Congenital Muscular Dystrophy
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Dr.Pradeep
Autosomal recessive Hypotonia & muscle weakness at birth. Contractures Syndromic multiple systems with brain malformations and developmental delay Non syndromic muscular disease without cerebral involvement Merosin (laminin α2) in extracellular matrix linking protein for dystroglycan complex
alpha dystroglycan
Genetic defects that disrupt post-translational modification of alpha dystroglycan
Multiple systems, brain malformations and developmental delay CNS : disturbed cellular migration to cortex polymicrogyria, lissencephaly and heterotopia Fused frontal lobes, hydrocephalus, periventricular cyst, optic nerve atrophy, pyramidal tract hypoplasia, AHC↓, leptomeningitis
Disease
Gene
Fukuyama
FCMD
Muscle-eyePOMGNT1 brain
Protein Merosin↓ Merosin N
POMT1
WalkerWarburg syndrome
POMT2 1
Type 1D
LARGE
Fukutin errors in glycosylation
Merosin↓
errors in O-mannosylation
Glycosyltransferase-like protein LARGE
most common 40% Chr 6q22. Abnormal laminin More severe with later onset Resp insufficiency at birth Sitting unsupported best motor achievement. Significant delay Intelligence is normal or borderline
HYPOTONIA
TORTICOLLIS
ARTHROGRYPOSIS
CLUB FOOT
CK ↑ at birth and then ↓ CK ↑ in asymptomatic family members
EMG : myopathy
Biopsy : Fibres vary in size with central nucleation, fibrosis and adipose proliferation Regenerating and degenerating fibres Molecular genetic analysis T2 MRI : white matter hypomyelination of occipital horns. periventricular White-matter changes Structural occipital cortex disturbances
25% prev H/O spontaneous abortion Poor fetal movements. At birth hypotonia, expressionless face, weak suck and cry. Proximal muscles >distal Elbow and knee contractures. Absent DTR. 50% calf pseudohypertrophy 2-8 yr, can sit never stand 10 yr DCM and CHF Progressive weakness and respiratory failure, die in the mid teens. CNS: Seizures occur in 50% usually 1st manifestation Global delayed development, microcephaly, severe retardation Eye: Mild : ↓movements, poor pursuit, strabismus. Severe : retinal detachment, microphthalmos, cataracts, myopia.
COBBLESTONE
LISSENCEPHALY
AGYRIA
DCM
Neonatal hypotonia, developmental delay, and ocular Severe: can’t sit, no visual contact, die 1-2 yr. Moderate: sit, speak few words. severe myopia Mildly : walk short time, speak sentences, vision normal. EYE : optic.N hypoplasia, coloboma, glaucoma, cataract, and retinal detachment CNS: Seizures & mental retardation. Mild : cerebellar cysts, vermal hypoplasia, and flat pons Severe : Similar to fukayama. Absent corpus callosum, obstructive hydrocephalus
RETINAL DETACHMENT
ABSENT CORPUS CALLOSUM
COLOBOMA
OBSTRUCTIVE HYDROCEPHALUS
Most severe Similar to MEB Hypotonia, poor suck and swallow,contractures. Requiring gastrostomy feeding. Progressive with death in 9 mo. CK↑ EMG myopathy Proliferating adipose tissue and collagen out of proportion to fibre degeneration Posterior fossa abnormalities hypoplastic brainstem.
Merosin +
Merosin -
Partial Merosin -
ULLRICH RIGID SPINE SYNDROME
Mutated col VI loss of collagen links necrosis Neonate : hypotonia, kyphosis, contractures, Intelligence and brain MRIs are normal. Distal weakness more than proximal Never walk Progressive disability Respiratory insufficiency at 20yr
MICROGNATHIA
KELOID
ATROPHY CALF
HYPERLAXITY
CONTRACTURES
Chr 1p35 Early spine rigidity, scoliosis Nocturnal hypoventilation Progressive resp failure
spinal rigidity and scoliosis. Present at birth or within first year proximal weakness and hypotonia. Most eventually walk Scapular winging and facial and bulbar weakness. contractures at 3-10 yr. Respiratory insufficiency. FVC 18-65% Ventilatory assistance to treat nocturnal hypoventilation. Normal Intelligence and brain MRI. cardiac system is are normal.
