# 611523

PONTOCEREBELLAR HYPOPLASIA, TYPE 6; PCH6


Alternative titles; symbols

ENCEPHALOPATHY, FATAL INFANTILE, WITH MITOCHONDRIAL RESPIRATORY CHAIN DEFECTS


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
6q15 Pontocerebellar hypoplasia, type 6 611523 AR 3 RARS2 611524
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Other
- Failure to thrive
HEAD & NECK
Head
- Microcephaly, progressive
Face
- Dysmorphic features described in 1 patient
- Bitemporal narrowing
Eyes
- Deep-set eyes
- Dysconjugate eye movements
Nose
- Prominent nasal bridge
Mouth
- Narrow palate
RESPIRATORY
- Apneic episodes
ABDOMEN
Gastrointestinal
- Poor sucking
- Feeding difficulties
MUSCLE, SOFT TISSUES
- Hypotonia
- Edematous hands and feet (1 patient)
- Reduced activity of mitochondrial respiratory chains (1 family)
NEUROLOGIC
Central Nervous System
- Developmental delay, profound
- Lack of speech
- Poor head control
- Seizures
- Limb spasticity
- Hyperreflexia
- Cerebral atrophy
- Cerebellar atrophy
- Brainstem atrophy
LABORATORY ABNORMALITIES
- Increased serum lactate
- Increased CSF lactate
MISCELLANEOUS
- Onset at birth or in first days or life
- Progressive disorder
- Variable severity
- Death in childhood may occur
MOLECULAR BASIS
- Caused by mutation in the mitochondrial arginyl-tRNA synthetase gene (RARS2, 611524.0001)
Pontocerebellar hypoplasia - PS607596 - 27 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p34.1 Pontocerebellar hypoplasia, type 7 AR 3 614969 TOE1 613931
1p13.3 Pontocerebellar hypoplasia, type 9 AR 3 615809 AMPD2 102771
1q25.3 Pontocerebellar hypoplasia, type 2F AR 3 617026 TSEN15 608756
3p25.2 Pontocerebellar hypoplasia type 2B AR 3 612389 TSEN2 608753
3q12.1-q12.2 Pontocerebellar hypoplasia, type 11 AR 3 617695 TBC1D23 617687
4p15.2 Pontocerebellar hypoplasia type 2D AR 3 613811 SEPSECS 613009
4q27 Pontocerebellar hypoplasia, type 1D AR 3 618065 EXOSC9 606180
5q22.1 Pontocerebellar hypoplasia, type 1E AR 3 619303 SLC25A46 610826
6p21.2 Pontocerebellar hypoplasia, type 14 AR 3 619301 PPIL1 601301
6q15 Pontocerebellar hypoplasia, type 6 AR 3 611523 RARS2 611524
6q16.2 Pontocerebellar hypoplasia, type 17 AR 3 619909 PRDM13 616741
6q21 ?Pontocerebellar hypoplasia, type 15 AR 3 619302 CDC40 605585
7q21.11 ?Pontocerebellar hypoplasia, type 3 AR 3 608027 PCLO 604918
9p13.2 Pontocerebellar hypoplasia, type 1B AR 3 614678 EXOSC3 606489
10q23.2 Pontocerebellar hypoplasia, type 16 AR 3 619527 MINPP1 605391
10q24.1 ?Pontocerebellar hypoplasia, type 1F AR 3 619304 EXOSC1 606493
11q12.1 Pontocerebellar hypoplasia, type 10 AR 3 615803 CLP1 608757
11q13.1 Pontocerebellar hypoplasia, type 13 AR 3 618606 VPS51 615738
13q13.3 Pontocerebellar hypoplasia, type 1C AR 3 616081 EXOSC8 606019
14q32.2 Pontocerebellar hypoplasia type 1A AR 3 607596 VRK1 602168
16q24.3 Pontocerebellar hypoplasia, type 8 AR 3 614961 CHMP1A 164010
17p13.3 Pontocerebellar hypoplasia, type 2E AR 3 615851 VPS53 615850
17q21.2 Pontocerebellar hypoplasia, type 12 AR 3 618266 COASY 609855
17q25.1 Pontocerebellar hypoplasia type 2A AR 3 277470 TSEN54 608755
17q25.1 ?Pontocerebellar hypoplasia type 5 AR 3 610204 TSEN54 608755
17q25.1 Pontocerebellar hypoplasia type 4 AR 3 225753 TSEN54 608755
19q13.42 ?Pontocerebellar hypoplasia type 2C AR 3 612390 TSEN34 608754

TEXT

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 6 (PCH6) is caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial arginyl-tRNA synthetase (RARS2; 611524) on chromosome 6q15.


