Autosomal dominant congenital fibre type disproportion: a - Brain

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.

Congenital fibre type disproportion Brain (2005), 128, 1716–1727 1717

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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 (+++).

1718 Brain (2005), 128, 1716–1727 M. J. Sobrido et al.

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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).

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50

75

100

125

150

Nu

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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

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1 (84.1%)

2 (15.9%)

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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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ovember 2018

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id

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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