A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients.

MICU1 encodes a Ca2+ sensing, regulatory subunit of the mitochondrial uniporter, a selective calcium channel within the organelle's inner membrane. Ca2+ entry into mitochondria helps to buffer cytosolic Ca2+ transients and also activates ATP production within the organelle. Mutations in MICU1 have previously been reported in 17 children from nine families with muscle weakness, fatigue, normal lactate, and persistently elevated creatine kinase, as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts. In this study, we report the clinical features of an additional 13 patients from consanguineous Middle Eastern families with recessive mutations in MICU1. Of these patients, 12/13 are homozygous for a novel founder mutation c.553C>T (p.Q185*) that is predicted to lead to a complete loss of function of MICU1, while one patient is compound heterozygous for this mutation and an intragenic duplication of exons 9 and 10. The founder mutation occurs with a minor allele frequency of 1:60,000 in the ExAC database, but in ~1:500 individual in the Middle East. All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive, as well as additional variable features we tabulate. Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes. Our work helps to better define the clinical sequelae of MICU1 deficiency. Furthermore, our work suggests that targeted analysis of the MICU1 founder mutation in Middle Eastern patients may be warranted.

Mucolipidosis II: first report from Saudi Arabia.

BACKGROUND AND OBJECTIVES: Mucolipidosis II (MLII) is characterized by severe global developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. It is caused by a deficiency in N-acetylglucosamine-1 phosphotransferase. DESIGN AND SETTINGS: This is a case series study conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2008-2012. PATIENTS AND METHODS: We described three unrelated Saudi children who presented with neonatal hyperparathyroidism, microcephaly, craniosynostosis, coarse facial features, cardiac involvement, and skeletal deformities. RESULTS: The MLII diagnosis was confirmed by assaying enzyme activities in fibroblasts, which showed a severe reduction in hydrolyzed substrates compared to controls, and by identifying a pathogenic homozygous GNPTAB gene mutation. One of the children died at 2 months of age due to severe pulmonary hypertension, and the other two children were still alive at 12 months and 18 months of age, respectively. Both surviving children had severe global developmental delay at 2 months of age. CONCLUSION: Clinicians should investigate any child presenting with neonatal hyperparathyroidism, craniosynostosis, skeletal deformities, and coarse facial features for MLII.