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Pontocerebellar Hypoplasia

National Organization for Rare Disorders, Inc.

Important
It is possible that the main title of the report Pontocerebellar Hypoplasia is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Pontocerebellar Hypoplasia, Type 1 (PCH1)
  • Pontocerebellar Hypoplasia with Infantile Spinal Muscular Atrophy
  • Pontocerebellar Hypoplasia with Anterior Horn Cell Disease
  • Pontocerebellar Hypoplasia, Type 2 (PCH2)
  • Pontocerebellar Hypoplasia with Progressive Cerebral Atrophy
  • Volendam Neurodegenerative Disease
  • Pontocerebellar Hypoplasia, Type 3 (PCH3)
  • Cerebellar Atrophy with Progressive Microcephaly, (CLAM)
  • PCH with Optic Atrophy
  • Pontocerebellar Hypoplasia, Type 4 (PCH4)
  • Encephalopathy, Fatal Infantile, With Olivopontocerebellar Hyperplasia
  • Pontocerebellar Hypoplasia, Type 5 (PCH 5)
  • Fetal-Onset Olivopontocerebellar Hypoplasia
  • Olivopontocerebellar Hypoplasia, Fetal-Onset
  • Pontocerebellar Hypoplasia, Type 6 (PCH6)
  • Arginyl-tRNA Synthetase 2 (RARS2

Disorder Subdivisions

  • None

General Discussion

Pontocerebellar hypoplasias (PCH) are a group of rare heterogeneous conditions characterized by prenatal development of an abnormally small cerebellum and brain stem, which is usually associated with profound psychomotor retardation. Although the clinical features vary widely, pontocerebellar hypoplasias are usually associated with profound intellectual disability and delayed or absent psychomotor milestones. In most cases, the disease is uniformly fatal early in life. Life span has ranged from death in the perinatal period to about 20-25 years of age. Only a few individuals have survived to the second and third decades of life. Six types of Pontocerebellar hypoplasias have been described.

Pontocerebellar hypoplasia type 1 (PCH type 1)

In Pontocerebellar hypoplasia type 1, there is central and peripheral motor dysfunction from birth leading to early death, mostly before 1 year of age. In addition to an abnormally small cerebellum and brainstem including the pons, there is a degeneration of the anterior horn cells. Because of the anterior horn cell involvement, PCH type 1 has some resemblance to infantile spinal muscular atrophy. The hypoplasia of the pons and cerebellum and spinal anterior horn cell degeneration is also associated with pronounced reactive changes (gliosis).

PCH type 1 is associated with reduced fetal movement. The pregnancy sometimes is complicated by polyhydramnios. In most cases, the condition is obvious during the newborn period when the newborn appears floppy and has respiratory insufficiency. At birth, multiple congenital contractures of large joints (arthrogryposis multiplex congenita) may be present. The newborn may show arreflexia, and combined motor signs. PCH type 1 has the hallmark of severe muscle weakness. The associated hypotonia may start prenatally or after birth. Mental retardation and cerebellar signs of visual impairment, nystagmus and ataxia follow the initial presentation.

It has also been found that some patients with PCH type 1 develop the signs of muscle weakness or developmental delay at the age of several months. These late presenting patients have a milder form and may live up to four years. However, the disease is uniformly fatal. Generally, affected babies have a life span not exceeding a few months in most cases.

In all patients, postmortem examinations reveal variable spectrum of cerebellar atrophy, neuronal loss in the anterior horns of the spinal cord, basal ganglia and brainstem suggesting a more widespread neuronal degeneration.

Unlike spinal muscular atrophy, which has been linked to the long arm of chromosome 5, and survival of motor neuron gene (SMN1), no genetic linkage is known yet for PCH type 1. The inheritance of PCH follows an autosomal recessive pattern.

Pontocerebellar hypoplasia type 2 (PCH type 2)

In PCH type 2 there is progressive microcephaly from birth combined with extrapyramidal dyskinesia. There is no motor or mental development. Severe chorea occurs, and epilepsy is frequent, while signs of spinal anterior horn involvement are absent in PCH type 2. The main feature distinguishing PCH type 1 from PCH type 2 is that anterior horn cells are spared in PCH type 2.

Characteristically, pregnancy is normal. However, at birth, the newborn may show breathing problems or respiratory failure that may require mechanical ventilatory support. Some may have sucking or feeding problems. Most patients with PCH type 2 are born with normal size head. Some already have microcephaly at birth. All affected children have worsening or progression of the microcephaly during infancy. Other features of dysmorphisms are absent. They have impaired mental and motor development. They have abnormal movements termed extrapyramidal movement disorder. All affected children develop marked extrapyramidal dyskinetic movement disorder with predominance of dystonia. Jerky movements and almost continuous dystonic choreoathetotic movements may be seen. These movement abnormalities are usually noticed during the neonatal period of these children.

They have severe to profound mental retardation. No patient with the classical PCH type 2 ever achieved the milestones of sitting, crawling, standing, walking, talking, or developed meaningful social contact skills. Visual fixation is persistently poor and only about one third of these patients are able to fixate and follow. Seizure disorder is frequent. Approximately half of these children may have seizures. A minority may also have hypotonia or hypertonia even as early as the newborn period. Minority may show spasticity.

