Childhood presentation of COL4A1 mutations

SIDDHARTH SHAH1 | SIAN ELLARD2 | RACHEL KNEEN3 | MING LIM4 | NIGEL OSBORNE5 | JULIA RANKIN6 |NEIL STOODLEY7 | MARJO VAN DER KNAAP8 | ANDREA WHITNEY9 | PHILIP JARDINE10

1 Department of Paediatric Neurology, Bristol Royal Hospital for Children, Bristol, UK. 2 Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter,UK. 3 Department of Paediatric Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. 4 Department of Paediatric Neurology, Evelina Children's Hospital, London,UK. 5 Department of Paediatrics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK. 6 Department of Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter,UK. 7 Department of Neuroradiology, North Bristol NHS Trust, Bristol, UK. 8 Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.9 Department of Paediatric Neurology, Southampton University Hospitals NHS Trust, Southampton, UK. 10 Department of Paediatric Neurology, Bristol Royal Hospital forChildren, Bristol, UK.

Correspondence to Dr Philip Jardine at Department of Paediatric Neurology, Level 6 Education Centre, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8AE, UK.Email: philip.jardine@bristol.ac.uk

PUBLICATION DATA

Accepted for publication 27th August 2011.Published online 16th January 2012.

AIM To describe the clinical and radiological features of four new families with a childhood

presentation of COL4A1 mutation.

METHOD We retrospectively reviewed the clinical presentation. Investigations included radio-

logical findings and COL4A1 mutation analysis of the four cases. Affected family members were

identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in

affected family members.

RESULTS The three male and one female index cases presented with recurrent childhood-onset

stroke, infantile hemiplegia ⁄ spastic quadriplegia, and infantile spasms. Additional features such

as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and develop-

mental delay ⁄ learning difficulties were present in three cases. Three cases had one or more family

member affected in multiple generations, with a total of 11 such individuals identified. The clinical

features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed

bilateral white matter change in all cases, except in one mutation-positive family member. Unilat-

eral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of

clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis

was between 1 year and 6 years for the children with presentation in infancy and 12 months after

stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1

gene.

INTERPRETATION COL4A1 mutations can present in children with infantile hemiplegia ⁄ quadri-

plegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter

change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made,

a careful search can identify affected family members.

COL4A1 mutations were recently identified as a monogeneticcause of weakness of the basement vascular membranes, result-ing in small vessel disease and haemorrhage.1 The manifesta-tions are widespread, involving the brain and eyes mostcommonly and other organs such as the kidneys. Families havebeen identified with a wide variety of clinical features and intra-familial variations.2–8 A rare systemic phenotype hereditaryangiopathy, nephropathy, aneurysms, and muscle cramps hasbeen described and more recently COL4A1 mutations havebeen shown to be responsible for a muscle-eye-brain (MEB)disease phenotype.4,9 While spontaneous haemorrhage andsilent bleeds have been described, triggers such as trauma,physical exercise, sports, and anticoagulant use are possible riskfactors for cerebral haemorrhage in affected individuals.10,11

There is a growing spectrum of paediatric presentations ofCOL4A1 mutations. The earliest presentation is antenatal orperinatal cerebral haemorrhage.7,12 Extensive encephaloclasticlesions secondary to venous haemorrhagic infarction havebeen described.13 Porencephaly presents as infantile hemiple-gia with or without recognized antenatal or perinatal events.Congenital cataracts, retinal arterial tortuosity, and anteriorchamber abnormalities of the Axenfeld–Rieger type have eachbeen shown to affect individuals in an autosomal dominanttrait in addition to brain involvement, some of which can beseen in infancy.3–6 Childhood stroke even in the absence ofporencephaly has been described.8 Epileptic seizures are alsoincluded within the spectrum although the semiology has notbeen described in detail.

ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press DOI: 10.1111/j.1469-8749.2011.04198.x 569

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY CASE REPORT

We describe four new families from the UK. All the indexcases presented and were diagnosed in childhood.

METHODThis study was conducted as a retrospective note review. In allfour cases, the index case presented to a paediatrician or paedi-atric neurologist. Investigations were performed in the clinicalsetting based on the presenting symptom. In all cases, adetailed family history was taken in an attempt to identifyaffected family members. We examined the clinical details ofall the cases, looking at all the clinical features present, and theinvestigations included radiological investigations andCOL4A1 mutation analysis.

