Daniella Nishri1, Simon Edvardson2, Dorit Lev3, Esther Leshinsky-Silver4, Liat Ben-Sira5, Marco Henneke6, Tally Lerman-Sagie7, Lubov Blumkin8. 1. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Child Development Center, Central District, Maccabi Health Services, Tel Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel. 2. Pediatric Neurology Unit, Hadassah Medical Center, Jerusalem, affiliated to Hebrew University, Jerusalem, Israel. 3. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel. 4. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel; Molecular Genetics Laboratory, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5. Pediatric Radiology Unit, Tel Aviv Medical Center, Tel Aviv, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 6. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Germany. 7. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel. 8. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address: luba.blumkin@gmail.com.
Abstract
INTRODUCTION: There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging. PATIENT AND METHODS: We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed. RESULTS: The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease. CONCLUSIONS: Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.
INTRODUCTION: There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging. PATIENT AND METHODS: We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed. RESULTS: The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease. CONCLUSIONS: Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.
Authors: Saskia B Wortmann; David A Koolen; Jan A Smeitink; Lambert van den Heuvel; Richard J Rodenburg Journal: J Inherit Metab Dis Date: 2015-03-04 Impact factor: 4.982