Friday 1 April 2016

Cardiac + Myopathy



CARDIAC + MYOPATHY


Amyloid
Cardiomyopathies
  Dilated
  Hypertrophic
  Isolated
Carnitine Disorders
Drugs 		  Dystrophies
  Barth
  Desmin
  Dystrophinopathies
  Emery-Dreifuss
  Limb-girdle
  McLeod
  Myofibrillar
  Myosin
  Myotonic
  Scapuloperoneal "+"
  Triangular 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)
  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

  • 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
    • 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
    • Muscle
    • 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

  • Carnitine palmitoyltransferase II (CPT2) deficiency
    ● CPT2 ; Chromosome 1p32.3; Recessive & Semi-Dominant
    • General
      • Genetics 15
        • > 70 different mutations identified
        • Null mutations produce: Lethal neonatal
        • Amino acid substitution (Missense) mutations: Produce varyiung severity depending on degree of effect on enzyme activity
        • R631C
        • Mutations
      • 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
        • 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
    • Clinical types
    • Adult onset form
      • Epidemiology: Most common metabolic cause of repeated myoglobinuria
      • Genetics
        • Clinical syndromes & Mutations
          • ~20 mutations described
          • Most cases with common mutations ± Heterozygous for 2nd mutation
            • Ser113Leu: 60% of adult myopathy cases; Mild disease
            • 413delAG: Ashkenazi Jews
            • Pro50His: 10%
          • Arg503Cys: Malignant hyperthermia with variable myopathy
        • Residual enzyme activity present with adult forms
        • Some mutations with 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
      • CPT2 Protein
      • Clinical
        • Onset age
          • Adolescent or Adult
          • Mean 13 years
          • Range 1 to 40 years
          • No relation between early onset age & genotype
        • Rhabdomyolysis
          • Triggers: Activities requiring fatty acid oxidation
            • Prolonged exercise
            • Cold
            • Diet: Low-carbohydrate, high-fat diet; Fasting
            • Infections
            • 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
        • More often symptomatic in males (80%)
        • Systemic: Renal failure with rhabdomyolysis
      • Lab
        • Serum CK
          • Normal or mildly elevated (50%) between episodes
          • High with rhabdomyolysis
        • Serum long chain acylcarnitines & carnitine
          • 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 activity: Reduced by 80% to 90% in homozygotes
      • 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
    • Infantile form, hepatic type II
      • Genetics
        • Most cases with different mutations
        • Residual enzyme activity: Minimal (< 10%)
        • Tyr628Ser, Glu174Lys, Phe383Tyr mutations
          • Severe clinical disease: Infant form
          • Lower CPT2 enzyme activity
          • Hepatic involvement
      • Clinical
        • Hepatic
        • Cardiac
        • Muscle
    • Lethal neonatal
      • 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
    • 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
    • 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 (MADD; Glutaricaciduria IIA)
    ● Electron transfer flavoprotein, α polypeptide (ETFA) ; Chromosome 15q24.2-q24.3; Recessive
    • Allelic with: Coenzyme Q10 deficiency
    • 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
    • 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
      • Muscle pathology
        • Lipid storage: Type 1 fibers
        • ? Vacuolar myopathy
        • SDH stain: Reduced intensity
    • Treatment
      • Riboflavin (100 mg/day)
      • ± Carnitine (4 g/day)
      • Coenzyme Q10
      • Corticosteroids
    • Neonatal forms: Features
      • Acidosis
      • Hypoglycemia
      • Sweaty feet odor
      • Death

  • 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 : 2 phenotypes + Asymptomatic
    ● Short-chain acyl-CoA dehydrogenase (ACADS) ; Chromosome 12q24.31; Recessive
    • General: Metabolic features, on 2 occasions under non-stressed conditions
    • 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
    • Asymptomatic
      • Often in patients detected by newborn screening programs
    • External link: GeneReviews

