and the clinical manifestations are
reminiscent of those associated with CFTD (Brooke, 1973;
Glick et al., 1984; Clarke and North, 2003). Some peculiarities,
however, should be noted in our patients. Although CFTD
patients are often hypotonic infants (Caille et al., 1971; Argov
et al., 1984; Clarke and North, 2003), only rarely were affected
individuals in the present family described as floppy at birth.
No information on Apgar scores or other parameters upon
delivery were available to us. However, interviewed family
members generally considered pregnancies, intrauterine
movements and deliveries as normal. In contrast to most
CFTD cases, with onset of symptoms generally before the
first month of age (Clarke and North, 2003), affected mem-
bers of our family showed the first signs of disease in infancy
or early childhood. Respiratory or sucking difficulties in the
newborn period were absent in our patients. Motor mile-
stones were not or slightly delayed and weakness was first
noticed upon starting to run or climb. A variable clinical
picture has been reported previously in CFTD even among
members of the same family (Eisler and Wilson, 1978; Clancy
et al., 1980; Kula et al., 1980; Sulaiman et al., 1983). In con-
trast, the pattern of muscle involvement was fairly consistent
in all affected individuals of the present family. Weakness
predominated in the proximal limb muscles and foot dor-
siflexors were almost constantly affected. DTRs were hypo-
active or absent, with invariable preservation of the ankle jerk.
Extraocular, bulbar, face and neck muscles were preserved in
our patients, while involvement of facial muscles, ophthal-
moplegia and bulbar or respiratory muscles have been
previously reported in up to 35% of mild or moderate
CFTD cases and in up to 70% of severe cases (Clarke and
North, 2003). CFTD is frequently regarded as a static muscle
disorder, without significant deterioration after early child-
hood and even improvement with age (Brooke, 1973; Curless
and Nelson, 1977; Cavanagh et al., 1979). In our patients,
however, there was slow but steady progression of weakness.
Although two affected individuals in their ninth decade were
severely disabled, lifespan was not shortened in this family
and none of the patients was wheelchair-bound. Worsening
of the symptoms with pregnancy, reported by female patients
of the present family, may also occur in other neuromuscular
disorders (Rossi et al., 1985; Rudnik-Schoneborn et al., 1997;
Chaudhry et al., 2002). Although CFTD generally carries a
benign prognosis, the natural history of this myopathy is
variable and weakness may be severe in up to 25% of patients,
with recurrent respiratory failure and early death (De Reuck
et al., 1977; Carboni et al., 1981; Mizuno and Komiya, 1990;
Torres and Moxley, 1992; Clarke and North, 2003). Associated
defects common in CFTD were absent in our family, such as
a high-arched palate, short stature, hip dislocation, scoliosis,
joint laxity, joint contractures and pes cavus. A long face is
also a common finding among reported CFTD patients. Cases
V-2 and VI-1 of the present kindred had long, thin faces, but
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so had individual VI-3, who otherwise showed no signs
of muscle disease, whereas all other definitely affected family
members examined had a normal face. There were no signs
of cardiopathy in this family, as disclosed by clinical exam-
ination, ECG and routine chest X-ray. Likewise, cardiac
involvement is uncommon in CFTD (Sulaiman et al., 1983;
Banwell et al., 1999). Cognitive and social development was
normal in our patients, as it is in most cases with a reported
diagnosis of CFTD (Sulaiman et al., 1983; Jaffe et al., 1988;
Clarke and North, 2003).
