Case Report: Gamma-Sarcoglycanopathy Plus RYR1- and TCAP-Mutations: Do Further Mutations Explain Clinical Variations in Phenotypes of Neuromuscular Diseases?

Background: Gamma-sarcoglycanopathy (LGMD2C) is caused by SGCG gene mutations and manifests in the first ten years as a progredient limb girdle muscular weakness. Loss of ambulation, cardiomyopathy and respiratory distress subsequently develop during adolescence, milder phenotypes are described as well. We report a case of severe gamma-sarcoglycanopathy with early cardiac involvement in a toddler.

Case Report: Second child of healthy, unrelated Moroccan parents, 8-month-old girl, presented with highly elevated creatine kinase (CPK) up to 36.000 U/L (<180 U/L) and mild motor development delay. At 13 months, left ventricular hypertrophy in echocardiography, 3 months later ECG showed ST elevation. Now, at 20 months, exercise-induced myalgia and pseudohypertrophy of the calves. The first daughter suddenly died at age of two in Morocco, autopsy findings: hepatomegaly and pericardial thickening. Diagnostics: Disclosed muscle specimen (M. vastus lateralis right) with dystrophic changes. Immunohistology staining: dystrophin (ab 1–3), α-/β-dystroglycan, α-/β-/&δ-sarcoglycan with reduced expression; for γ-sarcoglycan no expression. Genetics: MLPA-analysis/point mutation analysis of the DMD gene: unsuspicious. Myopathy gene panel: homozygous pathological mutations c.525delT in the SGCG gene. Both parents: carriers of the SGCG mutation. Furthermore, heterozygous, probably pathological mutations in the RYR1 gene (dominant function): c.14482C>G (detected also in the father) and in the TCAP gene (dominant function in association with cardiomyopathies): c.209G>A (also mother).

Conclusion: The severe course of our patient with cardiac involvement under the age of 2 years is very uncommon in gamma-sarcoglycanopathy. This may be caused in concert with other mutations in the TCAP gene and the RYR1 gene.