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Differential diagnosis of congenital muscular dystrophies
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Official Journal of the European Paediatric Neurology Society
Original article
Differential diagnosis of congenital muscular dystrophies Andrea Kleina,b, Emma Clementb, Eugenio Mercurib,c, Francesco Muntonib, a
Department of Neurology, University Children’s Hospital Zurich, Switzerland Dubowitz Neuromuscular Unit, Hammersmith Hospital, Imperial College, London, UK c Department of Child Neurology, Catholic University, Rome, Italy b
art i cle info
ab st rac t
Article history:
Congenital muscular dystrophies (CMDs) are defined by signs of muscle weakness in the
Received 13 July 2007
first 6 months of life with myopathic changes in muscle biopsy. The progress in the last
Received in revised form
decade has helped to make molecular and genetic diagnoses in the majority of patients
13 September 2007
fulfilling these criteria. In a number of patients a definite diagnosis cannot be reached and
Accepted 3 October 2007
these individuals are often grouped together as ‘‘merosin positive’’ congenital muscular dystrophy. In the last 5 years, 25 patients referred for assessment as possible congenital
Keywords: Congenital muscular dystrophy Early presentation Differential diagnosis
muscular dystrophy have been found to have alternative diagnoses. This paper aims to highlight these conditions as the common differentials or more difficult to diagnoses to consider in patients presenting as CMD. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Congenital myopathy Arthrogryposis Emery-Dreifuss muscular dystrophy
1.
Introduction
Congenital muscular dystrophies (CMD) are a heterogeneous group of disorders characterised by muscle weakness in the first months of life and muscle biopsy changes that range from myopathic to overtly dystrophic depending on the muscle biopsied and the age at biopsy. Distinctive clinical features and immunohistochemical studies can often help to direct genetic testing and to diagnose a specific form of CMD but despite the molecular advances that have allowed the identification of 13 genetically distinct forms of CMD1–3 there remain a number of patients that fulfill the criteria for CMD in whom all known variants can be excluded. In some of these cases, a definitive diagnosis may not be reached and the question arises as to whether, despite the early weakness and pathological
changes on muscle biopsy, they might be affected by a condition other than CMD. Muscle biopsy may help in such cases; histological findings such as cores or rods may indicate a diagnosis of congenital myopathy rather than CMD. In other cases however, early clinical and biopsy findings may not be indicative of a specific alternative diagnosis. Hammersmith Hospital is commissioned by the National Commissioning Group (NCG) for the diagnosis and management of CMD and congenital myopathies in the UK. In the last 5 years, in excess of 400 patients were referred to this quaternary service with the possible diagnosis of CMD. In the majority of these cases, an integrated approach combining clinical and pathological findings and screening of the known CMD genes has enabled a precise diagnosis to be reached. In a number of other cases, review of the clinical and
Corresponding author. Department of Paediatrics, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12ONN, UK. Tel.: +44 2083833295; fax: +44 2087462187. E-mail address: [email protected] (F. Muntoni). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.10.002
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pathological findings has suggested alternative diagnoses that clinically overlap with CMDs. In this paper, we want to draw attention to these cases discussing the more common conditions that mimic CMD but also highlighting the rarer diagnoses that were more difficult to make.
2.
Methods
This was a retrospective study of patients reviewed by Hammersmith NCG CMD service in the last 5 years. Criteria for inclusion in this review were either (1) new referrals of ‘possible CMD’ with myopathic or dystrophic features on muscle biopsy and no specific findings suggesting a structural congenital myopathy or (2) follow-up patients with a diagnosis of ‘‘merosin positive’’ CMD in whom the genetically known forms of CMD had been excluded. From this cohort, we selected the patients in whom a diagnosis other than CMD was reached. Patients with congenital myotonic dystrophy were not included in this study. The clinical notes of these patients were reviewed to obtain a clear picture of presentation, muscle biopsy findings, evolution and complications.
3.
Results
In the past 5 years, in excess of 400 patients had been referred or were followed at the Hammersmith as part of the NCG service. Of this group, 25 patients were found to have diagnosis other than CMD. A total of 13 different diagnoses were reached in those 25 patients. The largest groups consist of early and severe presentation of known muscular dystrophies (n ¼ 5) or congenital myopathies with atypical pathological features (n ¼ 3), neurogenic disorders (n ¼ 5) and metabolic (n ¼ 5) or syndromic disorders (n ¼ 7). Ten of these patients had concomitant CNS involvement and/or multisystemic involvement. Table 1 summarises the clinical details of all patients, including presentation and additional features that helped to make the diagnosis. Table 2 describes the evolution of clinical signs and complications. Muscle biopsy findings ranged from unspecific myopathic changes to overtly dystrophic. In the few cases where specific features led to the diagnosis, more details will be provided in the text.
3.1.
Other muscular dystrophies with early onset
Four patients were found to have a de novo mutation in the Lamin A/C gene. They presented between the ages of 4 weeks and 5 months with axial weakness, lack of head control, proximal weakness affecting the arms more than the legs and bilateral talipes in one case. In some there was a reduced muscle bulk predominantly affecting the biceps and the calf muscles. They did not have prominent facial weakness and feeding difficulties were not a presenting feature. Their CK was between 600 and 1291 U/l.
12 (2008) 371 – 377
On follow-up they all developed early flexion contractures, rigidity of the spine and scoliosis. Respiratory involvement led to early nocturnal hypoventilation and one patient presented with cardiac arrhythmia at age 3 years during general anaesthesia. None had a cardiomyopathy in infancy. All had progressive weakness, one child died suddenly at the age of 3 years during a respiratory tract infection and only one child achieved independent walking with knee–ankle–foot orthosis (KAFOs), but lost it at age 4 years. One patient has been previously reported.4 One child was diagnosed with de novo Facio Scapulo Humeral (FSH) muscular dystrophy. He presented at birth with facial weakness and feeding difficulties. At the age of 3 months, he had lack of head control, marked shoulder weakness, absent facial expression and absent tendon reflexes. On follow-up he had achieved independent walking, subsequently lost at the age of 5 years, required a gastrostomy at age 4 years, and noninvasive nocturnal ventilation at age 6 years. Contractures other than TA tightness were not a feature. In addition to his muscular weakness he had learning difficulties, hearing impairment and myopia.
3.2.
