NORD gratefully acknowledges Said Omar, MD, FAAP, Professor and Medical Director, Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, and Ayodeji Ajibola, MD, Neonatology, Former NICHD Fellow, Pediatric Scientist Development Program, Department of Microbiology and Molecular Genetics, Michigan State University, for the preparation of this report.
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-usually patients with PCH type 2-have survived to the second and third decades of life. At least 6 types of PCH have been described and a few rare variants are now being identified.
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. Intellectual disability 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.
The inheritance of PCH follows an autosomal recessive pattern. Sequence analysis of the entire coding region, prenatal diagnosis and carrier testing are available for PCH type 1.
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 dysmorphism 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.
Affected children have severe to profound intellectual disability. 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.
Mutations in 3 tRNA splicing endonuclease genes (TSEN) have been identified in PCH type 2 and Type 4. This has formed the basis of classifying PCH type 2 into types 2A, 2B, and 2C respectively associated with TSEN54, TSEN2 and TSEN34.
Sequence analysis of the entire coding, region, linkage analysis, prenatal diagnosis, and carrier testing are available for TSEN2, TSEN34, and TSEN54 related PCH. In addition, deletion/duplication analysis is available also for TSEN54 related PCH.
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, 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.
Sequence analysis of the entire coding region, deletion/duplication analysis, prenatal diagnosis, and carrier testing are available for PCH type 6.
Severe PCH/atrophy with testicular regression that has onset in the fetal period; possiblly PCH type 7.
Deletion in part of chromosome 19 has been identified in a patient with PCH who had multiple congenital anomalies.
Symptoms of pontocerebellar hypoplasia vary from case to case and from one PCH type to another. New types of PCH are being added almost every few years. In most infants, there is a small head, (microcephaly) without evidence of other congenital anomalies. Affected infants often experience seizures, postnatal growth retardation, and microcephaly, a term used to describe head circumference that is smaller than would be expected for a child’s age and sex. As affected infants age, they may experience significant delays in speech and in reaching motor milestones such as walking independently. Most of these children will never talk, walk, sit, stand, or even roll over. They may be completely dependent for all activities of daily living.
In early life, there may be feeding difficulties warranting feeding by tubes. They may be at risk of aspiration. Usually they are very susceptible to respiratory infections. If not already born with contractures, they may later develop contractures. Seizures are common, and can be fairly controlled with anti-seizure medications.
Profound intellectual disability is the norm. Social skills are absent. Patient lacks all ability to develop activities of daily living. Speech is often absent. Patients cannot learn sign language. Motor milestones are always severely delayed. Birth defects (dysmorphism) are rare in pontocerebellar hypoplasia, but deformities such as contractures and clubfoot and short stature have been reported.
Pontocerebellar hypoplasia is considered to be inherited as an autosomal recessive disorder because it occurs mostly in consanguineous families (families where both parents are related). Therefore, each offspring of parents carrying the genetic abnormality has a one in four chance of suffering from pontocerebellar hypoplasia. However there is a two out of three chance that a sibling of an affected child may have one of the abnormal genes that on its own will not cause the disease in that sibling. Brain imaging (MRI or CT) shows small cerebellum and pons.
There is a one in four chance that an offspring of such parents will not inherit any of the genes. At each conception, there is a three out of four chance that the offspring may not be affected. This is a characteristic of traits that are autosomal recessive in inheritance.
The disease affects both males and females without a predilection for either sex. More than 100 cases have been reported in the medical literature. The exact incidence of pontocerebellar hypoplasia is unknown.
Molecular genetic diagnosis is available and has been described above with each PCH type for which it is available. Genetic tests are available for PCH types 1, 2A, 2B, 2C, 4 and 6. Prenatal diagnosis is now available for some forms of PCH.
Serial ultrasound scans are sometimes used for diagnosis, but can be operator dependent and has very low sensitivity. Radiological diagnosis always lags behind the process of hypoplasia or degeneration of the cerebellum and pons.
Most of the tests are done to investigate other known causes of brain abnormalities. These tests include testing for CDG (isoelectric focusing of transferrins), as described above, MRI of the brain and spinal cord, computed axial tomography of the brain and ultrasounds scans.
Metabolic evaluation including plasma amino acid profiles, urine organic acids,
electromyography, nerve conduction studies, electroencephalography, are sometimes conducted. Invasive studies like muscle, nerve and skin biopsies have been done in some cases. These may only be useful after excluding PCH types with known genetic mutations. Ophthalmological evaluation is needed in most cases.
Genetic evaluations for syndromes known to be associated with congenital contractures like karyotype and fluorescent in situ hybridization analysis for Miller Dieker and Prader Willi syndromes may be indicatd. In 2003, Rajab et al mapped genetic locus for PCH type 3 to chromosome 7q11-2111.
PCH type 6 results from a mutation in a non-coding region of a gene called RARS2 on chromosome 6 (chromosome 6q16.1). They found a homozygous intronic mutation in RARS2 in all the affected members that was carried by the parents who also had two healthy children. This gene mutation leads to a defect in mitochondrial respiratory chain complexes in affected patients.
Recent reports have indicated that mutation in three subunits of the tRNA splicing endonuclease (TSEN) gene is associated with pontocerebellar hypoplasia types 2 and 4. This points to RNA processing as a new basic cellular impairment in neurological disorders.
The treatment of PCH is entirely symptomatic and supportive. The primary physician should serve as a medical home coordinating the care of this chronically ill child. The comprehensive care involves the services of a multidisciplinary team that may include the pediatrician, pediatric neurologist, pediatric surgeon, speech pathologist, ophthalmologist, physical therapist, occupational therapist and other specialist as warranted on case-by-case basis. Healthcare professionals may need to collaborate, systematically develop and implement a comprehensive care plan tailored to the need of the child.
Gastrostomy tube may be required for feeding; fundoplication may be needed to prevent aspiration. The neurologist needs to be involved in the management of these patients especially for seizure management because their seizures sometimes could be intractable. Surgery may be performed to treat specific contractures, and tendon release. Supportive care may include physical, occupational, speech and therapy.
The treatment of PCH is directed toward the specific symptoms that are apparent in each individual. Respiratory management may extend from non invasive ventilation to full mechanical ventilation. Some patient may require the mechanical ventilator for respiratory failure. Parents need to be empowered to make decision for the children.
Informed decision making regarding palliative care versus participation in clinical investigatory interventions including the use of heroic and other extraordinary measures to maintain survival of the child will need to be carefully discussed with parents. The primary physician needs to discuss end of life care and issues like "do not resuscitate" and use of heroic treatments well in advance in anticipation of possibilities. Attention should be paid to issues such as day care, respite care, and linking up the patients with available social support services.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For further information, please contact these physicians as follows:
Said Omar, MD, FAAP
Professor and Medical Director
Division of Neonatology
Department of Pediatrics and Human Development
College of Human Medicine
Michigan State University, East Lansing, MI
Regional Neonatal Intensive Care Unit, Sparrow Hospital,
1215 E Michigan Ave, Lansing, MI
Ayodeji Ajibola, MD, FAAP
Former NICHD Fellow, Pediatric Scientist Development Program
Department of Microbiology and Molecular Genetics
Michigan State University
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