Homozygous mutation p. Arg375X as the cause of mucolipidosis II alfa/beta: analysis of two cases

Introduction. Mucolipidosis II alpha/beta (ML IIA/B) is a rare autosomal recessive disorder from the group of lysosomal storage diseases. This is a slowly progressive multisystem pathology, which is manifested from birth and leads to the death of patients in early childhood. Here we report two cases of mucolipidosis II A/B due to homozygous p. Arg375X mutation in GNPTAB gene. Patients and methods. Patient 1 was first examined by a geneticist at the age of 9 days. Мicrocephaly, brachycephaly, craniofacial dysmorphiс features, funnel chest, hernia the white line of the abdomen, inguinal hernia, shortening and deformity of the shoulder bones, the excess folds of skin in the shoulder area, long fingers, shortening and deformity of hips, severe varus and saber deformity of the shins, fracture, pronounced folds of the skin on the thighs, heel feet, hepatomegaly were mentioned. Laboratory examination revealed thrombocytopenia and significant increase of lysosomal enzymes activity in plasma and ML II was diagnosed. At the age of 3 years and 4 months, the boy presents severe growth and psychomotor development retardation, every month he suffers from acute respiratory diseases. Dry skin, hypertrichosis of the back, shoulders, neck, craniofacial dysmorphism, short neck, barrel chest, thickening of the wrist and ankle joints, restriction of mobility of large joints, wide hands, limiting extension of the interphalangeal joints, diastasis of direct abdominal muscles, bilateral inguinal-scrotal hernia, aortic and mitral valves dysfunction, partial atrophy of the optic nerves were found. Patient 2 was first examined by a geneticist at the age of 9 months due to short stature and psychomotor development retardation. The diagnosis of ML II was made one year later. At 1 year and 10 months, the boy had global developmental delay, coarse facial features, short neck, short chest, thoracolumbic kyphosis, limited mobility in large joints, wide hands and feet, brachydactyly and camptodactyly, aortic dilatation, dysfunction of the aortic valves, mitral valve insufficiency of the 2nd degree with signs of volume overload of the left atrium; dysplasia of the left ventricle cavity and a decrease in myocardial contractility. The child often suffered from respiratory infections, which were twice accompanied by pulmonary cardiac decompensation and pulmonary edema. The boy’s life span was 3 years and 2 months. Molecular genetic studies for the search for mutations in the GNPTAB gene were performed for patient 1 and his parents, as well as for parents and healthy siblings of patient 2. The nucleotide sequence of the GNPTAB gene was analyzed by direct sequencing on an ABI 3500 automated analyzer. Results and discussion. Patient 1 turned out to be a homozygous carrier of the p.Arg375X mutation in the tenth exon of the GNPTAB gene; this allele was found in its parents in the heterozygous state. Parents of patient 2 turned out to be heterozygous carriers of the p.Arg375X mutation. Thus, the boy was obviously a homozygous carrier of this mutation. Despite the same genotype, significant differences in the course of the disease in the described patients are evident: in patient 1, the disease manifested from birth with severe dysmorphia and skeletal deformities, but the heart function remained compensated, and the first signs of valvular lesions were detected only at the age of three years and four months. The severity of the patient’s 2 condition, on the contrary, was due to increasing heart failure due to early damage to the valvular apparatus of the heart, which led to the death of the child. Conclusion. ML IIA/B is a severe progressive disease characterized by variable clinical manifestations and course of the pathological process even in patients with the same genotype. Life expectancy for ML IIA/B is determined, in accordance with our experience, by the degree of damage of the cardiovascular system. Neither the age of appearance of the first signs of the disease, nor the severity of bone pathology, are predictors of the rate of disease progression and life expectancy in patients with ML IIA/B.

муколипидоз II альфа/бета, GNPTAB, лизосомные болезни, mucolipidoses II II alpha/beta, GNPTAB, lysosomal storage disorders