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CARDIAC + MYOPATHY

Amyloid Cardiomyopathies   Dilated   Hypertrophic   Isolated Carnitine Disorders Drugs   Dystrophies   Barth   Desmin   Dystrophinopathies   Emery-Dreifuss   Limb-girdle   McLeod   Myofibrillar   Myosin   Myotonic   Scapuloperoneal "+"   Triangle tongue   Glycogenoses   Acid Maltase (Infantile)   Branching enzyme   Debrancher   Lamp-2   Triosephosphate isomerase Mitochondrial disorders Nemaline rod Other myopathies Periodic paralyses Polymyositis (SRP)

Also see: Selective disorders of cardiac muscle

Carnitine Disorders

Biochemistry   Fatty acid & Carnitine transport pathways   Fatty acid oxidation pathways General principles 1° Carnitine deficiencies   Multiple acyl–CoA dehydrogenase deficiency   Reduced Muscle carnitine uptake   Myopathic   Renal (OCTN2; SLC22A5)   Systemic disorders 2° carnitine deficiencies Carnitine-acylcarnitine translocase deficiency CPT II deficiency

Carnitine

• Carnitine metabolism: General principles
  • Carnitine: General
    • Sources
      • Dietary (75%): Meat, fish, dairy products
      • Synthesis: Endogenous
        • From lysine & methionine in liver, brain & kidney
        • Synthetic pathway not present in muscle or heart
    • Distribution: 90% in muscle
    • Low molecular weight polar compound
    • Types
      • Active form: L-carnitine
      • Free carnitine (or L-carnitine): Nonacetylated form
      • Acyl-L-carnitine
        • All short-, medium- & long-chain esters
        • Involved in transfer of acyl groups from acyl coenzyme A (CoA)
    • Turnover
      • Absorption: Transport-mediated from GI tract
      • Reabsorption
        • Saturable renal tubular
        • 95–99% of filtered load
        • Vegetarians excrete markedly less L-carnitine than omnivores
        • Preferential excretion of short-chain carnitine esters
    • Plays roles in fatty acid metabolism: Oxidation of long-chain fatty acids
      • Transport of fatty acids from cytoplasm to mitochondria
        • Conversion of fatty acids to Fatty acid-CoA
        • Carnitine & Carnitine palmitoyltransferases I & II mediate transport
      • Modulates cellular & mitochondrial ratio of acyl CoA to free CoA
      • Transfer of acetyl and other short-chain acyl groups from peroxisomes to mitochondria
      • Oxidation of branched chain amino acids
      • Reesterification of triacylglycerol in the endoplasmic reticulum before secretion as very low density lipoproteins
      • Stabilization of cell membranes by removing long-chain acyl CoAs
      • Removal of excess acyl groups from the body
    • Energy source
      • Mitochondrial oxidation of fatty acids provides energy source
      • Chief energy sources for: Prolonged fasting; Skeletal muscle during exercise; Cardiac muscle
    • Types of deficiency
      • Primary: Due to deficient transport of carnitine into cells
      • Secondary
        • Free carnitine ® acyl-carnitine esters ® Lost in urine
        • Organic acidosis: Similar metabolic profile to Reyes & Valproate hepatic encephalopathy
        • Renal disease: End stage; Dialysis
          • Long term dialysis (Especially > 12 months): Reduces skeltal muscle carnitine by 30% to 50%
    • Loss of carnitine results in
      • Reduced Buffering of toxic acyl-CoA esters
      • Inhibition of mitochondrial systems
    • Hereditary disorders: 10 genetic defects in fatty acid pathway in infants & children
  • Clinical features: General
    • Coma after a period of starvation
    • Hypoketosis: Low serum ketone concentrations
    • Cardiomyopathy
    • Muscle: Weakness
  • Specific enzyme defects can include
    • LCAD
    • MCAD
    • Plasma-membrane carnitine transporter
    • Carnitine palmitoyltransferase I (CPT I)
    • CPT II deficiency
    • SCAD deficiency : 2 phenotypes
  
  
• Carnitine deficiency: Myopathic Form
  ● ? Autosomal Recessive
  • Clinical
    • Onset age: Childhood - Early adult
    • Weakness: Symmetric; Proximal; ± Face & Tongue
    • No pain or rhabdomyolysis
    • Progression: Usually slow; Rarely acute; ? Exacerbations 2° pregnancy
    • Cardiac: Cardiomyopathy & Congestive heart failure in some patients
  • Laboratory
    • Serum CK: Moderately high
    • EMG: Myopathic
    • Muscle biopsy
      • Lipid storage
      • Low carnitine levels
  • Treatment
    • Diet: Low fat
    • Carnitine: 2 to 4 g/day (Children 100 mg/kg/day)
    • Drugs: ? Prednisone; Riboflavin
  
