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.

Passive immunization.

Passive immunization employs preformed antibodies provided to an individual that can prevent or treat infectious diseases. There are several situations in which passive immunization can be used: for persons with congenital or acquired immunodeficiency, prophylactic administration when there is a likelihood of exposure to a particular infection, or treatment of a disease state already acquired by the individual. Passive immunization is limited by short duration (typically weeks to months), variable response, and adverse reactions. This article focuses on specific immunoglobulins for preventing or treating infectious diseases, as these are the most likely scenarios one might encounter in primary care practice.

Diagnosis of childhood cancer.

Childhood cancer is uncommon but remains the leading cause of disease-related death in children. Symptoms are often vague or insidious; they may suggest a more common alternative diagnosis, and they are quite different from those associated with adult malignancy. The skilled office practitioner must consider cancer as a diagnosis when symptoms/signs persist or when multiple symptoms point toward a possible diagnosis of malignancy. Early diagnosis is critical, as survival rates have increased dramatically over the past decades. Prolonged delay in diagnosis is common, especially for brain tumors and certain lymphomas (Hodgkin disease). When one encounters symptoms suspicious for a childhood malignancy, it is imperative that the child be referred to a pediatric cancer center. These centers possess not only the ability to further evaluate and manage children with malignancy, but also are able to provide support for patients and their families. This evaluation may include further imaging, but often involves obtaining tissue for histologic review. This will require appropriate tumor or bone marrow biopsy, preferably before the start of treatment. Depending upon the type of suspected malignancy, direct tumor biopsy can be facilitated by imaging-guided biopsy (ultrasound, CT, or MRI), which spares the patient additional surgery. This optimally is performed by a skilled team: hematologist/oncologist, surgeon, radiologist, and pathologist. Best results depend upon early referral by the thoughtful practitioner.