Keywords
Cerebral palsy - COL4A1 gene mutation - epilepsy; gliosis - magnetic resonance imaging
- paediatric congenital cataract
Introduction
COL4A1 encodes for Collagen type 4 alpha 1, an important component of the hetero-trimers
presents in nearly all vascular basement membranes.[[1]] It is particularly in the brain, muscles, eyes and kidneys. Most mutations are
dominantly inherited and lead to structural instability of the affected basement membranes.
These are missense mutations that replace g glycine with another amino acid. A wide
variety of presentations are described with mutations in COL4A1 including Hereditary angiopathy with neuropathy, aneurysms and muscle cramps (HANAC)
due to mutations in exons 24 and 25 of the gene.[[2]]
The first report of a mutation in this gene was in mice in 2005, since then there
have been reports of COL4A1 mutations causing intrauterine foetal cerebral haemorrhage with secondary porencephaly;
schizencephaly; and micro and macro haemorrhages with white matter changes noted in
adulthood.[[3], [4]] In the paediatric age group, clinical presentations include epilepsy, developmental
delay and problems with vision. Genetic studies have also demonstrated that manifestations
can vary widely within affected families.[[5], [6], [7]]
Case Report
A 18-year-old girl initially presented to us when she was 11 years old. The pregnancy
and delivery had been uneventful. Bilateral cataracts were noted after delivery and
these were removed at 5 months of age. She started having focal seizures with secondary
generalization at 6 months of age. Her development was delayed, and she was at a special
needs school. Her parents and 11-year-old brother were in good health. There was no
known family history of note including for stroke, cataracts and epilepsy or any extra
CNS manifestations.
On examination, she had right hemiparesis. Her gross and fine motor difficulties did
not deteriorate over time. She wore spectacles.
On brain MRI, she had volume loss with gliosis involving the left fronto-parietal
periventricular white matter, centrum semi-ovale and ganglio-capsular regions with
associated ex-vacuo dilatation of the left lateral ventricle. Confluent hyperintense
signal was also noted involving the right fronto-parietal periventricular white matter
and centrum semi-ovale on Fluid-attenuated Inversion Recovery (FLAIR) images suggestive
of ischemic white matter changes. There was no evidence of acute ischemia or previous
hemorrhage. Time-of-Flight) MR Angiography revealed paucity of insular and opercular
branches of the left middle cerebral artery. There was no dolichoectasia or aneurysm
formation [[Figures 1], [2], [3], [4]].
Figure 1 (A-D): Sequential FLAIR axial (A-D) MRI revealed gliosis with volume loss (yellow arrows)
involving the left fronto-parietal periventricular white matter and ganglio-capsular
regions with associated ex vacuo dilatation of left lateral ventricle (shown by star).
Confluent hyperintense white matter ischemic changes (white arrows) were noted involving
right fronto-parietal periventricular white matter
Figure 2 (A-C): (A-C): Sequential Gradient Echo (GRE) axial MRI showed no significant ‘blooming’
at the site of gliosis in left periventricular white matter and centrum semiovale
to suggest hemorrhage or hemosiderin residue
Figure 3 (A-C): (A-C): Sequential high ‘b’ value diffusion weighted (DWI) axial MRI did not show
any abnormal hyperintense signal representing diffusion restriction involving the
brain parenchyma to suggest acute ischemic changes
Figure 4 (A-C): (A-C): Axial (A), coronal (B) and Sagittal (C) 3D projections of TOF Angiography
MRI reveals paucity of insular and opercular branches of left middle cerebral artery.
No evident significant stenosis is noted involving visualized intracranial segment
of internal carotid arteries, vertebro-basilar system and its branches. No evident
aneurysm was noted
Due to the absence of any peri-natal complications to explain the brain injury, and
after investigations and excluding other possibilities such as congenital infections,
single gene testing of COL4A1 was requested. This revealed a novel c.2327G>T p.(Gly776Val) heterozygous mutation
reported to be a likely pathogenic mutation. The parents have not been tested for
the mutation.
