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BY- ABDUL QAVI
Congenital myopathy: Definition, classification, clinical
features, differential diagnosis, investigations,
Approach to a case of floppy infant
Congenital muscular dystrophy: Definition, classification,
clinical features, investigations, management.
Definition of congenital myopathy:
The term “congenital myopathy” is applied to muscle
disorders presenting in infancy with generalized
muscle weakness and hypotonia followed by delayed
Neurol J Southeast Asia 2001; 6. Clinical and pathologic aspects of
congenital myopathies Ikuya NONAKA MD
First report of a congenital myopathy was in 1956, when a patient
with central core disease (CCD) was described.
In 1969, Dubowitz clarified the classification with his delineation of
new myopathies later termed congenital myopathy.
The myopathy has been differentiated diagnostically on the basis of
their morphologic characteristics.
With the advent of electron microscopy, enzyme histochemistry,
immunocytochemistry, molecular genetic analysis , a number of
morphologically distinct congenital myopathies have grown.
The mode of inheritance and gene loci are variable.
Incidence:6 per 100,000 live births or 1/10th of all
neuromuscular disorders. (wallgreen peterson 1990)
0.06% of all muscle diseases( ischizo nishino 2007)
Regional studies in Northern Ireland and Western
Sweden suggest prevalence between 3.5–5.0/100,000
in a pediatric population (Jungbluth H. Orphanet J Rare Dis
1.12% of the muscle disease( Deepali jain,
Rohit Bhatia 2008)
Onset in early life with hypotonia, hyporeflexia, generalized
weakness that is more often proximal than distal,
Poor muscle bulk
Unique morphological features on histochemical or ultrastructural
examination of the muscle biopsy sample that originate within
Some cases have been reported as adult onset or as a progressive
North K. What's new in congenital myopathies?. Neuromuscul
Disord. Jun 2008;18(6):433-42
1. Myopathies with protein
a. Nemaline myopathy
b. Myosin storage myopathy
c. Cap disease
d. Reducing body myopathy
2. Myopathies with cores
a. Central core disease
b. Core-rod myopathy
c. Multiminicore disease
3. Myopathies with central
a. Myotubular myopathy
b. Centronuclear myopathy
4. Myopathies with fiber size
Congenital fiber type disproportion
Congenital Myopathies with identified gene loci:
Disorder inheritance Protein/gene chromosome
a. NEM I
2. Central core
AD/Sporadic Ryanodine(RYR1) 19q13.1
3. Core rod myopathy AD Ryanodine(RYR1) 19q13.1
AR Ryanodine(RYR1) 19q13.1
X linked Myotubularin Xq28
6. Multi minicore AR Selenoprotein N 1p36
7. Hyaline body
AD Cardiac myosin heavy
Incidence of congenital myopathy
(1979-2000: National Center of Neurology and Psychiatry)
Neurol J Southeast Asia December 2001
Types of congenital myopathy Number of patients (%)
Nemaline myopathy 121 (27%)
Severe infantile form 43
Benign congenital form 53
Adult onset form 25
Central core disease 27 (6%)
Myotubular (centronuclear) myopathy 42 (9%)
Severe infantile myotubular myopathy 30 (7%)
Congenital fiber type disproportion 89 (20%)
Congenital myopathy without specific
Miscellaneous 109 (24%)
Congenital myopathies: A clinicopathological study of 25 cases
Deepali Jain, Rohit Gulati
Type % cases
Central core disease 24
Congenital myopathies: Clinical and Pathological Study.
Annals of Indian Academy of Neurology, 2007 by N. Gayathri, A. Nalini, F.
Type of myopathy No of cases (total 39)
Central core 2
Tubular aggregates 1
Clinical signs in a floppy infant
Observation of a ‘frog-leg’ posture.
