Niemann-Pick type C disease: Journey to diagnosis

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This survey was sponsored by Actelion Pharmaceuticals Ltd and conducted by Insight Research Group

Date of preparation: November 2010ZAV 162

An introduction to Niemann-Pick type C disease

What is Niemann-Pick type C disease?

• Affects 1 in 120,000 people1

• Autosomal recessive, neurological condition2

• Characterized by toxic accumulation of lysosomal lipids2

• e.g. unesterified cholesterol and glycosphingolipids, which damage cells and tissues2

• Typically presents in mid-to-late childhood2,3

• Early symptoms generally affect liver and spleen2,3

• Highly variable, progressive, neurological symptoms increase in severity as disease progresses2,3

Symptoms of NP-C1,2

Systemic symptoms Neurological symptoms

• Hepatomegaly (enlarged liver)

• Splenomegaly (enlarged spleen)

• Neonatal jaundice

• Pulmonary infiltrates (in NPC2)

• Vertical supranuclear gaze palsy (eye movement problems)

• Ataxia (balance disorder)

• Cognitive dysfunction (problem with information processing or memory)

• Dysphagia (difficulty swallowing)

• Dysarthria (slurred and irregular speech)

• Dystonia (sustained muscle contraction)

• Gelastic cataplexy (episodes of sudden muscular weakness)

Diagnosing NP-C1

• Complex diagnosis due to:• low prevalence

• wide range of non-specific symptoms

• oligosymptomatology (symptoms can be few and mild)

• Often misdiagnosed or unnoticed for many years

• Confirmation of NP-C involves complex diagnostic testing• biochemical testing (limited to a number of specialist centers)

• histological analyses

• genetic testing

• imaging techniques

Treatment and management of NP-C

Supportive care

• Physical therapy to help maintain mobility2

• Speech or occupational therapy2

• Prevention or management of secondary complications, such as chest infections or severe constipation2

Pharmacological management

Examples include:• Anti-cholinergics1

• Tricyclic anti-depressants1

• CNS stimulants1

• Anti-epileptics1

• Melatonin or nocturnal sedatives1

• First NP-C-specific disease therapy; miglustat:- reduces accumulation of glycosphingolipids in brain2-5

- can stabilize key measures of neurological disease progression2-5

NP-C patient and HCP survey:Design and methodology

Aims of the NP-C patient and HCP surveys

Raise awareness of NP-C through patient / carer experiences of the journey to diagnosis

Increase accurate diagnosis of the disease and reduce time to receiving a diagnosis so effective

management of the condition can be started

Communicate the emotional impact of receiving a diagnosis and share access to information, including experiences and practices across different countries

Highlight the value of receiving a diagnosis of NP-C from a patient / carer perspective

Expert steering committee

Bruno Bembi, Pediatrician and GeneticistDirector of Regional Coordinator Center for Rare Diseases, University Hospital "Santa Maria della Misericordia", Italy

Hans Klünemann, MD PhD, Professor of PsychiatryUniversity of Regensburg School of Medicine, Germany

Frits Wijburg, Metabolic Pediatrician and ProfessorAcademic Medical Center in Amsterdam, The Netherlands

Jackie Imrie, Clinical Nurse Specialist - Niemann-Pick diseases UK

Jim Green, patient group representative Chairman, Niemann-Pick Disease Group (UK), NPDG (UK)Co-ordinator, International Niemann-Pick Disease Alliance, (INPDA)

Sergio Vidal, patient group representativeFundación Niemann Pick de España, Spain

Survey methodology

•The research was conducted by Insight Research Group in January and February 2010

Patient survey:26 in-depth interviews with carers

FranceGermany

Italy

SpainNetherlands

Patients aged between 3 and 36 years

- 11 males- 17 females

Healthcare professional survey:4 in-depth interviews with specialists

Italy

Germany

UK

Netherlands

GeneticistPsychiatristPediatrician

NP-C Nurse specialist

Niemann-Pick type C disease: Journey to diagnosis

Patient report

Niemann-Pick type C disease: Journey to diagnosis

HCP reports

NP-C patient and HCP survey:Results

Results: The journey to diagnosis

The journey to diagnosis is lengthy and challenging for parents, carers and patients

Time to diagnosis is strongly influenced by:• type of symptoms• speed of symptom recognition

Increased awareness and greater knowledge of NP-C symptoms amongst HCPs could facilitate earlier referral for specialist care

Average time from onset of noticeable symptoms to diagnosis was slightly over five years

Results: The journey to diagnosis

Healthcare professional“The symptoms will have been there for years, just that they become more severe. They will be severe enough to not just be noted by the patient and close family, but the doctor will also have to admit that this is not just a bad day.”