  
• Systemic (Primary) Deficiency of Carnitine (CDSP)
  ● Na⁺-dependent carnitine transporter (OCTN2; SLC22A5) ; Chromosome 5q31.1; Recessive
  • Genetics: Mutations
    • Most produce null alleles
    • Homozygous missense (E452K): Disease onset 7 years; Cardiomyopathy
    • Mutation effects on carnitine: Reduced carnitine-transporter
      • Impaired muscle uptake
      • Decreased renal tubular reabsorption
  • OCTN2 protein
    • Family: Carnitine/organic cation transporter
    • Expressed on surface membrane of cardiomyocytes
    • Upregulated by: Nuclear receptor PPARα
    • Other substrates: Quinidine; Verapamil
    • Function: Transports carnitine across cell membranes
  • Clinical
    • Onset age: Infancy to 1st decade; Intrafamilial variation
    • General: Fatigability; Vomiting; Abdominal pain; Low height & weight
    • Hypoglycemia: May occur in infants
    • Encephalopathy: Episodic; r/o Reyes syndrome
    • Myopathy: Generalized weakness
    • Cardiomyopathy
      • Dilated
      • Ventricular hypertrophy
      • Heterozygous OCTN2 mutations: Predisposed to late-onset benign cardiac hypertrophy
      • Cardiac failure may occur < 10 years
    • Hepatomegaly
    • May occur in asymptomatic women
  • Lab
    • Carnitine levels (Total & Free)
      • Low or absent in plasma & many tissues
      • Total carnitine in muscle: < 5%
    • Hyperammonemia
    • Urine: Low dicarboxylic acids; Leakage of carnitine
      • Normal in 2° carnitine deficiencies
  • Muscle
    • Lipid storage (Droplets): Predominantly in type 1 muscle fibers
    • Type 2 muscle fiber atrophy
  • Mouse model: Juvenile visceral steatosis (jvs)
  • Treatment
    • Acute episode: Intravenous glucose infusion
    • Avoid fasting
    • Low fat diet
    • L-carnitine (100 - 150 mg/kg/d oral)
  
  
• Carnitine deficiency: Produced by Systemic disorders ¹³
  • Pathogenesis
    • Reduced Protein synthesis ® Reduced number of Carnitine carriers
    • Competitive inhibition for carnitine uptake
    • Increased excretion
  • Clinical
    • Hypotension: Intradialytic
    • Heart failure
    • Anemia:Eerythropoietin-resistant anemia
    • Muscle: Weakness; Low exercise capacity
  • Disorders
    • Systemic disease
      • Malnutrition
      • Sepsis
      • Organ failure: Renal; Liver; Endocrine
      • Organic aciduria
      • Reye's syndrome
      • Chronic myopathies
    • Treatment-related: Valproate; Zidovudine; Total parenteral nutrition
    • Pregnancy
    • Mitochondrial disorders
    • HIV infection: Especially with zidovudine treatment
    • Plasma acyl carnitines in 2° carnitine deficiency
    • Diphtheria toxin
  
  
• Carnitine palmitoyltransferase II (CPT2) deficiency ¹⁹
  ● CPT2 ; Chromosome 1p32.3; Recessive & Semi-Dominant
  • Genetics ¹⁵
    • > 100 different mutations identified
    • Mutations
      • Null mutations produce: Lethal neonatal
      • Amino acid substitution (Missense) mutations: Produce varying severity depending on degree of effect on enzyme activity
      • Some mutations produce thermolabile protein
      • Phe383Tyr: Japanese
      • R631C
        • Present in both infantile & adult onset CPT2 deficiency syndromes
        • Associated with Calabria
      • External database
    • Allelic disorders
      • Adult onset, Myopathy/Rhabdomyolysis
      • Manifesting heterozygous carriers: Reported in 3 professional athletes
      • Infant onset + Hypoglycemia
      • Lethal neonatal + Cardiomyopathy
      • Acute infection-induced encephalopathy, Susceptibility 4 (IIAE4)
  • CPT2 Protein
    • Single isoform
    • Homotetramer
    • Location: Inner mitochondrial membrane
    • CPT system also includes CPT1 on Outer mitochondrial membrane
      • CPT1A : Liver
      • CPT1B : Muscle
    • Function
      • Mediates transport of Fatty acid-CoA across inner mitochondrial membrane
      • Involved in fatty acid β-oxidation
    • Metabolic defect promotes glycogen depletion
    • CPT2 Biochemistry: Suggests CPT2- or carnitine-acylcarnitine-translocase- deficiency
      • Elevations of long-chain acylcarnitines: C14:0-, C16:0-, C16:1- and C18:1-acylcarnitines
      • Increased ratio of (C16 + C18:1)/C2
      • Newborn screening: (C16 + C18:1)/C2 & C14/C3; May not detect muscle form of CPT2 deficiency
      • May be normal in anabolic conditions
      • See: Acylcarnitine patterns
      • Activity of CPT II: Represents 20% to 40% of total CPT activity
      • Disease
        • Muscle symptoms: Enzyme activity < 25%
        • Severe muscle phenotype
          • Enzyme activity < 15%
          • Homozygous mutations: S113L (15%) or R631C (7%)
          • Heterzygous with 1 Null
  • CPT2 deficiency: Adult onset, Episodic, Myopathic form ¹⁶
    