•Complete merosin deficit •Severe hypotonia •Contractures,scoliosis •Abn white matter signal 4 mo •IQ normal •Seizures •Poor feeding •Respiratory difficulties •Onset : birth •Walk :never •Die :10 yr
•Partial merosin deficit •Mild hypotonia •Rigid spine •Abnormal white matter •Structural abnormalities •Onset : 1-12 yr •Walk :2-3 yr : variable •Die
Medical history, physical examination, neurologic examination, family history, neuroimaging, serum CK , and muscle biopsy Family history: congenital weakness or neonatal death Physical examination : ocular abnormalities (fukuyama CMD, MEB, WWS) MRI: Syndromic brain malformations/abnormal neuronal migration Merosin deficiency benign white matter changes
Disease
Serum CK (norma l 35160 µ/L)
Muscle biopsy
Immunostain
Fukuyama
Fiber size variation 2-15x Increased connective tissue Central nuclei
Fukutin: deficient Glycosylated alpha dystroglycan: deficient Beta dystroglycan: normal
MEB
Increased number of regenerating fibers seen by age one year 2-15x Muscle biopsy shows dystrophic changes, with excess infiltration of fat and connective tissue by age one year
Partial reduction of merosin Partial reduction of glycosylated alpha dystroglycan Increase in laminin beta 2
WWS
2-15 Myopathic
Merosin: normal or reduced Glycosylated alpha dystroglycan: deficient Beta dystroglycan: normal
Disease
RSS
Ullrich
Serum CK
Muscle biopsy
Immunostain
Variable fiber size Occasional necrotic fibers Normal Merosin: normal Minimally increased endomysial connective tissue Fiber size variation 2-3x Necrotic fibers Mild endomysial fibrosis
Merosin: normal COL6: severely reduced
Disease
Complete merosin deficiency
Serum CK (normal 35-160 µ/L)
Markedly elevated
Partial merosin deficiency Markedly elevated
Merosin-positive
Moderately high
Muscle biopsy Neonatal: inflammatory changes End stage: dystrophic changes loss of staining for laminin-α2 & α-dystroglycan Childhood: variable fiber size Increased endomysial connective tissue no necrosis. Partial staining for laminin-α2 Myopathic changes (mild necrosis, regeneration, and fatty replacement)
PRENATAL TESTING direct and flash-frozen chorionic villi at about 10-12 weeks' gestation by immunostaining both accurate and sensitive molecular testing for mutations (that have been previously identified in proband Fukuyama, MEB, WWS, type 1C 1D, RSS DNA fetal cells obtained by amniocentesis at about 15-18 weeks CVS at about 10-12 weeks Both disease-causing alleles of an affected family member must be identified before prenatal testing Preimplanation genetic diagnosis may be available for families in which the disease-causing mutations have been identified
Other Problems to Be Considered Congenital myopathy Congenital myotonic dystrophy Congenital fascioscapulohumeral dystrophy Congenital myasthenic syndromes Leukodystrophies Mitochondrial myopathies Ehlers-Danlos and Marfan syndromes for UCMD
No definitive treatment. Weight control Prevent and correct scoliosis, foot deformities, and contractures, Passive stretching, bracing, spinal fusion Seizure management, gastric tube feedings, ophthalmologic care Social and emotional support and stimulation
Pulmonary complications : monitoring with noninvasive bilevel positive airwaY pressure/CPAP Tracheostomy DCM : ACE inhibitors and beta-blockers
Autosomal recessive Hypotonia & muscle weakness at birth. Contractures Syndromic multiple systems with brain malformations and developmental delay Non syndromic muscular disease without cerebral involvement Merosin (laminin α2) in extracellular matrix linking protein for dystroglycan complex
alpha dystroglycan
Genetic defects that disrupt post-translational modification of alpha dystroglycan
Multiple systems, brain malformations and developmental delay CNS : disturbed cellular migration to cortex polymicrogyria, lissencephaly and heterotopia Fused frontal lobes, hydrocephalus, periventricular cyst, optic nerve atrophy, pyramidal tract hypoplasia, AHC↓, leptomeningitis
Disease
Gene
Fukuyama
FCMD
Muscle-eyePOMGNT1 brain
Protein Merosin↓ Merosin N
POMT1
WalkerWarburg syndrome
POMT2 1
Type 1D
LARGE
Fukutin errors in glycosylation
Merosin↓
errors in O-mannosylation
Glycosyltransferase-like protein LARGE
most common 40% Chr 6q22. Abnormal laminin More severe with later onset Resp insufficiency at birth Sitting unsupported best motor achievement. Significant delay Intelligence is normal or borderline
HYPOTONIA
TORTICOLLIS
ARTHROGRYPOSIS
CLUB FOOT
CK ↑ at birth and then ↓ CK ↑ in asymptomatic family members
EMG : myopathy
Biopsy : Fibres vary in size with central nucleation, fibrosis and adipose proliferation Regenerating and degenerating fibres Molecular genetic analysis T2 MRI : white matter hypomyelination of occipital horns. periventricular White-matter changes Structural occipital cortex disturbances
25% prev H/O spontaneous abortion Poor fetal movements. At birth hypotonia, expressionless face, weak suck and cry. Proximal muscles >distal Elbow and knee contractures. Absent DTR. 50% calf pseudohypertrophy 2-8 yr, can sit never stand 10 yr DCM and CHF Progressive weakness and respiratory failure, die in the mid teens. CNS: Seizures occur in 50% usually 1st manifestation Global delayed development, microcephaly, severe retardation Eye: Mild : ↓movements, poor pursuit, strabismus. Severe : retinal detachment, microphthalmos, cataracts, myopia.