Healthcare professional“The symptoms will have been there for years, just that they become more severe. They will be severe enough to not just be noted by the patient and close family, but the doctor will also have to admit that this is not just a bad day.”

Parent, Germany“There were things that we didn’t even notice as parents; for example, he could no longer hold the fork properly or hold his own cup, and whilst others would take note of that, we thought that perhaps he was simply mimicking his baby brother in order to attract attention.”

Parent, Germany“There were things that we didn’t even notice as parents; for example, he could no longer hold the fork properly or hold his own cup, and whilst others would take note of that, we thought that perhaps he was simply mimicking his baby brother in order to attract attention.”

Results: The three types of patient

Symptom type Key symptoms Time to diagnosis

Visceral symptoms Hepatomegaly or splenomegaly and/or suffering from jaundice

Average 9 months

Developmental delay

Clumsiness, ataxia or declining academic performance

Average 6 years

Psychiatric symptoms

Hallucinations, aggressive behavior or paranoia (often in their teens)

Up to 19 years

Results: NP-C is often misdiagnosed

NP-C

SYMPTOMS

MISDIAGNOSES

Year 1

Clear hepatosplenomegaly

Viral disease

Immune disease

Year 4-8

Non-specific symptoms (clumsiness, ataxia, reduced

performance

Progressive cognitive dysfunction (also mood /

behavior disturbance

Learning disorder / disability (children)

Year 10 (+)

Clear neurological presentation: ataxia; dystonia; cataplexy; dysarthria; eye palsy

Dementia

Rare metabolic disease

Non-specific neuro-degenerative disease / movement disorder

SchizophreniaMS

Results: Targets and symptoms for earlier diagnosis of NP-C

Specialists Typical symptoms they might see

• Hepatology / liver specialists

• (Neuro-) psychiatrists

• Pediatricians (if also see teenagers)

• (General) neurologists

• Ophthalmologists

• Prolonged neonatal jaundice/hepatomegaly or splenomegaly

• Ataxia

• Dystonia

• Dysarthria

• Dysphagia

• Cognitive dysfunction (may include behavioral disturbance; paranoia; hallucinations)

• Vertical supranuclear gaze palsy

Encourage HCPs to discuss symptoms with colleagues in other disciplines

Could facilitate earlier diagnosis by allowing symptoms to be linked together and then linked to the possibility of NP-C

Results: Linking the symptoms – what changes are needed?

Greater prompting of parents by HCPsCould help parents to share more background information

about seemingly unrelated symptoms

Sharing of information between different specialists / departments

Could help physician to take a holistic view of the patient’s clinical signs and symptoms

Symptom checklist for identifying metabolic disease Could help reduce the time taken to confirm a diagnosis

Heightened awareness amongst the various specialists who may see and treat individual symptoms

Could help achieve earlier diagnosis and early initiation of treatment aiming to stabilize disease progression in those

patients with neurological symptoms

Greater symptom awareness in the community or educational setting (e.g. GPs, school doctors)

Could help identify children appropriate for further investigation

Results: The emotional impact of receiving a diagnosis of NP-C

1. SHOCK• Especially if symptoms before diagnosis have been mild or suggested diagnoses were less severe

2. FRUSTRATION• Experts missed the child’s illness• Support not immediately available• Complex information provided too quickly / insensitively• Parents confused about where to turn for more information and help

6. RELIEF• Child’s illness is no longer a mystery• Stigma of naughty child or over-anxious parent disappears• Can access support and treatment

