AN INSIGHT INTO THE MANAGEMENT OF NIEMANN PICK TYPE C DISEASE SANGITA DEY; AMIT MONDAL BSc 2nd year ; DR.SHYMALINA BISWAS*; DEPARTMENT OF BIOCHEMISTRY,ASUTOSH COLLEGE ABSTRACT:
NIEMANN PICK DISEASE TYPE C [NPC] IS A RARE, IRREVERSIBLE, GENETICALLY INHERITED NEUROVISCERAL LYSOZOMAL LIPID STORAGE DISEASE. THE NPC1 GENE OR NPC2 GENE LOCATED IN CHROMOSE 18 AND 14 RESPECTIVELY, IF MUTATED THEN THAT MUTATION IS INHERITED AUTOSOMAL RESESSIVELY AND CAUSE AN IMPAIRED INTRACELLULAR TRANSPORT OF CHOLESTEROLS AND OTHER LIPIDS AND THUS PROGRESSIVE NEUROLOGICAL AND DEVELOPEMENT AL PROBLEM ARISES.THE SYMPTOMS FOR CHILDREN BEING DELAY IN DEVELOPEMENTAL MOTOR SKILLS, JAUNDICE [IN CASE OF INFANTS],LEARNING DIFFICULT IES,DECREASED MUSCLE TONE ETC.IN ADULT ONSET PROGRESSIVE COGNITIVE IMPAIRMENT IS OBSERVED AND RESPIRATORY FAILURE MOSTLY LEADS TO DEATH.THE DIAGNO SIS IS DONE BY EXAMINING FAMILY HISTORY,GENETIC ANALYSIS OF NPC1 AND NPC2 GENES AND BLOOD TEST TO DETECT BIO MARKERS LIKE BILE ACID METABOLI TES AND OXYSTEROLS. THE DISEASED IS MANAGED BY SUPPORTIVE THERAPY, DRUGS LIKE MIGLUSTST ARE USED TO SLOW NEUROGICAL DECLINE, BUT THERE IS NO PARTICULAR DRUG FOR THE DISEASE THOUGH A LOT OF DRUGS ARE IN HUMAN TRIALS .
RARE DISEASE :
THE NATIONAL ORGANIZATION OF RARE DISORDERS( NORD) SAYS A RARE DISEASE IS A
DISEASE THAT AFFECTS A SMALL PERCENTAGE OF POPULATION (that is fewer than 200000 americans) HENCE IT IS CALLED A RARE DISEASE. NIEMANN PICK DISEASE TYPE C USUALLY AFFECTS THE CHILDREN OF SCHOOL AGE WITH ONE HALF OF PATIENTS BEING DIAGNOSED BEFORE 7 YEARS, BY INTERFERING WITH THEIR CHOLESTEROL METABOLISM INSIDE THE CELL. IT AFFECTS 1 OUT OF 100000 TO 120000 BIRTHS HENCE IT IS RARE.
RELATIVE DISTRIBUTION OF PHENOTYPES OF NPC NPC1
NPC2(or HE1 gene)
Mutation probabilit y
95% of patients
Rest 5% of patients
Position of Gene
Chromos ome 18q
Chromos ome 14q
NC (9.5%) Adult (22.9%) Juvenile (20.0%)
Perinatal lethality (6.7%)
ETIOLOGY OF NIEMANN PICK DISEASE TYPE C NPC-1 GENE PRODUCES PROTEIN INVOLVED IN THE MOVEMENT OF CHOLESTEROL AND LIPIDS WITHIN THE CELLS NPC-2 GENE PRODUCES PROTEIN THAT BINDS AND TRANSPORTS CHOLESTEROL
IN NORMAL CELLS FROM EARLY ENDOSOME IT GOES TO LATE ENDOSOME AND THEN TO LYSOSOME WHERE IT IS DIGESTED
UNESTERIFIED CHOLESTEROL IS TAKEN INTO EARLY ENDOSOMES OF CELLS VIA ENDOCYTOSIS BY LDL RECEPTORS
BIND TO NPC1, LOCATED IN THE MEMBRANES, AND NPC2 AND TRANSPORTED TO ER AND GOLGI FOR RECLYCLING WITHIN THE CELLS.
WHEN NPC-1 OR NPC-2 IS MUTATED THAT IS DISEASED UNESTERIFIED CHOLESTEROL IS TAKEN BY EARLY AND LATE ENDOSOMES RESPECTIVELY
THEN FROM LATE ENDOSOME IT GOES TO LYSOSOME WHERE IT IS ACCUMULATED DUE TO THE MISFUNCTION OF NPC1 NAD NPC2
IF NPC 2 MUTATED THEN DUE TO INABILITY OF THE CELL TO TRANSFER CHOLESTEROL TO GOLGI, TOXICITY OF THE CELL INCREASED AND CAUSES CELL DEATH
DIAGNOSIS OF NIEMANN PICK DISEASE TYPE C
Severe infantile (21.9%) Late infantile (19.0%)
SYMPTOMS PROGRESSION OF NIEMANN PICK DISEASE TYPE C
1
•PERINATALS(SHORT BEFORE AND AFTER BIRTH) CAN SUFFER FROM JAUNDICE OR CHEMOTAXIS ,DECREASED MUSCLE TONE AND DELAY IN DEVELOPEMENTAL MOTOR SKILLS.