Eye assessment was performed by an ophthalmologist andall the families were seen by a geneticist. All the brain mag-netic resonance imaging (MRI) was reviewed by a single neu-roradiologist to identify previously reported neuroradiologicalfeatures of COL4A1 mutations and to review any variants inthis group of patients.

COL4A1 mutation analysis was performed using sequenceanalysis of the DNA. It was performed in all index cases butwas it not possible in all affected family members.

Consent for genetic testing and publication of case and fam-ily history was obtained from all families.

RESULTSThe main findings are summarized in Table I. The mutationshave not been seen in 1094 population controls sequenced inthe 1000 Genomes Project.

Case 1This case was a female born at 35 weeks’ gestation via vento-use following an induction for pre-eclampsia. No resuscitationwas required but she was admitted to the neonatal unit for

Table I: Summary of the main clinical findings, neuroimaging findings, and COL4A1 mutation analysis

Case no. Family member Neurological featuresOphthalmologicalfindings Other findings MRI findings

COL4A1 mutationanalysis

1 Index case,female

Epilepsy withinfantile spasms andmyoclonic jerks, four-limb motor disorder,microcephaly,developmental delay

Congenital cataracts,anterior segmentdysgenesis,microopthalmia,hypermetropia,astigmatism

Creatine kinaseraised

WMC (Fig. 1) Heterozygousnovel mutationpGly882Asp(c.2645G>A)

Mother None Congenital cataracts No abnormalitiesdetected

HeterozygousmutationpGly882Asp(c.2645G>A)

2 Index case, male Spastic quadriplegia,microcephaly, stroke

Congenital cataracts WMC (Fig. 2) Heterozygousnovel mutationp.Gly773Arg(c.2317G>C)

Sibling Infantile hemiplegia Congenital cataracts WMC, left PC Heterozygousnovel mutationp.Gly773Arg(c.2317G>C)

Mother Congenital cataracts Not performed Not tested3 Index case, male Infantile hemiplegia,

focal seizures,microcephaly

Nystagmus,hypermetropia,astigmatism

WMC, right andleft PC (Fig. 3)

Heterozygousnovel mutationp.Gly1266Arg(c.3796G>C)

Mother Infantile hemiplegia,epilepsy

None WMC, right PC,MH

Heterozygousnovel mutationp.Gly1266Arg(c.3796G>C)

Aunt (maternal) Migraine,microcephaly

Nystagmus WMC, BG, MH Not tested

Mother’s cousin Infantile hemiplegia None WMC, PC Not testedGrandmother(maternal)

Stroke in adulthood None Renal andhepaticcysts, atrialfibrillation

WMC, BG, H,MH

Not tested

4 Index case, male Childhood stroke,mild learningdifficulties

Congenital cataracts,hypermetropia,astigmatism

ChromosomesXYY

WMC, BG, H(Fig. 4)

Heterozygousmutationp.Gly755Arg(c.2263G>A)

MRI, magnetic resonance imaging; WMC, white matter change; PC, porencephalic cyst; MH, microhaemorrhage; BG, basal ganglia involvement;H, haemorrhage.

What this paper adds• We describe four new families with a COL4A1 mutation, with particular atten-

tion given to the clinical presentation in children.• We describe three new missense mutations in the COL4A1 gene.

570 Developmental Medicine & Child Neurology 2012, 54: 569–574

hypothermia. Bilateral congenital cataracts were diagnosed at48 hours of age and subsequently microophthalmia andanterior segment dysgnesis were confirmed. She also hashypermetropia and astigmatism. She developed seizures ataround 7 months that were clinically and electrophysiologi-cally classified as infantile spasms. They were treated withvigabatrin. At this stage she was also recognized to have anevolving motor disorder involving all four limbs with someasymmetry affecting the right more than the left. Her seizureshave evolved into a generalized seizure disorder includingmyoclonic jerks responding to sodium valproate and topira-mate. She is now 7 years old and has been seizure free since3 years 2 months of age. She has developed progressive micro-cephaly and has significant learning difficulties. She has notdeveloped muscle cramps.

Renal function tests, investigations to look for an underlyingmetabolic disease, and white cell lysosomal enzymes were nor-mal. An MRI was performed at 7 months of age and repeated2 years later which shows a periventricular white matterchange bilaterally and also involvement of the internal capsule(Fig. 1). Creatine kinase was elevated at 343 to 463 IU ⁄ L onthree separate occasions. At 6 years of age the diagnosis wasconsidered owing to the MRI findings, presence of cataracts,and family history of the same. Sequence analysis identified anovel heterozygous COL4A1 missense mutation, p.Gly882Asp(c.2645G>A).

