Peripheral nervous system defects in a mouse model for peroxisomal biogenesis disorders.

Peroxisome biogenesis disorders (PBD) are autosomal recessive disorders in humans characterized by skeletal, eye and brain abnormalities. Despite the fact that neurological deficits, including peripheral nervous system (PNS) defects, can be observed at birth in some PBD patients including those with PEX10 mutations, the embryological basis of the PNS defects is unclear. Using a forward genetic screen, we identified a mouse model for Pex10 deficiency that exhibits neurological abnormalities during fetal development. Homozygous Pex10 mutant mouse embryos display biochemical abnormalities related to a PBD deficiency. During late embryogenesis, Pex10 homozygous mutant mice experience progressive loss of movement and at birth they become cyanotic and die shortly thereafter. Homozygous Pex10 mutant fetuses display decreased integrity of axons and synapses, over-extension of axons in the diaphragm and decreased Schwann cell numbers. Our neuropathological, molecular and electrophysiological studies provide new insights into the embryological basis of the PNS deficits in a PBD model. Our findings identify PEX10 function, and likely other PEX proteins, as an essential component of the spinal locomotor circuit.

Development of early postnatal peripheral nerve abnormalities in Trembler-J and PMP22 transgenic mice.

Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated with peripheral neuropathy in mice and humans. Although PMP22 is strongly expressed in peripheral nerves and is localised largely to the myelin sheath, a dual role has been suggested as 2 differentially expressed promoters have been found. In this study we compared the initial stages of postnatal development in transgenic mouse models which have, in addition to the murine pmp22 gene, 7 (C22) and 4 (C61) copies of the human PMP22 gene and in homozygous and heterozygous Trembler-J (TrJ) mice, which have a point mutation in the pmp22 gene. The number of axons that were singly ensheathed by Schwann cells was the same in all groups indicating that PMP22 does not function in the initial ensheathment and separation of axons. At both P4 and P12 all mutants had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. C22 and homozygous TrJ animals could be distinguished by differences in the Schwann cell morphology at the initiation of myelination. In homozygous TrJ animals the Schwann cell cytoplasm had failed to make a full turn around the axon whereas in the C22 strain most fibres had formed a mesaxon. It is concluded that PMP22 functions in the initiation of myelination and probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities may result from a failure of differentiation but more probably from defective interactions between the axon and the Schwann cell.

Intrauterine onset of a mononeuropathy: peroneal neuropathy in a newborn with electromyographic findings at age one day compatible with prenatal onset.

Mononeuropathies are unusual at birth, and electromyographic (EMG) definition the first day of life has not been reported previously. Although neonatal mononeuropathies may be related to obstetric complications, prenatal mechanisms also merit consideration. We report an infant, born with a peroneal neuropathy, whose EMG was performed 18 h after birth. An isolated peroneal nerve lesion with lack of compound muscle action potential and the presence of fibrillation potentials, confined to the tibialis anterior muscle, suggested a primary intrauterine mechanism for this mononeuropathy. Because of an infant's small size, the temporal profile used in adults for appearance of EMG signs of wallerian degeneration may not apply. Inaccurate conclusions may result if the EMG standards for timing adult nerve injury are applied to newborns. To our knowledge, previous published cases of neonatal mononeuropathies have not included babies whose first EMG was performed before age 4 days. Therefore, an EMG study shortly after birth needed to be accomplished if strong support for the hypothesis of a prenatal onset were to be generated. Our findings are compatible with an intrauterine onset of this baby's peroneal neuropathy.

Neurotoxic effects of 2,5-hexanedione on rapidly growing unmyelinated peripheral nerve axons of a rat fetus: dose-effect relationship.

To investigate the potential neurotoxicity of 2,5-hexanedione (2,5HD) on developing axons we examined peripheral nerves of rat fetuses. Pregnant female Sprague-Dawley rats were injected subcutaneously with 680 mg/kg of 2,5HD once a day from Day 12 of gestation (GD12) to GD16 in one group and with 340 mg/kg of 2,5HD once a day from GD12 to GD20 in the other group. On GD20 live fetuses were removed from the uteri and their sciatic nerves were examined morphologically. By electron microscopical observations, affected nerves revealed axons which were aggregated and fused together, but there were no axons aggregated with neurofilaments. The diameter distributions of axons revealed an increase in the number of small-size axons in the nerves of the 340 mg/kg group and showed an enlargement of part of the axons in the nerves of the 680 mg/kg group, suggested by the appearance of a second peak at a diameter larger than that of the first peak.

Effects of ethanol exposure on myelination and axon numbers in the L2 dorsal root of the neonatal rat.

Previous studies have demonstrated that exposure to ethanol during development delays the rate at which axons in certain central nervous system tracts acquire myelin. This delay appears to be related to an alteration in oligodendrocyte function and not to an aberrancy in axon size or number. The present study was designed to determine if alterations similar to those observed in the central nervous system also occur in peripheral nerves, specifically the L2 dorsal root. Dams were fed either an ethanol-containing or control liquid diet 2 weeks prior to pregnancy and throughout gestation. The pups born to the pregnant dams were artificially reared from postnatal day (PD) 4 to PD 10 on a similar ethanol-containing or control diet. The pups were sacrificed on PD 10, L2 dorsal roots removed and processed for electron microscopy. The numbers of axons in various states of myelination were quantified. No difference was observed in the number of unmyelinated axons in the L2 dorsal roots from ethanol-exposed and control pups. In roots from ethanol-exposed pups, there was a significant decrease in the number of axons possessing myelin arranged in compact lamellae, but a significant increase in the number of axons surrounded by myelin lamellae in which the Schwann cell cytoplasm had not yet been extruded (noncompact). However, when the number of axons possessing noncompact myelin and a compact myelin sheath were summed, no significant difference was observed. These data suggest that the delay in myelination following ethanol exposure may be a ubiquitous phenomenon throughout the nervous system.

Polyaxonal myelination in developing dystrophic and normal mouse nerves.

Myelin-forming Schwann cells in the peripheral nervous system characteristically surround and myelinate only single axons. Polyaxonal myelination is an anomaly of this one-to-one relationship whereby one normal-appearing Schwann cell myelinates multiple axons. We examined the ventral roots and the proximal sciatic and posterior tibial nerves of developing normal mice and of dy2J/dy2J dystrophic mice with proximal failure of myelination. Polyaxonal myelination was a rare feature in normal nerves. Examples of polyaxonal myelination were observed six times more often in dystrophic than in normal mice and were most abundant in proximal sciatic nerves. Polyaxonal myelination could result from either an axonal or a Schwann-cell abnormality, or it may be the nonspecific response of uncommitted Schwann cells to an early failure of myelination.

Segmental embryonic peripheral neuropathy.

Based on a new interpretation of the radiology, the author has proposed the hypothesis that reduction deformities of the limbs are of sensory neuropathic origin. This hypothesis is examined in terms of the segmental sensory innervation of the skeleton. The predicted effect of sclerotome subtraction is compared with the radiological malformations, and is found to support the hypothesis.