Discussion
COL4A1 and COL4A2 located on chromosome13q34, encode for the collagen 4 alpha 1 and 2 chains respectively,
and together form hetero-trimers that provide the supporting basement membrane of
the vasculature of various tissues. Since the first description of mutations in mice
leading to haemorrhage and porencephaly, and subsequent single and familial case reports,
the spectrum of this disease has increased. The phenotype has grown not only in terms
of possible CNS manifestations but also extra CNS manifestations. Subsequent to COL4A1 mutations, COL4A2 mutations have been reported to cause a milder but similar phenotype, and this not
surprising as they are both important components of the heterotrimers.[[8]] There have been reports of patients from all ethnicities and both genders. There
have been reports from South East Asia including a few reports from India,[[9]] however many cases remain underdiagnosed probably due to lack of recognition of
these neurological presentations and lack of testing, as exemplified in our case in
whom an initial diagnosis of a non-genetic form of cerebral palsy had been made.
Neurological presentations in childhood are usually the sequelae of porencephaly,
schizencephaly, polymicrogyria, focal cortical dysplasia, and nodular heterotopia
and associated white matter changes.[[3], [4], [5], [6], [7]] Epileptic seizures reported include epileptic spasms, focal seizures as in our
case, and generalized seizures. Adult case series reports indicate that the presentation
tends to be that of a small vessel disease with ischemic and haemorrhagic infarction.
Ocular phenotypes include congenital cataracts, microphthalmia, bilateral retinal
arterial tortuosity, and anterior segment anomaly of the Axenfeld–Rieger type in which
anterior chamber abnormalities comprising of congenital iris abnormalities, posterior
embryotoxon, micro-cornea and glaucoma have been observed.[[2]] A recent large series reported patients with isolated congenital renal and urinary
tract anomalies with non-glycine COL4A1 mutations.[[9]]
MRI findings[[10], [11], [12], [13]] tend to be nonspecific and include widespread confluent, bilateral, symmetric white
matter T2 hyper-intensities with relative sparing of subcortical U-fibers and dilated
perivascular spaces. There may be associated small lacunar infarcts predominantly
involving the centrum semiovale, deep grey matter, or the brainstem. Cerebral micro-haemorrhage
may be present particularly in the basal ganglia region because the microvasculature
in these areas possesses sparse supporting tissue and the vessels branch at large
angles.[[14]] Van der Knapp et al.[[15]] and Gould et al.[[1]] have suggested that focal disruptions of the vascular basement membrane may predispose
to haemorrhage and vessel wall abnormality, where as swelling of vascular endothelial
cells and accumulation of fragmented basement membrane products may lead to narrowing
of vessels and ischemic damage. No significant micro- or macro-hemorrhages were noted
in our case.
If porencephalic cysts are noted these are often unilateral.[[10]] In our case there was left sided gliosis with associated ex-vacuo dilatation of
left lateral ventricle. The differential diagnoses for such changes in the paediatric
age group include mitochondrial diseases such as Mitochondrial Myopathy, Encephalopathy,
Lactic Acidosis, Stroke-like episodes (MELAS), and central nervous system vasculitis
especially when acute or in the chronic non-progressive form a prenatal or neonatal
brain injury. In older individual’s differential diagnoses include Cerebral Autosomal
Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL),
hypertensive microangiopathy, hereditary vascular retinopathy, cerebral amyloid angiopathy;
Hereditary Endotheliopathy with Retinopathy, Nephropathy and Stroke (HERNS); Cerebral
Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
(CARASIL); and Fabry disease.
In our case, brain MRI changes and congenital cataracts were both present. In places
with a very high prevalence of cerebral palsy, including India, similar static clinical
findings and brain changes may mistakenly be attributed to brain injury due to perinatal
events or congenital infections such as those caused by cytomegalovirus or toxoplasmosis.
However, whilst strabismus and refractive errors have a high incidence in children
with cerebral palsy, congenital cataracts are not a common occurrence and should lead
to the consideration of other underlying diagnoses, especially in the absence of a
clear neonatal history as in this case.
Conclusion
In summary, we present a case of a novel glycine COL4A1 mutation in an Indian patient presenting with bilateral congenital cataracts, epilepsy
and abnormal brain MRI. The presence of associated ocular abnormalities such as congenital
cataract, in the absence of a birth history that could lead to brain injury, should
prompt consideration of a mutation in the COL4A1 gene leading to genetic testing. As genetic testing becomes reliable and more readily
available, together with increasing awareness of such conditions, more cases will
be confirmed and reported. Genetic counselling is very important as COL4A1 is an autosomal dominant disease with variable intra-familial presentation. Finally,
as we begin to understand more about this gene and the resulting pathophysiological
processes resulting from mutations within it, specific treatments initiated at an
early stage may also become a realistic possibility in the future.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