    • Epidemiology
      • Most common metabolic cause of repeated myoglobinuria
      • Males: 75%
    • Genetics
      • Clinical syndromes & Mutations
        • ~60 mutations described
        • Most cases with common mutations ± Heterozygous for 2nd mutation
          • Ser113Leu: 60% of adult myopathy cases; Mild disease; Caucasians
          • 413delAG: Ashkenazi Jews
          • Pro50His: 10%
        • Mutaton locations: Often in exon 4; May occur in all 5 exons
        • Arg503Cys: Malignant hyperthermia with variable myopathy
      • Residual enzyme activity present with adult forms
      • Some mutations with possible manifestations in heterozygotes: Ser113Leu, Arg503Cys
      • Polymorphisms: 3 identified
        • May contribute to reduced CPT2 activity in combination with disease allele
      • Mutations most common in exons 4 & 5
    • Clinical
      • Onset age
        • Common: Early Childhood (60%) to Adolescent or Adult
        • Mean 13 years
        • Range 1 to 40 years
        • No relation between early onset age & genotype
      • Rhabdomyolysis (86%)
        • Triggers: Activities requiring & promoting fatty acid oxidation
          • Prolonged exercise
          • Cold exposure
          • Diet: Low-carbohydrate, High-fat diet; Fasting
          • Infections & Fever
          • Valproate treatment ⁷
          • Anaesthesia
        • Other symptoms: Malaise; Asthenia
        • Attack frequency: Reduced by behavior modification
      • Myopathy
        • Early: Normal strength between attacks
        • Late: Weakness in some patients
      • Discomfort
        • Myalgias (94%): Less severe than VLCAD deficiency
        • Cramps
      • More often symptomatic in males (80%)
      • Systemic: Renal failure with rhabdomyolysis
      • Treatment
        • Diet
          • Triheptanoin (anaplerotic) ¹²
            • Dose: 30% of calories in diet
            • Effect: Increased exercise tolerance
          • ? Low fat; High carbohydrate
          • ? Frequent meals
        • Bezafibrate 200 mg 3x/day ¹⁴
          • Increases palmitoyl L-carnitine oxidation levels
          • Reduces attacks
        • General anesthesia: IV glucose before & during
        • Behavioral: Avoid triggers of rhabdomyolysis
          • Exercise with fasting or infection
          • Dehydration
          • Excess heat exposure
    • Lab
      • Serum CK
        • Normal or mildly elevated (50%) between episodes
        • High with rhabdomyolysis
      • Serum long chain acylcarnitines & carnitine
        • Long-chain acylcarnitines: High in 50%
        • High ratio of: (Palmitoylcarnitine (C16:0) + Oleoylcarnitine (C18:1))/Acetylcarnitine (C2)
        • Normal serum carnitine
      • Fasting: Normal rise of ketone bodies; No myoglobinuria
      • IV glucose: Improves exercise tolerance; Oral glucose not effective
    • EMG: Myopathic or Normal
    • Muscle
      • Morphology: Normal or Varied fiber size (Small type 1)
      • Type 2 muscle fiber predominence
      • Lipid: Increased in muscle fibers (50%)
      • CPT II
        • General: Reduced activity by 80% to 90% in homozygotes
        • Muscle: Non-detectable to Normal
        • CPT II protein
          • Often present in normal amounts in muscle
          • Sensitive to inhibition by malonyl-CoA, Triton X-100 and fatty acid metabolites
          • S113L mutation: Normal activity; Abnormal thermal destabilization at 40°C & 45°C
  • CPT2 deficiency: Infantile form, hepatic type II, with hypoglycemia
    
    • Genetics
      • Most cases with different mutations
      • Residual enzyme activity: Minimal (< 10%)
      • Tyr628Ser, Glu174Lys, Phe383Tyr (Japanese) mutations
        • Severe clinical disease: Infant form
        • Lower CPT2 enzyme activity
        • Hepatic involvement
    • Clinical
      • Recurrent attacks
      • Hepatic: Acute liver failure
      • Cardiac
      • Muscle
      • CNS
        • Coma
        • Seizures
      • Course: May persist into adulthood
    • Laboratory
      • Hypoketotic hypoglycemia
  • CPT2 deficiency: Lethal neonatal with Cardiac disorders
    • Genetics
      • Homozygosity or compound heterozygosity for any null mutations
    • Clinical
      • Cardiac abnormalities: Arrythmias
      • Congenital anomalies
      • Neurologic: Lethargy, Seizures, Hypotonia, Hyperreflexia
      • Death: 1st weeks
    • Laboratory
      • Hypoketotic hypoglycemia
      • Carnitine: Reduced total & free
      • CPT II activity: Severely reduced
  • CPT2 deficiency: Infection-induced acute encephalopathy 4, Susceptibility
    • Epidemiology: Chinese &. Japanese patients
    • Genetics: Missense mutations, Phe352Cys & Val368Ile
    • CPT2 protein: Mutation causes thermolability
    • Clinical
      • Fever
      • Seizures
      • Coma
      • Multiorgan failure
      • Brain edema
    • Laboratory
      • Acylcarnitine ratios: High
  