Congenital myopathies
Three patients were diagnosed as affected by core myopathies and were found to have a de novo mutation of the muscle Ryanodine Receptor gene (RYR1). They presented at birth with proximal weakness, contractures, normal CK and absent tendon reflexes. They had a clearly dystrophic pattern on muscle biopsy; in two patients occasional cores were seen. Weakness was more predominant in the lower limbs and there was mild facial weakness in one. On follow-up one died in the first 3 weeks of life, the others achieved walking in KAFOs one independently, one with the help of a walker. These two patients had predominant weakness of the lower legs and developed a scoliosis at the age of 3 years.
3.3. Congenital spinal muscular atrophy (SMA) with predominant lower limb involvement Four patients had congenital SMA with predominant lower limb involvement. They all presented arthrogryposis at birth with a distinctive pattern of joint involvement, which was restricted to the lower limbs, short legs and weakness of the lower limbs. They had normal CK. In these patients early muscle biopsies of the quadriceps showed a marked increase of fat, reduced variability in fiber size and predominance of type I fibers that were reported as indicative of a myopathic pattern. On review of the muscle biopsy there was a suggestion of fibre grouping although this was difficult to appreciate because of the type I fibre predominance. Two of the four had neurogenic electro myography findings (EMG) later in life. One of them had a positive family history suggesting a dominant disorder with foot deformities, distal weakness with peroneal wasting and a relatively stable course, myopathic changes in muscle biopsy but a neurogenic pattern in EMG with normal nerve conduction studies (NCV and CMAP). The index patient also had a congenital onset with talipes and dislocated hips but had more severe
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Table 1 – Clinical details of all patients: age of presentation, first symptoms and additional features that helped in finding the diagnosis Diagnosis
Presentation
First symptoms
CK
DTR
EDMD2
4 weeks
946
nr
EDMD2
5 months
1000
EDMD2
5 months
1291
nr
EDMD2
2 months
Axial and proximal weakness No head control, weakness arms4legs Delayed motor milestones, proximal weakness Axial, weakness arms4legs, wasting of biceps
600
Additional features
Facioscapulohumeral muscular dystrophy
Birth
Feeding difficulties, reduced facial expression
Normal
RYR1-associated
Birth
Normal
RYR1-associated
Birth
Normal
RYR1-associated
Birth
Contractures, hip dislocation, proximal weakness: legs4arms Contractures, hip dislocation, proximal weakness: legs4arms Contractures, hip dislocation, proximal weakness: legs4arms
Normal
Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement
Birth
Contractures, weakness of lower limbs
Normal
nr
Short legs, typical MRI pattern
Birth
Contractures, weakness of lower limbs, dislocation of hips Contractures, weakness of lower limbs, dislocation of hips Dorsiflexed ankles, dislocation of hips, axial, distal weakness and wasting
Normal
nr
Short legs, typical MRI pattern
Normal
nr
Short legs, typical MRI pattern
Normal
+
Neurogenic EMG
Contractures: hip in flexion, knee and wrist in extention, talipes Contractures of elbows, hips, knees, talipes, proximal weakness
Normal
nr
Neurogenic EMG, weak cry and respiratory diff. at birth
Normal
+
Distinct pattern of joint position
Delayed motor milestones, head lag, proximal weakness Delayed motor milestones
750
+
Cerebellar ataxia and atrophy at age 2 years, membranous whorls on EM
1945
+
Ataxia, proximal weakness, cataract age 5 years Microcephaly, optic nerve atrophy, MR, ataxia, cataract 9 years, demyelinating neuropathy, growth retardation Retinopathy 7 m, cataracts 5 years, calcifications of basal ganglia, epilepsy, microcephaly, MR, distinct features Nystagmus, epilepsy at 18 m, short stature, microcephaly, chorea Epilepsy age 6, ataxia, dysarthria, saccadic eye movements
Birth
Birth
Neurogenic arthrogryposis
Birth
Amyoplasia
Birth
Marinesco Sjoegren Syndrome (MSS)
5 months
Marinesco Sjoegren Syndrome COFS/MSS
4–5 months
Cerebro-Oculo-FacioSkeletal Syndrome (COFS) Mitochondrial depletion Mitochondrial depletion Infantile systemic hyalinosis Pompe
Mental retardation, hearing loss, myopia
5 months
Axial and proximal weakness
2000
Birth
Axial and proximal weakness
504
2 months
Talipes, floppy, proximal and axial waekness Delayed, hypotonia, reduced head control
1000
880
Birth
Contractures, reduced movements, feeding diff.
Normal
Pain, thickened skin, ‘‘bruising’’
4 months
Reduced movement, motor delay
1500
Reduced movements, fatigue
6 months
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Table 1 (continued )
Diagnosis
Presentation
First symptoms
CK
DTR
Additional features
Ehlers Danlos Syndrome 6b
Birth
Hypotonia, no antigravity movements, joint laxity, dislocated hip
Normal
(+)
Loose skin, blue sclera, distinct features, deafness, MR
Translocation 9;13
Birth
Normal
nr
Translocation 9;13
Birth
Floppy, axial weakness, motor delay Floppy, axial weakness, motor delay
Microcephaly, epilepsy, joint laxity, distinct features Microcephaly, epilepsy, joint laxity, distinct features
Normal
CK, creatin kinase; DTR, deep tendon reflexes; MR, mental retardation; nr, not reported.
weakness also involving proximal muscles especially of hip abductors and facial muscles. She made functional progress and achieved independent walking. On follow-up they had all achieved independent walking, contractures were stable and all had a distinctive appearance with proximal and distal wasting of the lower limbs only and a forward leaning posture while standing; there was no wasting or weakness in the upper limbs. They all showed the same pattern of muscle MRI findings with atrophic appearance of the muscle bulk and sparing of the adductor longus and semitendinosus in the thigh.5
3.4.
Arthrogryposis
Two children had arthrogryposis. One was diagnosed as affected by neurogenic arthrogryposis. She had contractures in all large joints, joint laxity distally as well as feeding and respiratory difficulties at birth. Her neonatal quadriceps muscle biopsy was clearly myopathic with abnormal variability in fibre size, extensive fat, and increase of connective tissue and signs of de- and regeneration. Her weakness and contractures remained stable, she is only able to walk a few steps with KAFOs hands held. Hand tremor suggested a neurogenic disorder and an EMG was conducted at the age of 8 years and showed signs of neurogenic features with de- and re-innervation, NC studies were normal. The second patient was diagnosed as having sporadic arthrogryposis with amyoplasia. She did have proximal weakness especially of hip-girdle muscles at presentation; her quadriceps muscle biopsy was comprised almost entirely of fat. The clinical picture with joint contractures, internally rotated shoulders, extended elbows, palmar-flexed wrists and dimples led to the diagnosis. She has made good progress and started to walk at the age of 3.5 years with AFOs with some weakness remaining in her shoulder muscles.
