Neuromuscular Disorders and Noncompaction Cardiomyopathy Flashcards
What clinical manifestations are associated with mutations in the DMD gene?
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), isolated dilated cardiomyopathy (DCM)
DMD is one of the most prevalent muscular dystrophies in children, while BMD is a milder form of DMD.
How does the X-chromosome location of the DMD gene affect female carriers?
Female carriers may manifest clinically depending on random inactivation of the mutated/non-mutated chromosome.
What is the common phenotypic feature in DMD, BMD patients, and DMD-carriers?
Cardiac involvement, including conduction defects, arrhythmias, and DCM.
What percentage of DMD/BMD patients in a study from Japan presented with LVHT?
19% (35 out of 186 patients).
What was the death rate during follow-up for LVHT DMD/BMD patients compared to those without LVHT?
37% in the LVHT group vs. 14.6% in the non-LVHT group.
What is Barth syndrome characterized by?
DCM (or HCM, LVHT, or fibroelastosis), myopathy, and neutropenia.
What is the significance of LVHT in Barth syndrome?
It is regarded as a hallmark of the disease.
What gene encodes a protein involved in cardiolipin remodeling?
G4.5/TAZ.
What are the phenotypes associated with mutations in the G4.5/TAZ gene?
Barth syndrome, DCM, HCM, endocardial fibroelastosis, isolated LVHT.
What is the role of the DTNA gene?
It encodes for alpha-dystrobrevin, a component of the dystrophin-associated protein complex.
What type of heart defects are associated with DTNA mutations?
Various congenital heart defects and LVHT.
What do mtDNA genes encode?
Subunits of respiratory chain complexes, tRNAs, and rRNAs.
Which mtDNA gene mutations have been reported in association with LVHT?
ND1 and ND4.
What is the function of the GARS gene?
It is an aminoacyl-tRNA synthetase that links glycine to its corresponding tRNA.
What is the most severe phenotype associated with HADHB mutations?
CMP, lactic acidosis, hypoketotic hypoglycemia, and neonatal death.
What does the MIPEP gene encode?
Mitochondrial intermediate peptidase, critical for mitochondrial protein import.
What syndrome is caused by mutations in the MIPEP gene?
Developmental delay, epilepsy, metabolic myopathy, severe hypotonia, cataracts, infantile death, and LVHT.
What is the role of the SDHD gene?
It encodes for a subunit of complex-II of the respiratory chain.
What is the phenotypic manifestation of LDB3 mutations?
DCM, sudden cardiac death (SCD), myopathy, or LVHT.
Fill in the blank: LVHT has been first reported in _____ patients carrying a LDB3 variant.
three.
True or False: Mutations in the G4.5/TAZ gene only affect males.
False.
What does ZASP encode for?
Z-band alternatively spliced PDZ-motif protein (ZASP)
ZASP is a major component of the Z-disc proteins in skeletal and cardiac muscle.
What is the role of ZASP in muscle cells?
Stabilizing the Z-disc through PDZ-mediated interaction with alpha-actin-2 (ACTN2) and F-actin
ZASP is crucial for maintaining the structural integrity of muscle fibers.
What phenotypes are associated with mutations in LDB3?
DCM, sudden cardiac death (SCD), myopathy, or LVHT
LDB3 mutations can lead to serious cardiac and muscular conditions.
What is the function of the DMPK gene?
Encodes for dystrophia myotonia protein kinase
The specific function is unknown, but it is believed to be involved in signaling and regulation.
What condition is associated with CTG-repeat expansion in the DMPK gene?
Myotonic dystrophy type-1 (MD1)
Severity of MD1 correlates with the size of the CTG-expansion.
What types of cardiac involvement are frequent in MD1?
CMP, ventricular arrhythmias
CMP may manifest as HCM, DCM, or LVHT.
What does the LMNA gene encode?
Lamin A/C
Lamin A/C is associated with the inner nuclear membrane.
What is a characteristic of LMNA mutations?
Strong phenotypic heterogeneity
Manifestations can include various muscular dystrophies and cardiac conditions.
What is the role of AMPD1?
Encodes for myo-adenylate deaminase
It is involved in the deamination of AMP molecules.
What symptoms may arise from mutations in AMPD1?
Fatigue, cramps, muscle pain, or recurrent myoglobinuria
Symptoms can range from asymptomatic to significant muscle issues.
What does MYH7 encode for?
Beta-myosin heavy chain
This protein is predominantly expressed in skeletal and cardiac muscle.