They are severely handicapped with no voluntary motor function. The children have severe cognitive and language impairment, and with no verbal or non-verbal communication.

There is a near total loss of Purkinje fibers in the cerebellar hemisphere and an undetectable dentate nucleus. Neuronal loss is marked in the basal ganglia and thalamus without any anterior horn cell involvement when autopsy is done. The vermis is also relatively spared. These features are similar to those seen in PCH type 5 and suggest a continuum of pathology between both PCH type 2 and PCH type 5.

The clinical findings, the severity of movement disorder and the developmental delay do not correlate with the degree of pontine or cerebellar hypoplasia on MRI. It is possible that there is a continuum of severe neonatal and infantile types rather than clearly defined groups.

Death during early childhood has been attributed to respiratory and infectious complications.

Pontocerebellar hypoplasia type 3 (PCH type 3)

PCH type 3 has many features in common with PCH type 2. However, in PCH type 3, extrapyramidal symptoms (dyskinesia) are absent. The children may have seizures and microcephaly, which are the result of poor brain development and small size of the cerebellum and pons that affect the overall size of the brain.

PCH Type 3 is a unique form described in three sibs of a consanguineous family from the Sultanate of Oman. Clinical features in these affected children include developmental delay, progressive microcephaly with brachycephaly and seizure in the first year, truncal hypotonia with exaggerated deep tendon reflexes, short stature and optic atrophy. One of the three children had thoracic scoliosis contractures of the elbows and knees, and clubfoot. Visual impairment including optic atrophy may be seen in affected patient. Other features include brachycephaly, prominent eyes, and low-set ears. There was no extrapyramidal involvement or dyskinesia.

Imaging studies of the brain showed small brainstem, small cerebellar vermis, and atrophy of the cerebellum and cerebrum. PCH type 3 has been mapped to chromosome 7q11-21 and fine mapping is in progress.

Pontocerebellar hypoplasia type 4 (PCH type 4)

PCH type 4 is associated with severe neonatal encephalopathy, microcephaly, myoclonus, and muscular hypertonia. There is a severe loss of neurons in pontine and olivary nuclei in addition to the hypoplasia of the cerebellum and a diffuse gliosis in white matter of both the cerebellum and all areas of the brain. This is a more severe and fatal variant of PCH type 2, which is associated with death within the first few weeks of life, is known as PCH type 4.

Pontocerebellar hypoplasia type 5 (PCH type 5)

PCH type 5 is similar to PCH type 4, but differs in having in-utero fetal seizure-like activity. These patients show evidence of severe olivopontocerebellar hypoplasia and degeneration, dysplastic, c-shaped inferior olivary nuclei, absent or immature dentate nuclei and cell paucity more marked for the cerebellar vermis than the hemispheres.

Pontocerebellar hypoplasia type 6 (PCH type 6)

PCH type 6 manifests as early as the first day of life or within the first month of life as infantile encephalopathy, with generalized hypotonia, lethargic, poor sucking and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition.

Although head size may be normal at birth, for those infants surviving beyond the newborn period, the growth of the head is arrested and progressive microcephaly is noticed. Like other forms of PCH, no developmental milestone is achieved. The initial hypotonia may progress to hypertonia with spasticity. Fundoscopy is usually unremarkable. In the index family where this condition was described, two of three affected siblings had crib deaths. These three affected children died at ages of 14, 2 and 3 months respectively.

Neonatal MRI of the brain reveals cerebellar and vermian hypoplasia but normal brain volume while follow-up studies portray evidence of progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved.

Resources

Contact A Family
209-211 City Road
London, Intl EC1V 1JN
United Kingdom
Tel: 020 7608 8700
Fax: 020 7608 8701
Email: info@cafamily.org.uk
Internet: http://www.cafamily.org.uk/

NIH/National Institute of Child Health and Human Development
31 Center Dr
Building 31, Room 2A32
MSC2425
Bethesda, MD 20892
Fax: (866)760-5947
Tel: (800)370-2943
TDD: (888)320-6942
Email: NICHDInformationResourceCenter@mail.nih.gov
Internet: http://www.nichd.nih.gov/

MUMS National Parent-to-Parent Network
150 Custer Court
Green Bay, WI 54301-1243
USA
Tel: (920)336-5333
Fax: (920)339-0995
Tel: (877)336-5333
Email: mums@netnet.net
Internet: http://www.netnet.net/mums/

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
TDD: (888)205-3223
Internet: http://rarediseases.info.nih.gov/GARD/

Fetal Hope Foundation
9786 S Holland Street
Littleton, CO 80127
USA
Tel: (303)932-0553
Tel: (877)789-4673
Email: info@fetalhope.org
Internet: http://www.fetalhope.org

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders (NORD). A copy of the complete report can be downloaded free from the NORD website for registered users. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational therapies (if available), and references from medical literature. For a full-text version of this topic, go to www.rarediseases.org and click on Rare Disease Database under "Rare Disease Information".

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.

It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report

This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

For additional information and assistance about rare disorders, please contact the National Organization for Rare Disorders at P.O. Box 1968, Danbury, CT 06813-1968; phone (203) 744-0100; web site www.rarediseases.org or email orphan@rarediseases.org

Last Updated:  1/27/2009
Copyright  2009 National Organization for Rare Disorders, Inc.

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