Description

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).


Clinical Features

Edvardson et al. (2007) investigated 3 patients, the products of a consanguineous Sephardic Jewish marriage, who had infantile encephalopathy and a putative defect in mitochondrial translation. The eldest of the 3 affected children showed generalized hypotonia and poor sucking at several hours of age, and brain magnetic imaging (MRI) at age 3 days showed cerebellar and vermian hypoplasia but normal brain volume. Recurrent apnea from age 1 week was controlled by phenobarbital, but intractable seizures starting at age 2 months were resistant to multidrug therapy. Microcephaly became evident at age 1 year. No developmental milestones were attained, and muscle tone became spastic. The results of funduscopic observations were normal. Serial brain MRI revealed progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. The patient died at age 16 months. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved. The fourth child in the family and the second to be affected was a boy who was markedly hypotonic and lethargic from birth. He was found dead in his crib at age 7 weeks. The fifth child in the family and the third to be affected was normal on neurologic examination on the first day of life, but an apneic episode occurred on the second day. At age 3 weeks, poor feeding, lethargy, and generalized hypotonia became evident. At 4 months, she developed generalized seizures, and head growth was arrested. Brain MRI at age 3 months revealed general atrophy, with most marked changes in the pons and cerebellum.

Rankin et al. (2010) reported a girl, born of unrelated British parents, with PCH6. After a normal birth, she was admitted after 19 hours with poor feeding and high respiratory rate. Laboratory studies showed increased serum lactate, which resolved with treatment. She later developed severe hypotonia, myoclonic seizures, profound developmental delay with absence of social smiling and poor head control, and poor feeding requiring gastrostomy. Brain MRI at age 14 months showed generalized cerebral atrophy, thinning of the pons, and atrophy of the cerebellar hemispheres. Examination at age 2 and 3 years showed severe progressive microcephaly and dysmorphic features, such as bitemporal narrowing, deep-set eyes with prominent nasal bridge, full cheeks, and narrow palate. She also had edematous hands and feet, and required a tracheostomy for upper airway obstruction due to hypotonia. Muscle biopsy showed normal respiratory chain activity. Rankin et al. (2010) noted some phenotypic overlap with PEHO syndrome (260565), but their patient lacked optic atrophy.

Li et al. (2015) reported 2 Hispanic sibs with PCH6. Both presented in the first year of life with hypotonia and delayed psychomotor development after normal early development in the first months of life. Variable features included head lag or poor head control, weak reflexes that progressed to increased reflexes, and dysconjugate eye movements. The brother developed seizures at age 9 months. At age 4.5 years, he had microcephaly, progressive visual loss, no functional speech, refractory seizures, clinodactyly, and adducted thumb, and he required tube feeding. Brain imaging showed small posterior fossa, cerebellar vermis hypoplasia, small pons, cerebellar atrophy, and increased subarachnoid space over the frontotemporal regions. The sister was less severely affected: at age 18 months, she was able to sit with support and had started to babble; brain imaging showed cerebellar hypoplasia. She did not have seizures or visual loss.


Inheritance

The transmission pattern of PCH6 in the family reported by Li et al. (2015) was consistent with autosomal recessive inheritance.


Mapping

In a consanguineous Sephardic Jewish family with pontocerebellar hypoplasia, Edvardson et al. (2007) identified an identical haplotype in a region of chromosome 6 within a 22.46-Mb region between markers D6S1546 and D6S268 in all 3 affected patients by homozygosity mapping.


Molecular Genetics

In a consanguineous Sephardic Jewish family with infantile encephalopathy mapping to chromosome 6q16.1 and a putative defect in mitochondrial translation, Edvardson et al. (2007) sequenced the RARS2 gene and identified a homozygous intronic mutation (611524.0001) that segregated with the disorder in the family.

In a British girl, born of unrelated British parents, with PCH6, Rankin et al. (2010) identified compound heterozygous mutations in the RARS2 gene (611524.0002 and 611524.0003). Each unaffected parent was heterozygous for 1 of the mutations.