2
•DURING THE EARLY CHILDHOOD ( UPTO 6 YEARS) THE PATIENT CAN SUFFER FROM CLUMSINESS,SEIZURES OR CATAPLEXY, ATTENTION OR CONCENTRATION PROBLEMS; EYE PROBLEMS; DIFFICULTY IN SWALLOWING, SLEEPLING, LEARNING ETC.
3
•IN JUVENILE AND ADULT PATIENTS(6 TO 15 AND ABOVE) DEMENTIA OCCURS AND THE RESPIRATORY FAILURE LEADS TO THE DEATH OF THE PATIENT. SOURCE : GOOGLE
PROBABLE TREATMENTS OF NPC 1.
2.
3. 4. 5. 6.
7.
MIGLUSTAT ( ZAVESCA, BRAZAVES) IS A SMALL IMINOSUGAR MOLECULE WHICH REVERSIBLY INHIBITS THE GLYCOSPHINGOLIPID SYNTHESIS, WHICH IS THE ONLY DISEASE-SPECIFIC DRUG FOR THE TREATMENT OF PROGRESSIVE NEUROLOGICAL PROBLEMS OF NP-C.THOUGH MIGLUSTAT IS NOT APPROVED BY THE FDA,SEVERAL OTHER COUNTRIES LIKE SOUTH KOREA, BRAZIL, RUSSIA, AUSTRALIA AND EUROPEAN UNION HAS APPROVED THIS DRUG. HYDROXY-PROPYL-BETA-CYCLODEXTRIN (HPBCD) CAN BE USED AS A DRUG FOR NPC . LOW CHOLESTEROL DIET AND CHOLESTEROL LOWERING DRUGS SHOULD BE PROVIDED TO THE NPC PATIENT. OCCUPATIONAL THERAPY, SPEECH THERAPY & PHYSIOTHERAPY CAN BE PROVIDED AS SUPPORTIVE CARE. TO REDUCE THE EATING DIFFICULTIES GASTROSTOMY TUBE(G-TUBE) CAN BE USED. IN CASE OF RESPIRATORY FAILURE TRACHEOSTOMY PLACEMENT ,LIVER TRANSPLANT FOR LIVER FAILURE CAN BE DONE. ANECDOTALLY, ORGAN TRANSPLANT HAS BEEN ATTEMPTED WITH LIMITED SUCCESS . THERE ARE OTHER TREATMENTS LIKE (I) CHOLESTEROL MOBILIZATION (II) NEUROSTEROID ( HORMONE AFFECTING BRAIN NERVE CELLS AND BRAIN) REPLACEMENTS, (III) CURCUMIN (A POTENT ANTI-INFLAMMATORY & ANTIOXIDANT AGENT) (IV) PREGNANE X-RECEPTOR (STEROID AND XENOBIOTIC SENSING NUCLEAR RECEPTOR, A POTENTIAL TARGET)
AUTOSOMAL RECESSIVE INHERENTANCE PATTERN OF NP-C: in 25% cases the children is diseased CARRIER FATHER
CARRIER MOTHER
(Aa)
A
(Aa)
a
A
a
AA (normal) Aa(carrier)
Aa (carrier)
RESEARCHES TO MANAGE NPC 1. EFFICACY AND SAFETY OF DRUG AIRMOCLOMOL AND PLACEBO 2.EFFECTIVENESS OF PLURIPOTENT STEM CELLS FOR NEIMANN PICK 3.EFFICACY OF INTRAVENOUS TRAPPSOL CYCLO ( HPβCD) IN NPC 4. BIOMARKER VALIDATION FOR NPC;SAFETY AND EFFICACY OF NACETYL CYSTEINE 5. STUDY OF VORINOSTAT THERAPY IN NPC
aa (diseased)
REFERENCES: 1. GOOGLE,WIKIPEDIA, 2.www.slideshare.net 3.https://ghr.nlm.nih.gov/condition/niemann-pick-disease#diagnosis 4. https://rarediseases.org/for-patients-and-families/information-resources/rare-disease-information/ 5. https://clinicaltrials.gov/ct2/results?cond=%22niemann-pick+disease%22 6.Early miglustat therapying infantile NPC Di rocco1,Dardis A, Madeo A ,Barone R, Fiumara A.2012 July
ACKNOWLEDGEMENT: UNIVERSITY GRANTS COMMISION *FOR CORRESPONDANCE