Severe form of congenital cerebral and cerebellar atrophy: a neurodegenerative disorder of fetal onset.

Infantile olivopontocerebellar atrophy (OPCA) is a rare congenital disorder likely due to an intrauterine neurodegenerative condition. Characteristic presentations are failure to thrive, cerebellar ataxia, respiratory insufficiency, and hypotonia or hypertonia. A few cases with severe manifestations (eg, the Pena-Shokeir phenotype) presenting in the neonatal period have also been reported. We present a case of infantile OPCA with the Pena-Shokeir II phenotype and severe atrophy of the cerebellum and cerebral hemispheres. Comparison of prenatal sonographic findings of the fetal brain at 30 weeks' menstrual age and CT findings during the neonatal period indicated prenatal onset of the neurodegenerative process, which progressed rapidly during the last trimester.

Fatal outcome in a case of pontocerebellar hypoplasia type 2.

Pontocerebellar hypoplasia (PCH) is a very rare congenital (autosomal recessive) condition with fetal onset. Only a few cases have been published on the basis of both clinical data (symptoms/neuroradiological imaging) and autopsy results. This paper reports on such a case involving a 1.5-year-old male infant. The child suffered from severe psychomotor delay, extrapyramidal dyskinesia and epileptic seizures, but did not exhibit signs of spinal muscular atrophy as related to PCH type 1. Magnetic resonance imaging (MRI) at the age of 6 months demonstrated olivo-pontine and bilateral cerebellar hypoplasia. The boy was unexpectedly found dead. Autopsy disclosed a severe aspiration of gastric contents as the final cause of death. The neuropathological examination confirmed PCH type 2 (according to Barth [Brain Dev., 15 (1993) 411-422]) with marked microcephaly and olivopontocerebellar hypoplasia. Histologically, decreased density of olivo-pontine neurons, reduction of granular and Purkinje's cell layers of the cerebellum, slight astroglial proliferation and fragmented appearance of the dentate nuclei were observed. The immunohistochemical expression pattern was determined using antibodies against glial fibrillary acidic protein, synaptophysin and neurofilament protein. Summarizing, typical features of PCH type 2 were present and proved by clinical course, MRI and autopsy. Despite severe symptoms due to a natural disease this rare neurogenetic entity can become of forensic interest, when sudden unexpected death occurs.

Pontocerebellar hypoplasia associated with respiratory-chain defects.

Pontocerebellar hypoplasias are congenital disorders of brain morphogenesis which include such diverse etiologies as carbohydrate-deficient glycoprotein syndrome type 1, cerebromuscular dystrophies (Walker-Warburg syndrome, Fukuyama syndrome, muscle-eye-brain disease) and at least two types of autosomal recessive neurodegenerations known as pontocerebellar hypoplasia type I and II. Pontocerebellar hypoplasia type 1 is a lethal phenotype and clinical features include congenital contractures, respiratory insufficiency, central and peripheral motor dysfunction and spinal anterior horn degeneration. Type 2 is characterized by progressive microcephaly, extrapyramidal dyskinesia and normal spinal cord findings. In this paper, we describe a girl, born at 33 weeks of gestation, presenting with respiratory insufficiency and multiple contractures. MRI scan of the brain demonstrated pontocerebellar hypoplasia and cortical and diffuse periventricular white matter abnormalities. Postmortem examination showed pontocerebellar hypoplasia with extensive gliosis of the periventricular white matter and of the basal ganglia with normal spinal cord findings. Histology of skeletal muscle was normal. Biochemical analysis demonstrated multiple deficiencies of respiratory chain enzymes in skin fibroblasts. This case demonstrates a lethal phenotype of pontocerebellar hypoplasia without spinal cord abnormalities associated with a respiratory-chain disorder. The diagnostic workup in a patient whose brain image shows pontocerebellar hypoplasia should include a search for respiratory-chain impairment.

Congenital olivopontocerebellar atrophy: report of two siblings with paleo- and neocerebellar atrophy.