In 2 Hispanic sibs with PCH6, Li et al. (2015) identified a homozygous mutation in the promoter of the RARS2 gene (611524.0004). Patient cells showed decreased expression of RARS2 compared to controls, and luciferase studies in HEK293 cells transfected with the mutation showed a 40% reduction of promoter activity compared to wildtype.


REFERENCES

  1. Edvardson, S., Shaag, A., Kolesnikova, O., Gomori, J. M., Tarassov, I., Einbinder, T., Saada, E., Elpeleg, O. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J. Hum. Genet. 81: 857-862, 2007. [PubMed: 17847012, images, related citations] [Full Text]

  2. Li, Z., Schonberg, R., Guidugli, L., Johnson, A. K., Arnovitz, S., Yang, S., Scafidi, J., Summar, M. L., Vezina, G., Das, S., Chapman, K., del Gaudio, D. A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. J. Hum. Genet. 60: 363-369, 2015. [PubMed: 25809939, related citations] [Full Text]

  3. Rankin, J., Brown, R., Dobyns, W. B., Harington, J., Patel, J., Quinn, M., Brown, G. Pontocerebellar hypoplasia type 6: a British case with PEHO-like features. Am. J. Med. Genet. 152A: 2079-2084, 2010. [PubMed: 20635367, related citations] [Full Text]


Cassandra L. Kniffin - updated : 8/13/2015
Cassandra L. Kniffin - updated : 1/10/2011
Creation Date:
Victor A. McKusick : 10/11/2007
carol : 07/22/2016
alopez : 08/14/2015
mcolton : 8/13/2015
ckniffin : 8/13/2015
terry : 4/22/2011
wwang : 1/31/2011
ckniffin : 1/10/2011
ckniffin : 1/10/2011
alopez : 11/6/2008
wwang : 10/23/2007
alopez : 10/12/2007
alopez : 10/11/2007

# 611523

PONTOCEREBELLAR HYPOPLASIA, TYPE 6; PCH6


Alternative titles; symbols

ENCEPHALOPATHY, FATAL INFANTILE, WITH MITOCHONDRIAL RESPIRATORY CHAIN DEFECTS


SNOMEDCT: 718606005;   ORPHA: 166073;   DO: 0060275;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
6q15 Pontocerebellar hypoplasia, type 6 611523 Autosomal recessive 3 RARS2 611524

TEXT

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 6 (PCH6) is caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial arginyl-tRNA synthetase (RARS2; 611524) on chromosome 6q15.


Description

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).


Clinical Features

Edvardson et al. (2007) investigated 3 patients, the products of a consanguineous Sephardic Jewish marriage, who had infantile encephalopathy and a putative defect in mitochondrial translation. The eldest of the 3 affected children showed generalized hypotonia and poor sucking at several hours of age, and brain magnetic imaging (MRI) at age 3 days showed cerebellar and vermian hypoplasia but normal brain volume. Recurrent apnea from age 1 week was controlled by phenobarbital, but intractable seizures starting at age 2 months were resistant to multidrug therapy. Microcephaly became evident at age 1 year. No developmental milestones were attained, and muscle tone became spastic. The results of funduscopic observations were normal. Serial brain MRI revealed progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. The patient died at age 16 months. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved. The fourth child in the family and the second to be affected was a boy who was markedly hypotonic and lethargic from birth. He was found dead in his crib at age 7 weeks. The fifth child in the family and the third to be affected was normal on neurologic examination on the first day of life, but an apneic episode occurred on the second day. At age 3 weeks, poor feeding, lethargy, and generalized hypotonia became evident. At 4 months, she developed generalized seizures, and head growth was arrested. Brain MRI at age 3 months revealed general atrophy, with most marked changes in the pons and cerebellum.

