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Publication Details

Title :

Further Delineation of the phenotypic spectrum of ISCA2 Defect: A Report of Ten New Cases

Journal:

European Journal of Paediatric Neurology

Impact Factor:

2.013

Authors:

Alfadhel M1, Nashabat M2, Alrifai MT3, Alshaalan H4, Al Mutairi F2, Al-Shahrani SA5, Plecko B6, Almass R7, Alsagob M7, Almutairi FB7, Al-Rumayyan A3, Al-Twaijri W3, Al-Owain M5, Taylor RW8, Kaya N9.

Affiliations:

1 Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Riyadh, Saudi Arabia. Electronic address: dralfadhelm@gmail.com.

2 Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

3 Neurology Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

4 Medical Imaging Department, King Abdullah Specialized Children Hospital, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.

5 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia.

6 Division of Child Neurology, University Children’s Hospital, Zurich, Switzerland.

7 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

8 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.

9 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address: namikkaya@gmail.com.

Year of Publication:

2017

DOI:

10.1016/j.ejpn.2017.10.003

Abstract:

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.

October 16, 2017