Reduced spontaneous movement, with the legs fully abducted and
arms lying beside the body either extended or flexed
Significant head lag on traction or pull-to-sit manoeuvre and
excessively rounded back when sitting (>33 weeks)
Rag-doll posture on ventral suspension
Vertical suspension test – feeling of ‘slipping through the hands’ when
the infant is held under the arms
Various associated examination findings such as flat occiput or
congenital dislocation of the hips, arthrogryposis
Hypotonia pith frog position
Indicators of hypotonia of central
• Social and cognitive impairment
• Dysmorphic features
• Fisting of hands
• Normal or brisk tendon reflexes
• Features of pseudobulbar palsy
• brisk jaw jerk
• crossed adductor response or
scissoring on vertical suspension
• Features that may suggest an
underlying spinal dysraphism
• History suggestive of HIE, birth
trauma or symptomatic
Indicators of peripheral hypotonia
• Delay in motor milestones with
relative normality of social and
• Family history of neuromuscular
• Reduced or absent deep tendon
jerks and increased range of joint
• Frog-leg posture or ‘jug-handle’
• Myopathic facies (open mouth with
tented upper lip, poor lip seal when
sucking, lack of facial expression,
ptosis and restricted ocular
• Muscle fasciculation
Creatine kinase level
Normal or mildly elevated.
Moderately in central core disease (CCD) and also in asymptomatic
carriers of the ryanodine receptor mutation in CCD.
Electromyography and nerve conduction studies
Nerve conduction study is normal.
EMG is normal or shows myopathic pattern.
Rule out other diseases such as spinal muscular atrophy, congenital
myasthenia, and hereditary neuropathy.
Imaging: Ultasound, MRI of the muscle may be helpful.
Muscle biopsy: Gold standard
Light microscopy(H/E stain), Gomori trichrome stain, enzyme
Ultrastructural examination of muscle is often necessary, since several
of the pathologic features are based on the EM appearance of muscle.
Not required for diagnosis
Very sensitive and specific in CCD
Only a research level tool
Shy et al and Conen et al first described the disease in 1963
Classified into 3 major forms including the
1) severe infantile (congenital)
2) benign congenital (mild, nonprogressive or slowly progressive)
3)adult onset forms
Incidence: 0.2 per 1000 live births
More common in finland and 1 in 500 in Amish community
o.53% of all muscle disease and 22.6% of all congenital
myopathies. (MC Sharma, S Gulati Neurology India 2007)
6 Genetic types
Disorder inheritance Protein/gene
1. NEM I AD α-tropomyosin 3
2. NEM 2 AR Nebulin
3.NEM 3 AD/AR/Sporadic alpha-actin
4. NEM 4 AD β-tropomyosin
5. NEM 5 AR Troponin T1
6. NEM 7 AR Cofilin 2
Benign congenital form Adult onset form
•Muscle weakness and
hypotonia at birth.
•high arched palate
•usually die before 1 year
• respiratory failure or
•Neck flexor weakness is
or predominantly proximal
non-progressive or only
minimal facial muscle
•Minimal proximal muscle
Sr CK normal o minimally elevated
Increased echogenecity in affected muscles on muscle USG
Myopathic pattern on EMG
Muscle MRI reveals patchy fatty degeneration of muscle
Gomori trichrome stain H/E Stain
Central core disease:
Term coined by Greenfield in 1958
Mutation in the ryanodine receptor(CH 19q12.q13.2)
Autosomal dominant inheritance.
Onset is at birth or in early childhood
Nonprogressive limb weakness, mild facial weakness,
Skeletal abnormalities include congenital hip
dislocation, kyphoscoliosis, and foot deformities.
Autosomal recessive (and autosomal dominant) inheritance
have been described with several different presentations.
Presentation in infancy includes generalized weakness and
atrophy, external ophthalmoplegia, and bulbar and
Asymptomatic individuals may also present with a high
creatine kinase (CK) level or malignant hyperthermia.
About 25% of patients with CCD are susceptible to malignant
Sr CK- Normal to mildly elevated
Muscle ultrasound- increase in echogenecity
Muscle MRI-selective involvement of following thigh muscles-
sartorius, adductor magnus, gastrosoleus, peroneal group.
Oxidative stains: cores are hypostained
Electron microscopy: excessive disorganisation of sarcomeres in
the cores, severe fragmentation and decrease of Z bands.
Genetic analysis: PCR for CCD-RYR1 gene mutation(>60% positive)
Oxidase staining: Central cores
Central core disease - ultrastructural disorganization (Z-band
Defined pathologically by the presence of central nuclei in
increased number of fibres.
First reported as myotubular myopathy by spiro et al in 1966.
AD, AR and X linked forms
X linked form
The most common is the severe X-linked form due to a mutation in
At birth, severe weakness and hypotonia, feeding difficulty, and
respiratory distress are present.