3. GUILT• Regret over lost time• Child may have been disciplined unnecessarily or made to struggle in mainstream education• Parent may feel that in some way they are responsible because NP-C is an inherited disease

5. DESPAIR• Even if diagnosis removes the uncertainty, it always has a huge emotional impact

4. DETERMINATION• Parents/carers are determined to achieve the best quality of life for their child, gathering information and accessing support wherever they can

Results: The value of having a diagnosis

• Benefits of early diagnosis:

• Helps families access support, advocacy and appropriate treatment earlier

• Helps them to prepare emotionally and physically for their child’s future

• Allows decisions that allow them to spend more quality time with their child before the disease progresses

• Allows planning for the future

Healthcare professional“I think that patients definitively have this unmet need [for early diagnosis]. If you look at cases that are left without a diagnosis, family members will be wondering why their children are ‘different’, why can they no longer do certain things? …

…diagnosis is not only a relief in terms of a social and psychological context, but also because it is now possible to start a treatment that is dealing with the root cause of the illness.”

Healthcare professional“I think that patients definitively have this unmet need [for early diagnosis]. If you look at cases that are left without a diagnosis, family members will be wondering why their children are ‘different’, why can they no longer do certain things? …

…diagnosis is not only a relief in terms of a social and psychological context, but also because it is now possible to start a treatment that is dealing with the root cause of the illness.”

The importance of support

Most valuable forms of support

A voice on the phone – someone to talk to about a child’s day-to-day symptoms

A central point of coordination for advocacy – someone who knows what services and treatment are available and can help prepare all the necessary documentation

Coordination of services– a wider team that provides consistency of in-home services and supports the family in caring for the patient

Most valuable forms of support

A voice on the phone – someone to talk to about a child’s day-to-day symptoms

A central point of coordination for advocacy – someone who knows what services and treatment are available and can help prepare all the necessary documentation

Coordination of services– a wider team that provides consistency of in-home services and supports the family in caring for the patient

A call to action for everyone affected by NP- C

1. Increase awareness of NP-C symptoms amongst healthcare professionals:

- Better HCP knowledge of visceral (classic) symptoms- Facilitate earlier referral of infants and children who present in early school years with visceral symptoms

1. Increase awareness of NP-C symptoms amongst healthcare professionals:

- Better HCP knowledge of visceral (classic) symptoms- Facilitate earlier referral of infants and children who present in early school years with visceral symptoms

3. Share information:

-Parents: share more background information and history about child’s symptoms-Generalists and specialists: share all disease history information when referring to other specialists- Parents and carers: seek the support of teachers or other social networks to gain extra evidence when presenting concerns to HCPs

3. Share information:

-Parents: share more background information and history about child’s symptoms-Generalists and specialists: share all disease history information when referring to other specialists- Parents and carers: seek the support of teachers or other social networks to gain extra evidence when presenting concerns to HCPs

2. Consider a diagnosis beyond the obvious:

- Specialists need to be informed about all the signs and symptoms of NP-C to link together seemingly unrelated features

2. Consider a diagnosis beyond the obvious:

- Specialists need to be informed about all the signs and symptoms of NP-C to link together seemingly unrelated features

4. Seek support:

- Parents and carers should be proactive in seeking support from patient organizations, social services and family networks to ease the emotional impact of receiving a diagnosis of NP-C and to help manage challenges in coping with the condition

4. Seek support:

- Parents and carers should be proactive in seeking support from patient organizations, social services and family networks to ease the emotional impact of receiving a diagnosis of NP-C and to help manage challenges in coping with the condition

What should we do next?

• Review unresolved / undiagnosed patients

• What symptoms do they have?

• Can their symptoms be linked together?

• Identify any patients that may be in the early stages of NP-C

• How could they be managed / referred to speed diagnosis?

• [Insert details of local referral / specialist center]

• Understand availability of diagnostic tests at [insert institution / region]

• Ensure familiarity with NP-C support services in [insert region]

• Review support packages for existing NP-C patients

• Ensure patients diagnosed in future are provided with support information

• [Insert patient support groups, social services, helplines etc]

• Consider educational activities for new team members to ensure knowledge of NP-C symptoms

Provided by Professor Frits Wijburg, Metabolic Pediatrician and Professor at the Academic Medical Center, Amsterdam

Why is the survey important for Pediatricians?

