Niemann-Pick Type C Ali Talea

Pediatric EndocrinologistMetabolic Disorders Research Center

Molecular-cellular Endocrinology &Metabolism Research Institute

Tehran University of Medical Sciences

دباشانسان بزرگی ھیچکس مجبورنیست آلبرکامو...انسان بودن کافیستتنھا

Disease name and synonyms

• juvenile Niemann-Pick disease, juvenile dystonic lipidosis, atypical cerebral lipidosis, neurovisceral storage disease with vertical supranuclear ophthalmoplegia, maladie de Neville, DAF (down-gaze paresis, ataxia, foam cell) syndrome, adult dystonic lipidosis, adult neurovisceral lipidosis, giant cell hepatitis, and lactosylceramidosis

The NPC1 and NPC2 proteins

• The mature native NPC1 is a large (1252 amino acids) glycoprotein with 13 transmembrane domains, that resides primarily in late endosomes and interacts transiently with lysosomes and the trans-Golgi network .It possesses a sterol-sensing domain (amino acid residues 615-797) showing homologies with those of HMG-CoA reductase, SCAP, patched and NPC1L, the exact role of which is still unclear although it appears necessary for protein function

NPC

• Disorders of Lipid Trafficking : Niemann-Pick type C

• - lysosomal storage disorder characterized by a defect in lipid transport

• cellular trafficking of exogenous cholesterol is defective resulting in the accumulation of unesterified cholesterol; others lipids such as the gangliosides GM2 and GM3 also build up

• Brain: 5% of body mass, contains 25% of cholesterol (mostly in myelin)

• In brain tissue, neither cholesterol nor sphingomyelinovertly accumulate, but significant alterations of glycosphingolipids occur, especially for gangliosides GM2and GM3 (10-20 fold increase). Free sphingosine levelsare much less elevated in brain (x3) than in liver or spleen

• In liver and spleen, a complex pattern, with no predominating compound, is observed.Accumulated lipids include unesterifiedcholesterol andsphingomyelin (2- to 5-fold increase in human patients),

•bis(monoacylglycerol) phosphate (also named LBPA orBMP), glycolipids (essentially glucosylceramideand lactosylceramide), and free sphingosine and sphinganine. In human patients, the level of storage is more pronounced in the spleen than in the liver

Clinical manifestation

• Individuals with NPC can have onset of symptoms at different ages that have been grouped historically as:

• perinatal (shortly before and after birth),• early infantile (3 months to < 2 years), • late infantile (2 to < 6 years),• juvenile (6 to < 15 years), • adult (15 years and greater).

Clinical presentation

In neonates and children, NPC may initially present as a

systemic disease with subtle neurological manifestations, but

for practical purposes, NPC is best classified according to the

age of onset of neurological manifestations as follow:

1. visceral-neurodegenerative form: - Early-infantile (< 2 years)

2. neurodegenerative form: - Late-infantile (2–6 years) &-

Juvenile (6–15 years)

3. Psychiatric-neurodegenerative form: - Adult (> 15 years)

perinatal NPC

• In perinatal NPC, the accumulation of fluid in the fetal abdomen (fetal ascites) may be present and persist after birth. These infants often have prolonged severe interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency.

• Perinatal presentationcause of liver disease in early life. Fetal hydropsor fetal ascites, a prolonged neonatal cholestatic icterus, appearing in the first days or weeks of life and usually associated with progressive hepatosplenomegaly is present in close to half of patients, although with very variable intensity.

•In most cases, the icterus resolves spontaneously by 2 to 4months of age, and only hepatosplenomegaly remains fora highly variable period, preceding onset of neurologicsymptoms .In about 10% of these patients,however, the icterus quickly worsens and leads to liverfailure. Children with this dramatic "acute" neonatalcholestatic rapidly fatal form usually die before the age of6 month

perinatal NPC 2

• (hepatomegaly) or (splenomegaly) is present in a high percentage of affected individuals in this age group. Lipid-containing (foam) cells may accumulate in the lungs, resulting in lung disease. Liver and lung disease can progress to cause life-threatening complications during this period. Surviving individuals will develop neurological symptoms at a later age.

Early infantile period

• additional symptoms develop including lack of muscle tone (hypotonia) often by 1 or 2 years of age. may also experience delays in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development).

• Some other infants, especially (but notexclusively) those having mutations in the NPC2 gene, present with a severe respiratory insufficiency (together with hepatosplenomegalyor more severe liver disease)that may also be fatal.

• In two patients, lung lavage, radiology and histology showed signs of pulmonary alveolarlipoproteinosis

• Patients with NP-C do not showneurological manifestations during the neonatal period (important for differential diagnosis).