  
• Carnitine-acylcarnitine translocase deficiency
  ● SLC25A20 (CACT) ; Chromosome 3p21.31; Recessive
  • Protein
    • Mitochondrial-membrane carrier protein
    • Shuttles substrates between cytosol & intramitochondrial matrix space
  • Clinical
    • Encephalopathy: Fasting induced coma & seizures
    • Cardiomyopathy
    • Muscle weakness
    • Respiratory: Episodic neonatal apnea
    • Course: High neonatal mortality
  • Metabolic
    • Hypoketosis
    • Hypoglycemia
    • Hyperammonemia
  • Treatment
    • Peritoneal dialysis with a permanent Tenckof catheter in situ
    • Enteral feeding
      • Frequent
      • High calories
      • Low protein
      • Long-chain fatty acids
      • Medium-chain triglyceride oil
  
  
• Multiple acyl–CoA dehydrogenase deficiency IIA (MADD; Glutaricaciduria IIA)
  ● Electron transfer flavoprotein, α polypeptide (ETFA) ; Chromosome 15q24.2-q24.3; Recessive
  • Genetics
    • Mutations: Missense & Deletion
    • Allelic with
      • MADD neonatal
  • Clinical
    • Onset age
      • Usual: Adult; 3rd & 4th decade
      • Range: 6 to 64 years
    • Myopathy ²
      • Proximal
      • Weakness: May become severe
      • Myalgias: Some patients
      • Progression: Subacute over months
    • Treatment
      • Riboflavin (100 mg/day)
      • ± Carnitine (4 g/day)
      • Coenzyme Q10
      • Corticosteroids
  • Laboratory
    • Urine: High glutaric & ethylmalonic acids
      • Consistent with defective dehydrogenation of isovaleryl CoA & butyryl CoA
    • Serum CK: High; 2x to 20x
    • EMG: Myopathic, Neuropathic or Normal
    • Muscle biochemistry
      • Carnitine levels Reduced
      • Catalytic activity of mitochondrial complex I Reduced
    • Muscle pathology
      • Lipid storage: Type 1 fibers
      • ? Vacuolar myopathy
      • SDH stain: Reduced intensity
  • MADD variant: Neonatal forms
    • Features
      • Acidosis
      • Hypoglycemia
      • Sweaty feet odor
      • Death
  
  
• Multiple Acyl-CoA Dehydrogenase (MADD) & Combined Respiratory-Chain Deficiency (LSMFLAD)
  ● Flavin adenine dinucleotide synthetase, S. Cerevisiae, homolog of (FLAD1; FADS) ; Chromosome 1q21.3; Recessive
  • Epidemiology: 9 patients
  • Genetics
    • Mutations: Biallelic, Frameshift, Missense or 1 amino acid deletion
    • Mutation locations
      • Molybdopterin binding (MPTb) domain, upstream of FADS domain: More severe phenotype
      • FADS domain: Milder phenotype, Riboflavin responsive
  • FLAD1 protein
    • Function: Essential for cellular supply of FAD cofactors
    • Mutation: Some FADS activity preserved
  • Clinical
    • Onset ages: Birth to 44 years
    • Hypotonia
    • Bulbar: Swallowing & Speech difficulties
    • Scoliosis (3 patients)
    • Cardiomyopathy (1 patient)
    • Myopathy
      • Slow running
      • Prolonged exercise: Illness (Vomiting, Weight loss); Myalgias
      • Pregnancy: Myalgias; High CK; Weakness
      • Weakness: Proximal or Distal; Arms & Legs
      • Muscle atrophy
    • Course
      • Severe phenotype: Death in 1st year
      • Mild phenotype: Survival to adulthood
    • Treatment: Riboflavin (100 mg daily) ± Carnitine (2 g/day) in some
  • Laboratory
    • Blood acylcarnitines: Increased
    • MADD patterns
    • Muscle
      • Lipid storage
      • SDH & COX stain reduced in some
      • Respiratory chain activities: Multiple deficient or Normal
    • EMG: Mild myopathy
    • Serum CK: 380 to 6,000
  
  
• Reduced muscle carnitine uptake ¹
  • Onset: Infantile
  • Respiratory insufficiency
    • Chronic central alveolar hypoventilation
    • Nocturnal respiratory disorder (Ondine syndrome): Sleep apnea
    • Acidosis
  • Motor dysfunction: Hypotonia; Feeding disorder
  • Cardiomyopathy: Cardiomegaly
  • Muscle
    • Low carnitine
    • Lipid storage myopathy
    • ? Disorder of sarcolemmal carnitine carriers
  • Lab: Plasma carnitine normal
  • Treatment: ? Carnitine supplementation
  