4.
Forms with concomitant CNS involvement
Eight patients had early clinical and histopathology features compatible with CMD but they also had CNS involvement and additional distinctive features suggestive of an alternate diagnosis. The presence of cataracts, ataxia, nystagmus, characteristic features or neuropathy led to the final diagnosis of Marinesco
Sjoegren Syndrome (MSS) in two patients, Cerebro-OculoFacio-Skeletal Syndrome (COFS) in two, mitochondrial disorders in two and an unbalanced translocation in two sisters.
4.1.
Other conditions
Three patients belonged to this heterogenous group. One patient had a non-typical presentation of an infantile Pompe’s disease. She presented weakness, reduced movements and fatigability at the age of 4 months. She then made some motor progress and was starting to cruise along furniture at the age of 20 months when she developed respiratory difficulties with frequent chest infections associated with hypoventilation. There was no cardiac involvement at the time of diagnosis at the age of 2 years. In another patient, a diagnosis of Ehlers Danlos Disease (EDS) type 6B was made because of marked skin hyperelasticity. He was profoundly weak from birth, was born in breech position after a pregnancy with reduced movements and oligohydramnios. He did not have any antigravity movements, marked joint laxity, feeding difficulties and cleft palate. He started to improve at the age of 7 months. EDS type 6A was excluded by normal lysyl hydroxylase in urine analysis. The diagnosis of systemic hyalinosis was reached in one patient. At birth multiple contractures were noted, he had feeding difficulties and failure to thrive. Joint movement was very limited and while initially the lack of movement was interpreted as secondary to weakness, it became increasingly clear with time that the reason for this was related to pain. At the referral at 10 months of age he had contractures in all major joints, a very stiff neck, handling appeared painful, he was crying and sweating. He had some distinct features including hypertrophic gingiva and thickened skin with reddish discolouration over the joints. There were no antigravitiy movements in his legs. A muscle biopsy was not performed but his muscle ultrasound was very hyperechogenic, in keeping with our previous report which suggests a muscle involvement in this condition.6
5.
Discussion
Until the last decade the diagnosis of CMD was based on a combination of clinical signs, mainly early onset of weakness
Table 2 – Clinical details of evolution and complications Diagnosis
Scoliosis
Contractures
Cardiac involvement
NIVV
EDMD2
20 m
Hip, knee, ankle, elbows, wrist, rigidity of spine
Not until death
EDMD2
3y
Not until age 6y
EDMD2
8y
Hip, TA, elbows, shoulders, wrists, rigidity of spine, 8 m Rigidity of spine, hip, TA, knee, wrist
Age 2y 3.5 y
EDMD2
RYR1-associated RYR1-associated RYR1-associated
lower limb
10 y
Maximal functional achievement
Died age 3y Progressive
Sit supported
Progressive
Walking with KAFOS, lost age 4 y Sit supported
TA, hips, knees, rigidity of spine age 8 m
At age 3 y (rhythm) Not at age 3 y
2.5 y
Yes
Progressive
No
No
6y
PEG 4 y
Progressive
Walking achieved, lost age 5y
Improving Improving Died age 3w
Walks in KAFOS Walks in KAFOS
Improving
Walks
Mild hip, knee, TA
Cobb 601 at 11 y Stable-better
Improving
Walks age 2.4 y
lower limb
Stable-better
Improving
Walks
lower limb
Progressiv TA
Stable
Walks
Progressiv hip contactures
Stable
Stable: elbow, talipes, knee
Improving
Walks with KAFOs and K Walker Walks at 3.5 y
Neurogenic arthrogryposis
Cobb 121 at 8y
Amyoplasia Marinesco Sjoegren Syndrome (MSS)
No
Rigid spine, TA Hips, knees
12 y
PEG 10 y
Not available Stable Progressive Progressive
At age 13 y
TA
10 y
PEG 11 y
Progressive Progressive
Sit supported Walks age 2 y, lost age 5 y
Age 10 m
All joints, spinal stiffness
Progressive
No sitting, seen age 10 m
Marinesco Sjoegren Syndrome COFS/MSS Cerebro-Oculo-Facio-Skeletal Syndrome (COFS)
Cobb 751 at 12 y
Mitochondrial depletion Mitochondrial depletion Infantile Systemic Hyalinosis
No
Pompe Ehlers Danlos Syndrome 6b
Yes
Not at age 2 y 4y
Translocation 9;13 Translocation 9;13
Walks age 3 y Walks 18 m Sit supported
Progressive
Cruising at 20 m than lost
Improving
Walks age 4 1/2 y with AFO
Stable Stable
Walks 4 y Walks 10 y
375
m, months; NNIV, non invasive nocturnal ventilation; PEG, percutaneous gastrostomy; TA, tendon achilles tightening; w, weeks; y, years.