Bilateral ptosis, facial weakness, and ophthalmoplegia are
Skeletal features include pectus carinatum, knee and hip
contractures, elongated birth length, narrow face, and
Systemic features may include cryptorchidism, pyloric stenosis,
gallstones, hepatic dysfunction, spherocytosis, renal calcinosis.
The prognosis is poor
At least one third of those affected dying in the first
year of life.
Seventy-five percent of survivors older than 1 year
need ventilatory support
Most carriers are asymptomatic.
Mutations in amphiphysin 2.
Features include hypotonia, proximal weakness, facial
weakness, ptosis, and ophthalmoplegia.
Other features can include contractures and dilated
The course is slowly progressive, with more than 50%
of patients surviving childhood.
Mutations in dynamin 2 (DNM2)
Most patients have a mild phenotype
Onset in adolescence or adulthood
Axial as well as distal more than proximal limb
weakness and slow progression.
Facial weakness, high-arched palate, ptosis,
ophthalmoplegia, joint hyperlaxity, and contractures
MUSCLE PATHOLOGY IN
Minicore (multicore) myopathy
So named because of the presence of core structures in the muscle
Around half of cases caused by a genetic error in one of two genes-
Selenoprotein N1 (SEPN1) and Ryanodine receptor 1 (RYR1).
Progressive form with hand involvement.
Antenatal form with arthrogryposis multiplex congenita (AMC).
Prognosis: variable course
• More type 1 fibres than type 2.
• Within these fibres, there are structures which are called ‘cores’;
which can be seen under the microscope.
These structures are not specific to minicore myopathy, and so
the clinical signs must be considered together with the muscle
sample to give a diagnosis of minicore myopathy
Congenital fibre type disproportion:
Rare disease first described by Brooke
Genetics: mutation in TPM3(75%), Selenoprotein N(1O%) and
Child presents as presents as hypotonia, delayed motor
milestones and dysmorphic facies.
Other clinical features can include facial, bulbar, and respiratory
weakness; short stature; low body weight
Multiple joint contractures; scoliosis; long, thin face; and high-
Nemaline +++ +++ - +++ ++ +
CCD ++ + - + +++ +
Core rod + + - - ++ -
myotubular +++ +++ +++ +++ ++ -
Centronuclear ++ ++ ++ +++ +++ -
Multiminicore +++ + + +++ +++ ++
CFTD ++ - - + +++ -
Sarcotubular ++ - - - - -
Reducing body ++ ++ - +++ ++ -
Special clinical features:
Clinical feature Congenital myopathy
Myopathy with tubular aggregates
Calf hypertrophy Centronuclear myopathy
Myasthenic fatures Myopathy with tubular aggregates
Malignant hyperthermia CCD, Core rod
Neonatal lethal form X linked myotubular
Cardiomyopathies associated with congenital myopathies
Cytoplasmic body myopathy
Dilated Nemaline myopathy
Restrictive Desmin myopathy
Floppy infant with pred proximal
Facial muscle &
of Cong myopathy
LM, IHC, EHC,EM ,
NCS/EMG Sr CK elevated
in Central core
• No definitive treatment.
• Physiotherapy, occupational therapy
• Use of splints, braces and orthosis
• Contracture release, corrective surgeries.
• Chest physiotherapy, prevention and management of
aspiration pneumonitis, non invasive ventilation.
• Nutrition and gastrostomy feeding.
• Management of heart failure.
Congenital muscular dystrophy
• 1903, Batten described 3 children who had proximal muscle weakness
from birth whose biopsy showed chronic myopathic changes
• In 1908, Howard coined the term congenital muscular dystrophy
(CMD) when he described another infant with similar features.
• Ullrich first described the combination of joint hyperlaxity and proximal
contractures in 1930 in the German literature; which is known as
Ullrich congenital muscular dystrophy.
• In 1960, Fukuyama et al described a common congenital muscular
dystrophy in Japan that always had features of muscular dystrophy and
Congenital muscular dystrophies are characterised by
Autosomal recessive disease
severe proximal weakness at birth
slowly progressive or nonprogressive.
Contractures are common
CNS abnormalities can occur.