• Long road to a diagnosis of NP-C is burden for many patients and their families

• Pediatricians play a fundamental role in making links between symptoms

• Symptoms might present at different times

• Some symptoms may appear to have been resolved

• This report shows how important a diagnosis is to the patient and their family

• The burden of unrecognized symptoms and undiagnosed disease is lifted

• Treatment can be made available

• Early diagnosis means treatment can be started early when it is most effective

• Access to patient support groups, family networks and access to relevant information about the disease

(For Pediatricians – delete as appropriate)

• Long road to a diagnosis of NP-C is burden for many patients and their families

• Important for neurologists to link disparate symptoms / neonatal symptoms with those presenting later in life

• The neurologist will often be the HCP to communicate the diagnosis of NP-C to the patient or their family or carer

• Must understand the significant emotional impact

• This report shows how important a diagnosis is to the patient and their family

• The burden of unrecognized symptoms and undiagnosed disease is lifted

• Treatment can be made available

• Early diagnosis means treatment can be started early when it is most effective

• Access to patient support groups, family networks and access to relevant information about the disease

Provided by Professor Frédéric Sedel, Hospital Practitioner, Coordinator of Neurometabolic Unit, Reference Center for Lysosomal Diseases, Pitié-Salpêtrière Hospital, Paris

Why is the survey important for Neurologists?

(For Neurologists – delete as appropriate)

Provided by Professor Ed Wraith, Manchester Academic Health Service Centre, University of Manchester

Why is the survey important for Metabolic Disease Specialists?

(For Metabolic Disease Specialists – delete as appropriate)

• Long road to a diagnosis of NP-C is burden for many patients and their families

• Metabolic disease specialists will likely be aware of the classic symptoms of NP-C such as hepatosplenomegaly, childhood ataxia and dystonia• Will probably be unfamiliar with the psychiatric presentation of NP-C

• Alongside neurologists, metabolic disease specialists play a large role in communicating with NP-C patients and families to help manage their disease• Must know the nature of the disease, what treatment is available and best management for that

individual NP-C patient

• Must also be aware of the emotional impact that NP-C can have on the patient and the family

• This report shows how important a diagnosis is to the patient and their family• The burden of unrecognized symptoms and undiagnosed disease is lifted

• Treatment can be made available

• Early diagnosis means treatment can be started early when it is most effective

• Access to patient support groups, family networks and access to relevant information about the disease

• Long road to a diagnosis of NP-C is burden for many patients and their families

• Very little is known about NP-C in psychiatric community so:• NP-C is often undiagnosed or misdiagnosed for many years

• Patients can deteriorate considerably before receiving a diagnosis

• NP-C among psychiatric patients might not be as rare as previously thought

• Psychiatrists can help speed up time to diagnosis if they are able to recognize the neurological symptoms of NP-C such as gaze palsy

• This report shows how important a diagnosis is to the patient and their family• The burden of unrecognized symptoms and undiagnosed disease is lifted

• Treatment can be made available

• Early diagnosis means treatment can be started early when it is most effective

• Access to patient support groups, family networks and access to relevant information about the disease

Provided by Professor Hans Klünemann, Professor of Psychiatry, University of Regensburg School of Medicine, Germany

Why is the survey important for Psychiatrists?

(For Psychiatrists – delete as appropriate)

NP-C patient case reports: Pediatrics

(For Pediatricians – delete as appropriate)

The following case histories were provided by Professor Frits WijburgMetabolic Pediatrician and Professor at the Academic Medical Center in Amsterdam

Pediatric case report – Patient 1

• Four year old boy presented to his healthcare clinician with symptoms

that were diagnosed as ataxia and epilepsy

• He experienced continuous progressive deterioration over subsequent

years, went on to suffer from severe dystonia and eventually had to be

fed artificially via a tube

• After 10 years of decline, at the age of 14 he was eventually diagnosed

with NP-C by a pediatric neurologist who recognized the symptom of

vertical supranuclear gaze palsy (VSGP) and linked it with his other

symptoms to reach a diagnosis

• The boy died soon after diagnosis. As he was diagnosed at such a late

stage in the progression of the disease his family did not receive the

support they needed and it was too late to start treatment

(For Pediatricians – delete as appropriate)

Pediatric case report – Patient 2

• 18 year old girl experienced a sustained period of severe jaundice as a neonate, she nearly had a liver transplant but before this went ahead her liver improved

• Lived a normal life until about the age of seven years when she started to show difficulties in schooling

• Referred to pediatrician who picked-up on the liver disease she had as a neonate and also saw that she was displaying the symptoms of ataxia• Pediatrician conducted library research, which led to recognition that she

was exhibiting vertical supranuclear gaze palsy (VSGP)

• This thorough investigation allowed the pediatrician to link together the symptoms of severe jaundice, ataxia and VSGP leading to a confirmed diagnosis of NP-C

• Due to diagnosis at relatively early stage of disease progression she was started on treatment• She is now 18 years old, her NP-C disease progression is stable and she

lives a relatively normal life despite some intellectual disabilities

(For Pediatricians – delete as appropriate)

NP-C patient case reports: Neurology

The following case histories were provided by Professor Frédéric Sedel

Hospital Practitioner, Coordinator of Neurometabolic Unit, Reference Center for Lysosomal Diseases, Pitié-Salpêtrière Hospital, Paris

(For Neurologists – delete as appropriate)

Neurology case report – Patient 1

• Female patient aged 40 years

• Normal school life except difficulty in looking downwards as a child

• As an adult she married, had children and became an educational worker for young

children

• At 39 years, she began to exhibit further symptoms:

• Ataxia and frontal dementia

• Lacked concentration

• Had difficulty in making decisions and she became less inclined to perform normal daily

activities such as bathing

• No psychiatric symptoms

• Was referred to dementia department

• Neurologist who had experience with diagnosing NP-C patients examined her eyes,

establishing the cause was not purely frontal dementia

• Recognition of vertical supranuclear gaze palsy (VSGP) led to diagnosis of NP-C

(For Neurologists – delete as appropriate)

Neurology case report – Patient 2

• Male patient aged 40 years was diagnosed with NP-C following his sister

receiving a diagnosis a few months previously

• Experienced developmental delay since childhood, with problems learning to read

and write – his only symptom in childhood, which stabilized

• At about 40 years, started to show lack of interest and concentration in carrying

out daily tasks and after visiting a neurologist it was recognized that he was

displaying signs of vertical supranuclear gaze palsy (VSGP)

• His sister had presented with more classical symptoms from 15 years of age:

• Included heart and cognitive problems, labored walking and lack of concentration

• Had a child at the age of 17 but did not take care of the baby

• Displayed symptoms of frontal dementia, ataxia, VSGP and deafness at the age of

20

(For Neurologists – delete as appropriate)

Neurology case report – Patient 3

• Male patient, diagnosed at age of 45 years

• Had experienced ataxia for approximately four years

• Physicians believed this was due to his excessive alcohol consumption

and that the ataxia was brought on by alcohol intoxication

• However, he did not show the other symptoms of alcohol intoxication

such as blood abnormalities

• He clearly showed signs of vertical supranuclear gaze palsy (VSGP)

and cerebral ataxia which then led to the diagnosis of NP-C

(For Neurologists – delete as appropriate)

NP-C patient case reports: Metabolic disease

(For Metabolic Disease Specialists – delete as appropriate)

The following case histories were provided by Professor Ed WraithManchester Academic Health Service Centre, University of Manchester

Metabolic disease case report – Patient 1

• 20 year old female, unknown birth history and neonatal data

• Showed signs of developmental delay and attended a specialist school from the age of five

years - developmental problems were associated with adverse social situation

• Continued to perform poorly at school, was tested for absence epilepsy and prescribed

sodium valproate at 15 years

• At 16 years, had increasing motor difficulties and problems with short term memory

• Following two generalized convulsions an MRI scan was performed that revealed cerebral

and cerebellar atrophy

• Was referred to the neurology department for assessment at 17 years of age

• On examination she was markedly ataxic, had dystonic posturing of the hands and feet and she

was unable to look up

• No other neurological abnormalities and the liver and spleen were not palpable

• Filipin staining of skin fibroblasts was positive and esterification studies confirmed she had NP-

C (classical biochemical phenotype)

• Over the next six months she developed neurological dysphagia, had increasing pyramidal

signs in her lower limbs and required gastrostomy feeding

(For Metabolic Disease Specialists – delete as appropriate)

Metabolic disease case report – Patient 2• 26 year old male, normal birth and neonatal history

• Aged five: delayed speech, referred to Speech and Language Therapist but was never seen

• Cognitively normal but severely clumsy and not allowed to participate in cookery or sewing at school

• Aged 16 years: problems with everyday activities, for example riding a bike

• Avoided all sports and had difficulty producing legible handwriting and fluent accurate speech

• Clinical examination revealed dysmetria, dysdiadochokinesis and brisk lower limb muscle reflexes

• No comment was made on eye movements and he was diagnosed as having “dyspraxia” by his local

pediatrician

• Referred for occupational therapy and physiotherapy

• Over the next year his motor skills deteriorated further and at 17 years, physiotherapist felt movement

disorder was not typical of dyspraxia and that he also had significant dystonia

• At the age of 18 he was reviewed at a neurology clinic and found to have gaze palsy in addition to his

cerebellar sign, dystonia and brisk reflexes in his lower limbs

• Plasma chitotriosidase was found to be modestly elevated, filipin staining of skin fibroblasts was positive and

esterification studies confirmed a classical biochemical phenotype

• Diagnosed at 18 and as a result of the diagnosis became severely depressed

• Then developed an acute psychosis with both delusions and auditory hallucinations, which has made

him resistant to treatment

(For Metabolic Disease Specialists – delete as appropriate)

NP-C patient case reports: Psychiatry

(For Psychiatrists – delete as appropriate)

The following case histories were provided by Professor Hans KlünemannProfessor of Psychiatry, University of Regensburg School of Medicine, Germany

Psychiatrist case report – Patient 1

• Mother in her forties with a teenage daughter first started to appear clumsy at work in her early thirties

• Visited healthcare professional who diagnosed her with multiple sclerosis

• Despite having no oligoclonal bands in first lumbar puncture

• Her diagnosis was questioned because of the presence of splenomegaly

• In her late thirties her condition deteriorated and she presented with:

• Slight ataxia

• Slowed movement

• Snout reflex

• Results of her physical examination diagnosed her with mania with a history of depression

• She has since been diagnosed with an organic storage disorder and an 18-FDG-PET showed

hypofrontal metabolism

• DNA samples revealed two heterozygous mutations in NPC1 gene

• Diagnosis of NP-C took 10 years and she is now bedridden and cared for in a nursing home

(For Psychiatrists – delete as appropriate)

• 45-year old female experienced memory problems

• Thought she might have Alzheimer’s disease

• Physical examination revealed she was unable to look up and down but she presented no

splenomegaly

• Her behavior was spontaneous and adynamic

• She would sing her words instead of speaking them

• Displayed impaired cognitive flexibility

• After three years the lady contracted pneumonia and passed away

• Only then at autopsy she was diagnosed with NP-C

• The lady’s sister was admitted to hospital in her thirties with schizophrenic psychosis after she

attacked her husband

• On physical examination she was disorientated, acutely psychotic and disorganized

• Following the diagnosis of her sister, she was tested for NP-C and was found to have a homozygous

mutation in the NPC2 gene

(For Psychiatrists – delete as appropriate)

Psychiatrist case report – Patient 2

Thank you

This survey is sponsored by Actelion Pharmaceuticals Ltd

Actelion Pharmaceuticals Ltd

Gewerbestrasse 16

4123 Allschwil, Switzerland

Phone: +41 61 565 65 65

Fax: +41 61 565 65 00

© Actelion Pharmaceuticals Ltd, 2011

Date of preparation: November 2010

ZAV 162