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.
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 antiseizure medications.
Profound mental retardation 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 (dysmorphisms) 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.
Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis.
Congenital Disorder of Glycosylation, Type Ia (CDG1A)
CDG is a disease caused by mutation in the phosphomannomutase 2 gene, is inherited in an autosomal recessive fashion. It has two clinical presentations - solely neurologic form and a neurologic-multivisceral form. It may present prenatally as fetal hydrops and mortality approximately 20% in first 2 years
CDG is characterized by growth failure, failure to thrive and has multisystemic features. Microcephaly with prominent forehead and large ears, abnormal eye movements, internal strabismus retinitis pigmentosa, nystagmus, flat nasal bridge, thin upper lip, pericardial effusion, and cardiomyopathy.
Clinical features also include hepatomegaly with hepatic fibrosis, steatosis, feeding problems and diarrhea with vomiting. It may be complicated by nephritic syndrome, osteopenia, kyphosis and abnormal subcutaneous fat distribution. It presents with muscle weakness, hypotonia, psychomotor retardation, ataxia, hyporeflexia, stroke-like episodes, and seizures. Most patients are wheelchair-bound and have olivopontocerebellar hypoplasia, and peripheral neuropathy. Endocrine involvement includes hypothyroidism and decreased thyroxine-binding globulin. Hypergonadotropic hypogonadism may be seen.
Laboratory abnormalities in CDG include abnormal isoelectric focusing of serum transferrins (type 1 pattern), abnormal serum glycoproteins, elevated transaminases, Proteinuria, decreased copper, iron, and zinc level, hypocholesterolemia, hypoalbuminemia and phosphomannomutase deficiency in leukocytes, fibroblasts, or liver.
Diagnosis Prenatal diagnosis is currently not available. Serial ultrasound scan has been used but found to 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. 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, karyotype analysis. In 2003, Rajab et al mapped genetic locus for PCH type 3 to chromosome 7q11-2111. No genetic marker or specific gene has been identified in that area yet.
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 in heterozygosity by the parents and 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.
Treatment 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.
The treatment of PCH is directed toward the specific symptoms that are apparent in each individual. Some patient may require the mechanical ventilator for respiratory failure and parents need to be empowered to make decision for the children including the use of heroic and other extraordinary measures to maintain survival 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 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:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
Studies of the genetics of pontocerebellar hypoplasia are being conducted by Dr. Said Omar and Dr. Ajibola at Michigan State University.
For further information, please contact these physicians as follows:
Said Omar, MD, FAAP Associate Professor Dept. of Pediatrics and Human Development College of Human Medicine Michigan State University, East Lansing, MI Attending Neonatologist, Sparrow Hospital, 1215 E Michigan Ave, Lansing, MI Telephone 517-364-2670 Fax 517-364-3994 e-mail: omar@msu.edu Ayodeji Ajibola, MD Neonatalogy NICHD Fellow, Pediatric Scientist Development Program Department of Microbiology and Molecular Genetics Michigan State University 5163 Biomedical Physical Sciences East Lansing, MI 48824 Email: Ajibola@msu.edu
Barth, PG, Blennow, G, Lenard, HG, Begeer, JH, van der Kley, JM, Hanefeld, F, Peters, AC, Valk, J. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology 1995 45: 311-317
Alessandro Malandrini, Silvia Palmeri, Marcello Villanova, Emma Parrotta, Francesco Sicurelli, Daniela Amato, Danilo DeFalco, Gian Carlo Guazzi A syndrome of autosomal recessive pontocerebellar hypoplasia with white matter abnormalities and protracted course in two brothers. Brain Dev. 1997 Apr; 19(3):209-11.
S Lefebvre, L Burglen, J Frezal, A Munnich, and J Melki. The role of the SMN gene in proximal spinal muscular atrophy. Hum. Mol. Genet. 7: 1531-1536.
Sabine Rudnik-Schöneborn, László Sztriha, Gururaj R. Aithala, Gunnar Houge, et al. Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy. American Journal of Medical Genetics (2003). 117A: 10-17
Giangennaro Coppola, Ida Muras, Antonio Pascotto. Pontocerebellar hypoplasia type 2(PCH2): report of two siblings. Brain and development. (2000) 22: 188-192
Peter G. Barth, Eleonora Aronica, Linda de Vries, Peter G.J. Nikkels, Wiep Scheper, Jeroen J. Hoozemans, Bwe -Tien Poll-The, and Dirk Troost. Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropathol (2007) 114: 373-386
Maja Steinlin, Andrea Klein, Karin Haas-Lude, Dimitrios Zafeiriou, et al. Pontocerebellar hypoplasia type 2: Variability in clinical and imaging findings, European Journal of Paediatric Neurology Volume 11, Issue 3, May 2007, Pages 146-152.
Rajab, A., Mochida, G. H., Hill, A., Ganesh, V., Bodell, A., Riaz, A., Grant, P. E., Shugart, Y. Y., Walsh, C. A. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003 60: 1664-1667.
Sung-Hye Park, Sara Becker-Catania, Richard A. Gatti, Barbara F. Crandall, Jessica K. Emelin, H. V. Vinters. Congenital olivopontocerebellar atrophy report of two siblings with paleo- and neocerebellar atrophy. Acta Neuropathol (1998) 96: 315-321
Zelnik N, Dobyns WB, Forem SL, Kolodny EH.Congenital pontocerebellar atrophy in three patients: clinical, radiologic and etiologic considerations. Neuroradiology. 1996 Oct; 38(7): 684-7.
Simon Edvardson, Avraham Shaag, Olga Kolesnikova, John Moshe Gomori, Ivan Tarassov, Tom Einbinder, Ann Saada, and Orly Elpeleg. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J. Hum. Genet. 2007; 81: 857-862.
Birgit S Budde, Yasmin Namavar, Peter G Barth, Bwee Tien Poll-The, Gudrun Nürnberg, et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nature Genetics. 2008; 40:1113 - 1118
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