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Phenotypic heterogeneity in two unrelated Danon patients associated with the same LAMP-2 gene mutation
E Bertini1, M A Donati, P Broda
1Unit of Molecular Medicine, Division of Metabolism, Bambino Gesù Children's Hospital Rome and Palidoro, Italy. ebertini@tin.it.
Abstract:
Danon disease, an X-linked cardioskeletal myopathy caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2), is clinically characterized by cardiomyopathy, myopathy, and variable mental retardation. The pathological hallmark of the disease is the absence of LAMP-2 immunohistochemical staining in muscle. The LAMP-2 gene mutations reported thus far are generally private mutations. We describe two cases of Danon disease with different clinical presentation, in whom we identified the same exon skipping mutation c.928G>A in the LAMP-2 gene. The first patient was affected by an early onset myopathy and hypertrophic cardiomyopathy (HCM) that partially improved with drug treatment. A first muscle biopsy at age 4 months showed markedly increased glycogen, and acid maltase deficiency was ruled out biochemically. A second muscle biopsy, performed at age 3(1/2) years, showed very mild abnormalities. The second child at age 15 years had mild, diffuse muscle weakness and wasting, moderate mental deficiency, and HCM. Two serial biopsies performed at age 8 and 15 years showed similar findings of multiple esterase-positive vacuoles in type I myofibers. In both patients the immunohistochemical study demonstrated the absence of LAMP-2 in skeletal muscle.
Insights
Danon disease, a genetic disorder affecting muscle and heart, stems from LAMP-2 gene mutations. This study identifies a shared mutation in two patients with varied symptoms, highlighting diagnostic challenges.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Danon disease is an X-linked cardioskeletal myopathy resulting from lysosome-associated membrane protein-2 (LAMP-2) deficiency.
- Clinical manifestations include cardiomyopathy, myopathy, and intellectual disability, with absent LAMP-2 on muscle biopsy being a key diagnostic feature.
- Mutations in the LAMP-2 gene are typically private, making genetic diagnosis complex.
Observation:
- Two unrelated patients with Danon disease presented with distinct clinical phenotypes.
- The same exon skipping mutation (c.928G>A) in the LAMP-2 gene was identified in both individuals.
- Muscle biopsies revealed varying degrees of abnormalities, including increased glycogen and esterase-positive vacuoles, with absent LAMP-2 immunohistochemical staining.
Findings:
- Despite different clinical presentations, both patients shared the c.928G>A LAMP-2 gene mutation.
- The first patient showed early-onset myopathy and hypertrophic cardiomyopathy (HCM), with some improvement after treatment.
- The second patient exhibited milder muscle weakness, moderate intellectual deficiency, and HCM, with consistent biopsy findings over time.
Implications:
- This case series underscores the genetic heterogeneity and variable expressivity of Danon disease.
- Identifying a shared mutation in patients with diverse clinical courses emphasizes the need for comprehensive genetic analysis in suspected cases.
- Understanding the molecular basis of Danon disease aids in accurate diagnosis and potentially informs therapeutic strategies for this rare genetic disorder.
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