Cavitating Leukoencephalopathy With Posterior Predominance Caused by a Deletion in the APOPT1 Gene in an Indian Boy

Abstract

A 5-year-old Indian boy presented with subacute onset regression of milestones associated with seizures and spasticity. The symptoms started after an attack of measles. The magnetic resonance imaging (MRI) of the brain showed cavitating leukodystrophy with posterior predominance. Molecular analysis of the APOPT1 gene, a recently described gene associated with mitochondrial leukodystrophy, showed the patient to be homozygous for a 12.82-kilobase deletion, including coding exon 3. Deletion of exon 3 produces a frameshift, predicting the translation of a truncated protein (p.Glu121Valfs*4). The patient was started on mitochondrial cocktail regimen of thiamine, riboflavin, coenzyme Q and carnitine. Although he initially showed some improvement, he died 6 months after the onset of his illness.

APOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS

“…Despite being targeted to mitochondria, the expression levels evaluated by immunofluorescence of APOPT1‐203‐M1 GFP and APOPT1‐203‐M14 GFP were lower than the full‐length APOPT1‐201 version in all the tested cell lines (), and the HA‐tagged versions were undetectable by Western blot and immunofluorescence (), which suggests that the protein is not folding correctly and is rapidly degraded. This idea was reinforced by the fact that deletion of APOPT1 exon 3 causes the pathological phenotype of COX deficiency and encephalopathy (Melchionda et al , ; Sharma et al , ). Both APOPT1‐201‐M1 and APOPT1‐201‐M14 tagged with HA and GFP produce the same size proteins (), being both targeted to mitochondria, leading to the conclusion that the starting methionine is M14, as was proposed in our original report (Melchionda et al , ).…”

COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

“…We describe the eighth patient known to date with pathogenic mutations in COA8 (table). 2,3 The remarkable clinical course with rapid clinical deterioration affecting both cognitive and motor functions over months followed by stabilization and slow improvement over several years appears to be a characteristic finding in this disease since it has been described in some of the 7 previously reported cases (table). 2,3 This benign course is otherwise unusual in mitochondrial encephalomyopathies with isolated COX deficiency.…”

“…2,3 The remarkable clinical course with rapid clinical deterioration affecting both cognitive and motor functions over months followed by stabilization and slow improvement over several years appears to be a characteristic finding in this disease since it has been described in some of the 7 previously reported cases (table). 2,3 This benign course is otherwise unusual in mitochondrial encephalomyopathies with isolated COX deficiency. 1 In addition, the MRI findings showing cavitating leukoencephalopathy affecting mainly the posterior parts of the white matter and the adjacent corpus callosum and sparing the infratentorial regions seem to be a very characteristic pattern and different from other cavitating leukoencephalopathies (table 1).…”

“…One child died 6 months after disease onset because of aspiration pneumonia. 3 In this study, we describe a 25-year-old woman presenting in late infancy with leukoencephalopathy, COX deficiency, and loss of complex IV subunits associated with a homozygous nonsense mutation in COA8. Follow-up including repeat muscle biopsy and clinical investigations revealed a period with regression, followed by stabilization and partial improvement over the years.…”

“…Loss of function mutations in APOPT1/COA8 (hereafter COA8) encoding cytochrome c oxidase assembly factor 8 have been associated with cavitating leukoencephalopathy with COX deficiency in 7 reported individuals. 2,3 The disease was characterized by onset in childhood or adolescence of a leukoencephalopathy with cystic lesions predominantly in the posterior part of the cerebrum and sparing of the infratentorial parts of the brain. The presentation has been variable with an acute encephalopathy in early childhood or subtle neurologic signs in adolescence.…”