Congenital Muscular Dystrophy Due To Lmna Mutation

A rare congenital muscular dystrophy characterized by prominent axial hypotonia, predominantly proximal muscle weakness in upper limbs and distal in lower limbs, joint contractures (initially distal, later proximal), spinal rigidity, and progressive respiratory insufficiency, in the presence of moderately elevated serum creatine kinase. Cardiac arrhythmias and sudden death have also been reported.

Epidemiology

To date over 100 cases of congenital muscular dystrophy due to LMNA (L-CMD) have been reported in the literature; both genders are equally affected.

Clinical description

The expressivity, severity and progression of the disease are variable but all present a predominant axial and scapula-humeral topography of muscle weakness and atrophy. Motor symptoms appear during the first two years of life and show often a rapid course. In the most severe patients, no head or trunk support are achieved. In milder patients, a more characteristic picture is observed, with a striking loss of head support (dropped-head syndrome), associated with arm weakness but relatively preserved hip and thigh strength in the initial stages. Skeletal manifestations include muscle and joint contractures, spine rigidity, scoliosis and thoracic lordosis. A progressive thoracic stiffness is associated to the respiratory insufficiency favoring recurrent respiratory infections. Severe cases might show swallowing difficulties. Cardiac arrhythmias and sudden death are not uncommon in this group of patients after the first decade or life.

Etiology

The disorder is due to mutations in the LMNA gene (1q22), coding for type A/C lamins, two intermediate filaments that form cytoplasmic and nuclear networks and shape the nuclear envelope. Myoblasts from L-CMD patients show altered nuclear structure, defective mechanosensing responses and abnormal cell differentiation. Milder phenotypes, known as Emery-Dreifus muscular dystrophy, are also associated with LMNA mutations.

Diagnostic methods

Diagnosis mostly relies on clinical observation, typically of early onset axial muscle weakness with distal progression, muscle and joint contractures, dropped-head syndrome, loss of walking and sitting abilities and cardiac arrhythmias in the first or second decade of life. A moderated elevation of serum creatine kinase levels reflects muscle damages. Genetic screening of mutations in the LMNA gene confirms the diagnosis.

Differential diagnosis

Differential diagnosis includes other congenital muscular dystrophies (laminin subunit alpha 2-related CMD, Ullrich CMD due to COL6 gene defects), early onset myopathies that present increased CK levels, joint contractures or spinal stiffness (SEPN1-related myopathies, titinopathies, Pompe disease, mitochondrial myopathy in particular TK2-related), and myasthenic syndromes where loss of head support can also be observed.

Antenatal diagnosis

Reduced fetal movements observed by prenatal ultrasounds should raise suspicions, but is not specific. In families with a proband, prenatal genetic testing may be advised due to the possibility of germinal mosaicism.

Genetic counseling

The disorder is autosomal dominant. Almost all reported cases arise de novo, although germinal mosaicism is a possibility. Genetic counseling should be offered to affected families.

Management and treatment

The evaluation and management of respiratory, gastro-intestinal, orthopedic and cardiac troubles associated with L-CMD require a multidisciplinary approach. Annual cardiac monitoring by Holter-ECG and ultrasound is recommended to detect cardiac arrhythmias and signs of heart failure. Implantable cardiac monitoring might be considered in some cases. BNP (brain natriuretic peptide) may help to detect cardiac insufficiency. Diuretic drugs, beta-blockers, aldosterone antagonists and ACE (angiotensin-converting-enzyme) inhibitors might improve cardiac function. Some patients have been reported to show motor improvement on corticoid treatment but prospective studies are required to confirm these results.

Prognosis

In the first decade, respiratory insufficiency is the main cause of death. Thereafter, cardiac dysfunction and arrhythmias leading to sudden death, which are very frequent in young adults, determines the vital prognosis. Embolic complications due to conduction disorders and right heart failure may worsen the poor prognosis. Respiratory insufficiency and recurrent pulmonary infections reduce the lifespan or may lead to permanent ventilation or tracheostomy.