Yes
Sitting (last seen age 2 y)
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lower limb
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Congenital SMA with involvement Congenital SMA with involvement Congenital SMA with involvement Congenital SMA with involvement
At age 3 y At age 3 y
PEG 3 y
Evolution
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Facioscapulohumeral muscular dystrophy
Feeding difficulties
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and hypotonia, and myopathic/dystrophic changes on muscle biopsy. In 1995, the discovery that approximately half of the patients with CMD were lacking an extracellular protein called merosin allowed the first attempt at classifying CMDs. This was initially based on immunohistochemical findings which have more recently been complemented by genetic studies. With the progress of the last decade, it is now possible to pursue a molecular genetic diagnosis in 13 known forms of CMD. Immunohistochemical staining in the muscle biopsy will help to identify patients with disorders of laminin alpha 2, glycosylation of alpha dystroglycan and Collagen 6 and helps to direct genetic testing. When the above tests are normal in a myopathic or dystrophic muscle biopsy and there are no additional features such as cores, inclusions or rods, suggesting a congenital myopathy, a definite diagnosis is often difficult to reach. The patients presented in this paper illustrate the possible differential diagnosis reached in a group of patients with an initial diagnosis of CMD in whom a different diagnosis was subsequently reached. The most common diagnosis was that of early and severe presentation of laminopathies. The most striking features at presentation in these patients was the predominant axial and upper limb weakness with head drop, weakness more predominant in the arms, wasting of biceps and calf muscles and lack of facial weakness. All these children later developed contractures in ankles and elbows and rigidity of the spine. Cardiomyopathy was not an early feature, but nocturnal hypoventilation requiring NNIV in the first decade of life was seen in all four patients. Early presentation of laminopathy has been reported before by our group associated with severe early signs4 but has also been recently reported with a milder form characterised by prominent axial weakness with ‘‘head drop’’.7 Another patient in our cohort had an early and severe presentation of FSH that was suspected because of the profound facial and shoulder girdle weakness. FSH is one of the most frequent muscular dystrophies usually presenting in the second decade of life, but early presentation with Moebius syndrome like facial weakness has been reported before.8–11 In cases with early and severe presentations extramuscular features such as hearing loss, retinal telangiectasia, learning difficulties and epilepsy are more prevalent12 and can be the presenting features.13,14 De novo RYR1 gene mutations were found in three patients with presentation at birth with weakness, hip dislocation and contractures. Their biopsies showed mainly myopathic and dystrophic features with only few cores or core like areas. There is a wide spectrum of muscle biopsy findings in RYR1 gene mutations ranging from the classical core myopathy with well demarcated central cores that run along the whole length of the muscle fibre to type 1 uniformity, minicores or peripheral cores.15 Cores can also be a nonspecific finding in CMD such as Ullrich CMD. Early presentations with reduced fetal movements, hip dislocation at birth and hypotonia in infancy or even fetal akinesia have been described in dominant and recessive mutations of the RYR 1 gene before16,17. The clue to the diagnosis in these patients was the uniformity of fibre types together with the exclusion of other forms of CMD with similar clinico-pathological features such as UCMD. The reported facial weakness and
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ophthalmoplegia especially on upward gaze was not prominent or not observed in our patients.17,18 It is of interest that another primary muscle disorder was found in less than half of the patients who had an alternative diagnosis. Surprisingly, we found that five of the patients with an initial diagnosis of CMD had neurogenic forms despite the early muscle biopsy showed marked fatty infiltration and some changes that were interpreted as myopathic. Congenital SMA with predominant lower limb involvement was diagnosed in 4/24. Typical features of this condition are the lower limb predominance of contractures and weakness, and a stable course of weakness with progress in functional abilities. There is no cardiac and respiratory involvement. EMG reveals an underlying neurogenic cause. A distinctive pattern of muscle involvement on MRI has been recently reported5 but in the published cases the scans were always performed after the first years of life. Linkage to chromosome 12q23-q24 has been shown in a large family with a dominant inheritance,19 but later it has been shown that not all cases with the same pattern of weakness and appearance show linkage to this locus.20 While the long-term follow-up and repeated investigations helped to clearly differentiate these patients from CMD, they posed a diagnostic challenge when they were assessed in infancy. Amyoplasia is usually diagnosed by the typical posture of joints as described by Hall.21 In severe cases weakness may be marked and muscle biopsy shows fatty replacement, mimicking an underlying myopathy or dystrophy. In half of our patients, muscle involvement was part of a metabolic disorder or other disease with multisystemic involvement. This included a case of non-typical infantile Pompe’s disease with marked muscle and respiratory involvement with no cardiac involvement until 2 years of age. The diagnosis of systemic hyalinosis was made in one patient. Regarding EDS the profound early weakness and absent antigravity movements in the first few months of life can pose a significant diagnostic challenge. It is of note that in the group of eight patients presenting with muscle weakness, dystrophic or myopathic biopsy findings and predominant CNS involvement the final diagnosis became apparent only after a period of follow-up as symptoms and additional features evolved. In the last few years, it has become increasingly obvious that the concomitant involvement of early muscle involvement and structural brain changes on MRI is typical of the forms of CMD with defective glycosylation of alpha-dystroglycan. When these forms are excluded and alpha dystroglycan is normal on muscle biopsy, alternative diagnosis such as mitochondrial disorders, found in two of our eight cases with CNS involvement should be considered. In both, multisystemic involvement became apparent after the first year and a possible mitochondrial disorder was suspected because of mild changes on muscle biopsy such as the presence of a few cytochrome C oxidase (COX) negative fibres or pale fibres on COX staining Although a final genetic diagnosis has not yet been made in these patients, they both fulfill the criteria for ‘‘definite’’ mitochondrial disease as recently published.22 Our findings also confirm recent studies suggesting that the MSS (OMIM248800) and the COFS (OMIM 214150) are frequent and should be considered in the differential diagnosis of infants
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with muscle involvement, mental retardation and signs of CNS involvement. Symptoms include characteristic eye abnormalities, brain MRI findings and dysmorphic features, myopathy and ataxia. In some patients, it may be difficult to distinguish between these two entities because of the clinical overlap. In MSS mutations in SIL1 can be found in a number of patients but there is genetic heterogeneity.23 There are specific electron microscopy biopsy findings in some of the patients including membranous whorls and dense membranes associated with the nucleus.24,25 This was present in one of our patients.
6.
6.
7.
8.
9.
Conclusion 10.
Our findings highlight the difficulties in reaching a final diagnosis in early infancy in patients with clinical signs of weakness and biopsy findings of muscle involvement that could be classified as CMDs. While in some cases there were additional features such as skin changes or marked joint laxity that may suggest an alternative diagnosis, such as in the cases of systemic hyalinosis or EDS, in many others it is only longer follow-up and the systematic exclusion of the know CMD variants that leads to the diagnosis. Our series also suggests that one should consider severe/early/atypical presentations of wellknown muscle diseases in this phenotypic group.
11. 12.
13.
14.
15.
