Myopathy + CNS

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MYOPATHY + CENTRAL NERVOUS SYSTEM (Encephalomyopathy)

Congenital Muscular Dystrophy
Dystrophy/Myopathy
- 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
Myopathy with Muscle Fiber Necrosis
- with Encephalopathy
- with Pipestem capillaries
Thyroid
Other
- Marinesco-Sjögren
- IBMPFD
- ?? Camera-Marugo-Cohen Syndrome
- Myopathy + CNS
  - CIAO1
  - CONRIBA
  - DNMT3A
  - FILIP1
  - Golga2
  - HADDTS: CTBP1
  - PURA
  - ? WASHC4

Encephalopathy + Myopathy with Fiber Necrosis

● Autosomal Recessive

Epidemiology: Turkish family, consanguineous
Clinical
- Myopathy
  - Congenital
  - Hypotonia
  - Muscle fiber necrosis
- CNS: Corpus callosum atrophy; White matter atrophy
- Cardiomyopathy
- Cataracts

MMDS 10: Myopathy + Learning Disabilities ¹⁰

● WD40 Repeat-containing protein CIAO1 (CIAO1, CIA1, WDR59)

; Chromosome 2q11.2; Recessive

Epidemiology: 6 patients
Genetics
- Mutations
  - Missense: Most; Arg65Trp, His302Pro
  - Exon 7 deletion
CIAO1 protein
- Cytoplasmic Fe-S assembly (CIA) complex
Clinical
- Onset age: Birth to 17 years
- Weakness
  - Proximal & Axial > Distal
  - Respiratory
  - Face
  - Bulbar
  - Course: Slow progression
- Fatigability
- Muscle size: Calf hypertrophy
- Skeletal
  - Contractures: Ankles
  - Other joints: Hyperextensible
- CNS: Learning disability
Laboratory
- Serum CK: Normal to 4,300
- Muscle pathology
  - Fiber necrosis: Clustered & Scattered
  - Fiber sizes: Varied
  - Internal nuclei
  - MHC1 up-regulation by muscle fibers
  - Punctate material: Type 1 fibers; Mitochondrial
  - Endomysial connective tissue: Mild increase
  - Ultrastructure: Mitochondria Enlarged, Abnormal shapes, Clustered
  - CIA & Fe-S component proteins: Reduced
- Anemia (50%)
- Muscle MRI
  - Fat: Proximal > Distal muscles; Posterior thigh & Sartorius
  - Hypertrophy: Gastrocnemius & Soleus
- Brain MRI: Increased Iron in deep nuclei

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

Developmental delay with hypotonia, myopathy & brain abnormalities (DEDHMB) ⁴

● Golgi autoantigen, Golgin subfamily A2 (GOLGA2; GM130)

; Chromosome 9q34.11; Recessive

Epidemiology: 3 patients
Genetics
- Homozygous; Stop; Frameshift
GOLGA2 protein
- Link between Golgi apparatus & cytoskeleton
- Assembly of Golgi apparatus as single complex
- Other associations: Vesicle tethering, Cell proliferation, Autophagy, Dendritic branching
Clinical
- Onset age: 4 months
- Microcephaly & Brachycephaly
- Hypotonia
- Failure to thrive
- Strabismus
- Infantile spasms
- Face: Tented upper lip, Micrognathia
Laboratory
- Brain MRI: Atrophy; Delayed myelination; Corpus callosum thin
- Serum CK: 959 to 1368
- Muscle pathology: Myopathy, chronic; Muscle fiber atrophy

Myopathy + CNS (PURA syndrome) ⁵

● Purine-rich element-binding protein A (PURA)

; Chromosome 5q31.3; de novo Dominant

Epidemiology: > 30 patients
Genetics
- Mutations: Missense or Stop
- Allelic disorders
  - Neurodevelopmental disorder with Neonatal respiratory insufficiency, hypotonia & feeding difficulties (NEDRIHF)
  - PURA syndrome + Congenital MG
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
Variant syndrome: PURA + NMJ disorder
- Epidemiology: 3 patients
- Genetics
  - Inheritance: Dominant
- Clinical
  - Onset age: Neonatal to 5 years
  - Hypotonia
  - Weakness: Fluctuating
  - Treatments: Varied; Cholinesterase inhibitors or Salbutamol
- Laboratory
  - Repetitive nerve stimulation: Varied responses