Her mother has congenital cataracts and has been investi-gated with MRI: the brain and abdomen were both reportedas normal. She is heterozygous for the p.Gly882Asp mutation.There is no other significant family history.

Case 2This case was a male born at 35 weeks’ gestation followingemergency caesarean section due to maternal pre-eclampsia.During the neonatal period he required brief ventilatorysupport and phototherapy for jaundice, and he had mild

feeding difficulties. The first concerns with developmentalprogress and vision were at 8 weeks of age. At 3 months ofage he was diagnosed with bilateral cataracts and reducedvisual acuity. During infancy he developed signs of a spasticquadriplegia. At 4 years of age, following a febrile illness (pre-sumed to be viral), he had an episode of ‘stroke’ where he losthis ability to speak, lost his muscle tone generally and requiredfeeding support owing to a bulbar ⁄ pseudobulbar weakness.He has microcephaly.

Investigations performed include a normal karyotype andinvestigations for a metabolic condition. He underwent brainMRI at 2.5 years of age and again 2 years later which shows awhite matter change with asymmetric ventricles and irregularventricular margins (Fig. 2). At 5 years of age a COL4A1mutation analysis was performed which confirmed him to beheterozygous for a novel COL4A1 missense mutation,p.Gly773Arg (c.2317G>C).

His sibling is also heterozygous for this mutation and has aright-side infantile hemiplegia and very mild cataracts. MRIshowed a white matter change and porencephalic cyst. Theirmother has bilateral congenital cataracts. She has three sistersand two brothers. It is of note that one sister has experienceddisabling migraine but has not been investigated further. Thematernal grandfather also experienced migraine and thematernal grandmother had a stroke in her 80s but no otherneurological problems.

Case 3This case was a male born at 39 weeks’ gestation. He wasfound to have nystagmus at an early age and subsequently wasconfirmed to have hypermetropia and astigmatism requiringcorrection, but no cataracts. He developed an infantile hemi-plegia and started having focal seizures with secondary

Figure 1: (Index case 1) Axial T2-weighted scan showing a diffuseincreased signal in periventricular white matter without significantventriculomegaly. A high signal is also seen in the internal and externalcapsules.

Figure 2: (Index case 2) Axial T2-weighted scan showing a diffuseincreased signal bilaterally in periventricular white matter and asymmetricalventricles.

Case Report 571

generalization. He has a progressive microcephaly. He hasmild global developmental delay.

An MRI was performed at 12 months of age which con-firmed white matter change and porencephalic cysts on eitherside of the lateral ventricles (Fig. 3). A baseline metabolicscreen and chromosomal analysis were normal. Mutation anal-ysis at 12 months of age showed a heterozygous novelCOL4A1 missense mutation, p.Gly1266Arg (c.3796G>C).

His mother has longstanding left-side hemiplegia and epi-lepsy attributed to lack of oxygen at the time of birth. Herbrain MRI showed a white matter change, porencephalic cysts,and possible microhaemorrhages within the white matterchange. Mutation analysis confirmed the same mutation in theCOL4A1 gene. The maternal grandmother had a mild strokein her 40s and a similar event at 65 years of age. Imagingshows her to have similar changes and larger areas of haemor-rhages in both cerebral hemispheres and the cerebellum. Shehad a history of hypertension and took warfarin. DNA wasunavailable but her husband was found not to carry the famil-ial COL4A1 mutation. The maternal aunt has nystagmus,microcephaly, and headaches classified as migraine, and onMRI the brain had abnormalities consistent with a COL4A1mutation. The maternal grandmother’s brother has a son withinfantile hemiplegia and epilepsy and MRI confirmed aporencephic cyst.

Case 4This case was a male born at term following a normal preg-nancy. He presented at 14 years of age with a sudden onset ofweakness while playing on a trampoline. Four days prior tothis he had had a dental extraction under general anaesthesiafor malposition of teeth. The weakness involved his left leg

and arm but rapidly resolved by the time he was seen in theemergency department. Two days later he had recurrence ofthe weakness, following which he was admitted and investi-gated further. He had congenital cataracts, hypermetropia,and astigmatism, as well as a left-convergent squint. He hasmild learning difficulties.