Acknowledgements The authors wish to thank the Muscular Dystrophy Campaign for the centre Grant and the Research grant on CMD supporting the Dubowitz Neuromuscular Centre. The authors also wish to thank the support from NCG for funding the diagnostic work on CMD; the patients who participated in this study and the colleagues who have referred patients to the service. EC is a Muscular Dystrophy Campaign clinical research fellow; grant number: PC0916. R E F E R E N C E S
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Official Journal of the European Paediatric Neurology Society
Original article
Differential diagnosis of congenital muscular dystrophies Andrea Kleina,b, Emma Clementb, Eugenio Mercurib,c, Francesco Muntonib, a
Department of Neurology, University Children’s Hospital Zurich, Switzerland Dubowitz Neuromuscular Unit, Hammersmith Hospital, Imperial College, London, UK c Department of Child Neurology, Catholic University, Rome, Italy b
art i cle info
ab st rac t
Article history:
Congenital muscular dystrophies (CMDs) are defined by signs of muscle weakness in the
Received 13 July 2007
first 6 months of life with myopathic changes in muscle biopsy. The progress in the last
Received in revised form
decade has helped to make molecular and genetic diagnoses in the majority of patients
13 September 2007
fulfilling these criteria. In a number of patients a definite diagnosis cannot be reached and
Accepted 3 October 2007
these individuals are often grouped together as ‘‘merosin positive’’ congenital muscular dystrophy. In the last 5 years, 25 patients referred for assessment as possible congenital
Keywords: Congenital muscular dystrophy Early presentation Differential diagnosis
muscular dystrophy have been found to have alternative diagnoses. This paper aims to highlight these conditions as the common differentials or more difficult to diagnoses to consider in patients presenting as CMD. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Congenital myopathy Arthrogryposis Emery-Dreifuss muscular dystrophy
1.
Introduction
Congenital muscular dystrophies (CMD) are a heterogeneous group of disorders characterised by muscle weakness in the first months of life and muscle biopsy changes that range from myopathic to overtly dystrophic depending on the muscle biopsied and the age at biopsy. Distinctive clinical features and immunohistochemical studies can often help to direct genetic testing and to diagnose a specific form of CMD but despite the molecular advances that have allowed the identification of 13 genetically distinct forms of CMD1–3 there remain a number of patients that fulfill the criteria for CMD in whom all known variants can be excluded. In some of these cases, a definitive diagnosis may not be reached and the question arises as to whether, despite the early weakness and pathological
changes on muscle biopsy, they might be affected by a condition other than CMD. Muscle biopsy may help in such cases; histological findings such as cores or rods may indicate a diagnosis of congenital myopathy rather than CMD. In other cases however, early clinical and biopsy findings may not be indicative of a specific alternative diagnosis. Hammersmith Hospital is commissioned by the National Commissioning Group (NCG) for the diagnosis and management of CMD and congenital myopathies in the UK. In the last 5 years, in excess of 400 patients were referred to this quaternary service with the possible diagnosis of CMD. In the majority of these cases, an integrated approach combining clinical and pathological findings and screening of the known CMD genes has enabled a precise diagnosis to be reached. In a number of other cases, review of the clinical and
Corresponding author. Department of Paediatrics, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12ONN, UK. Tel.: +44 2083833295; fax: +44 2087462187. E-mail address: [email protected] (F. Muntoni). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.10.002
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pathological findings has suggested alternative diagnoses that clinically overlap with CMDs. In this paper, we want to draw attention to these cases discussing the more common conditions that mimic CMD but also highlighting the rarer diagnoses that were more difficult to make.
2.
Methods
This was a retrospective study of patients reviewed by Hammersmith NCG CMD service in the last 5 years. Criteria for inclusion in this review were either (1) new referrals of ‘possible CMD’ with myopathic or dystrophic features on muscle biopsy and no specific findings suggesting a structural congenital myopathy or (2) follow-up patients with a diagnosis of ‘‘merosin positive’’ CMD in whom the genetically known forms of CMD had been excluded. From this cohort, we selected the patients in whom a diagnosis other than CMD was reached. Patients with congenital myotonic dystrophy were not included in this study. The clinical notes of these patients were reviewed to obtain a clear picture of presentation, muscle biopsy findings, evolution and complications.
3.
Results
In the past 5 years, in excess of 400 patients had been referred or were followed at the Hammersmith as part of the NCG service. Of this group, 25 patients were found to have diagnosis other than CMD. A total of 13 different diagnoses were reached in those 25 patients. The largest groups consist of early and severe presentation of known muscular dystrophies (n ¼ 5) or congenital myopathies with atypical pathological features (n ¼ 3), neurogenic disorders (n ¼ 5) and metabolic (n ¼ 5) or syndromic disorders (n ¼ 7). Ten of these patients had concomitant CNS involvement and/or multisystemic involvement. Table 1 summarises the clinical details of all patients, including presentation and additional features that helped to make the diagnosis. Table 2 describes the evolution of clinical signs and complications. Muscle biopsy findings ranged from unspecific myopathic changes to overtly dystrophic. In the few cases where specific features led to the diagnosis, more details will be provided in the text.
3.1.
Other muscular dystrophies with early onset
Four patients were found to have a de novo mutation in the Lamin A/C gene. They presented between the ages of 4 weeks and 5 months with axial weakness, lack of head control, proximal weakness affecting the arms more than the legs and bilateral talipes in one case. In some there was a reduced muscle bulk predominantly affecting the biceps and the calf muscles. They did not have prominent facial weakness and feeding difficulties were not a presenting feature. Their CK was between 600 and 1291 U/l.
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On follow-up they all developed early flexion contractures, rigidity of the spine and scoliosis. Respiratory involvement led to early nocturnal hypoventilation and one patient presented with cardiac arrhythmia at age 3 years during general anaesthesia. None had a cardiomyopathy in infancy. All had progressive weakness, one child died suddenly at the age of 3 years during a respiratory tract infection and only one child achieved independent walking with knee–ankle–foot orthosis (KAFOs), but lost it at age 4 years. One patient has been previously reported.4 One child was diagnosed with de novo Facio Scapulo Humeral (FSH) muscular dystrophy. He presented at birth with facial weakness and feeding difficulties. At the age of 3 months, he had lack of head control, marked shoulder weakness, absent facial expression and absent tendon reflexes. On follow-up he had achieved independent walking, subsequently lost at the age of 5 years, required a gastrostomy at age 4 years, and noninvasive nocturnal ventilation at age 6 years. Contractures other than TA tightness were not a feature. In addition to his muscular weakness he had learning difficulties, hearing impairment and myopia.
3.2.
