Is the Next Generation Sequencing the Essential Tool for the Early Diagnostic Approach in Congenital Muscular Dystrophy? New Mutation in the Gen LMNA Associated with Serious Phenotype
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333448
Source of Support: None, Conflict of Interest: None
Keywords: Congenital muscular dystrophy, LMNA gene, new mutation
Laminopathies are a group of diseases caused by mutations in the LMNA gene, located on chromosome 1 in q21.1–21.3. This gene encodes for the nuclear envelope proteins lamin A and C, and its mutations are associated with 4 phenotypes (neuromuscular, cardiac, metabolic, and premature aging syndromes), which comprise more than 13 entities and more than 500 mutations, related to muscle, peripheral nerve, cardiac, fat, bone, and skin disorders.
A correlation between genotype and phenotype is not clearly defined. Muscle involvement is part of a continuous spectrum, with the following three well-defined entities: congenital muscular dystrophy, Emery–Dreifuss muscular dystrophy (EDMD), and limb-girdle muscular dystrophy.
The first known mutations in the lamin gene were described in 1999 in association with EDMD. In 2004, the first description of a patient with a congenital dystrophy phenotype was published. A year later, the “dropped head” syndrome was defined, but it was not until 2008 when 11 de novo heterozygous mutations in the LMNA gene were identified and a new entity was defined: LMNA-related congenital muscular dystrophy (L-CMD).
L-CMD is a rare disease, with fewer than 100 cases described. Symptoms include hypotonia and atrophy with rapidly progressing muscle paresis. The most affected children cannot hold their head, sit up, or rollover. Less affected children are initially able to walk until weakness is evident, with very early involvement of the cervical extensor musculature. Other signs include scoliosis, flexion deformities of the joints, and retractions in the elbows. Children develop respiratory involvement and severe cardiac compromise.[4–6] Isolated cases with cognitive impairment have been described, with lesions on neuroimaging. Creatine kinase (CK) levels are three or four times the normal value. Histological analysis shows dystrophic changes in 50% of cases, occasionally associated with peri-/endomysial inflammatory infiltrate, with normal lamina immunohistochemistry.
A male with normal motor development during the first year of life. By 2 years of age, he cannot run or jump and needs support to get up off the ground. At the age of 3, the patient loses fine motor skills and begins to have a gait disorder. At that time, the physical examination revealed global hypotonia, bilateral winged scapula, lumbar hyperlordosis, areflexia, hip and knee flexion posture, and positive Gowers maneuver. Progressively, he develops generalized muscle weakness with loss of neck tone, functional impairment, and inability to walk autonomously at 5 years.
The initial CK showed mildly high values (373 UL), with a normal electromyographic study. The first muscle biopsy showed a disproportion of muscle fibers. Three years later, dystrophic alterations were evidenced, with infiltration of connective and fat tissues, atrophic fibers with basophilic and necrotic plaques, and minimal mononuclear inflammatory infiltrates. Human leukocyte antigen-ABC (HLA-ABC) was positive. The immunohistochemistry for sarcoglycans, dystrophin, collagen VI, dysferlin, and merosin was normal, and the western blot of calpain. Lamin A/C immunostaining was not performed. Genetic studies for spinal cord atrophy and Steinert's disease were negative, as well as the study for Pompe's disease.
During follow-up, the patient worsened progressively. At the age of 22, he presented severe tetraparesis. He is able to write and use a computer. The patient does not have autonomy for food, hygiene, or clothing. He sleeps with splints on his legs and arms. He does not report dysphagia, although he swallows better lying down. He has been using noninvasive mechanical ventilation (nocturnal BIPAP) since June 2012. He has no current heart disease.
Current examination shows: Normal cortical functions. Cervical flexion 0/5, extension 3/5. Normal cranial nerves. Axial hypotonia and generalized atrophy, especially of the hands and feet. Several tetraparesis predominantly proximal. Global areflexia. Fixed retractions in flexion of elbows (10°) and knees (30°). Retractions in wrists and interphalangeal joints. No sensitive deficit.
A genetic panel of dystrophies was requested, and two variants were detected in the LMNA gene:
The family segregation study showed that her mother was not a carrier and her father was a carrier of the missense variant p.Arg644Cys.
The diagnosis of L-CMD is established by de novo mutation in the LMNA gene.
We present a patient with L-CMD associated with an undescribed mutation. To date, more than 20 mutations have been identified, most due to a single aa change, but few of them due to the gain or loss of several aa like in our patient., Most of the identified cases are caused by de novo mutations in exons 1 and 6, being the greatest association with heart disease, responsible for the death of these patients. In our patient, the mutation is demonstrated in exon 4, within the central rod domain (2A). A recent study raises the possibility of a relationship between mutations in exons 1, 4, and 6 (head and domain 2A) with the presence of a more severe phenotype. The relationship between the development of neuromuscular involvement and the degree of cardiac involvement is not well established. There could be a linear progression: initial arrhythmias, followed by atrioventricular block, sinus disease, and cardiomyopathy. Interstitial myocardial fibrosis is diagnosed by biopsy, although recent magnetic resonance imaging (MRI) studies, demonstrating gadolinium enhancement.
The early diagnosis of this disease, with monitoring of the cardiac involvement, allows a greater survival. It is not established whether steroids modify cardiac function. It has not been associated with an improvement in the Medical Research Council scale. They improve diarrhea from protein-losing enteropathy occasionally associated.,
The delay in diagnosis is usually motivated by the difficulty in accessing the new massive sequencing techniques, with initially nonspecific muscle biopsy, with normal immunohistochemistry. Exploratory findings, such as early loss of cervical tone and flexion contractures in the lower limbs, could help to establish an early diagnosis to anticipate the cardiac complications so frequent in this pathology.
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