Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.

Comprehensive vestibular and balance testing in the dizzy pediatric population.

OBJECTIVE: To describe the spectrum of balance disease in a large population of children presenting to a tertiary care vestibular and balance laboratory. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care pediatric hospital. MAIN OUTCOME MEASURES: Results of audiometric, vestibular, and balance tests and final diagnosis. SUBJECTS AND METHODS: Retrospective review of audiometric, vestibular, balance testing, and final diagnosis from a patient database. RESULTS: Between September 2003 and September 2007, 132 children were evaluated at the Alfred I. duPont Hospital for Children Vestibular Disorders Program. Sixty-nine of the patients were boys and 63 were girls. The average age was 9.7 ± 5.0 years (range, 1-17 years). Although not all were able to complete the entire test battery (99 children completed at least 50% of the tests in the protocol), a diagnosis was achieved in most cases. The most common diagnoses were peripheral vestibulopathy (29.5%), migraine/benign recurrent vertigo of childhood (24.2%), motor/developmental delay (10.6%), traumatic brain injury (9.8%), and central nervous system structural lesion (9.1%). CONCLUSIONS: Peripheral vestibular deficits and migraine disease account for most of the pathology in the pediatric population. With a multidisciplinary approach, diagnosis of the source of vertigo and imbalance is possible in most children.