Congenital myopathies
Three patients were diagnosed as affected by core myopathies and were found to have a de novo mutation of the muscle Ryanodine Receptor gene (RYR1). They presented at birth with proximal weakness, contractures, normal CK and absent tendon reflexes. They had a clearly dystrophic pattern on muscle biopsy; in two patients occasional cores were seen. Weakness was more predominant in the lower limbs and there was mild facial weakness in one. On follow-up one died in the first 3 weeks of life, the others achieved walking in KAFOs one independently, one with the help of a walker. These two patients had predominant weakness of the lower legs and developed a scoliosis at the age of 3 years.
3.3. Congenital spinal muscular atrophy (SMA) with predominant lower limb involvement Four patients had congenital SMA with predominant lower limb involvement. They all presented arthrogryposis at birth with a distinctive pattern of joint involvement, which was restricted to the lower limbs, short legs and weakness of the lower limbs. They had normal CK. In these patients early muscle biopsies of the quadriceps showed a marked increase of fat, reduced variability in fiber size and predominance of type I fibers that were reported as indicative of a myopathic pattern. On review of the muscle biopsy there was a suggestion of fibre grouping although this was difficult to appreciate because of the type I fibre predominance. Two of the four had neurogenic electro myography findings (EMG) later in life. One of them had a positive family history suggesting a dominant disorder with foot deformities, distal weakness with peroneal wasting and a relatively stable course, myopathic changes in muscle biopsy but a neurogenic pattern in EMG with normal nerve conduction studies (NCV and CMAP). The index patient also had a congenital onset with talipes and dislocated hips but had more severe
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Table 1 – Clinical details of all patients: age of presentation, first symptoms and additional features that helped in finding the diagnosis Diagnosis
Presentation
First symptoms
CK
DTR
EDMD2
4 weeks
946
nr
EDMD2
5 months
1000
EDMD2
5 months
1291
nr
EDMD2
2 months
Axial and proximal weakness No head control, weakness arms4legs Delayed motor milestones, proximal weakness Axial, weakness arms4legs, wasting of biceps
600
Additional features
Facioscapulohumeral muscular dystrophy
Birth
Feeding difficulties, reduced facial expression
Normal
RYR1-associated
Birth
Normal
RYR1-associated
Birth
Normal
RYR1-associated
Birth
Contractures, hip dislocation, proximal weakness: legs4arms Contractures, hip dislocation, proximal weakness: legs4arms Contractures, hip dislocation, proximal weakness: legs4arms
Normal
Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement Congenital SMA with lower limb involvement
Birth
Contractures, weakness of lower limbs
Normal
nr
Short legs, typical MRI pattern
Birth
Contractures, weakness of lower limbs, dislocation of hips Contractures, weakness of lower limbs, dislocation of hips Dorsiflexed ankles, dislocation of hips, axial, distal weakness and wasting
Normal
nr
Short legs, typical MRI pattern
Normal
nr
Short legs, typical MRI pattern
Normal
+
Neurogenic EMG
Contractures: hip in flexion, knee and wrist in extention, talipes Contractures of elbows, hips, knees, talipes, proximal weakness
Normal
nr
Neurogenic EMG, weak cry and respiratory diff. at birth
Normal
+
Distinct pattern of joint position
Delayed motor milestones, head lag, proximal weakness Delayed motor milestones
750
+
Cerebellar ataxia and atrophy at age 2 years, membranous whorls on EM
1945
+
Ataxia, proximal weakness, cataract age 5 years Microcephaly, optic nerve atrophy, MR, ataxia, cataract 9 years, demyelinating neuropathy, growth retardation Retinopathy 7 m, cataracts 5 years, calcifications of basal ganglia, epilepsy, microcephaly, MR, distinct features Nystagmus, epilepsy at 18 m, short stature, microcephaly, chorea Epilepsy age 6, ataxia, dysarthria, saccadic eye movements
Birth
Birth
Neurogenic arthrogryposis
Birth
Amyoplasia
Birth
Marinesco Sjoegren Syndrome (MSS)
5 months
Marinesco Sjoegren Syndrome COFS/MSS
4–5 months
Cerebro-Oculo-FacioSkeletal Syndrome (COFS) Mitochondrial depletion Mitochondrial depletion Infantile systemic hyalinosis Pompe
Mental retardation, hearing loss, myopia
5 months
Axial and proximal weakness
2000
Birth
Axial and proximal weakness
504
2 months
Talipes, floppy, proximal and axial waekness Delayed, hypotonia, reduced head control
1000
880
Birth
Contractures, reduced movements, feeding diff.
Normal
Pain, thickened skin, ‘‘bruising’’
4 months
Reduced movement, motor delay
1500
Reduced movements, fatigue
6 months
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Table 1 (continued )
Diagnosis
Presentation
First symptoms
CK
DTR
Additional features
Ehlers Danlos Syndrome 6b
Birth
Hypotonia, no antigravity movements, joint laxity, dislocated hip
Normal
(+)
Loose skin, blue sclera, distinct features, deafness, MR
Translocation 9;13
Birth
Normal
nr
Translocation 9;13
Birth
Floppy, axial weakness, motor delay Floppy, axial weakness, motor delay
Microcephaly, epilepsy, joint laxity, distinct features Microcephaly, epilepsy, joint laxity, distinct features
Normal
CK, creatin kinase; DTR, deep tendon reflexes; MR, mental retardation; nr, not reported.
weakness also involving proximal muscles especially of hip abductors and facial muscles. She made functional progress and achieved independent walking. On follow-up they had all achieved independent walking, contractures were stable and all had a distinctive appearance with proximal and distal wasting of the lower limbs only and a forward leaning posture while standing; there was no wasting or weakness in the upper limbs. They all showed the same pattern of muscle MRI findings with atrophic appearance of the muscle bulk and sparing of the adductor longus and semitendinosus in the thigh.5
3.4.
Arthrogryposis
Two children had arthrogryposis. One was diagnosed as affected by neurogenic arthrogryposis. She had contractures in all large joints, joint laxity distally as well as feeding and respiratory difficulties at birth. Her neonatal quadriceps muscle biopsy was clearly myopathic with abnormal variability in fibre size, extensive fat, and increase of connective tissue and signs of de- and regeneration. Her weakness and contractures remained stable, she is only able to walk a few steps with KAFOs hands held. Hand tremor suggested a neurogenic disorder and an EMG was conducted at the age of 8 years and showed signs of neurogenic features with de- and re-innervation, NC studies were normal. The second patient was diagnosed as having sporadic arthrogryposis with amyoplasia. She did have proximal weakness especially of hip-girdle muscles at presentation; her quadriceps muscle biopsy was comprised almost entirely of fat. The clinical picture with joint contractures, internally rotated shoulders, extended elbows, palmar-flexed wrists and dimples led to the diagnosis. She has made good progress and started to walk at the age of 3.5 years with AFOs with some weakness remaining in her shoulder muscles.
