Pontocerebellar hypoplasia

Peter G Barth MD PhD (Dr. Barth of the University of Amsterdam has no relevant financial relationships to disclose.)
Joseph R Siebert PhD, editor. (Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.)
Originally released January 19, 1995; last updated October 9, 2017; expires October 9, 2020

This article includes discussion of pontocerebellar hypoplasia, pontoneocerebellar hypoplasia, spinal muscular atrophy, chorea, and microcephaly. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Pontocerebellar hypoplasias represent a heterogenous group of inherited progressive neurodegenerative disorders with fetal onset and autosomal recessive inheritance. Their common characteristic is prenatal onset hypoplasia or atrophy of the cerebellum and pons as pictured by MRI and a clinical course resulting in progressive microcephaly and severe motor and cognitive impairments. Ten types have been defined (PCH 1 to 10) as well as numerous subtypes. Gene defects associated with all types and subtypes have been identified. PCH1, PCH2, PCH4, and PCH6 are the most frequently reported types. Not enough patients have been identified with types 7 to 10 for a full characterization of their clinical course. The X-linked MicPCH (microcephaly pontocerebellar hypoplasia) due to CASK mutations is etiologically unrelated to the former, because it is not regressive but malformative in its mechanism, but it is discussed here because of similarities in MR presentation. In this updated article, the author provides coverage of these subtypes. Milder expression of the gene defects that cause pontocerebellar hypoplasia may result in a modified picture of cerebellar hypoplasia reminiscent of postnatal onset cerebellar atrophy without attenuation of the pons, and the cerebellar volume approaching the level seen in hereditary cerebellar ataxias. Pontocerebellar hypoplasia also involves supratentorial structures, causing microcephaly, severe intellectual delay, and central motor deficits. A typical aspect of all pontocerebellar hypoplasias is the predominance of supratentorial symptoms, rather than cerebellar symptoms. The author has a special interest in pontocerebellar hypoplasias and has contributed to their classification, their neuropathology, and the identification of the genetic basis of types 1, 2, 4, and 5.

Key points

 

• Pontocerebellar hypoplasias represent a heterogenous group of autosomal recessive progressive disorders characterized by fetal onset of pontine and cerebellar growth impairment and microcephaly. Clinical findings are varied but include symptoms of supratentorial involvement, including microcephaly, intellectual impairments and involvement of long tracts. In some subtypes, not enough clinical data are available for an elaborate clinical characterization. Extracranial dysmorphisms and visceral involvement are absent.

 

• Less severe cases, corresponding to milder defects of the associated genes, may display less severe cerebellar hypoplasia and normal aspect of the pons, evoking similarity in imaging aspects, but not in symptomatology to the spinocerebellar ataxias (SCA).

 

• Neurologic expression includes anterior spinal horn impairment in type 1 and its subtypes.

 

• Differential diagnosis is large and includes tubulinopathies, CASK deficiency, congenital brainstem disconnection, and pontine tegmental cap dysplasia, dystroglycanopathies in congenital disorders of glycosylation.

 

• The group includes 10 distinct types, not including subtypes.

 

• In 2 types (PCH1 due to SLC25A46 mutations, PCH6), mitochondrial functions are involved.

Historical note and terminology

The first mention of pontocerebellar hypoplasia in a neuropathologic treatise by Brun in 1917 antedates clinical awareness of that entity by 5 to 6 decades (Brun 1917). Pathologic studies by Brouwer, Koster, and Krause delineated an entity consisting of general hypoplasia of the cerebellar hemispheres, lack of development of primary and secondary folia with relative sparing of vermis, flocculi, and paraflocculi, and ventral pontine hypoplasia or atrophy (Brouwer 1924; Koster 1926; Krause 1929). The main microscopic findings were depletion of internal granule cells, mostly in the cerebellar hemispheres with the vermis and flocculonodular lobes relatively spared, paucity of myelin in the central white matter and within folia, and a peculiar fragmentation of the dentate nuclei into isolated clusters of neurons, remarkably different from the normal festoon-like appearance of the dentate nucleus.

Image: Pontocerebellar hypoplasia type 2 (synaptophysin stain)

Norman reported the association with spinal anterior horn degeneration (Norman 1961), Krause (Krause 1929) and Peiffer and Pfeiffer (Peiffer and Pfeiffer 1977) reported the association with spastic pareses and with chorea. Based on these diverging clinical and pathologic features, Barth proposed an initial subdivision of pontocerebellar hypoplasia in types 1 and 2 (Barth 1993). Patel and colleagues proposed a further subdivision based on 5 subtypes (Patel et al 2006).

Type 6 (PCH6) was the first for which the causative gene defect was identified (Edvardson et al 2007), followed by PCH2 (Budde et al 2008). Presently 10 types are catalogued as such by OMIM, and at least 1 defective gene is allocated to each.

Widely different etiologies and pathogenic mechanisms underlie the various subtypes. The neuroradiological features of pontocerebellar hypoplasia are helpful for a group diagnosis, but further subtyping is required for molecular-genetic diagnosis, therapeutic advice, and genetic counseling.

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