Routine laboratory workup of affected individuals disclosed
no specific abnormalities, including muscle enzymes. This is
consistent with previously reported CFTD cases, in which
serum creatine kinase and aldolase have been normal usually
or slightly elevated (Eisler and Wilson, 1978; Sulaiman et al.,
1983; Gerdes et al., 1994; Clarke and North, 2003). Vestergaard
et al. (1995) described two brothers with CFTD and insulin-
resistant diabetes mellitus. Fasting blood glucose was normal in
our cases. Nerve conduction studies were normal ruling out a
peripheral neuropathy. Concentric needle EMG showed un-
equivocal myopathic changes often associated with abnormal
spontaneous activity, more severe in the tibialis anterior mus-
cle. EMG evaluation in published CFTD cases, often not quant-
itative, showed either no abnormality or signs of myopathy
with fibrillation potentials and small polyphasic motor unit
potentials (Cavanagh et al., 1979; Rowinska-Marcinska et al.,
1991). Fibre density was normal or slightly increased in all
muscles. As fibre type disproportion may lead to suspicion
of fibre type grouping, this finding indicates a normal concen-
tration of muscle fibres in the motor units, thus ruling out a
chronic neurogenic process (Rowinska-Marcinska et al., 1991).
The availability of three successive generations for MRI
study allowed us to observe the progression of muscle changes
with age. The pattern of muscle involvement was strikingly
uniform in the present family. The proximal upper limbs,
paraspinal muscles and glutei were affected in all individuals
examined. In the lower limbs there was early involvement of
the vasti and relative long-term preservation of the rectus
femoris, semitendinosus, sartorius and gracilis muscles.
Interestingly, the pattern of thigh muscle involvement in our
family is similar to that reported by Jungbluth and colleagues
in congenital myopathies associated with RYR1 mutations,
with selective involvement of vasti and adductor magnus
and relative sparing of the rectus femoris, gracilis and ad-
ductor longus (Jungbluth et al., 2004a). However, within
the lower leg these authors report a relative sparing of the
tibialis anterior, which is the most affected muscle in our
patients. In an extensive MRI study in nemaline myopathy,
two different patterns have been distinguished (Jungbluth
et al., 2004b). Muscle involvement in patients with
nebulin-related nemaline myopathy was pronounced in the
lower leg, especially the tibialis anterior, with sparing of all
muscle groups within the thigh in the early stages. On the
other hand, patients with mutations in the ACTA1 gene
showed more diffuse involvement of the thigh and lower
leg, with relative sparing of the gastrocnemii. Our patients
are similar to the Nebuline (NEB) group in the early and
constant involvement of the ankle dorsiflexors, but similar
to the ACTA1 group in that the extensors of the knees were
weaker than the flexors. MRI has been proposed as a useful
method for the study of congenital myopathies and other
neuromuscular disorders (Mercuri et al., 2002). However,
to our knowledge there are no published reports of muscle
imaging in CFTD.
The pathogenesis of CFTD is unknown. While some
authors favour the concept of type 1 fibre atrophy (Kinoshita
et al., 1975), other investigators have proposed a maturation
delay or hypotrophy of a particular population of muscle
fibres (Fardeau et al., 1975; Ricoy and Cabello, 1981,
1985). In the patients described here, the absence of a redund-
ant and folded basal lamina in small fibres may be suggestive
of hypotrophy rather than atrophy. A family history of disease
has been reported in about 40% of CFTD cases in the liter-
ature (Clarke and North, 2003). Most of the original cases
reported by Brooke (1973) had a family history suggestive of
neuromuscular disease, three of them with a similar disorder
in a first-degree relative. The mode of inheritance of CFTD
(OMIM No. 255310; Online Mendelian Inheritance in
Man: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id =
255310) is not well defined and pedigrees consistent with both
an autosomal dominant (Brooke, 1973; Fardeau et al., 1975;
Kinoshita et al., 1975; Eisler and Wilson, 1978) and an auto-
somal recessive (Curless and Nelson, 1977; Cavanagh et al.,
1979; Jaffe et al., 1988) mode of inheritance have been repor-
ted. Establishing the inheritance of CFTD may be hampered
because of the small size of reported families and mildness of
symptoms in some patients. In the present paper we report a
large, multigenerational kindred in which the disease is trans-
mitted following an autosomal dominant pattern with high
penetrance. Previously published families with a diagnosis of
muscle fibre type disproportion and autosomal dominant
inheritance are scarce and generally comprise only a few in-
dividuals. The clinical characteristics of dominant kindreds
are varied, some of them including a history of congenital
hypotonia and lack of progression of muscle weakness usually
associated with CFTD (Fardeau et al., 1975; Kinoshita et al.,
1975). Eisler and Wilson (1978) described two members of a
family with slow progression of muscle weakness starting in
early childhood and without a history of floppy babies. Mus-
cle biopsy from these patients demonstrated type 1 fibre pre-
dominance and the authors suggested that this might be a
distinct syndrome.