• But there are many examples of patients dying from a severe perinatal formhaving siblings with a neurologic infantile or juvenile onset form

0-3 months

•Enlargement of the liver (hepatomegaly)•Jaundice in newborns•Enlargement of the spleen (splenomegaly)•Accumulation of bile in the liver (cholestasis)

•Not usually recognized

Age at onset

Non-neurological symptoms Neurological symptoms

Severe early infantile neurologic onset form

• In these infants, hepatosplenomegaly has almost invariably been present since birth or the first months of life. Delay of developmental motor milestones from the age of 8-9 months and central hypotonia constitute the first neurologic symptoms, which become evident between the age of 1 and 2 years. Subsequent clinical course includes a loss of acquired motor skills, proportionally less marked mental regression, followed by pronounced spasticity with pyramidal tract involvement.

Severe early infantile neurologic onset form 2

• Many of these children never learn to walk. Intention tremor is frequently present; supranuclear gaze palsy is usually not recognized. Seizures are uncommon. Brain imaging (MRI and MRS) shows signs of leukodystrophy and cerebral atrophy. Survival rarely exceeds 5 years. This form seems to be more frequent in Southern Europe (where it constitutes > 20% of the cases) and the Middle East

Early infantile period (2 months-2 years)

• Systemic stage• An isolated hepatosplenomegaly can be

discovered at this age period, which may well stay isolated for many years, in spite of the early onset. Once the diagnosis of NP-C is made, a regular neuropediatric follow up should be initiated.

2months-2 years •Enlargement of the liver or spleen

•Decreased muscle tone (hypotonia)•Learning difficulties•The inability to rapidly move the eyes up and down voluntarily (vertical supranucleargaze palsy) (not always recognized )•Hearing loss

Age at onset Non-neurological symptoms

Neurological symptoms

Severe early infantile neurologic onset form 2

• Many of these children never learn to walk. Intention tremor is frequently present; supranuclear gaze palsy is usually not recognized. Seizures are uncommon. Brain imaging (MRI and MRS) shows signs of leukodystrophy and cerebral atrophy. Survival rarely exceeds 5 years. This form seems to be more frequent in Southern Europe (where it constitutes > 20% of the cases) and the Middle East

Late infantile period (2 to 6 years)

• Systemic stage• Many patients start their disease by discovery

of an isolated hepatosplenomegaly or splenomegaly during this period. Regular neuropediatric follow-up should be initiated, as above.

2-6 years •Enlargement of the liver or spleen

•Balance disorder, clumsiness and frequent falls (ataxia)•Difficulty swallowing (dysphagia)•Slurred and irregular speech (dysarthria)•Involuntary, sustained muscle contractions that can cause abnormal twisting or posture (dystonia)•Decreased muscle tone (hypotonia)•Vertical supranuclear gaze palsy•Seizures•Episodes of sudden muscular weakness potentially leading to collapse during moments of strong emotion, such as laughter or extreme happiness (gelastic cataplexy)•Learning difficulties•Hearing loss

Age at onset

Non-neurological symptoms Neurological symptoms

Juvenile period (6-15 years) (classical form)

• Systemic stage• Discovery of an isolated splenomegaly (or,

rarely, of a hepatosplenomegaly) at this period may again be the inaugural sign of the disease, and these patients should later be appropriately monitored.

6-15 years

•Enlargement of certain organs, commonly the liver or spleen

•Learning difficulties•Behavioral problems•Balance disorder, clumsiness and frequent falls (ataxia)•Difficulty swallowing (dysphagia)•Slurred and irregular speech (dysarthria)•Involuntary, sustained muscle contractions that can cause abnormal twisting or posture (dystonia)•Decreased muscle tone (hypotonia)•Gelastic cataplexy•Seizures•Vertical supranuclear gaze palsy

Age at onset

Non-neurological symptoms Neurological symptoms

Adolescent and adults (>15 years)

• Systemic adult form of NP-C• The finding of three patients aged 53-63 years

with isolated splenomegaly and a biochemical and molecular diagnosis of NP-C ,suggests the existence of a rare non-neuronopathic form of the disease (possibly corresponding to the ill-described historical "type E"). Nevertheless, apart from these exceptional cases and from infants with early death, as stated above, all NP-C patients develop neurologic symptoms

• NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral). Symptoms arise at different times and follow independent progression. Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.

15 years and over

•Balance disorder, clumsiness and frequent falls (ataxia)•Vertical supranuclear gaze palsy•Problems with information processing or memory (cognitive dysfunction)•Gradual change in normal brain function and its abilities including memory, thinking, language, judgment and behavior (dementia)•A change in the way of thinking, feeling and behaving, perhaps being unable to distinguish between reality and imagination (psychosis)•Seeing or hearing things that may not be there (hallucinations)•Seizures

Age at onset

Non-neurological symptoms Neurological symptoms

Suspicion index

• The SI provides a risk prediction score (RPS) based on NP-C manifestations within and across domains (visceral, neurological, and psychiatric).

• patients’ RPS were analyzed by logistic regression. Cooccurrence of manifestations within groups of suspicion level(low, medium, high)

• Early diagnosis of NP-C is essential so that uninterrupted miglustat therapy can start at the onset of neurological manifestations

• (www.NPC-SI.com;Wijburg et al. 2012).• A risk prediction score (RPS) is calculated by

the presence of key clinical manifestationsof NP-C within and across three domains plus family history information.

two important aspects in NP-C diagnosis: (1) the number of

symptoms presented by a patient, and; (2) the strength of the relationship

between these symptom

• Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement,suggestiveof a preneurological phase of the disease

• In patients >4 years, prominent leading manifestation–associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline .

• Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment-resistant psychiatric symptoms

• Risk prediction scores (RPS) are based onindividual signs and symptoms; however, it was hypothesised that symptom combinations would support more accurate prediction.

• Conclusions The SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants<4 years. The SI is also informative regarding the association and co-occurrence of manifestations in patients with NP-C.

• The disease is characterized by heterogeneous• and oligosymptomatic presentation of

visceral,neurological, and psychiatric manifestations, making for difficult and often delayed diagnosis

• Diagnosis of NP-C is made via physical assessment of the patient, biochemical tests involving filipin staining of skin fibroblasts, and genetic sequencing of the NPC1 and NPC2 mutations

• RPS ≥70 indicated high suspicion of NP-C and recommendation for immediate testing at an NP-C specialist center

• RPS score between 40 and 69 indicated moderate suspicion for NP-C and recommendation for follow-up observation as well as further discussion with an NP-C referral center.

• RPS <40 indicated a low probability of NP-C.• Subanalyses involved categorization of all

patients by age: infantile patients<4 years• juvenile patients 4–16 years and adolescent

patients >16 years

• Additionally, patients >4 years ofage displayed an increased frequency of combined manifestations across the visceral/psychiatric, visceral/neurological, and , and neurological/psychiatric domains

• Patients with a total RPS <70 points demonstrated a noticeable lack of psychiatric findings and lower levels of neurological involvement, indicating a more visceral phenotype

• Increased presence of VSGP, splenomegaly, ataxia, and all psychiatric manifestations were associated with high suspicion of NP-C (RPS >150 points).

• The two leading psychiatric manifestationswere cognitive decline (a strong indicator of NP-C) and psychosis (a moderate indicator of NP-C). NP-C-positive patients showing manifestations of cognitive decline• Manifestation–association in patients ≥4 years

• The leading manifestation in the visceral domain was splenomegaly a strong indicator of NP-C

• Discriminatory power by age• The discriminatory performance of the NP-C SI

in infantile patients(<4 years of age) was poor,

• Infantile patients displayed frequent manifestations of prolonged neonatal jaundice,splenomegaly, and delayed developmental milestones.

• This was as expected due to these signs being highly characteristic of NP-C in this age group

• Infants <4 years of age also demonstrated fewer cross-domain manifestations compared with juvenile and adolescent patients, particularly the near absence of psychiatric manifestations. VSGP and gelastic cataplexiaare the two strongest neurological indicators

for NP-C according to the SI tool.

• These manifestations are usually present in low frequencies in infantile patients, if found

at all.• If VSGP is present, it may not be recognized,

and the presence of gelastic cataplexia usually appears during the late infantile period (>3 years of age)

• Common neurological manifestations in infantile patients <4 years of age can include delays in developmental motor milestones, hypotonia, and language/speech delay

• Whereas visceral manifestations appeared less frequently in adolescent patients (>16 years of age) with NP-C, neurological manifestations, including VSGP, dystonia, and dysarthria/dysphagia, showed an increased frequency compared with infant and juvenile patients.

• Co-occurrence of manifestations both within and across domains greatly increases the suspicion level of NP-C, as evidenced by a high total RPS. Cross-domain manifestations

• in all three domains were experienced in higher proportions in patients >4 years of age than in infantile patients <4 years of age.

• Manifestations found across the visceral/psychiatric and visceral/neurological domains were the strongest indicators of NP-C, resulting in a higher point score within

• the NP-C SI tool than manifestations found across the neurological/psychiatric domains.

• The SI tool is less able to discriminate NP-C in infants <4 years of age. This could be due to an inability to detect specific neurological manifestations and the lack of development of psychiatric manifestations in this age group.

• The NP-C SI tool is designed to allow physicians to objectively assess the likelihood of NP-C in undiagnosed patients.

• As such, it is not, and should not be, used as a differential diagnosis tool.

• It is possible that patients with other neurological disorders may score high on the NP-C SI (e.g. Alzheimer’s disease patients

• the precise diagnosis of these patients• should be confirmed by further routine

testing; it is also expected that incorrect diagnoses will become less common as physicians gain more experience using the SI tool.

• strengths and limitations• The current SI tool categorizes delayed

developmental milestones in the ancillary category (allocated one point); however, this manifestation could be a stronger indicator of NP-C for this age group.

• This does not include patients who were never detected due to the atypical or nonspecific presentation of manifestations

• As the disease is progressive, changing from visceral to neuropsychiatric in nature, the cross-sectional, retrospective nature of the data set makes it difficult to assess the usefulness of the SI in aiding early detection and predicting progression of NP-C in these patients.

• These retrospective analyses were conducted to assess two important aspects in NP-C diagnosis: (1) the number of symptoms presented by a patient, and; (2) the strength of the relationship between these symptoms.