In their Letter to the Editor, Karakaya et al. (2017) present
an interesting case report describing the clinical course
involving secondary microcephaly of a 3-year-old Turkish
boy found to be homozygous for a frameshift mutation in
PRUNE1 identified through whole exome sequencing. The
child presented with congenital hypotonia, contractures and
global developmental delay with respiratory insufficiency
and seizures developing in the first year of life. The authors
note that the affected child’s head circumference plotted on
the 75th centile at birth, and that by 38 months of age he
had developed microcephaly. Neuroimaging at 14 months
revealed cerebral and cerebellar atrophy consistent with
other patients described with Prune syndrome (Karaca
et al., 2015; Costain et al., 2017; Zollo et al., 2017).
Although the child had abnormal neurology from birth,
there was a period of early developmental regression.
Peripheral spasticity in the lower extremities and optic atrophy
were not documented until 38 months. In addition to
the PRUNE1 variant, Karakaya et al. also identified a
second homozygous variant in the CCDC14 gene in the
Turkish child’s whole exome sequencing data that, while
listed to have an allele count of 108 in the current Genome
Aggregation Database (gnomAD) release, is notably absent
in homozygous fashion (Lek et al., 2016). CCDC14 is
known to be expressed in human brain, reported to negatively
regulate centriole duplication and interact with proteins
previously associated with primary microcephaly
(Firat-Karalar et al., 2014). Thus, while it seems likely
that the homozygous PRUNE1 variant is primarily responsible
for the clinical presentation in the Turkish child, it is
impossible to determine whether there may be any phenotypical
contribution from this additional homozygous
sequence variant.
Recently, Costain et al. (2017) described a homozygous
consensus splice site variant in PRUNE1 (c.521-2A4G;
NM_021222.1) in a 2-year-old Oji-Cre male who presented
with congenital hypotonia and talipes, whose head circumference
was large at birth ( +3 standard deviations), but by
2 years and 2 months plotted on the 50th centile, with a
weight and height on the 95th and 75th centiles, respectively.
However, it should be noted that the child’s father
is macrocephalic ( +4 standard deviations), the published
clinical photographs at 2 years 5 months of age illustrate
bitemporal narrowing, a sloping forehead and large ears,
consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He
developed respiratory insufficiency shortly after birth, and
infantile spasms in the first year of life (Costain et al., 2017).
It remains to be determined how the phenotypical outcomes
stemming from proposed loss-of-function mutations
defined by Karakaya et al. and Costain et al., relate to
missense mutations published by Karaca et al. and also
Zollo et al., which are likely to involve at least partial
gain-of-function outcomes in PRUNE1 activity. However,
as more cases are investigated and published, the phenotype
associated with autosomal recessive Prune neurodevelopmental
disorder, and the functional outcomes of
PRUNE1 mutation, are becoming clearer. It is now apparent
that while some patients have a small head at birth and
others a head circumference in the normal range, the key
component of the microcephaly is that it is progressive, and
associated with characteristic neuroimaging findings with a
thin or hypoplastic corpus callosum and cortical and cerebellar
atrophy developing in early childhood. Although all
patients with Prune syndrome described to date are neurologically
impaired from birth, there also appears to be a
neurodegenerative component with progression of the disorder.
In our manuscript, we described clinical overlap of
Prune syndrome with the neurodegenerative condition associated
with homozygous mutations in TBCD (Zollo et al.,
2017). TBCD encodes one of the five tubulin-specific chaperones
that are required for a/b-tubulin de novo heterodimer
formation and the disorder is characterized by
developmental regression, seizures, optic atrophy and secondary
microcephaly, cortical atrophy with delayed myelination,
cerebellar atrophy and thinned corpus callosum
(Edvardson et al., 2016; Flex et al., 2016; Miyake et al.,
2016; Pode-Shakked et al., 2017). The neurodegenerative
phenotype documented in the Turkish child by Karakaya
et al. further demonstrates the similarities with the TBCD
disorder and Prune syndrome, and confirms optic atrophy
to be a feature of Prune syndrome. Interestingly, it is also
becoming clear that respiratory insufficiency is a common
feature of Prune syndrome, having been documented by
Karakaya et al. and in the Oji-Cre child, as well as the
youngest affected Omani child described in our manuscript