COBBLESTONE
LISSENCEPHALY
AGYRIA
DCM
Neonatal hypotonia, developmental delay, and ocular Severe: can’t sit, no visual contact, die 1-2 yr. Moderate: sit, speak few words. severe myopia Mildly : walk short time, speak sentences, vision normal. EYE : optic.N hypoplasia, coloboma, glaucoma, cataract, and retinal detachment CNS: Seizures & mental retardation. Mild : cerebellar cysts, vermal hypoplasia, and flat pons Severe : Similar to fukayama. Absent corpus callosum, obstructive hydrocephalus
RETINAL DETACHMENT
ABSENT CORPUS CALLOSUM
COLOBOMA
OBSTRUCTIVE HYDROCEPHALUS
Most severe Similar to MEB Hypotonia, poor suck and swallow,contractures. Requiring gastrostomy feeding. Progressive with death in 9 mo. CK↑ EMG myopathy Proliferating adipose tissue and collagen out of proportion to fibre degeneration Posterior fossa abnormalities hypoplastic brainstem.
Merosin +
Merosin -
Partial Merosin -
ULLRICH RIGID SPINE SYNDROME
Mutated col VI loss of collagen links necrosis Neonate : hypotonia, kyphosis, contractures, Intelligence and brain MRIs are normal. Distal weakness more than proximal Never walk Progressive disability Respiratory insufficiency at 20yr
MICROGNATHIA
KELOID
ATROPHY CALF
HYPERLAXITY
CONTRACTURES
Chr 1p35 Early spine rigidity, scoliosis Nocturnal hypoventilation Progressive resp failure
spinal rigidity and scoliosis. Present at birth or within first year proximal weakness and hypotonia. Most eventually walk Scapular winging and facial and bulbar weakness. contractures at 3-10 yr. Respiratory insufficiency. FVC 18-65% Ventilatory assistance to treat nocturnal hypoventilation. Normal Intelligence and brain MRI. cardiac system is are normal.
•Complete merosin deficit •Severe hypotonia •Contractures,scoliosis •Abn white matter signal 4 mo •IQ normal •Seizures •Poor feeding •Respiratory difficulties •Onset : birth •Walk :never •Die :10 yr
•Partial merosin deficit •Mild hypotonia •Rigid spine •Abnormal white matter •Structural abnormalities •Onset : 1-12 yr •Walk :2-3 yr : variable •Die
Medical history, physical examination, neurologic examination, family history, neuroimaging, serum CK , and muscle biopsy Family history: congenital weakness or neonatal death Physical examination : ocular abnormalities (fukuyama CMD, MEB, WWS) MRI: Syndromic brain malformations/abnormal neuronal migration Merosin deficiency benign white matter changes
Disease
Serum CK (norma l 35160 µ/L)
Muscle biopsy
Immunostain
Fukuyama
Fiber size variation 2-15x Increased connective tissue Central nuclei
Fukutin: deficient Glycosylated alpha dystroglycan: deficient Beta dystroglycan: normal
MEB
Increased number of regenerating fibers seen by age one year 2-15x Muscle biopsy shows dystrophic changes, with excess infiltration of fat and connective tissue by age one year
Partial reduction of merosin Partial reduction of glycosylated alpha dystroglycan Increase in laminin beta 2
WWS
2-15 Myopathic
Merosin: normal or reduced Glycosylated alpha dystroglycan: deficient Beta dystroglycan: normal
Disease
RSS
Ullrich
Serum CK
Muscle biopsy
Immunostain
Variable fiber size Occasional necrotic fibers Normal Merosin: normal Minimally increased endomysial connective tissue Fiber size variation 2-3x Necrotic fibers Mild endomysial fibrosis
Merosin: normal COL6: severely reduced
Disease
Complete merosin deficiency
Serum CK (normal 35-160 µ/L)
Markedly elevated
Partial merosin deficiency Markedly elevated
Merosin-positive
Moderately high
Muscle biopsy Neonatal: inflammatory changes End stage: dystrophic changes loss of staining for laminin-α2 & α-dystroglycan Childhood: variable fiber size Increased endomysial connective tissue no necrosis. Partial staining for laminin-α2 Myopathic changes (mild necrosis, regeneration, and fatty replacement)
PRENATAL TESTING direct and flash-frozen chorionic villi at about 10-12 weeks' gestation by immunostaining both accurate and sensitive molecular testing for mutations (that have been previously identified in proband Fukuyama, MEB, WWS, type 1C 1D, RSS DNA fetal cells obtained by amniocentesis at about 15-18 weeks CVS at about 10-12 weeks Both disease-causing alleles of an affected family member must be identified before prenatal testing Preimplanation genetic diagnosis may be available for families in which the disease-causing mutations have been identified
Other Problems to Be Considered Congenital myopathy Congenital myotonic dystrophy Congenital fascioscapulohumeral dystrophy Congenital myasthenic syndromes Leukodystrophies Mitochondrial myopathies Ehlers-Danlos and Marfan syndromes for UCMD
No definitive treatment. Weight control Prevent and correct scoliosis, foot deformities, and contractures, Passive stretching, bracing, spinal fusion Seizure management, gastric tube feedings, ophthalmologic care Social and emotional support and stimulation
Pulmonary complications : monitoring with noninvasive bilevel positive airwaY pressure/CPAP Tracheostomy DCM : ACE inhibitors and beta-blockers
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