2. INTRODUCTION
• Neurogenetic diseases are surprisingly common
• Typically devastating-Robbing individuals of the Quality of life
• A high index of suspicion for genetic causes and a thoughtful
evaluation of simplex (sporadic) cases is often necessary
3. Rationale
• Vast majority of neurological and neurodegenerative disorders –still
lack effective therapies
• Why different neurons degenerate in distinct clinico-pathological
entities has been an important question to address
• with obvious importance for therapy development.
4. Genetics of neurological disorders
• Chromosomal disorders
• caused by structural mutations of one or several chromosomes.
• Chromosome abnormalities-common cause of developmental
disorders
• complex phenotype and frequently involve intellectual disability.
• Mostly diagnosed in childhood.
5. Mendelian disorders
• caused by a mutation in a single gene and are therefore also known
as monogenic disorders.
• most common mutations
missense
nonsense mutations within the coding region of a gene.
7. Autosomal dominant
• It manifests in both males and females equally
• can be transmitted by either parent to approximately 50 percent of
their offspring
• SCA
• Huntington
• Myotonic dystrophy
• hereditary spastic paraplegia.
8. Autosomal recessive
• it manifests equally in both males and females
• alleles can be transmitted by either parents
• parents are almost always unaffected
25 % -affected individual’s,25 % will harbor no mutations, 50 % will be
carriers.
9. • There is typically no history of disease in prior generations.
• Due to the low prevalence of these mutations, there is often a history
of consanguinity
• Tay-Sachs disease
• Krabbe and metachromatic leukodystrophy
• Friedreich’s ataxia
• Wilson disease
10. Sex-linked
• Inherited on either the X or Y chromosome.
• X-linked traits can only be passed from fathers to daughters;
• they cannot be passed from fathers to sons
• X-linked inheritance can be dominant or recessive
• X-linked recessive inheritance is most common.
11. • X-linked recessive disorders - predominance of clinical manifestations in
males
• X-linked dominant traits occur more commonly in females than do X-linked
recessive traits.
• X-linked dominant disease is often more severe in males.
• Fragile X
• DMD
• BMD
12. Mitochondrial
• Usually inherited from the mother.
• mutations are often present in only a proportion of the mitochondria
(heteroplasmy),
• predicting the clinical consequences can be difficult.
• Leber’s hereditary optic neuropathy
• myoclonic epilepsy with ragged red fibers (MERRF)
• mitochondrial encephalomyopathy with lactic acidosis and stroke-like
episodes
14. Complex disorders
• presumably caused by interplay between a large number of genetic,
environmental .
• large numbers of loci that contribute to the genetic basis of complex
traits.
• limited role for genetic testing
Examples
Multiple sclerosis
15. Factors Affecting Genetic Disease Manifestations
Penetrance
• This is the chance that a given gene mutation will manifest itself in an
individual or not.
• Penetrance may be 100%, as in Down’s syndrome .
• Penetrance can be is age-dependent- von Hippel-Lindau disease
• Incomplete penetrance-In some inherited conditions, despite the
presence of a disease allele, disease may never develop.
16. Expressivity
• variation in severity of disease manifestations in an individual.
• The expression of a particular gene mutation may vary considerably
between individuals with the same gene mutation.
• Anticipation- appearance of a more severe clinical phenotype in successive
generations.(Huntington , myotonic dystrophy)
• Imprinting-variation in phenotype depending on the parent of origin of the
mutant allele. Example-Prader willi
17. • Genetic Heterogeneity
• Many diseases that appear similar clinically can be due to several
different genetic mechanisms.
SCA
Tuberous sclerosis
18. Clues to the presence of a neurogenetic
disease
• Positive family history
• Similarity to a known genetic syndrome
• Chronic, progressive clinical course
• Consanguinity
• Increased frequency in a specific ethnic group
19. IMPORTANCE OF FAMILY HISTORY
• positive family history-important - pay careful attention
• record it appropriately for future reference .
• If clues begin to accumulate -inquires about more distant relatives.
• types of questions need to be carefully tailored to the differential
diagnosis
20. • The drawing of a family tree or pedigree is a fast, easy, and concise
way of representing family history.
• indispensable tool for geneticists and clinicians
• Used to find the mode of inheritance and chance getting the disease
21.
22. ASSESSMENT OF SPORADIC/SIMPLEX CASES
• A sporadic, isolated, or simplex case means a single occurrence of a
disease without a positive family history
• sporadic cases can certainly have a genetic cause
23. Causes of a sporadic case having an apparent genetic phenotype
• Autosomal-recessive
• De novo mutation
• Decreased penetrance in family
• Mild expression in family
• Adoption
• Mitochondrial inheritance
24. Genetic syndrome
• constellation of signs and symptoms suggesting a known genetic
syndrome.
• This is often requires a detailed knowledge of, and memory for,
syndromic identification.
atypical facial “acne” , seizure disorder -tuberous sclerosis
progressive ataxia with loss of reflexes - Friedreich ataxia
25. Others clues
• most genetic diseases have a slow, subtle onset and prolonged,
chronic course.
• Many have onset in childhood, although it is not uncommon to have a
later onset, especially with autosomal-dominant conditions.
• Consanguinity (matings between blood relatives) is a clue to
autosomal recessive disorders.
