Affects in 120,000 people1 Affects in 120,000 people1

Affects 1 in 120,000 people1

• 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

Complex diagnosis due to:

• 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

Benefits of early 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

Review unresolved / undiagnosed patients

• 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

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

• 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

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

• 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

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

• 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

• 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

Four year old boy presented to his healthcare clinician with symptoms that were diagnosed as ataxia and epilepsy

• 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

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

• 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

Female patient aged 40 years

• 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

Male patient aged 40 years was diagnosed with NP-C following his sister receiving a diagnosis a few months previously

• 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

Male patient, diagnosed at age of 45 years

• 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

20 year old female, unknown birth history and neonatal data

• 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

26 year old male, normal birth and neonatal history

• 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

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

• 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

45-year old female experienced memory problems

• 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

This survey is sponsored by Actelion Pharmaceuticals Ltd

• This survey is sponsored by Actelion Pharmaceuticals Ltd

• Actelion Pharmaceuticals Ltd

• Gewerbestrasse 16

• 4123 Allschwil, Switzerland

• Phone: [phone]

• Fax: [phone]

• © Actelion Pharmaceuticals Ltd, 2011

• Date of preparation: November 2010

• ZAV 162