Muscle biopsy shows signs of dystrophy
Muntoni and Voit 2004
Group Disorder Gene locus Gene Protein
I Laminin α2 deficiency 6q2 LAMA2 Laminin a2
II.1 Fukuyama MDC 9q3 FUKUTIN Fukutin
II.2 MEB disease 1p3 POMGnT1 Omannosyl GlcNac
II.3 Walker Warburg 9q34 POMT1 Omannosyl
II.4 CMDIc/LGMD2I 19q13 FKRP Fukutin related
II.5 CMD1B 1q42 ? ?
II.6 CMD1D 22q LARGE Glycosyl transferase
III.1 Rigid spine muscular
1p35 SEPN1 Selenoprotein N
III.2 Ullrich CMD 21q22 COL6A1,A2 Collagen 6a1,a1
IV Integrin a7 deficiency ? INTEGRIN a7 Integrin a7
V Rare forms ? ? ?
• The incidence of CMD has been estimated at 4.7 x 10-5 and its
prevalence at 6.8 x 10-5 (Mostacciuolo et al. 1996 Genetic
epidemiology of congenital muscular dystrophy in a sample from
• The estimated prevalence is approximately 7-12 cases per 100,000
• In Japan, Fukuyama congenital muscular dystrophy is fairly common.
It is approximately 50% as common as Duchenne muscular
• Few cases from India. ( Merosin negative congenital muscular
dystrophy: a short report. Ralte AM, Sharma MC, Gulati S, Das M,
Emery-Dreifuss Muscular Dystrophy
Limb-Girdle Muscular Dystrophy
Spinal Muscular Atrophy
Congenital muscular dystrophy with laminin-α2 deficiency
(MDC1A, classic CMD, merosin-deficient CMD)
Accounts for 40-50% of all MDC.
Mutation on chr 6 in the LAMA2 gene that codes for laminin-
More than 90 different missense, nonsense, splice-site, and
deletion mutations have been described.
Expression of laminin-α2 is related to disease severity.
Laminin-α2 is expressed in the basement membrane of
striated muscle, cerebral blood vessels, Schwann cells, and
• At birth or in the first few months of life, patients may have severe
hypotonia, weakness, feeding difficulty, and respiratory insufficiency.
• Contractures are common.
• External ophthalmoplegia may occur late.
• Most infants eventually sit unsupported, but standing is rare.
• Weakness is static or minimally progressive
• Complications are related to respiratory compromise, feeding
difficulty, scoliosis, and (in approximately one third) cardiopulmonary
• A sensory motor demyelinating neuropathy is present in many
patients, but it may not be clinically relevant.
• CNS manifestations may be present.
– Mild mental retardation or perceptual-motor difficulties
– Seizures occur in up to 30% of patients.
– White-matter changes, most often in periventricular
– Structural brain changes include enlargement of the
lateral ventricles, focal cortical dysplasia, occipital
polymicrogyria and/or agyria, and hypoplasia of the pons
Sr CK- moderately high
Brain MRI- T2 Hyperintense white matter changes.
Histopathology: Variable fibe size
Increased endomysial connective tissue.
Increased internal nuclei, hypercontracted
Muscle laminin staining: Specific.
Merosin + Merosin - Somewhat
• Autosomal recessive disease
• Mutation in the fukutin gene on 9q
• Most common in Japan and rare elsewhere in the world.
• Fukutin is a putative glycosyltransferase. .
• Patients with Fukuyama congenital muscular dystrophies have
complete loss (or nearly complete loss) of glycosylated α-
dystroglycan in the brain and muscle.
• Present in utero with poor fetal movements.
• Characteristics: generalised weakness, abnormal eye function,
mental retardation and seizures.
• Progressive weakness and respiratory failure ensue, with death
usually occurring in the mid teens.
• Cardiac disease develops after age 10 years, resulting in dilated
cardiomyopathy and congestive heart failure.
• Severe cases may cause retinal detachment, microphthalmos,
cataracts, hyperopia, or severe myopia.
• Cerebral changes are always present.
Type II lissencephaly is the characteristic finding in this
disease, as in all other glycosyltransferases.
Abnormalities range from cobblestone polymicrogyria and/or
pachygyria to complete agyria due to neuronal migration
Dysplasia of the pyramidal tracts is common.
Ventricular dilation, if present, is mild.
