Maria*, a very sick little girl from Puerto Rico, was admitted to the Boston Children’s Hospital (BCH) with extreme failure to thrive.  She had a history of severe developmental delays and microcephaly after spasticity and arthrogryposis were identified at birth.  In addition to the known microcephaly, a brain MRI revealed a much smaller than expected cerebellum, as well as very small mid and hind brain structures, consistent with a diagnosis of pontocerebellar hypoplasia (PCH).  While undergoing an extensive clinical workup at BCH, the family expressed interest in research participation and enrolled in the studies of the Christopher Walsh Lab.  The parents also arranged enrollment for their healthy sons, who clearly relayed their wishes to help their little sister in any way during one of their visits to the hospital.  Unfortunately, as often happens in these situations, exhaustive biochemical, metabolic and genetic testing in the clinical setting failed to identify a cause of Maria’s symptoms. 

Upon review of Maria’s MRI in the research setting, there were noted similarities to a family enrolled, in collaboration with Dr. Bill Dobyns, by the Walsh Lab just a few months prior.  This second family was also of Puerto Rican background and included two sisters with a similar clinical picture of spasticity from birth, microcephaly and PCH.  Parental consanguinity was not known to be a factor in either of these two families.  A scan of dozens of broadly similar cases in the research cohort identified another multiplex family with similar MRI features. Interestingly, this family, showing milder symptoms, happened to be referred to the study by a collaborating geneticist in Peru within a six months of Maria’s family’s enrollment.

Genome-wide linkage analysis of both multiplex families, one from Peru and one from Puerto Rico, identified a shared region of homozygosity on chromosome 16q, greatly narrowing the gene-hunt.  It was also discovered that both the families of Puerto Rican ancestry shared the same haplotype, suggesting a founder effect.  Sequencing of all 42 genes in the chromosome 16 interval, many with no known associations with human disease, was initiated. A candidate gene emerged and extensive functional experiments eventually resulted in identification of homozygous mutations in a novel gene called CHMP1A (1).  Thus far we understand the CHMP1A gene to be involved in controlling cell proliferation but much is yet to be learned. 

Identification of mutations in the CHMP1A gene is another entry into the world of autosomal recessive PCH.  PCH is a complicated diagnosis with several subtypes identified over the years (2).  Although available imaging for the families affected by CHMP1A mutations have shown a stable course, in many cases this diagnosis implies a neurodegenerative condition (3).  Multiple genes have now been identified, including CASK, RARS2 and the TSEN genes, TSEN54, TSEN2, TSEN34 and TSEN15 (4, 3).

As with any diagnosis linked to newly characterized genes, prognosis and the full range of phenotypes for patients with homozygous or compound heterozygous CHMP1A mutations are currently uncertain.  Through continued enrollment and contact with participating families, the Walsh Lab hopes to gain better insight into such details.  Additionally, efforts are currently underway to generate patient-derived induced pluripotent stem cells (iPSCs).  The expectation is that iPSCs can be reprogrammed into neuronal cells to serve as a disease model and help us learn more about the CHMP1A gene, brain development and PCH.

Genetic testing for pontocerebellar hypoplasia is available at the University of Chicago Genetic Services.  Research studies of the genetics of brain development are available at the Walsh lab, affiliated with Harvard Medical School and Boston Children's Hospital.   For more information please visit  or email

*Names and other identifying information have been changed in order to protect this family’s privacy.

  1.  Mochida G et al., Nature Genetics 44,1260–1264 (2012)
  2. Namavar Y et al., Orphanet J Rare Disease 6:50 (2011)
  3. Namavar Y et al., Brain 134, 143-156 (2011)
  4. Valayannopoulos et al., Brain 135, 1-5 (2012)