Three siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly

doi:10.1016/S0387-7604(98)00014-X

Brain and Development

Volume 20, Issue 3, April 1998, Pages 169-174

https://doi.org/10.1016/S0387-7604(98)00014-X Get rights and content

Abstract

We report three male siblings born with fatal encephalopathy comprising microcephaly, myoclonus and muscle hypertonia. All three patients died during infancy. Postmortem examination on the brain revealed that all infants had neuronal loss in the cerebellar cortex, inferior olivary and pontine nuclei, which were more pronounced in the older subject than the younger ones. In addition, they were associated with polymicrogyria in the cerebral cortex of the insula, olivary and dentate nuclear dysplasia, and a hypoplastic corticospinal tract. The clinical and neuropathological findings in our cases were identical to those in fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microencephaly [Albrecht et al., Acta Neuropathol 1993;85:394–399], but an association of malformations suggests a new genetic factor in pathogenesis of olivopontocerebellar hypoplasia.

Introduction

Infantile olivopontocerebellar hypoplasia (OPCH) is a group of rare neurological disorders associated with decreased numbers of neurons in the pontine and inferior olivary nuclei, and a marked reduction in the size of the cerebellum occurring at birth. Included in this group of disorders are the conditions of so-called infantile olivopontocerebellar atrophy (OPCA) and pontoneocerebellar hypoplasia, which are characterized by reductions in the neuron number and cerebellar volume. The various reported cases also differ clinically in the mode of inheritance and the associated lesions, indicating that OPCH/A is a heterogeneous group of disorders. In this report we describe three siblings in the same family who showed clinically microcephaly, myoclonus and muscle hypertonia, and neuropathologically OPCH with a hypoplastic corticospinal tract and polymicrogyria.

Section snippets

Case reports

Three siblings were born to healthy and non-consanguineous parents. There was no family history of other neurological diseases, miscarriages, infantile deaths, or developmental delay. The parents were found to be normal on physical and neurological examination.

Gross findings

Cases 1, 2 and 3 were autopsied at 5 months of age, 35 and 27 GW, respectively.

The neuropathological findings were very similar in all cases. The brains of all three cases were reduced in size and weight. The brain weights of cases 1, 2 and 3 were 145 g (controls of 5 months of age, 746 g), 135 g (controls, 327 g), and 63 g (controls, 160 g), respectively. The cerebral hemispheres were symmetrical with a gyrational pattern compatible with gestational age in each case. Sylvian fissures were

Discussion

The three male siblings described in this report had very similar clinical manifestations, including microcephaly, muscle hypertonia, myoclonus and a rapid fatal course. Neuropathological changes were also similar in three siblings, and pronounced neuronal loss in the Purkinje cell layer, external and internal granular cell layers of the cerebellum, and inferior olivary nucleus of the medulla oblongata and pontine nuclei of the pons were more remarkable in older subjects than in the younger

