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Hypoplasia of the spinal cord in a case of foetal akinesia/arthrogryposis sequences

Lethal congenital contracture syndrome (LCCS) is an autosomal recessive disease, characterized by the foetal akinesia phenotype, with multiple contractures of joints and degeneration of motor neurones in the spinal cord as the main neuropathological findings [1–5]. Recent studies have shown that the defective gene underlying the lethal motor neurone syndrome LCCS1 is the mRNA export mediator GLE1 [6,7]. Herein we report a case showing generalized arthrogryposis and severe hypoplasia of the spinal cord, but without any definitive mutations in the GLE1 gene. The subject of this study was a Japanese female baby, showing akinesia and contracture of the joints of the upper and lower extremities, which were detected by foetal ultrasonography at 12 weeks of gestation. The subject had no remarkable family history, and the previous medical histories of her parents showed no marked or abnormal events. The subject was stillborn at 21 weeks, 3 days of gestation, with a birth weight of 230 g (353 125 g, according to the standards for measurements of stillborn infants [8]), and showing several contracture deformities, including hyperflexion of the bilateral elbows, campylodactyly, hyperflexion of the knees and ankles, a dislocated hip joint, an abnormally flexed knee and ankle, and rocker-bottom feet, but no pterygia (Figure 1A). The ribs were thin, with a herringbone-like pattern (Figure 1B). The brain was dolicocephalic and the hemispheres were separated with a primitive sylvian fissure. A premature dip of the Rolandic sulci was observed on the brain surface (Figure 1C). The sizes of the cerebral cortex, basal ganglia, thalamus, midbrain and pons were normal for the gestational age. Petechiae were observed in the subventricular zone of the occipital cortex. The spinal cord was extremely thin from the cervical to the sacral level (Figure 1D). The cerebellar hemispheres and caudal medulla were also small for the gestational age. Histologically, the spinal cord was small throughout its entire length, with thin anterior and posterior roots (Figure 1J). Premature motor neurones were observed in the anterior horn, but these were fewer in number than normal, with a reduced cell size and poor immunoreactivity for b-III tubulin (Tuj1) (Figure 1K,L). The posterior horn and anterior and lateral fasciculi were developed, but the posterior fasciculus was poorly developed with a normal dorsal ganglion. The volume of the motor nucleus of the facial nerve was relatively spared, but the hypoglossal nucleus and the nucleus ambiguus were hypoplastic, showing poorly differentiated motor neurones (Figure 1I). No destructive changes, microglia/ macrophage infiltration or gliosis were seen. In the putamen, bilateral multiple cystic changes were observed, containing swollen microglia/macrophages, and accompanied by a low number of neurones (Figure 1G,H). Similar cystic changes were also found bilaterally in the internal capsule. The cerebellar hemisphere was small for the gestational age, although it was composed of premature Purkinje cells and an external granule layer. The deep nuclei, such as the dentate nucleus, were normally formed. The dorsal forebrain was histologically normal, being composed of the cortical plate, the subplate, and the intermediate, subventricular and ventricular zones (Figure 1E,F). No evidence of either abnormal migration or heterotopia was observed. The caudate nucleus, pallidum and thalamus were normal. The pontine nuclei, the inferior olivary nucleus and the pyramids in the medulla were normal. The muscle fibres of the iliopsoas muscle and diaphragm showed group atrophy with a large number of round and small muscle fibres. The genetic analysis of GLE1 revealed heterozygous mutation of the A841G (Ile243Val) (Figure 2). However, it is not clear whether or not the A841G mutation was responsible for the phenotype seen in the present case. Neuropathological analysis in LCCS1 showed a lack of anterior horn motor neurones, severe atrophy of the ventral spinal cord, and hypoplastic, but nearly absent skeletal muscles [1–4]. Another clinical phenotype, slightly milder but also characterized by foetal akinesia, arthrogryposis and motor neurone loss, is known as lethal arthrogryposis with anterior horn cell disease (LAAHD) [9]. In this case, the neuropathological findings in LAAHD resembled those of LCCS1, but they were less severe. Although the pathogenesis of foetal akinesia might vary, depending upon the underlying disease, including disorders in motor neurone development and