Rankin et al. (2010) reported a girl, born of unrelated British parents, with PCH6. After a normal birth, she was admitted after 19 hours with poor feeding and high respiratory rate. Laboratory studies showed increased serum lactate, which resolved with treatment. She later developed severe hypotonia, myoclonic seizures, profound developmental delay with absence of social smiling and poor head control, and poor feeding requiring gastrostomy. Brain MRI at age 14 months showed generalized cerebral atrophy, thinning of the pons, and atrophy of the cerebellar hemispheres. Examination at age 2 and 3 years showed severe progressive microcephaly and dysmorphic features, such as bitemporal narrowing, deep-set eyes with prominent nasal bridge, full cheeks, and narrow palate. She also had edematous hands and feet, and required a tracheostomy for upper airway obstruction due to hypotonia. Muscle biopsy showed normal respiratory chain activity. Rankin et al. (2010) noted some phenotypic overlap with PEHO syndrome (260565), but their patient lacked optic atrophy.

Li et al. (2015) reported 2 Hispanic sibs with PCH6. Both presented in the first year of life with hypotonia and delayed psychomotor development after normal early development in the first months of life. Variable features included head lag or poor head control, weak reflexes that progressed to increased reflexes, and dysconjugate eye movements. The brother developed seizures at age 9 months. At age 4.5 years, he had microcephaly, progressive visual loss, no functional speech, refractory seizures, clinodactyly, and adducted thumb, and he required tube feeding. Brain imaging showed small posterior fossa, cerebellar vermis hypoplasia, small pons, cerebellar atrophy, and increased subarachnoid space over the frontotemporal regions. The sister was less severely affected: at age 18 months, she was able to sit with support and had started to babble; brain imaging showed cerebellar hypoplasia. She did not have seizures or visual loss.


Inheritance

The transmission pattern of PCH6 in the family reported by Li et al. (2015) was consistent with autosomal recessive inheritance.


Mapping

In a consanguineous Sephardic Jewish family with pontocerebellar hypoplasia, Edvardson et al. (2007) identified an identical haplotype in a region of chromosome 6 within a 22.46-Mb region between markers D6S1546 and D6S268 in all 3 affected patients by homozygosity mapping.


Molecular Genetics

In a consanguineous Sephardic Jewish family with infantile encephalopathy mapping to chromosome 6q16.1 and a putative defect in mitochondrial translation, Edvardson et al. (2007) sequenced the RARS2 gene and identified a homozygous intronic mutation (611524.0001) that segregated with the disorder in the family.

In a British girl, born of unrelated British parents, with PCH6, Rankin et al. (2010) identified compound heterozygous mutations in the RARS2 gene (611524.0002 and 611524.0003). Each unaffected parent was heterozygous for 1 of the mutations.

In 2 Hispanic sibs with PCH6, Li et al. (2015) identified a homozygous mutation in the promoter of the RARS2 gene (611524.0004). Patient cells showed decreased expression of RARS2 compared to controls, and luciferase studies in HEK293 cells transfected with the mutation showed a 40% reduction of promoter activity compared to wildtype.


REFERENCES

  1. Edvardson, S., Shaag, A., Kolesnikova, O., Gomori, J. M., Tarassov, I., Einbinder, T., Saada, E., Elpeleg, O. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J. Hum. Genet. 81: 857-862, 2007. [PubMed: 17847012] [Full Text: https://doi.org/10.1086/521227]

  2. Li, Z., Schonberg, R., Guidugli, L., Johnson, A. K., Arnovitz, S., Yang, S., Scafidi, J., Summar, M. L., Vezina, G., Das, S., Chapman, K., del Gaudio, D. A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. J. Hum. Genet. 60: 363-369, 2015. [PubMed: 25809939] [Full Text: https://doi.org/10.1038/jhg.2015.31]

  3. Rankin, J., Brown, R., Dobyns, W. B., Harington, J., Patel, J., Quinn, M., Brown, G. Pontocerebellar hypoplasia type 6: a British case with PEHO-like features. Am. J. Med. Genet. 152A: 2079-2084, 2010. [PubMed: 20635367] [Full Text: https://doi.org/10.1002/ajmg.a.33531]


Contributors:
Cassandra L. Kniffin - updated : 8/13/2015
Cassandra L. Kniffin - updated : 1/10/2011

Creation Date:
Victor A. McKusick : 10/11/2007

Edit History:
carol : 07/22/2016
alopez : 08/14/2015
mcolton : 8/13/2015
ckniffin : 8/13/2015
terry : 4/22/2011
wwang : 1/31/2011
ckniffin : 1/10/2011
ckniffin : 1/10/2011
alopez : 11/6/2008
wwang : 10/23/2007
alopez : 10/12/2007
alopez : 10/11/2007