  
• SCAD deficiency (ACADSD) : 2 phenotypes + Asymptomatic
  ● Short-chain acyl-CoA dehydrogenase (ACADS) ; Chromosome 12q24.31; Recessive
  • General: Metabolic features, on 2 occasions under non-stressed conditions
    • Tests: Acylcarnitine profile; Urine organic acids
    • Butyrylcarnitine (C4): High in plasma, and/or
    • Ethylmalonic acid (EMA) in urine: High
    • Differential diagnosis
      • MADD
      • Ethylmalonic encephalopathy
      • Mitochondrial respiratory chain defects
      • Jamaican vomiting sickness
  • Infant onset
    • Clinical
      • Failure to thrive
      • Developmental delay
      • Hypotonia
      • CNS: Seizures (22%); Dystonia; Behavior disorder
      • Face: Dysmorphic
      • Muscle weakness
      • Treatment: Avoid fasting longer than 12 hours
    • Laboratory
      • Acute metabolic acidosis
      • Ethylmalonate excretion: High
      • SCAD deficiency: Generalized
      • No episodes of nonketotic hypoglycemia
  • Middle age onset
    • Clinical
      • Ophthalmoplegia
      • Ptosis
      • Weakness
      • Scoliosis
    • Laboratory
      • Muscle
        • Lipid storage
        • Multicores
        • SCAD deficiency: Localized to skeletal muscle
  • Asymptomatic
    • Often in patients detected by newborn screening programs
  • External link: GeneReviews

Dilated cardiomyopathies ± Myopathy

• Epidemiology
  • Disease frequency: 0.5 to 1 per 100,000
• Genetics
  • Mutations
    • Usually produce stop codons
    • Types
      • Frameshifts with deletions
      • Point mutations: Stop codons
      • Missense mutations: 2 described
      • Splice site
    • Evenly distributed through gene
    • No clear correlation between mutation & phenotype
  • Large gene deletion may produce co-occurrence of
    • Duchenne dystrophy
    • Chronic granulomatous disease
    • Retinitis pigmentosa
  • Other polymorphisms define Kell blood groups
  • Some Japanese families without XK mutation
• Kell glycoprotein
  • Location: Erythrocyte membrane
  • Function
    • Zinc metalloproteinase
    • Cleaves endothelin-3 to bioactive peptide
    • Homology to CED-8: ? Role in programmed cell death
  • McLeod syndrome: Reduced expression on erythrocytes
  • ? Associated proteins
    • Huntingtin: Huntington's disease
    • Chorein: Autosomal-recessive Chorea-Acanthocytosis
  • Muscle location
    • Type II muscle fibers
    • Intracellular: Sarcoplasmic reticulum
    • Staining is absent in McLeod myopathy
• Clinical
  • Onset
    • Age: Adult; Range 27 to 72; Mean 5th decade
    • Signs: Fatigue; Movement disorder; Seizure
  • Weakness (65%)
    • Severity: Usually mild; Occasionally severe or none
    • Distribution: Proximal; Symmetric; Legs > Arms; Paraspinal
    • Course: Increases with age
  • Other muscle features
    • Muscle atrophy: May be generalized
    • Fatigue with exercise
    • Rhabdomyolysis ⁹: Associated with hyperkinesis & neuroleptic drugs
    • Serum CK: High
  • Polyneuropathy
    • Sensory loss: Reduced vibration sense in feet (40%)
    • Tendon reflexes: Reduced; Legs (90%) ± Arms (60%)
    • Symptoms: Rare
  • CNS
    • Movement disorders
      • Onset: 2nd to 6th decade
      • Distribution: Limbs; Trunk; Face
      • Types: Chorea (100%); Dystonia; Face hyperkinesia; Vocalizations; Dysarthria
    • Seizures: Onset > 40 years
    • Psychiatric syndromes (45% to 83%)
    • Cognitive disorders (54%): Memory & Executive functions
    • Pathology: Atrophy of cerebrum & caudate
  • Systemic
    • Hepato-Splenomegaly (40%)
    • Cardiomyopathy (66%)
      • Onset > 40 years
      • Cardiomegaly: Dilated or Restrictive
      • Atrial fibrillation
      • Congestive heart failure
      • Often cause of death
    • Hematologic
      • Acanthocytosis
      • Weak espression of Kell red blood cell antigens
      • Compensated hemolysis
    • Chronic granulomatous disease
      • Results from a contiguous gene deletion
  • Management
    • Autologous blood donation: Avoids incompatibility hazards
    • Symptomatic treatment: Epilepsy, Cardiac & Psychiatric features
    • Chorea: Porly responsive to treatment
• Laboratory
  • Hematologic
    • Acanthocytosis ⁶: 100%
      • Thorny shaped red cells
      • May be marked: 35%
      • Differential diagnosis: A-β-lipoproteinemia; Chorea-Acanthocytosis
    • Erythrocytes: Reduced Expression of Kell blood group & Kx surface antigen (100%)
    • Hemolysis: Persistent; Low grade
  • Serum enzymes
    • CK: High (100%); 900 to 5,000; Range 1.5 to 15x normal
    • LDH: High (91%)
  • EMG
    • Myopathic (14%)
    • Neuropathic (79%)
  • Nerve conduction testing
    • CMAPs: Small amplitude
    • SNAPs: Small amplitude
    • Conduction velocities: Normal
  • Muscle pathology ³: Myopathic
    • Variation in muscle fiber size
    • Nuclei: Internal
    • Necrosis & Regeneration of muscle fibers
      • Occasional
      • Severe cases: May be prominent
    • Cell infiltrates: Occasional patients; Predominantly macrophages; Few lymphocytes
    • Fiber type changes
      • Type I predominance
      • Type II atrophy
  • Nerve pathology
    • Axonal loss
    • ± Demyelination
  • Leg muscle imaging
    • MRI: Sparing of quadriceps
    • CT: Asymmetric involvement of thighs & lower legs (calves)
  • CNS imaging
    • Caudate atrophy
    • MR: Abnormal signal in basal ganglia, increased T2 in lateral putamen
• Female carriers: Occcasional female affected due to skewing of X-inactivation
  • Acanthocytosis: Mild
  • CNS: Chorea; Occasional psychiatric syndrome
  • Serum CK: Mildly increased