What is the association between MYH7 mutations and cardiac conditions?
HCM, DCM, Laing distal myopathy, and LVHT
MYH7 mutations have been linked to various myopathies and cardiac issues.
What does CNBP/ZNF9 encode for?
A protein with an unknown function
It is mainly expressed in the heart and muscle.
What condition is associated with expansions in CNBP/ZNF9?
Myotonic dystrophy type-2 (MD2)
MD2 is a multisystem disorder with significant manifestations in muscle and endocrine organs.
What does the GLA gene encode?
Alpha-galactosidase
This enzyme cleaves terminal galactose from ceramide trihexoside.
What disease results from mutations in the GLA gene?
Fabry’s disease
Cardiac involvement includes HCM and conduction defects.
What does RYR1 encode?
Ryanodine receptor-1
It is known as the skeletal muscle calcium release channel.
What conditions can mutations in RYR1 lead to?
Multiminicore myopathy, central core disease, malignant hyperthermia susceptibility
Cardiac disease in RYR1 mutation carriers is rare.
What is the significance of the MYH7B gene?
Encodes for myosin heavy chain 7B
It is expressed in skeletal and cardiac muscle.
What does LAMP2 encode?
Lysosome-associated membrane glycoprotein-2
It plays a role in lysosomal function and is associated with Danon disease.
What is the largest gene identified in humans?
TTN
It encodes for the giant protein titin, involved in muscle function.
What are the manifestations of TTN mutations?
Dominant DCM, HCM, cardiac septal defects, isolated LVHT
Mutations lead to significant variability in phenotypes.
What does PLEC1 encode?
Plectin
It is involved in cytoskeletal organization.
What condition is associated with mutations in PLEC1?
Epidermolysis bullosa simplex (EBS)
It can manifest with muscular dystrophy and skin fragility.
What is the onset age range for limb muscle weakness in LVHT?
Between infancy and the 4th decade of life
What condition was diagnosed in the 18-year-old Afro-American male with a PLEC1 mutation?
Epidermolysis Bullosa Simplex (EBS)
At what age did the patient with a PLEC1 mutation lose the ability to rise from the floor?
4 years old
What diagnostic method revealed LVHT in the patient at age 17?
Cardiac MRI (cMRI)
What does POMPT2 encode for?
Protein-O-manosyl-transferase
What condition is characterized by hypoglycosylation of alpha-dystroglycan?
Dystroglycanopathies
Which syndrome is the most severe form of dystroglycanopathies?
Walker-Warburg syndrome (WWS)
What are common clinical characteristics of WWS?
Eye and brain abnormalities
What is the genetic heterogeneity of WWS caused by?
Mutations in multiple genes including POMPT2, FKTN, FKRP, POMGnT1, POMGnT2, ISPD, B3GNT1, LARGE1
Is cardiac involvement common in WWS?
No, it is infrequent
What abnormalities were found in the ECG of a WWS patient with LVHT?
Incomplete left bundle branch block, left ventricular hypertrophy, T-wave inversion
What congenital heart defects were revealed by echocardiography in the WWS patient?
Atrial septal defect, muscular ventricular septal defect, LVHT
What is the typical referral reason for patients diagnosed with LVHT?
Syncope or palpitations in young patients, heart failure in older patients
Name some at-risk groups for LVHT.
[“Patients with chromosomal defects”, “Patients with neuromuscular disorders (NMD)”, “Black Africans”, “Pregnant females”, “Athletes”]
What is a shortcoming in the work-up of patients with LVHT?
Often not investigated for associated non-cardiac diseases or genetic backgrounds
What must all patients with LVHT be seen by?
A neurologist
What treatment is indicated for heart failure in LVHT with NMD?
Established therapy like ACE-inhibitors, beta-blockers, diuretics
What should be considered for patients with malignant ventricular arrhythmias?
Implantation of an implantable cardioverter defibrillator (ICD)
What is the outcome predictor for LVHT patients with NMD?
Increased age, heart failure, atrial fibrillation, bradycardia, presence of NMD
What is the prevalence of LVHT in the general population?
Low prevalence
What is the relationship between certain mutations and LVHT?
Causal relation has not been established
What is essential for patients with NMD regarding LVHT?
Prospective investigation for LVHT
What is the recommended approach for patients with LVHT regarding genetic defects?
Testing for concomitant genetic defects
What is the need for further studies regarding LVHT?
Prevalence in different NMDs and pathogenetic relation between NMDs and LVHT