A chromosomal analysis showed an XYY pattern. He is anMTHFR 677C>T carrier. Neuroimaging confirmed him tohave a periventricular white matter change and also signalchange within the basal ganglia. A diagnosis of clinical strokewas supported by the presence of acute haemorrhage (Fig. 4).After investigations looking for an alternative cause for thestroke were all negative, a COL4A1 mutation was considered.COL4A1 sequence analysis demonstrated a previouslyreported heterozygous missense mutation, p.Gly755Arg(c.2263G>A).

There is no family history of migraine, strokes, or cataracts.The parents have been evaluated by an adult neurologist andgeneticist and have been found to be asymptomatic. Neitherparent have had an MRI of their head. They have declinedasymptomatic testing for a COL4A1 mutation.

DISCUSSIONCOL4A1 mutations were first described as a cause of perinatalcerebral haemorrhage in mice and they were also identified inhumans with autosomal dominant porencephaly.1 Since then,COL4A1 mutations have been recognized as a cause of cere-bral small vessel disease. Apart from the brain, the eyes andkidneys are frequently involved. This was first confirmed inmouse studies and subsequently confirmed in humans.14 Theocular features include retinal arterial tortuosity, cataracts, andAxenfeld–Rieger anomaly, and renal involvement is in the

Figure 3: (Index case 3) Axial T2-weighted scan showing asymmetricalenlargement of both lateral ventricles with diffuse increased signal in theperiventricular white matter. Some squaring of the right frontal hornsuggests porencephaly possibly secondary to previous parenchymalhaemorrhage.

Figure 4: (Index case 4) Axial fluid-attenuated inversion recovery (FLAIR)sequences showing increased signal in the periventricular white matterand small bilateral parenchymal haemorrhages.

572 Developmental Medicine & Child Neurology 2012, 54: 569–574

form of haematuria, renal cysts, or renal failure.15 Twenty-twodifferent mutations (including 19 missense mutations affectingglycine residues) have been described. We describe four newfamilies with three novel mutations in the COL4A1 gene. Thenovel mutations p.Gly773Arg, p.Gly882Asp, andp.Gly1266Arg all affect highly conserved glycine residueswithin the triple helix domain of the COL4A1 protein and arehighly likely to be pathogenic. The broadly recognized pheno-types of COL4A1 are autosomal dominant type 1 porencephal-y, cerebral small vessel disease, and HANAC syndrome(hereditary angiopathy with nephropathy, aneurysm, andmuscle cramps).4 In case 1, the main neurological featuresincluded epilepsy and a four-limb motor disorder with micro-cephaly, secondary to cerebral small vessel disease. Hermother, who carries the same mutation, is asymptomatic andhas a normal MRI. Case 2 has a spastic quadriplegia alongwith a sibling who has an infantile hemiplegia. Their motheris likely to be affected but has not had brain MRI or mutationanalysis. Case 3 is an example of autosomal dominant poren-cephaly with cysts bilaterally. Case 4 presented with intracere-bral haemorrhage which was either spontaneous or followingminimal trauma. Intracerebral haemorrhage in the context ofCOL4A1 mutations can occur at any age from the perinatalperiod through to childhood and adulthood. In all three caseswith neurological features in infancy, microcephaly was alsopresent as a secondary feature to the underlying brain changes.Headaches or migraine were not reported in any of the child-hood cases.

Ocular involvement was the most consistent finding afterneurological involvement and in three of our four index caseswas a recognized clinical feature before neurological features,though not sufficient to make a diagnosis on its own. The rec-ognized eye features with COL4A1 mutations include retinalarterial tortuosity, retinal haemorrhages, congenital cataracts,and anterior segment dysgenesis.3–6,8,16 In this paediatric caseseries, congenital cataracts were present with either poren-cephaly or small vessel disease and haemorrhage, bothreported previously. Axenfeld–Rieger anomaly and small ves-sel disease has also been reported as seen in case 1. In family 3,

the prominent eye finding was a nystagmus associated withpoor vision. We did not find the presence of retinal arterialtortuosity in any of the cases. It is worth noting that themother of case 1 had congenital cataracts as the only clinicalfinding.

