Background: Autosomal recessive mutations in MPV17 (OMIM *137960) have been identified in the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS). Objective: To describe the clinical, morphologic, and genetic findings in 3 children with MPV17-related MDS from 2 unrelated families. Design: Case report. Setting: Academic research. Main Outcome Measures: We identified 3 novel pathogenic mutations in 3 children. Results: Two children were homozygous for nonsense mutation p.W120X. A third child was compound heterozygous for missense mutation p.G24W and for a macrodeletion spanning MPV17 exon 8. All patients demonstrated lactic acidosis, hypoglycemia, hepatomegaly, and progressive liver failure. Neurologic symptoms manifested at a later stage of the disease. Death occurred within the first year of life in all 3 patients. Conclusions: These data confirm that MPV17 mutations are associated with a 2-stage syndrome. The first symptoms are metabolic and rapidly progress to hepatic failure. This stage is followed by neurologic involvement affecting the central and peripheral systems.

The precise mechanism for the initiation of follicle growth and progression through the earliest stages of follicle development remains largely unknown. Activins play a role during early follicle development, and evidence suggests that the extracellular matrix plays a role during later stages of follicular growth. We investigated the role of activin-A and extracellular matrix in follicle growth initiation and early follicular development in the mouse ovary. Ovaries were collected from 5-day-old mice and cultured for 10 days on polylysine, collagen, or laminin in the presence or absence of recombinant human activin-A. Follicle density, indices of follicle growth initiation (primary:primordial follicle [PY:PD] and primary:total follicle [PY:TF] ratios), ratios of multilayer follicle:total follicle (ML:TF), and follicle growth rates were compared between groups. Follicle densities were significantly higher in the extracellular matrix treatment group compared with the polylysine group (P < 0.01). Also, compared with polylysine, both collagen and laminin significantly increased indices of follicle growth initiation (PY:PD ratio: P < 0.001, odds ratio of 3.3; PY:TF ratio: P < 0.001, odds ratio of 2.5), and these were not altered by activin treatment. In the absence of activin-A, exposure to neither collagen nor laminin had an effect on multilayer follicle development. When activin-A was added, collagen and laminin had opposing effects on multilayer follicle development. Activin-A stimulated multilayer follicle development in the presence of laminin (ML:TF ratio: P = 0.01, odds ratio of 10.8), whereas it suppressed follicle growth in collagen (P = 0.01). Activin-A did not affect the ML:TF ratio in the polylysine-treated groups. These results strongly suggest that extracellular matrix components and activin-A interact with each other, and that they regulate follicle growth initiation and multilayer follicle development.

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A 6-year-old boy had progressive muscle weakness since age 4 and emotional problems diagnosed as Asperger syndrome. His mother and two older siblings are in good health and there is no family history of neuromuscular disorders. Muscle biopsy showed ragged-red and cytochrome c oxidase (COX)-negative fibers. Respiratory chain activities were reduced for all enzymes containing mtDNA-encoded subunits, especially COX. Sequence analysis of the 22 tRNA genes revealed a novel G10406A base substitution, which was heteroplasmic in multiple tissues of the patient by RFLP analysis (muscle, 96%; urinary sediment, 94%; cheek mucosa, 36%; blood, 29%). The mutation was not detected in any accessible tissues from his mother or siblings. It appears that this mutation arose de novo in the proband, probably early in embryogenesis.

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