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Degenerative disorders of the newborn are relatively rare. Nonetheless, they are important to recognize because a few are treatable when diagnosed early. Dividing these disorders into those that primarily affect gray matter, white matter, or both is useful. Disorders of gray matter are characterized by seizures, myoclonus, spikes, or sharp activity on electroencephalogram, failure of cognitive development, and retinal disease. Some are accompanied by visceral storage including GM₁ gangliosidosis, GM₂ gangliosidosis, Niemann-Pick disease, Gaucher disease, Farber disease, and infantile sialic acid storage disease. Other gray matter disorders such as Tay-Sachs disease, congenital neuronal ceroid-lipofuscinosis, Alpers disease, and Menkes disease lack visceral storage. White matter disorders are characterized by marked motor deficits and slow activity on electroencephalogram and include Canavan disease, Alexander disease, Krabbe disease, Pelizaeus-Merzbacher disease, and Aicardi-Goutieres disease. Disorders that affect both white and gray matter often target subcellular structures (mitochondria, peroxisomes), target amino acid or neurotransmitter synthesis pathways, and can have regional selectivity for the cerebellum, pons, or basal ganglia. Examples include neonatal adrenoleukodystrophy, Zellweger syndrome, Leigh syndrome, mitochondrial encephalopathies, congenital disorders of glycosylation, pontocerebellar hypoplasias, neurotransmitter defects including serine synthesis deficiency, and Rett syndrome in males. We discuss each of these disorders briefly, focusing on clinical features, diagnosis, genetics, neuropathology, neuroimaging findings, current treatments, and emerging therapies.
Neonatal Hypertonia: II. Differential Diagnosis and Proposed Neuroprotection
2008, Pediatric Neurology
Citation Excerpt :
Most reports describe hypertonic neonates immediately after delivery as rigid or spastic as a result of chronic causes while in utero, independent to specific etiologies. Documentation of congenital brain anomalies or “remote” acquired injuries has been described on brain MRI, associated with hypertonic infants [27-29]. Overexpression of the subcorticospinal brainstem pathways without the inhibitory influence of cortical pathways is discussed in the companion article [1]; see also the Lawrence and Kuypers reviews of the effects of pyramidal and brainstem lesions [30,31].
More accurate documentation of a neonate's specific hypertonic state could be helpful as part of serial neurologic examinations. The clinician would then be in a more advantageous position to choose the appropriate neuroprotective drug or the procedure that best fits with the etiology, localization, and timing of injury. Ideally, choices for neuroprotection will integrate history, examination, and diagnostic findings before considering options for prophylaxis, neurorescue, or neurorepair. Measuring the efficacy of a neuroprotection protocol should include a complete list of life-course challenges, including motor, epileptic, cognitive, and behavioral outcomes as expressed at successively older ages.
Neonatal Hypertonia: I. Classification and Structural-Functional Correlates
2008, Pediatric Neurology
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Interactions between neocortical and cerebellar structures also require brainstem pontine nuclei [45], which provide an important interface between cerebral cortical and cerebellar structures in the establishment and refinement of motor skills at older ages. Isolated case reports suggest that hypertonic neonates can be associated with specific injuries or malformations within brainstem or cortical structures [46-50]. It has not yet been elucidated, however, what part the disruption of cerebellar pathways plays in the generation of neonatal hypertonic states, and to what degree.
Neonatal hypertonic states can be encountered as expressions of abnormal tone and posture. It would be useful for the neonatal neurointensivist to more precisely describe the various presentations of neonatal hypertonia, taking into consideration a classification scheme adopted for hypertonia in children at older ages. An understanding of the ontogeny of muscle tone and posture during fetal and postnatal preterm time periods with maturation to full-term ages will help conceptualize the developmental structural-functional correlates that subserve the evolving expression of this abnormal clinical sign. In the future, a more accurate description of neonatal hypertonic states should be part of the complete clinical examination to help integrate etiology, timing of injury, and neurologic localization before choosing the appropriate therapeutic intervention.
Pontocerebellar hypoplasia type 2: Variability in clinical and imaging findings
2007, European Journal of Paediatric Neurology
Citation Excerpt :
This difficulty of prenatal diagnosis was also experienced by Peter Barth (personal communication). In the literature there are several reports of severe neonatal variants of PCH, also categorized as type 4.6–9 There is suggestion, that these children differ by the presence of polyhydramnios, spasticity rather than hypotonia exhibited soon after birth and a severe neonatal course with respiratory and sucking insufficiency leading to early death.
We report 24 children (14 girls) who presented with the typical neuroimaging findings of pontocerebellar hypoplasia (PCH) to describe the clinical spectrum of type 2. Twenty-one presented with the classical form described by Barth; characteristic features (15/21) were breathing and/or sucking problems during neonatal period and early onset hyperkinetic movement disorder. Eighteen were normocephalic at birth, but all developed microcephaly during infancy. Development was severely affected with none of the children being capable of sitting, walking, or talking. Social contact and visual fixation were persistently poor. Dyskinetic movement disorder was present in all, in some together with mild spasticity. Seizures occurred in 14 (in 7 as neonates). Eight children died (age 1 day–6 years). Neuroimaging showed an absent or severely flattened pons, different degrees of vermian hypoplasia, with cerebellar hemispheres (wing-like structures) being equally or more affected.
Three (all girls) were less severely affected clinically and did not develop the dyskinetic movement disorder, motor and cognitive development were somewhat better. Microcephaly was also a prominent sign.
Severity of pontocerebellar neuroimaging findings did not differentiate between the typical and atypical clinical group and did not correlate with clinical outcome.
Neonatal rigid-akinetic syndrome and dentato-olivary dysplasia
2006, Pediatric Neurology
This report describes a male infant who presented since birth with rigidity and hypokinesia. Severe developmental delay, episodic central hypoventilation, and drug-resistant epilepsy progressively added to the extrapyramidal signs in the following months and led to the patient’s death at 10 months of age. Neuroradiologic and neurometabolic evaluations were negative. Normal cerebrospinal metabolites excluded a defect in dopamine metabolism, and treatment with levodopa failed to improve his motor symptoms. Neuropathologic findings demonstrated dentato-olivary dysplasia. While isolated dentato-olivary dysplasia has been described in a few cases of Ohtahara syndrome, to our knowledge, the association with infantile parkinsonism has not been previously reported.
Congenital Malformations of the Human Brainstem
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Congenital disorders of the brainstem often result in multiple severe neurodevelopmental problems. With the advent of magnetic resonance imaging and discovery of genes directing brainstem formation, a more coherent clinical picture of these disorders is emerging. Proper evaluation, management, and counseling for these disorders rests on the clinician having a framework through which to approach them.

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Original articleThree siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly

Abstract

Introduction

Section snippets

Case reports

Gross findings

Discussion

Brain Dev

Cell

Cell

Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microencephaly

Acta Neuropathol

Hypoplasia ponto-neocerebellaris

J Neurol

Congenital spongy degeneration of the brain (van Bogaert-Bertrand) associated with micrencephaly and ponto-cerebellar atrophy. (Contributions to the pathology of glial dystrophy of intrauterine origin)

Neuropaediatrie

Original article
Three siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly