The Experience of the first adult

Neurogenetics Clinic in Ireland

Dr Diana Olszewska (Neurology), Dr Terri McVeigh (Genetics), Professor Tim Lynch (Neurology)

Heritable Neurological Disease

• A number of neurological conditions have a genetic aetiology – Implications for wider family– Incurable disease

• Most can be handled appropriately within a routine neurology clinic with onward referral for genetic counselling if necessary

• e.g. Huntington’s disease

• However, some specific cases are complex, rare or uncertain and benefit from multi-disciplinary input

• It is recommended that there be a minimum of 1 clinical genetics post and 1 neurology post designated for Neurogenetics service for a population of 2 million1

1. Genetic Services for Neurological Disorders, ABN and Clinical Genetics Society Report, 2003

Neurology

• Rare disorders require extensive literature review and specialist diagnostic approach• Time constraints in routine clinics does not

facilitate this easily

• Limited time for explanation of inheritance, recurrence risks• Patient concerns regarding family planning,

prenatal diagnosis

• Practical issues regarding send-out of samples to specialist laboratories

Genetics

• Complex genetic conditions require careful explanation regarding natural history and implications for prognosis, family planning, and recurrence risk

• Genetic testing can be directed based on careful phenotyping

• Waiting list – Priority <4 months

– Routine ..6-18 months!

• Frequent failure to attend

• Hesitance in proceeding with pre-symptomatic testing

https://www.eshg.org/111.0.html.

Teamwork!

• Can combined clinic address these issues?

• Neurogenetics clinic

– 1 neurologist + 1 geneticist

• Real-time phenotyping

• Active discussion regarding possible differential diagnoses

• Valuable opportunity for detecting important or unresolved genetic issues

• Foundation for genetic counselling

Patient simultaneously reviewed by Registrars

1 Neurology

1 Genetics

Simultaneous review by Consultants

1 Neurology

1 Genetics

Brainstorming!

Likely diagnosis suggested

Workflow

• Detailed history • Personal and familial

• Pedigree drawing • Thorough neurological examination • Review of investigations performed to date

• Review of case

• Active patient input in discussion• Literature review • Differential diagnosis

• Specialist tests requested

• Inheritance pattern and recurrence risks outlined

Benefits

• Two heads are better than one! – Widens differential diagnosis

• One clinic visit – Reduced repetition for patient– Time efficient – Family members can attend together or separately

• Familiarity with Dublin Neurological Institute – Less anxiety

• Improves doctor-patient relationship• Active participation in discussion • Patient understands the process better• Dedicated “team” of doctors working on rare disorder

A bridge to Crumlin

• Introduction of concept of genetic counselling and/or pre-symptomatic testing for unaffected family members

– Can explain process

– Allay anxiety surrounding “the test”

• Explain no obligation

• Define risk to patient and family members

– Continuity of care

• Genetic registrar working in Department of clinical genetics

The Adult Neurogenetic ClinicDublin Neurological Institute

• First and only one in Ireland

• Once a month

• Commenced November 2014

• 1.5h dedicated per patient

– Reviewed by 4 doctors

Neurogenetic clinic

• 25 patients

– 16 families

– 3 returns

• Age 22-78

All-Ireland Service

Disorder N Action

Frontotemporal Dementia 10 Referral for Genetic Counselling /Pre-symptomatic testing Different genes in different families: MAPT, GRNAdvice re prenatal pre-implantation diagnosis Referral for psychology input 1 patient: Review of diagnosis - personality later attributed to organic (reversible) cause!

Leucodystrophy 1 Referral to international specialist

Ataxia-Telangiectasia 1 Referral for genetic counselling Advice for cancer risk for heterozygous carriers in family

Parkinson’s disease 3 Young onset – Parkin testing (n=2, 1 positive, 1 negative)Older onset (familial) – LRRK2 testing

Pure ataxia 2 Extensive diagnostic work up

Spastic Ataxia 2 Further testing (unknown genetic aetiology after multiple tests)

GLUT 1 deficiency 1 Referral for genetic counsellingConsideration: Triheptanoin therapy

Spinocerebellar ataxia with writer’s cramp

1 Diagnosis – SCA6

Familial MS 1 Counselling regarding potential genetic contribution Discussion re limitations of available genetic investigations

• Multiple family members affected• New mutation “+15”, dominant inheritance

– 50-50 chance

• Numerous members of the family: – 4 siblings – 1 cousin – 1 son

• Referral to Crumlin for counselling and pre-symptomatic testing

Brain. 2015 Oct;138(Pt 10):3100-9. By Prof T Lynch

Glut 1 deficiency

• 22 year old female • Episodic Myoclonic dystonia and tremor

– Increasing frequency with stress, fatigue, heat– Significant impact on quality of life

• No family history of note • Test:

– Next generation panel: Dystonia and Parkinsonism – Mutation identified in SLC2A1

• ? De novo event (father is deceased, mother unaffected)• 50/50 recurrence risk

• Declined referral for genetic counselling– Felt she had enough information for now

By Dr T McVeigh

Summary of outcomes

• Twenty-five patients have attended a pilot clinic

• Identification of pathogenic mutations directed screening and treatment, and facilitated onward referral of family members for genetic counselling (n=8, 33%).

• A number of novel mutations were identified in MAPT (“missing tau” mutation), SLCA1 and Progranulin.

• A number of patients had phenotypic features not previously reported; e.g. writer’s cramp in SCA6; paroxysmal myoclonus in GLUT1 deficiency.

Summary of outcomes II

• Appropriate referrals were made for non-neurological sequelae of genetic mutations, e.g. breast cancer screening for carriers of ATM mutations.

• New treatments were considered based on genetic diagnoses, e.g. triheptanoin in GLUT1 deficiency.

• We appropriately referred undiagnosed complex patients (n=2) to international experts.

Conclusions

• The Neurogenetics clinic

– Addresses a gap in service provision for complex families with neurogenetic disorders

– Allows timely identification of rare and atypical diagnoses.

• Role for other disciplines

– Psychology

– Cardiology for muscular dystrophies?

Neurogenetics

• Rare single gene disorders account for a small proportion of neurological presentations

– But require specific awareness, recognition and specialist referral

• Thank you