• Genetics
  • Mutations
    • Locations: In all exons & some adjacent intron sequences
    • Stop & Missense
  • No strong genotype-phenotype correlations
    • ? More severe heart disease with some exon 8 mutations
  • Allelic with Cardiomyopathy, Dilated 3A (X-linked fatal infantile)
  • Also see: Barth-like syndrome with mtRNA Leu mutations
• Tafazzin protein
  • Superfamily: Acyl transferases involved in phospholipid synthesis
  • Isoforms: 10 different proteins
    • Membrane anchored types
      • Contain hydrophobic N-terminus (1st 2 exons)
      • High levels in heart & skeletal muscle
    • Cytosolic types
      • Lack hydrophobic sequence
      • High levels in leukocytes & fibroblasts
  • Functions
    • Phospholipid acyltransferases
    • Remodeling of cardiolipin
    • Cardiolipin (CL)
      • Phospholipid
      • 1,3-bis(3-phosphatidyl)glycerol
      • Mitochondrial-specific
        • Major component of: Inner mitochondrial membrane
      • Tetralinoleoyl-cardiolipin (L4-CL): Dominant species of cardiolipin in heart & skeletal muscle
      • Cardiolipin Biosynthesis
        • CRLS1
        • PTPMT1
      • Roles
        • Maintain functional integrity & dynamics of mitochondria
        • Facilitates assembly & stability of large mitochondrial protein complexes
        • OXPHOS system
        • Mitochondrial contact site & cristae organizing system(MICOS)
      • Barth changes
        • Tetralinoleoyl-cardiolipin reduced
        • Membrane destabilization: Generalized electron transport chain dysfunction
      • Cardiolipin disorders
        • COXPD56: TAMM41
        • COXPD57: CRLS1
        • SPG20: Spartin
        • MEGDEL: SERAC1
        • Barth syndrome: TAZ
        • DCMA: DNAJC19
        • Neurodevelopmental: PTPMT1
        • Serum: Anti-cardiolipin antibodies
• Clinical features: Variable
  

  Onset Infancy Hypotonia Cardiomyopathy: Neonatal to < 1 year Low birth weight Myopathy: Non-progressive; Relatively mild Early Hypotonia Delayed motor development Weakness Proximal > Distal: May be diffuse Waddling gait Gower's sign Mild: No respiratory insufficiency or wheelchair dependence Myopathic facies: Some patients Muscle mass: Reduced Fatigue Myalgias CNS Learning disability Delays: Mathematics; Visual special tasks & short-term memory Headaches Short stature Proportionate (-2 SD) May eventually grow to normal height Delayed bone age Face Full cheeks Prominent ears Deep-set eyes Cardiac syndromes: May vary within families Noncompaction of left ventricular myocardium Isolated: No additional cardiac defects (pulmonary atresia) Lethal early course Ultrasonogram: Spongy structure of left ventricular wall Also caused by α-dystrobrevin mutations Dilated cardiomyopathy (CMD 3A) Ventricular hypertrophy Endocardial fibroelastosis: With longstanding cardiac disease Ventricular tachycardia: May be fatal Course Some progressive: May need cardiac transplantation Others resolve with time GI: Diarrhea Phenotype may vary greatly within and between families Course: Patients who survive childhood may become healthy adults

