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MYOPATHY + CENTRAL NERVOUS SYSTEM (Encephalomyopathy)
Congenital Muscular Dystrophy
Fukuyama
Mental retardation & Cerebellar cysts
Merosin-Deficient
Muscle-Eye-Brain Disorders
Muscle hypertrophy & Mental retardation
CNS atrophy & Polyneuropathy
Dystrophy
Duchenne
FSH
: Largest deletions
McLeod Syndrome
Myopathy + Intellectual disorder
Myotonic dystrophies
DM1
DM2
(PROMM)
Scapuloperoneal with retardation & cardiomyopathy
Mitochondrial
MELAS
;
MERRF
;
MNGIE
Metabolic
Acid Maltase
: CNS Aneurysms
AGAT deficiency
Phosphoglycerate Kinase
Triosphosphate isomerase
Necrotizing myopathy
with Encephalopathy
with Pipestem capillaries
Thyroid
Other
Marinesco-Sjögren
IBMPFD
??
Camera-Marugo-Cohen Syndrome
Myopathy + CNS
Golga2
PURA
CONRIBA
?
WASHC4
Encephalopathy with necrotizing myopathy
●
Autosomal recessive
Epidemiology: Turkish family, consanguineous
Clinical
Myopathy
Congenital
Hypotonia
Muscle fiber necrosis
CNS: Corpus callosum atrophy; White matter atrophy
Cardiomyopathy
Cataracts
Camera-Marugo-Cohen Syndrome
1
Epidemiology: Sporadic
Clinical
Motor
Weakness: Proximal & Distal; Legs > Arms 50%
Congential hypotonia
50%
Tendon reflexes: Reduced
CNS: Mental deficiency
Skeletal
Short stature
Body asymmetry
Fingers:
Contractures
; Syndactyly
Face: Cleft lip-palate; Retrognathia; Blepharoptosis
Genital: Hypogonadism; Micropenis
Obesity: Post-natal
Laboratory
EMG: Denervation & Reinnervation
Muscle biopsy: Grouped atrophy; Fiber type grouping
Cerebral Creatine Deficiency Syndrome 3 (CCDS3)
2
●
L-arginine:glycine amidinotransferase (GATM; AGAT)
; Chromosome 15q15.3; Recessive
Nosology: Arginine:Glycine Amidinotransferase Deficiency; AGAT deficiency
Epidemiology: 5 families
Genetics
Mutations: Ala97ValfsX11; Trp149X; Arg169X; Tyr203Ser; Met371AsnfsX6
AGAT protein
Location:
Mitochondrial intermembrane space
Converts L-arginine and L-glycine to L-ornithine and guanidinoacetate
Creatine synthesis: 1st step
Creatine deficiency syndromes, cerebral (CCDS): Differential diagnosis
CCDS1
: SLC6A8
CCDS2
: Guanidinoacetate methyltransferase (GAMT)
CCDS3:
AGAT
Clinical
Onset age: Childhood
CNS
Developmental delay: Language & Cognitive
Mental retardation: IQ 35 to 75
Speech: Poor executive & comprehensive
Weakness (75%): Proximal; Especially legs
Joints: Hyperlaxity at elbows
Treatment: Creatine
Dose: 5g/d or 400 mg/kg/d
Effects: Improved strength, cognition & language
Laboratory
Muscle biopsy
Fiber size: Variation & Atrophy
Plasma & Urine guanidinoacetate (GAA): Absent
Plasma creatine: Low
EMG: Myopathic
CK: Normal
Lactate: Normal
Brain MRI: Normal
Vici Syndrome
●
Ectopic P granules protein 5 homolog (EPG5)
; Chromosome 18q12.3-q21.1; Recessive
Nosology: Immunodeficiency with Cleft lip/palate, Cataract, Hypopigmentation & Absent corpus callosum
Epidemiology: 15 patients; Multiple ethnicities
Genetics
3
Mutation types: Truncating; Missense & Splice site
Homozygous or Compound heterozygous
Mutated in human cancer tissue
EPG5 protein
Functions
Autophagy
pathway: Clearance of autophagosomal cargo
Neuronal embryonic development
Expression: CNS, Skeletal & cardiac muscle, Thymus, Immune cells, Lung, Kidneys
Mutations
Defective autophagy: Reduced fusion of LC3 & NBR1 puncta with lysosomes
Normal processing of LC3-I to LC3-II
Clinical
CNS
Psychomotor retardation
Nystagmus
Seizures (50%)
Skeletal
Microcephaly
Facial dysmorphism: Cleft lip
Eye: Cataracts (100%); Optic neuropathy
Hypopigmentation (100%)
Cardiac (80%):
Hypertrophic cardiomyopathy
Ear: Deafness, Sensorineural (50%)
Infections: Recurrent
Death: Due to cardiac failure or infections; < 4 years
Laboratory
Immunodeficiency (100%)
IgE: Low
Lymphopenia: T- & B-cell
CNS Pathology
Corpus callosum: Absent (100%)
Other: Some patients
Cerebellar & Pontine hypoplasia
Paucity of white matter & Ventricular dilatation
Heterotopias
Abnormal septum pellucidum
Schizencephaly
Serum CK: High or Normal
Muscle pathology
Type 1 atrophy
Subsarcolemmal vacuoles:
Glycogen accumulation
Internal nuclei