4.
Forms with concomitant CNS involvement
Eight patients had early clinical and histopathology features compatible with CMD but they also had CNS involvement and additional distinctive features suggestive of an alternate diagnosis. The presence of cataracts, ataxia, nystagmus, characteristic features or neuropathy led to the final diagnosis of Marinesco
Sjoegren Syndrome (MSS) in two patients, Cerebro-OculoFacio-Skeletal Syndrome (COFS) in two, mitochondrial disorders in two and an unbalanced translocation in two sisters.
4.1.
Other conditions
Three patients belonged to this heterogenous group. One patient had a non-typical presentation of an infantile Pompe’s disease. She presented weakness, reduced movements and fatigability at the age of 4 months. She then made some motor progress and was starting to cruise along furniture at the age of 20 months when she developed respiratory difficulties with frequent chest infections associated with hypoventilation. There was no cardiac involvement at the time of diagnosis at the age of 2 years. In another patient, a diagnosis of Ehlers Danlos Disease (EDS) type 6B was made because of marked skin hyperelasticity. He was profoundly weak from birth, was born in breech position after a pregnancy with reduced movements and oligohydramnios. He did not have any antigravity movements, marked joint laxity, feeding difficulties and cleft palate. He started to improve at the age of 7 months. EDS type 6A was excluded by normal lysyl hydroxylase in urine analysis. The diagnosis of systemic hyalinosis was reached in one patient. At birth multiple contractures were noted, he had feeding difficulties and failure to thrive. Joint movement was very limited and while initially the lack of movement was interpreted as secondary to weakness, it became increasingly clear with time that the reason for this was related to pain. At the referral at 10 months of age he had contractures in all major joints, a very stiff neck, handling appeared painful, he was crying and sweating. He had some distinct features including hypertrophic gingiva and thickened skin with reddish discolouration over the joints. There were no antigravitiy movements in his legs. A muscle biopsy was not performed but his muscle ultrasound was very hyperechogenic, in keeping with our previous report which suggests a muscle involvement in this condition.6
5.
Discussion
Until the last decade the diagnosis of CMD was based on a combination of clinical signs, mainly early onset of weakness
Table 2 – Clinical details of evolution and complications Diagnosis
Scoliosis
Contractures
Cardiac involvement
NIVV
EDMD2
20 m
Hip, knee, ankle, elbows, wrist, rigidity of spine
Not until death
EDMD2
3y
Not until age 6y
EDMD2
8y
Hip, TA, elbows, shoulders, wrists, rigidity of spine, 8 m Rigidity of spine, hip, TA, knee, wrist
Age 2y 3.5 y
EDMD2
RYR1-associated RYR1-associated RYR1-associated
lower limb
10 y
Maximal functional achievement
Died age 3y Progressive
Sit supported
Progressive
Walking with KAFOS, lost age 4 y Sit supported
TA, hips, knees, rigidity of spine age 8 m
At age 3 y (rhythm) Not at age 3 y
2.5 y
Yes
Progressive
No
No
6y
PEG 4 y
Progressive
Walking achieved, lost age 5y
Improving Improving Died age 3w
Walks in KAFOS Walks in KAFOS
Improving
Walks
Mild hip, knee, TA
Cobb 601 at 11 y Stable-better
Improving
Walks age 2.4 y
lower limb
Stable-better
Improving
Walks
lower limb
Progressiv TA
Stable
Walks
Progressiv hip contactures
Stable
Stable: elbow, talipes, knee
Improving
Walks with KAFOs and K Walker Walks at 3.5 y
Neurogenic arthrogryposis
Cobb 121 at 8y
Amyoplasia Marinesco Sjoegren Syndrome (MSS)
No
Rigid spine, TA Hips, knees
12 y
PEG 10 y
Not available Stable Progressive Progressive
At age 13 y
TA
10 y
PEG 11 y
Progressive Progressive
Sit supported Walks age 2 y, lost age 5 y
Age 10 m
All joints, spinal stiffness
Progressive
No sitting, seen age 10 m
Marinesco Sjoegren Syndrome COFS/MSS Cerebro-Oculo-Facio-Skeletal Syndrome (COFS)
Cobb 751 at 12 y
Mitochondrial depletion Mitochondrial depletion Infantile Systemic Hyalinosis
No
Pompe Ehlers Danlos Syndrome 6b
Yes
Not at age 2 y 4y
Translocation 9;13 Translocation 9;13
Walks age 3 y Walks 18 m Sit supported
Progressive
Cruising at 20 m than lost
Improving
Walks age 4 1/2 y with AFO
Stable Stable
Walks 4 y Walks 10 y
375
m, months; NNIV, non invasive nocturnal ventilation; PEG, percutaneous gastrostomy; TA, tendon achilles tightening; w, weeks; y, years.