  From: The Barth Syndrome Foundation

• Laboratory
  • Serum CK: Normal
  • Muscle: Mild myopathic
    • ± Lipid accumulation, or Type 1 fiber predominance
  • Mitochondrial disorder
    • Electron transfer chain variably affected: Complex I deficiency + other
    • Morphologically abnormal inner mitochondrial membranes in cardiac muscle
    • Deficient mitochondrial phospholipid: Tetralinoleoyl-Cardiolipin (L₄-CL)
  • Endomyocardium: Mitochondria with tightly packed, concentric cristae
  • Blood: Increased 3-methylglutaconic; Low cholesterol
  • Immune deficiency
    • Neutropenia: Recurrent
      • Neutrophils 0 to 500
      • Maturation stop at promyelocyte stage
      • May be normal when patient is well
      • May predispose to lethal infections in neonatal period
      • Associated with chronic aphthous stomatitis: Usually due to Candida
      • Treatment: ? Granulocyte colony stimulating factor (G-CSF)
    • Early infections
    • Pyodermia
  • Urine
    • Increased levels of some branched-chain organic acids
      • 3-methylglutaconic acid
      • 3-methylglutaric acid
      • 2-ethylhydracrylic acid
    • 3-methylglutaconic acid may be high normal in urine in older patients
• Course
  • Some: Death in childhood due to cardiac failure or sepsis
  • Many: Slow improvement in cardiac, motor & infectious signs
• Treatment: Manage heart failure;? Pantothenic acid
• Variant syndrome: Isolated left ventricular noncompaction (LVNC)
• Female carriers
  • Clinically normal
  • Skewed X inactivation common
    • X chromosome with mutation often selectively inactivated
    • Usually occurs when mutated gene is on maternal chromosome
    • Inactivation may be > 95%
    • Other skewed inactivation syndromes
      • Wiskott-Aldrich syndrome
      • α-thalassemia/mental retardation syndrome
      • Bruton X-linked agammaglobulinemia
      • Increases in older females

• Genetics
  • Maternal inheritance
  • Mutation: A3243G
• Clinical
  • Onset: 1st months
  • Failure to thrive
  • Motor: Weakness; Milestones severely delayed; Respiratory failure
  • Cardiomyopathy: Dilated; Progress to congestive heart failure
• Laboratory
  • Lactic acidosis
  • CBC normal
  • Serum CK: Mildly elevated, early
  • Serum carnitine: Mildly reduced
  • Urine: High 3-methylglutaconic & 2-ethylhydracrylic acid
  • Cholesterol: Low in blood
  • Muscle
    • Histochemistry
      • Type 2 predominance
      • Varied fiber size
      • Ragged red fibers; Diffusely reduced COX activity; SDH increased
    • Mitochondrial biochemistry: Low Complexes I & IV

• Epidemiology: Canadian Dariusleut Hutterite population
• Genetics
  • Mutation: Splicing site; IVS3-1 G>C
  • Other DNAJ disorders
• DNAJC19 protein
  • Location: Mitochondrial inner membrane protein (TIM)
    • ? Component of TIM23 inner membrane translocase complex
  • Structure: DNAJ domain-containing
  • Functions
    • ? Involved in molecular chaperone systems of Hsp70/Hsp40 type
    • Formation of prohibitin scaffolds
      • Control cristae morphology & functional integrity of mitochondria
      • Segregate specific membrane domains
      • Restrict phospholipids, including cardiolipin (CL), into specific membrane domains
  • Other TIMM protein disorder: Mohr-Tranebjaerg syndrome
  • DnaJ proteins
    • Molecular co-chaperones for Hsp70
    • Aid folding of newly imported proteins
• Clinical
  • Cardiac
    • Cardiomyopathy: Dilated
    • Conduction defects: Long Q-T syndrome
    • Early-onset: < 3 years
  • Cerebellar
    • Ataxia
    • Motor delay
    • Course
      • 100% after 2 years of age
      • Non-progressive
      • Independent ambulation achieved
  • Other CNS
    • Failure to thrive
    • Optic atrophy: Some patients
    • Developmental delay
    • Seizures: Occasional patient
  • Systemic
    • Testicular dysgenesis: Cryptorchidism to severe perineal hypospadias
    • Growth failure (100%)
  • Skeletal muscle: No myopathy
• Laboratory
  • Organic aciduria (Methylglutaconic aciduria type V)
    • 3-methylglutaconic
    • 3-methylglutaric
    • Other organic aciduria: Barth syndrome
  • Hepatic enzymes: Mildly elevated
  • Anemia: Normochromic, Microcytic