Delayed myelination is noted on MRI.
Cerebellar cysts are common.
Brain imaging in FCMDAjay Garg, Sheffali Gulati Neurology India December 2004 Vol
52 Issue 4
severely retarded, had many
marked contractures of the
too weak to support her own
disease was nonprogressive.
Her two brothers also had the
• Moderate to marked elevation in Sr.CK
• Myopathic EMG
• MRI Brain
• HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
• Histology of muscle: Essentially a picture of dystrophic
• Immunohistochemistry: Decreased staining for dystrophin-
associated proteins and for merosin.
Muscle eye brain disease
• Mutations in POMT1, POMT2, POMGnT1, fukutin, and FKRP can cause
• In a series of 92 patients with congenital muscular dystrophy, 14 were
found to have muscle-eye-brain disease/Fukuyama congenital muscular
dystrophy phenotype.(Godfrey C, Clement Brain. Oct 2007;130(Pt 10).
• Seizures are common.
• CNS abnormalities are always present, including moderate-to-severe
• Eye abnormalities are similar but more severe than those of Fukuyama
• Cerebral changes are similar to those of Fukuyama CMD.
Mutations in all 6 glycotransferases have resulted in this most
severe form of congenital muscular dystrophy.
Most severe of all alpha dystroglycanopaties.
Eye abnormalities include microphthalmos, hypoplastic optic
nerve, ocular colobomas, retinal detachment, cataracts,
glaucoma, iris malformation, and corneal opacities, all of
which lead to blindness.
Brain abnormalities include complete type II lissencephaly
HIERARCHY OF ORGAN INVOLVEMENT IN ALPHA
Rigid-spine syndrome with muscular dystrophy
Mutation in the selenoprotein N gene (SEPN1).
Presentation is at birth or within the first year of life
Scapular winging and facial and bulbar weakness are common.
Contractures usually develop at age 3-10 years.
Respiratory insufficiency is common and progressive
Muscle weakness is slowly progressive.
The cardiac system is usually normal.
Intelligence and brain MRIs are normal.
Ullrich congenital muscular dystrophy
Autosomal recessive (or more rarely dominant) disorder
Mutation in 1 of the 3 collagen type VI genes (COL6A1, COL6A2,
Typical features include presentation in the neonatal period
with hypotonia, kyphosis of the spine, proximal joint
contractures, torticollis, and hip dislocation.
Distal joint hyperlaxity with a protruding calcaneus
Weakness involves distal more than proximal muscles.
Progressive disability, usually due to contractures, leads to loss of
ambulation after 2-10 years.
Respiratory insufficiency invariably develops in the first or second
Facial dysmorphism is common and includes micrognathia, a round
face with drooping of the lower lids, and prominent ears.
Skin changes can include follicular hyperkeratosis, keratosis pilaris,
Intelligence and brain MRIs are normal.
Cardiac function is normal.
UCMD: Report of nine cases from India
A Nalini, N Gayatri
Neurology India 2009
tive decline, seizures
Eye involvement, brain
malformations, raised CK
Distal > proximal weakness, distal
joint hyperlaxity, proximal
contractures, skin changes
No specific treatment is available for any of the congenital
Aggressive supportive care is essential to preserve muscle
activity, to allow for maximal functional ability, and to prolong
the patient's life expectancy.
Management of pulmonary and cardiac problems.
Non invasive ventilation:
G tube implantation:
Physiological and most acceptable way of feeding for long
• Orthopedic surgery is often necessary in patients who live several years
with their disease to prevent contractures and scoliosis
Post scoliosis Surgery:
Agrin which binds to laminin and to α-drystroglycan might be
able to functionally rescue the weakened muscle caused by
The Agrin transgene improved the general health, lifespan and
locomotory activity of the mutant mice.
This study demonstrates the potential for gene therapy using
non-homologous proteins that functionally compensate for gene
Congenital myopathies not so uncommon in india, and an
important diagnosis to be considered in a floppy infant
Muscle histopathology is the gold standard for diagnosis.
Of the congenital muscular dystrophies, only merosin
deficiency and Ullrich’s CMD are reported from india.
Contractures, Brain involvement and dystrophic changes in
muscle are the hallmark of CMD
Gene therapy in the coming years can bring in a definite
solution to the problems.