We report two sisters with congenital olivopontocerebellar atrophy, including immunohistochemical studies of autopsy brain tissue. Both cases showed microcephaly with disproportionately marked hypoplasia of the posterior fossa structures including pons, inferior olivary nuclei, and cerebellum. Microscopically, the pons was atrophic with near total loss of pontine nuclei and transverse pontocerebellar tracts (inferior and middle cerebellar peduncles). The medulla showed absent inferior olivary and arcuate nuclei. The cerebellum showed hypoplasia with rudimentary dentate nuclei, profound loss of Purkinje cells and external granule cell layer, a sparse internal granule cell layer of the entire dorsal vermis and the dorsal portions of the lateral folia, as well as markedly reduced underlying axon fibers in the white matter with marked astrogliosis. These features were highlighted by immunohistochemical study using antibodies against Purkinje cell epitopes, synaptophysin, neurofilament, glial fibrillary acidic protein, and tuberin. The cerebral hemispheres were unremarkable. Our cases are characterized by a pattern of diffuse posterior cerebellar involvement that has rarely been described in previous reports. An autosomal recessive pattern of inheritance is suggested. The abnormalities may result from antenatal degeneration or atrophy of neurons in the involved sites rather than hypoplasia or developmental arrest starting in the second and third month of late embryonic life.

Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset.

Cerebellar hypoplasia is common to a variety of congenital disorders. Both stable conditions and progressive (degenerative) disorders may cause cerebellar hypoplasia. Pontocerebellar hypoplasia (PCH) is distinct from cerebellar hypoplasias in general, because the ventral pons is affected. Reviewing both clinical and neuropathological evidence, two specific neurogenetic entities are delineated. It is proposed to call these, respectively, type 1 (PCH-1) and type 2 (PCH-2). In type 1 the hallmark is the presence of spinal anterior horn degeneration similar to Werdnig-Hoffmann disease. Presentation in the neonatal period is characterized by respiratory insufficiency, frequent congenital contractures, and a combination of central and peripheral motor signs. Patients die early, usually before 1 year of age. In type 2 the hallmark is the presence of chorea/dystonia, which is often severe, while spinal anterior horn pathology is absent. Patients have microcephaly and severely impaired mental and motor development. They frequently die during childhood. Neuronal degeneration in both types of PCH is non-specific. Reactive changes in the degenerated parts appear more extensive in type 1. Examples of both types are given. Differentiation of the two types appears straightforward and possible by clinical means. Carbohydrate-deficient glycoprotein syndrome, one other cause of (ponto)cerebellar hypoplasia, should be excluded in all cases of PCH by appropriate means.

Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs.

This report describes the clinical and neuropathological features in male and female sibs who died shortly after birth as a result of frequent convulsions and lack of spontaneous respiratory effect. Both sibs had a prominent occiput with mild contractures and the female also had overlapping fingers and rockerbottom feet. The genetic and neuropathological findings were consistent with a diagnosis of an autosomal recessive form of olivopontoneocerebellar hypoplasia/atrophy.

Neocerebellar hypoplasia with systemic combined olivo-ponto-dentatal degeneration in a 9-day-old baby: contribution to the problem of relations between malformation and systemic degeneration in early life.

Three different cerebral alterations, apparently formed consecutively, were observed in a 9-day-old baby. Marked cortico-neocerebellar hypoplasia was seen in a relatively well-developed paleocortex. Its teratological stage was apparently the 3rd fetal month. Almost total nerve cell loss and marked proliferation of protoplasmic and fibrous astrocytes were found in the nuclei pontis and inferior olive. Perihypoglossal and pararaphal nuclei, which are related to the cerebellum, were also affected. This degenerative process must have resulted from neuronal deprivation or inactivity, as the pertinent cortico-cerebellar area was hypoplastic, and therefore any neuronal imput was impossible (olivo-ponto-dentatal degeneration due to cortico-cerebellar hypoplasia). Massive symmetrical necrosis in the cerebral white and grey matter, basal ganglia, midbrain and bulbus, is interpreted as hypoxic damage due to perinatal convulsive attacks and cessation of respiration.