• Epidemiology: 1 Filipino family, 2 patients
• Genetics
  • Mutations: Missense; c.187C>T (p.Arg63Cys), c.133A>G (p.Asn45Asp)
• NPL protein
  • Sialic acid (Neu5Ac) catabolism
  • Neu5Ac → N-acetylmannosamine (ManNAc) & Pyruvate
  • Sialic acid disorders, other
    • Salla disease: SLC17A5
    • HIBM2: GNE; No Sialuria
    • Sialuria : GNE
    • Spondyloepimetaphyseal dysplasia, Genevieve type : NANS
    • Congenital disorder of glycosylation, type IIf : Cytidine monophosphate (CMP)–Sia transporter deficiency (SLC35A1)
  • Sialylated molecules
    • Lipids
    • Myelin-Associated Glycoprotein (MAG)
• Clinical
  • Fetal: Arrhythmia & Heart block
  • Cardiomyopathy: Dilated, progressive
  • Joints: Hypermobility
  • Weakness: Proximal; Arms & Legs
  • Course: Slow progression
  • Sibling: Has only myopathy
• Laboratory
  • Sialic aciduria (100x increased)

Hypertrophic Cardiomyopathy + Myopathy

• Hypertrophic cardiomyopathy with Central cores in skeletal muscle ¹⁸
    ● Myosin - Cardiac β heavy chain (MYH7) ; Chromosome 14q11.2; Dominant
  • Genetics
    • Mutations: Arg403Gln; Leu908Val
    • Allelic disorders
  • Clinical features
    • Cardiomyopathy: Hypertrophic
    • Strength: Normal or Distal
  • Muscle pathology
    • Central cores or Minicores
    • Type I muscle fiber predominance
    • Muscle fiber hypertrophy
  
  
• Cardiomyopathy: Mid-left Ventricular Chamber Type
  ● Myosin light chain, Ventricular and skeletal slow type (MYL3); Chromosome 3p21.31; Dominant
  
  • Genetics
    • ? Mutations at hinge region between heavy & light myosin chains
    • Allelic disorder: Familial hypertrophic cardiomyopathy 8
  • Muscle pathology: Myopathic with ragged red fibers
• FILC
• Mitochondrial

• Selective Cardiomyopathy
• Congenital & infantile
• Kearns-Sayre
• Multisystem
• PEO
• Congenital muscular dystrophy with mitochondrial structural change

Other disorders with cardiomyopathy

• Amyloid
• Congenital myopathy with spindle excess
• Desmin (Cardiomyopathy) Myopathy
• Encephalopathy with necrotizing myopathy, cardiomyopathy & cataracts
  ● Autosomal recessive
• Limb Girdle Dystrophy
  • Dysrhythmias
  • Type 2D: Rare
• Mulibrey Nanism
• Nemaline rod congenital myopathy: Dilated
• Periodic paralysis - Hyperkalemic & Hypokalemic: Cardiac failure
• Polymyositis: Cardiac failure or Arrhythmias
• Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy
• Uruguay Facio-Cardio-Musculo-Skeletal Syndrome
• Williams-Beuren syndrome

Drugs + Cardiomyopathy

• Hypertrophic cardiomyopathy
• Dilated cardiomyopathy
• Errors of Fatty acid oxidation - 2° disorders of carnitine metabolism
    (See 1° disorders of Carnitine metabolism)
• Mitochondrial
• Other
  • Congestive cardiomyopathy with conduction defects
  • Amyloid

Sudden Cardiac Death: Causes in Neuromuscular disorders

• Myotonic dystrophy, type 1
• Emery-Dreifuss
  • Emerin
  • Lamin A/C
  • FHL1
• Myofibrillar myopathies
  • Desmin
  • CRYAB
  • BAG3
• Dystrophinopathies
  • Becker
• Danon Disease
• Mitochondrial disease
  • Kearns-Sayre
  • Fatty acid oxidation defects
  • Barth syndrome
• Other related cardiomyopathies
  • MYH7
  • PRKAG2

MULIBREY NANISM

• Mutations
  • Frameshift, deletion or insertion
  • Produce truncated protein
  • Disease category: Peroxisomal biogenesis disorder
• Protein
  • Zinc finger protein: RING-B-box-coiled-coil (RBCC) family
  • Contains TRAF domain: Interacts with other proteins
  • Coiled-coil domain: Homo-oligomerization; Subcellular localization
  • E3 ubiquitin-protein ligase
  • Location: Peroxisomal; Granular cytoplasmic
  • Mutant proteins may have defective targeting or function
• Epidemiology
  • Most common in Finland
• Clinical: Muscle-Liver-Brain-Eye Nanism
  • Onset: Birth (Prenatal)
  • Muscle: Hypotonia 80%
  • Cardiac: Constrictive pericarditis
  • Skeletal
    • Prenatal growth failure
    • Slender stature
    • Cystic dysplasia of tibia (30%)
    • Long shallow (J-shaped) sella turcica (95%)
  • GI: Hepatomegaly
  • Skin: Naevi flammei (70%)
  • Small voice
  • Eye
    • Choroid hypoplasia
    • Retinal yellowish dots & pigment dispersion
    • Wilms tumor (4%)
  • Endocrine: Gland hypoplasia
  • CNS: Probably normal