Small darkly stained muscle fibers: NADH; Esterase
Ultrastructure
Redundancy of basal lamina, with material between layers, suggesting exocytosis of debris
Vacuole-like areas
Dense bodies: Possibly of lysosomal origin
Myofibrils: Lacking in many fibers
Mitochondria: Variable size; Abnormal distribution & morphology
Autophagy proteins p62 & NBR1: Upregulated; Punctae
Nerve conduction: CMAP amplitudes reduced
EMG
Myopathic
Spontaneous activity: Pseudomyotonia; Fibrillations; Complex repetitive discharges
Thymus hypoplasia: Some patients
Myopathy + CNS
4
●
Golgi autoantigen, Golgin subfamily A2 (GOLGA2; GM130)
; Chromosome 9q34.11; Recessive
Epidemiology: 1 Saudi patient
Genetics
Homozygous; Frameshift
c.1266_1269del; p.Glu423Argfs*6
GOLGA2 protein
Assembly of Golgi apparatus as single complex
Clinical
Onset age: 4 months
Microcephaly & Brachycephaly
Hypotonia
Failure to thrive
Strabismus
Infantile spasms
Face: Tented upper lip, Micrognathia
Laboratory
Brain MRI: Delayed myelination; Corpus callosum thin
Serum CK: 959 to 1368
Muscle biopsy: Muscle fiber atrophy
Myopathy + CNS (PURA syndrome)
5
●
Purine-rich element-binding protein A (PURA)
; Chromosome 5q31.3;
de novo
Dominant
Epidemiology: 3 patients
Genetics
Mutations: Missense or Stop
Allelic disorder: Mental retardation, autosomal dominant 31
PURA protein
DNA-binding
Affinity for a purine-rich element (GGN)n in initiation zones of eukaryotic DNA replication
Clinical
Onset: Neonatal
Hypotonia
Feeding difficulties
Face: Myopathic
Weakness
Respiratory insufficiency
Psychomotor development: Severely delayed
Gait: Ataxic
Seizures: Early-onset
Tendon reflexes: Reduced or Absent
Laboratory
Muscle biopsy: Type 1 larger than type 2
Serum CK: Normal or high
EMG: Myopathic
Brain MRI: Delayed myelination
Muscle MRI: Normal
Neurodegeneration, Childhood-onset, Hypotonia, Respiratory insufficiency & Brain imaging abnormalities (CONRIBA)
●
Chloride Channel 6 (CLCN6)
; Chromosome 1p36.22; Dominant
de novo
Epidemiology: 3 patients
Genetics
Mutation: Missense; Tyr553Cys
Allelic disorder: Infantile spasms, Glu200Ala mutation
CLCN6 protein
:
Chloride channel
Clincial
Onset: Infancy
Developmental delay: Global; Poor intellectual development & speech
Motor: Hypotonia (Trunk or Generalized); Feeding disorder; Inability to walk
Respiratory insufficiency
Nerve: Pain insensitivity; Sensory loss
Autonomic
: Hyperhidrosis, Temperature regulation abnormal (Hyperthermia); Neurogenic bladder
Eye: Cortical blindness, Optic disc elevation, Nystagmus, Esotropia & Strabismic amblyopia
Tendon reflexes: Reduced or Absent
Laboratory
EEG: Seizures
Brain MRI: Cortical atrophy, progressive; Diffusion restriction in corticospinal tracts, cerebellum & brainstem
Muscle: Varied fiber sizes; Subsarcolemmal mitochondria; Fat vacuoles
NCV: Sensory axon loss
Dysmorphisms, Intellectual disability, Developmental disorder, Skeletal muscle pathology
6
●
WASH Complex, subunit 4 (WASHC4)
; Chromosome 12q23.3; Recessive
Epidemiology: 2 sisters
Genetics
Mutation: Tyr1014Cys
Allelic disorder: Mental retardation, autosomal recessive 43
WASHC4 protein
Wiskott-Aldrich Syndrome Protein & SCAR Homolog
Cytoskeleton reorganization
Colocalize with actin
Promotes Arp2/3-dependent actin polymerization
Interacts with:
Valosin containing protein
(VCP)
Clinical
Onset: Neonatal
Motor
Hypotonia
Poor feeding
Gait disorder
Development delay
Dysmorphisms: Epicanthus; Ears, Low-set; Microphthalmia; Retrognathia
Seizures
Skeletal: Scoliosis; Joint Contractures
Tendon reflexes: Reduced
Pulmonary: Repeated infections
Course: Stable
Laboratory
Brain MRI: Pituitary abnormal
Brainstem evoked responses: Reduced
Muscle pathology
Type 2 fiber predominance: Mild
Fiber sizes: Atrophy
Mitochondrial oxidative enzymes: Normal
Return to
Myopathy & NMJ Index
References
1.
J Clin Neuromuscul Dis 2008;9:345-347
2.
Neurology 2010;75:186-188
,
Neuromuscular Disorders 2013; Online June
3.
Nature Genetics 2012; Online December
4.
Hum Genet 2016 Jan 7
5.
Neuropediatrics 2020 Dec 22
6.
J Pathol 2021 Oct 2
12/4/2021