The white matter change in COL4A1 when present tends tobe within the cerebral small vessel distribution affecting thedeep cerebral white matter and subcortical white matter butsparing the U-fibres. The distribution tends to be bilateral,anterior, and posterior in a symmetrical fashion. Out of the 11affected individuals identified in this case series, only one hadabsence of a white matter change. As in two affected familymembers here, signal change can also be seen in the basal gan-glia. The porencephaly when present can be unilateral orbilateral. Haemorrhagic stroke tends to be in the affectedwhite matter and is thought to result from rupture of theweakened small vessels due to the affected basement mem-brane in the cerebral hemisphere or cerebellum. In the case ofmicrohaemorrhages, this tends to be within the affected whitematter. These can be picked up on specific MR sequencessuch as the gradient 2D echo or susceptibility-weighted imag-ing. We did not identify cerebral aneurysms on any of theindex cases or family members, though a specific sequencesuch as MR angiography of the circle of Willis and neck ves-sels was not performed in each case.

A diagnosis of COL4A1 mutation in the paediatric cases ledto an explanation for clinical features in other family members.In case 4, we could not identify any clinical symptoms in eitherparents or in other generations. We have not been able to per-form brain MRI or carry out a mutation analysis on his par-ents and hence cannot be sure whether this represents asporadic case or non-penetrance. Intrafamilial variation inthe clinical features is a recognized feature of this condition.There is an overlap of clinical features between the broad phe-notypes of COL4A1 and related conditions. One of them, HA-NAC syndrome, is a specific constellation of clinical featuresassociated with mutations in the CB3 (IV) fragment ofCOL4A1 which includes the integrin-binding sites.4,17 Renalinvolvement, cardiac involvement, and a raised creatine kinase

Table II: Possible investigations that can be performed in a case suspected or proven to have a COL4A1 mutation

Body system involved Investigation Purpose of investigation

Brain MRI head including T1 saggital, T2 axial, andFLAIR axial images or similar sequences

White matter change, porencephaly,cerebral or cerebellar haemorrhage

Gradient 2D echo axial or similar sequence MicrohaemorrhageMRA of neck and brain vessels Cerebral aneurysms

Eyes Snellen chart or LogMAR Reduced visual acuityFundus and ⁄ or fluorescein angiography Retinal arterial tortuosity, retinal haemorrhagesSlit-lamp examination Cataracts, ocular dysgenesis

Kidneys Renal ultrasound scan and ⁄ or MRI abdomen Renal cystsUrine dipstick and ⁄ or 24-hour urine protein ⁄creatinine ratio

Proteinuria, haematuria

Heart Electrocardiogram ArrhythmiasSkin Biopsy for electron microscopy Abnormalities in basement membrane structureMuscle Creatine kinase Elevated creatine kinaseGene ⁄ protein Sequence analysis of the exons of COL4A1 Mutation in the COL4A1 gene

MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; MRA, magnetic resonance angiography.

Case Report 573

have all been reported as part of HANAC syndrome. Theindex case in case 1 had an elevated creatine kinase and thegrandmother of case 3 had the presence of hepatic and renalcysts confirmed by MRI of the abdomen as well as cardiac ar-rhythmias with an exon 43 mutation. Similarly, cerebral aneu-rysms have been described without the other features ofHANAC syndrome. Owing to this variable involvement ofbody systems in this systemic basement membrane disease itmight be necessary to consider one or more of the investiga-tions summarized in Table II. It is interesting to note that twoof the three mothers with a mutation also developed pre-eclampsia.

There are no specific therapies available for this conditionat present. Screening for aneurysms can be performed. If pre-senting with haemorrhage, contact sports, physical exercise,and head injury later in life may be triggers for further hae-morrhage. Caesarean section rather than vaginal delivery maybe considered to avoid perinatal haemorrhage, althoughhaemorrhage could be unpreventable as the process might

even originate in the fetus at an early gestation.10,12 Anticoag-ulant use should be avoided if possible in affected individuals.Actively looking for and managing risk factors such as hyper-tension and diabetes that are risk factors for small vessel dis-ease independently would also be logical.

CONCLUSIONCOL4A1 mutations leading to a systemic vascular basementdisease can present in early childhood with a broad range ofclinical features. When dealing with an unexplained neurolog-ical disease that has features such as white matter change, por-encephaly, or cerebral haemorrhage, especially with thepresence of eye features or a family history, a mutation analysisshould be considered. Confirmation of the diagnosis will helpavoid further investigations and will allow genetic counselling.In future, further genotype–phenotype correlations mayemerge and specific management measures may becomeavailable.

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