Dilated cardiomyopathies ± Myopathy

Myofibrillar myopathy (ARVC)
Barth syndrome: Tafazzins; Xq28
Barth-like syndrome: mtRNA Leu
Dilated cardiomyopathy (Isolated): 1q32; 9q13; 10q22
Dilated Cardiomyopathy with Ataxia: DNAJC19; 3q26
Dystrophinopathies: Xp21
Familial with Conduction Defect& Muscular dystrophy (CMD 1F): 6q23
Familial with conduction defect without dystrophy
  CMD 1A: Lamin A/C; 1p11-q11
  CMD 1E: 3p25-p22
McLeod syndrome: XK protein; Xp21
Mitochondrial
Myopathy + Cardiomyopathy: DPM3; 1q12
Nemaline (Rod) myopathy
Other familial dilated cardiomyopathy without myopathy
Selenium deficiency

Also see: Dilated cardiomyopathy without myopathy


McLeod syndrome 8
  ● Kell group protein (XK membrane transport protein) ; Chromosome Xp21.1; Recessive
  • 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
    • 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
    • Muscle location
      • Type II muscle fibers
      • Intracellular: Sarcoplasmic reticulum
      • Staining is absent in McLeod myopathy
  • Epidemiology
    • Disease frequency: 0.5 to 1 per 100,000
  • 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
      • 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
  • Female carriers: Occcasional female affected due to skewing of X-inactivation
    • Acanthocytosis: Mild
    • CNS: Chorea; Occasional psychiatric syndrome
    • Serum CK: Mildly increased
  • Laboratory
    • Hematologic
      • Acanthocytosis 6: 100%
      • Erythrocytes: Reduced Expression of Kell blood group & Kx surface antigen (100%)
      • Hemolysis: Persistent; Low grade
    • Serum enzymes
      • CK: High (100%); 2,000 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


X-linked dilated cardiomyopathy (Barth syndrome) 4
  ● Tafazzin (G4.5 gene; TAZ) ; Chromosome Xp28; Recessive
  • Genetics
  • 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)
        • Mitochondrial-specific phospholipid
        • Major component of inner mitochondrial membrane
        • Tetralinoleoyl-cardiolipin (L4-CL): Dominant species of cardiolipin in heart & skeletal muscle
        • Barth changes
          • Tetralinoleoyl-cardiolipin reduced
          • Membrane destabilization: Generalized electron transport chain dysfunction
  • Clinical features: Variable

    From: The Barth Syndrome Foundation
    • 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
  • 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 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


Barth-like syndrome with mitochondrial mtRNA Leu mutation 5
  ● Mitochondrial tRNA Leu (MTTL1)
  • 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


Dilated Cardiomyopathy with Ataxia (DCMA) 11
  ● DNAJC19 (TIM14) ; Chromosome 3q26.33; Recessive
  • Epidemiology: Canadian Dariusleut Hutterite population
  • Genetics
  • DNAJC19 protein
  • 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
    • Optic atrophy: Some patients
    • Mental retardation: Mild
    • Seizures: Occasional patient
  • Systemic
    • Testicular dysgenesis: Cryptorchidism to severe perineal hypospadias
    • Growth failure (100%)
  • Skeletal muscle: No myopathy
  • Laboratory


Isolated dilated cardiomyopathy
  ● Chromosome 1q32

  ● Chromosome 9q13

  ● Chromosome 10q22-q24


Hypertrophic cardiomyopathy with myopathy

  • Hypertrophic cardiomyopathy with central cores in skeletal muscle
      ● Myosin - Cardiac β heavy chain (MYH7) ; Chromosome 14q11.2; Dominant
    • Allelic disorders
    • Clinical features
      • Cardiomyopathy: Hypertrophic
      • Strength: Normal
    • Muscle biopsy
      • Central cores
      • Type I muscle fiber predominance
  • Mid-left Ventricular Chamber Type
    ● Myosin light chain, Ventricular and skeletal slow type (MYL3); Chromosome 3p21.31; Dominant
      l ? Mutations at hinge region between heavy & light myosin chains
  • Mitochondrial


Mitochondrial


 Cardiomyopathy: Hypertrophic or Dilated

Other disorders with cardiomyopathy


Drugs + Cardiomyopathy





Isolated cardiomyopathies; Hereditary

Sudden Cardiac Death: Causes in Neuromuscular disorders

MULIBREY NANISM

  ● Tripartite motif-containing protein 37 (TRIM37) ; Chromosome 17q22; Recessive
  • Mutations
  • 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
Return to Myopathy& NMJ Index

References
1. Neuromuscular Disorders 1999;9:320-322
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11/10/2015
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