Yes
Sitting (last seen age 2 y)
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lower limb
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Congenital SMA with involvement Congenital SMA with involvement Congenital SMA with involvement Congenital SMA with involvement
At age 3 y At age 3 y
PEG 3 y
Evolution
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Facioscapulohumeral muscular dystrophy
Feeding difficulties
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and hypotonia, and myopathic/dystrophic changes on muscle biopsy. In 1995, the discovery that approximately half of the patients with CMD were lacking an extracellular protein called merosin allowed the first attempt at classifying CMDs. This was initially based on immunohistochemical findings which have more recently been complemented by genetic studies. With the progress of the last decade, it is now possible to pursue a molecular genetic diagnosis in 13 known forms of CMD. Immunohistochemical staining in the muscle biopsy will help to identify patients with disorders of laminin alpha 2, glycosylation of alpha dystroglycan and Collagen 6 and helps to direct genetic testing. When the above tests are normal in a myopathic or dystrophic muscle biopsy and there are no additional features such as cores, inclusions or rods, suggesting a congenital myopathy, a definite diagnosis is often difficult to reach. The patients presented in this paper illustrate the possible differential diagnosis reached in a group of patients with an initial diagnosis of CMD in whom a different diagnosis was subsequently reached. The most common diagnosis was that of early and severe presentation of laminopathies. The most striking features at presentation in these patients was the predominant axial and upper limb weakness with head drop, weakness more predominant in the arms, wasting of biceps and calf muscles and lack of facial weakness. All these children later developed contractures in ankles and elbows and rigidity of the spine. Cardiomyopathy was not an early feature, but nocturnal hypoventilation requiring NNIV in the first decade of life was seen in all four patients. Early presentation of laminopathy has been reported before by our group associated with severe early signs4 but has also been recently reported with a milder form characterised by prominent axial weakness with ‘‘head drop’’.7 Another patient in our cohort had an early and severe presentation of FSH that was suspected because of the profound facial and shoulder girdle weakness. FSH is one of the most frequent muscular dystrophies usually presenting in the second decade of life, but early presentation with Moebius syndrome like facial weakness has been reported before.8–11 In cases with early and severe presentations extramuscular features such as hearing loss, retinal telangiectasia, learning difficulties and epilepsy are more prevalent12 and can be the presenting features.13,14 De novo RYR1 gene mutations were found in three patients with presentation at birth with weakness, hip dislocation and contractures. Their biopsies showed mainly myopathic and dystrophic features with only few cores or core like areas. There is a wide spectrum of muscle biopsy findings in RYR1 gene mutations ranging from the classical core myopathy with well demarcated central cores that run along the whole length of the muscle fibre to type 1 uniformity, minicores or peripheral cores.15 Cores can also be a nonspecific finding in CMD such as Ullrich CMD. Early presentations with reduced fetal movements, hip dislocation at birth and hypotonia in infancy or even fetal akinesia have been described in dominant and recessive mutations of the RYR 1 gene before16,17. The clue to the diagnosis in these patients was the uniformity of fibre types together with the exclusion of other forms of CMD with similar clinico-pathological features such as UCMD. The reported facial weakness and
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ophthalmoplegia especially on upward gaze was not prominent or not observed in our patients.17,18 It is of interest that another primary muscle disorder was found in less than half of the patients who had an alternative diagnosis. Surprisingly, we found that five of the patients with an initial diagnosis of CMD had neurogenic forms despite the early muscle biopsy showed marked fatty infiltration and some changes that were interpreted as myopathic. Congenital SMA with predominant lower limb involvement was diagnosed in 4/24. Typical features of this condition are the lower limb predominance of contractures and weakness, and a stable course of weakness with progress in functional abilities. There is no cardiac and respiratory involvement. EMG reveals an underlying neurogenic cause. A distinctive pattern of muscle involvement on MRI has been recently reported5 but in the published cases the scans were always performed after the first years of life. Linkage to chromosome 12q23-q24 has been shown in a large family with a dominant inheritance,19 but later it has been shown that not all cases with the same pattern of weakness and appearance show linkage to this locus.20 While the long-term follow-up and repeated investigations helped to clearly differentiate these patients from CMD, they posed a diagnostic challenge when they were assessed in infancy. Amyoplasia is usually diagnosed by the typical posture of joints as described by Hall.21 In severe cases weakness may be marked and muscle biopsy shows fatty replacement, mimicking an underlying myopathy or dystrophy. In half of our patients, muscle involvement was part of a metabolic disorder or other disease with multisystemic involvement. This included a case of non-typical infantile Pompe’s disease with marked muscle and respiratory involvement with no cardiac involvement until 2 years of age. The diagnosis of systemic hyalinosis was made in one patient. Regarding EDS the profound early weakness and absent antigravity movements in the first few months of life can pose a significant diagnostic challenge. It is of note that in the group of eight patients presenting with muscle weakness, dystrophic or myopathic biopsy findings and predominant CNS involvement the final diagnosis became apparent only after a period of follow-up as symptoms and additional features evolved. In the last few years, it has become increasingly obvious that the concomitant involvement of early muscle involvement and structural brain changes on MRI is typical of the forms of CMD with defective glycosylation of alpha-dystroglycan. When these forms are excluded and alpha dystroglycan is normal on muscle biopsy, alternative diagnosis such as mitochondrial disorders, found in two of our eight cases with CNS involvement should be considered. In both, multisystemic involvement became apparent after the first year and a possible mitochondrial disorder was suspected because of mild changes on muscle biopsy such as the presence of a few cytochrome C oxidase (COX) negative fibres or pale fibres on COX staining Although a final genetic diagnosis has not yet been made in these patients, they both fulfill the criteria for ‘‘definite’’ mitochondrial disease as recently published.22 Our findings also confirm recent studies suggesting that the MSS (OMIM248800) and the COFS (OMIM 214150) are frequent and should be considered in the differential diagnosis of infants
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with muscle involvement, mental retardation and signs of CNS involvement. Symptoms include characteristic eye abnormalities, brain MRI findings and dysmorphic features, myopathy and ataxia. In some patients, it may be difficult to distinguish between these two entities because of the clinical overlap. In MSS mutations in SIL1 can be found in a number of patients but there is genetic heterogeneity.23 There are specific electron microscopy biopsy findings in some of the patients including membranous whorls and dense membranes associated with the nucleus.24,25 This was present in one of our patients.
6.
6.
7.
8.
9.
Conclusion 10.
Our findings highlight the difficulties in reaching a final diagnosis in early infancy in patients with clinical signs of weakness and biopsy findings of muscle involvement that could be classified as CMDs. While in some cases there were additional features such as skin changes or marked joint laxity that may suggest an alternative diagnosis, such as in the cases of systemic hyalinosis or EDS, in many others it is only longer follow-up and the systematic exclusion of the know CMD variants that leads to the diagnosis. Our series also suggests that one should consider severe/early/atypical presentations of wellknown muscle diseases in this phenotypic group.
11. 12.
13.
14.
15.
Acknowledgements The authors wish to thank the Muscular Dystrophy Campaign for the centre Grant and the Research grant on CMD supporting the Dubowitz Neuromuscular Centre. The authors also wish to thank the support from NCG for funding the diagnostic work on CMD; the patients who participated in this study and the colleagues who have referred patients to the service. EC is a Muscular Dystrophy Campaign clinical research fellow; grant number: PC0916. R E F E R E N C E S
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