Disclosures Genetics for the general Chairman DSMB Sanofi gene - - PowerPoint PPT Presentation

12/4/2015 1

Genetics for the general

• phthalmologist

Anthony T Moore Ophthalmology Department School of Medicine UCSF

Disclosures

• Chairman DSMB Sanofi gene

therapy trials

• Chairman DSMB Oxford

Biomedica gene therapy trials

• Consultant Proretina

Making a genetic diagnosis Why does it matter?

• Having a specific diagnosis
• Genetic counselling

– Will I have another affected child? – Will my children have the disorder? – Can I avoid having an affected child?

• Information about prognosis
• Can I be recruited to trials of new

therapies ?

Making a diagnosis

Major advances in :-

• Clinical Electrophysiology
• Retinal imaging
• OCT
• FAF imaging
• adaptive optics imaging
• Molecular Genetics
• exome sequencing
• whole genome sequencing

Courtesy Joe Carroll

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Role of general ophthalmologist

• To recognise the possibility
• f diagnosis of inherited eye

disease

• Give advice if feel confident

to do so or make an appropriate referral

• To be able to recognise eye

abnormalities in patients with diagnosis of a syndromic disorders

• It helps to work closely with

your local clinical geneticist

Does this child have eye findings of this syndromic disorder?

Key points

• Take a good history

– Ocular and systemic

• Family History
• Parental consanguinity?
• Any other medical problems?
• Does the child look normal?

– Any dysmorphism – Any other obvious impairments

• Examine other family members

Case 1: Congenital cataract

• Age 4 months
• Dense bilateral

cataracts

• No family history of

cataract

• Parents ask 'What is the

risk of having another affected child?'

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Mother age 30 years Vision 20/20

Diagnosis AD CC 1 in 2 risk of having another affected child

Case 2 Presented with dense cataracts at birth No FH Usual investigations for cataract negative at birth

• Torch Screen
• reducing sugars
• Calcium and

electrolytes

• urinary aas

Mothers examination VA 20/20 OU

Lowe syndrome (OCRL)

• X-linked disorder
• Mental retardation
• Cataract
• Renal Fanconi syndrome

Female carriers have typical lens changes

Urinary amino acids repeated – positive Molecular genetic testing confirms diagnosis Major implications for management and genetic counseling

Does the child look normal ?

Case 3 Age 2 months Cataracts notes at 6 week check by family doctor Parental concerns about appearence Previous pediatric diagnosis

• f Pierre-Robin sequence

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Hallerman- Streiff syndrome Sporadic disorder Low recurrence risk Characteristic facies Micrognathia Airway problems Microphthalmos Cataract Spontaneous resorption common

Common misdiagnoses: Infantile onset nystagmus

Differential diagnosis

• Leber amaurosis
• Congenital stationary night

blindness

• Cone dysfunction syndromes
• achromatopsia
• S cone monochromatism
• Albinism
• CIMN

Case 4

9 year old girl Diagnosed in infancy with congenital nystagmus 'Not genetic' 4 years later newborn sibling had nystagmus Va 20/200 OU No color vision Absent cone ERG Normal rod ERG

Key points in infantile nystagmus

• Any FH of nystagmus?
• Photophobia or night

blindness?

• Nystagmus typical of CIMN
• r atypical
• Examine child on slit lamp
• iris translucency
• iris hypoplasia
• Refraction
• Key role of

electrophysiology

12/4/2015 5 Examine the mothers of all male infants with nystagmus on slit lamp

Diagnosis : Female carrier X-linked ocular albinism

Refraction

High refractive errors in:- Albinism Aniridia Retinal dystrophies

ERG and VEP in awake children ERG: Peri-orbital electrodes

Normal Lt eye Rt eye Photopic 30Hz DA

a- b- a- b-

(Courtesy of G.Holder)

Albino chiasmal misrouting

Normal Albino

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F, 7 yrs. EDD 35661. Oculo-cutaneous albinism. VAR, VAL 6/24

R eye

Pattern appearance

L eye

Flash

R eye L eye

Modern imaging techniques are very helpful in diagnosis

• In a child with unexplained poor

vision perform OCT especially if electrophysiology is not easily available

• Fundus autofluorescence imaging

helpful in specific diagnosis

8 year old boy . Failed school eye test . VA 20/50 OU 'Normal fundus'

Diagnosis X-linked retinoschisis

Age 7 years Failed school eye test Vision 20/60 ou Normal fundus 'Probable functional visual loss'

OCT confirms a retinal cause Diagnosis KCNV2 retinopathy

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Fundus autofluorescence imaging

Another tip Always keep diagnosis under review As new information becomes available may need to change diagnosis Family 1

Age 25 From Pakistan Severe RP Brother also affected Registered blind Myopia Diagnosis ARRP

Family 1 10 years later

• Niece of index case , age 9 yrs ,referred by
• ptician because of abnormal fundus
• Asymptomatic, normal acuity

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Tapetal reflex Diagnosis X-linked RP Think about X-linked inheritance in male sibships Examine mothers or daughters of males with severe RP Age 14 years female Night blindness 5 years No FH VA 6/9 OU No detectable rod responses and abnormal cone responses on ERG

What patients will ask ? What is diagnosis ? What is the treatment? What about new treatments? Stem cells Gene therapy ‘Bionic eye ‘ Eye transplants Placental extracts Cranial osteopathy Homeopathy Cannabis

For the clinician OMIM Orphanet Gene Clinics Pubmed

• Mr. Google – find out what your

patients are reading For the patient Foundation Fighting Blindness Other support groups Social media

Patient and clinical resources