Recently, missense mutations in the ACTA1 gene have been
reported in three unrelated cases of CFTD without a family
history of muscle disease (Laing et al., 2004). The three
children with mutations in ACTA1 represent severe cases
of CFTD with generalized weakness also affecting respiratory
muscles. ACTA1 mutations accounted for only 6% of cases
in the CFTD series analysed, pointing to genetic heterogeneity
in CFTD (Laing et al., 2004). Sequencing of the entire coding
region of ACTA1 did not disclose mutations in the present
family. This is not surprising, since the phenotype of the
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present family is different from the clinical picture described
in the CFTD cases with ACTAI mutations. The possibility of a
genetic alteration in introns or regulatory regions of ACTA1,
as well as gene large deletions or insertions affecting ACTA1,
cannot be ruled out in our patients. The discovery of the
genetic defect underlying fibre type disproportion in
the present kindred may help clarify the pathogenic
pathway leading to this disorder. Gerdes and colleagues
reported a patient with congenital fibre type disproportion
and a balanced chromosomal translocation t(10; 17),
suggesting that the translocation breakpoints are candidate
regions for a causal gene (Gerdes et al., 1994). The patient
described by them is different from our cases in that she also
had congenital dislocation of the hips and multiple
limb contractures. Another candidate locus resides on
chromosome 1p, since some features of the distal short
arm of chromosome 1 deletion syndrome overlap with
those found in CFTD, including fibre type disproportion
on muscle biopsy (Shapira et al., 1997; Slavotinek et al.,
1999; Okamoto et al., 2002). Although the molecular defect
responsible for the 1p deletion syndrome is unknown, it has
been proposed that the SKI proto-oncogene may contribute
to some of the phenotypic features (Colmenares et al., 2002;
Okamoto et al., 2002). Interestingly, this region harbours the
selenoprotein N gene (SEPN1), which has been implicated in
multiminicore myopathy and the rigid-spine syndrome,
in which type 1 fibre predominance can sometimes be
observed (Ferreiro et al., 2002). However, the SEPN1-
associated myopathies known to date have an autosomal
recessive inheritance. Other candidate genes in this region may
include those encoding agrin (AGRN), a crucial factor in the
formation of the neuromuscular junction, the actin family
gene ARPM2 and mitofusin 2 (MFN2), which mediates
mitochondrial organization and is mutated in the axonal
form of Charcot–Marie–Tooth disease. A link has also been
suggested between mutations in the insulin receptor gene
and the muscle alterations in two patients with CFTD
myopathy and insulin resistance (Vorwerk et al., 1999;
Klein et al., 1999). The large size of the pedigree reported here
offers enough power to pursue linkage analysis in the search
for the causal gene.
In conclusion, clinical and pathological features of the pedi-
gree reported here are strikingly homogeneous and support
the notion of fibre type disproportion myopathy as a separate
entity. Because there have been few large series of CFTD
reported in the literature, the present kindred provides a
thorough overview of this disorder. Although the character-
istics of our patients are reminiscent of other cases with mild
or moderate CFTD described in the literature, some peculi-
arities make this family somewhat different from typical
CFTD. Thus, whether the condition in this family represents
the same disorder as that usually recognized under the
eponym CFTD deserves future investigation. The study of
the present kindred at the molecular level should have im-
portant implications for a better understanding of the biology
of this condition.
AcknowledgementsWe are grateful to the patients and their relatives for their
participation in the study. We thank Dr Nigel G. Laing
(Nedlands, Australia) for his advice on ACTA1 analysis.
Nicolas Levy and Valerie Delague (Marseille, France)
performed some of the molecular analyses. This work was
supported in part by the Association Francaise contre les
Myopathies (AFM) dossier 9283, Fondo de Investigacion
Sanitaria FIS 01/1049, and G03/011.
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