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

Dysmorphism, Intellectual disability, Developmental disorder, Contractures, Skeletal muscle pathology ⁷

● Filamin-A-interacting protein 1 (FILIP1)

; Chromosome 6q14.1; Recessive

Epidemiology: 5 patients, 4 families
Genetics
- Mutations: Missense; Nonsense
- Allelic disorders
  - AMC + Microcephaly
  - Chromosome 6q deletion syndromes
FILIP1 protein
- Expression: CNS; Muscle
- Regulates cell polarity & motility in CNS during radial migration
- Binds to: Filamin C; Filamin A; Myosin, non-muscle; EB3
- Knockdown: Inhibits myogenic differentiation
Clinical
- Onset age: Congenital
- Hypotonia
- Neurodevelopmental: Intellectual disability; Speech delay
- Face dysmorphism: Ptosis, Epicanthus, Palpebral fissures down, Hypertelorism,
- Contractures
- Myopathy
Laboratory
- CNS pathology: Brain malformations
- Serum CK: Normal to mildly high
- Muscle
  - Morphology: Fiber size variation
  - Aggregates: FILIP1 + Filamin C; XIRP2
  - Ultrastructure: Myofibril disorganization; Myofibrillar protein aggregates; Z-disc Δ
FIPIP1 variant disorder: Arthrogryopsis Multiplex Congenita + Microcephaly ⁸
- Epidemiology: 5 patients, 3 families
- Genetics
  - Inheritance: Recessive
  - Mutations: Truncating
- Clinical
  - Onset age: Congenital
  - Face: Dysmorphism
  - Microcephaly
  - Contractures: Multiple joints, proximal & distal
  - Camptodactyly
  - Scoliosis
  - Skin: Reduced palmar & plantar folds; Translucent
  - Motor delay
- Laboratory
  - Brain imaging: Normal
  - Cardiac: Normal

Tatton-Brown-Rahman Syndrome + Congenital Myopathy ⁹

● DNA Methyltransferase 3A (DNMT3A)

; Chromosome 2p23.3; Dominant, de novo

Epidemiology: 1 patient
Genetics
- Mutation: Ala741Val; Heterozygous; de novo
- Allelic disorders
  - Acute myeloid leukemia, somatic
  - Heyn-Sproul-Jackson syndrome (HESJAS)
  - Tatton-Brown-Rahman syndrome (TBRS)
DNMT3A Protein
- de novo methyltransferase
- Methylates genes & sequences at late stages of embryonic development & after birth
- Hematopoietic stem cell development
- Tumor suppressor
- Mutation effect: Hypomethylation
- Also see: DNMT3B
Clinical
- Onset age: Congenital
- Hypotonia
- Developmental delay: Intellectual; Speech; Motor
- Face: Dysmorphism; Weakness, mild
- Dental: Micrognatia; Teeth crowding
- Pain: Myalgias; Chest pain, recurrent
- Rhabdomyolysis: Episodes; Onset 2nd decade
- Muscle size: Reduced
- Weakness: Arm external rotation; Hips; Respiratory
- Tendon reflexes: Normal
- Sensation: Normal
- Skeletal: Kyphoscoliosis; Pes planus; Tall stature
- Bladder: Retention; Recurent infections
Laboratory
- Serum CK: 161 to 5,000
- Cardiac: Mild dysfunction
- Muscle pathology: Fiber size variation
- Brain MRI: Normal

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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
7. Brain 2023 May 10
8. Hum Genet 2023;142:543-52
9. Neuromuscul Disord 2023;33:484-489
10. J Clin Invest 2024;134:e179559, Genet Med 2024;26:101104

7/2/2024

MYOPATHY + CENTRAL NERVOUS SYSTEM (Encephalomyopathy)

Encephalopathy + Myopathy with Fiber Necrosis

MMDS 10: Myopathy + Learning Disabilities 10

Camera-Marugo-Cohen Syndrome 1

Cerebral Creatine Deficiency Syndrome 3 (CCDS3) 2

Vici Syndrome

Developmental delay with hypotonia, myopathy & brain abnormalities (DEDHMB) 4

Myopathy + CNS (PURA syndrome) 5