26. Ethnic groups
• certain diseases are more common in specific ethnic groups.
• Agarwals-SCA 12
• Tay–Sachs disease in Eastern European Jewas
• Spinocerebellar ataxia type 3 in Portuguese
27. GENETIC COUNSELING
• Genetic counseling is an important aspect of the management of
every patient with a neurogenetic disorder
• Genetic counselling is a process by which patients or relatives at risk
of a disorder are advised of the consequences of the disorder, the
probability of transmitting it and of the ways in which it can be
prevented, avoided.
28. • Can be relatively uncomplicated-MS
• Families can raise complex issues that require detailed and time-
intensive counseling by an experienced professional
• knowledge of both the disease process and the genetic factors
29. Aspects of Genetic counseling
• Diagnosis
• Education
1. Recurrence risks
2. Expression
3. Penetrance
4. Natural history
5. Prognosis
• Need for further testing
1. DNA-based tests
2. Other tests
3. Other family members
30. • Genetic options
1. Prenatal testing
2. Adoption
3. Artificial insemination
4. Preimplantation diagnosis
5. Treatment options
• Referral to consultants
• Support groups
• Follow-up
31. Diagnosis
• The most important -correct diagnosis.
• The wrong diagnosis will lead to inaccurate and inappropriate genetic
counseling.
• It is better to state that the diagnosis is unclear and provide
nonspecific counseling rather than assume an erroneous diagnosis
and provide inaccurate counseling
32. Education
• Once the correct diagnosis has been established
• determination of recurrence risk – that is, determining who else in the
family is at risk ( inheritance pattern)
• prognosis and natural history of the specific neurogenetic disease.
• aware of variable expression-range of both severity and types of clinical
signs
33. Additional testing
• The counselor must also assess the need for additional testing.
• valuable to examine or test other family members to help arrive at
the correct diagnosis or to determine who else is affected.
• Additional test- EEG,EMG,MRI BRAIN
• DNA-based diagnostic tests
34. Genetic testing options
• Many families ask for information regarding genetic testing options
related to family planning.
• These options may include the availability of prenatal testing,
adoption, artificial insemination, and preimplantation diagnosis.
• The availability and relevance of such genetic options depend on the
specific disease and ever-changing technology
35. Treatment options
• Family members will also want the latest information regarding
treatment options.
• Traditionally neurogenetic diseases have been considered
“untreatable.”
• new treatment options are gradually coming
36. complete genetic counseling
• appropriate referrals to diagnostic or therapeutic consultants
• identification of disease-specific support groups
• arrangement for long-term clinical follow-up
37. Genetic testing
• Genetic testing - ever-expanding component
• Recent advances
increased both the scope and scale of conditions that can be tested
reduced cost and improved diagnostic accuracy.
40. "first" generation of DNA sequencing methods (Sanger sequencing)
• determines the sequence of large DNA fragments
• used clinically when the sequence of a specific gene is being tested. Ex-
suspected hemophilia B
• cannot provide information about large portions of the genome (eg,
multiple genes) at a practical cost and within a reasonable timeframe.
41.
42. Next-generation sequencing (NGS)
• This technology is based on the simultaneous execution of thousands of PCR and
sequencing reactions, with a highly sophisticated bioinformatic analysis .
• Reduced costs
NGS is reserved for clinical scenarios in which it is considered useful to determine
the sequences of multiple genes.
43. Next-generation sequencing (NGS)
• can be used to sequence every nucleotide in an individual's DNA
( the whole genome)
• limited to smaller portions of the genome such as the exome
• a preselected subset of genes(Multi gene panels)
44. Targeted gene panels
• provide sequence data for a limited subset of genes (typically 10 to 200 genes).
• used in settings-appropriate to sequence many genes to make a diagnosis
Examples
Ataxia
autism spectrum disorders
Muscular dystrophies
Preferable to exome sequencing
• cost advantage
• the lower likelihood of identifying variants of unknown significance
45. List of genetic tests
• Huntington 3000
• Fragile x 8220
• SCA NGS panel 11000
• Limb-girdle muscular dystrophy NGS panel 23000
• Pre natal testing 20000
• Whole genome sequencing 30000
• DMD/BMD 7500
• Chromosome snp micro array 23350
47. AIIMS
• Deletion studies in DMD 2000.00
• Prenatal diagnosis of DMD by deletion studies 2000.00
• Carrier screening in DMD 2000.00
• DNA based mutation detection on DMD or other diseases 3500.00
•
• DNA studies in SMA 1500.00
• Prenatal diagnosis of SMA 1500.00
• Prenatal Diagnostic services for Chromosomal abnormalities using amniotic cultures 7000
And conventional Karyotyping
• FISH (Molecular Cytogenetics) 4000
• Fragile X PCR study 1000.00
• Prenatal diagnosis of Ataxia Telengiectasia or Fragile X 6000.00
48.
49.
50. Exome sequencing
• exome- contains the portions of genes that encode proteins
• it represents only 1.5 to 2.0 percent of the genome
• (non-exomic) DNA consists of introns and regulatory regions that
control other aspects of gene function such as splicing and gene
expression levels.
51. • Reasonable approach-over 85 percent of known disease-causing mutations are
found in exons.
• reduces cost and data storage requirements compared with whole genome
sequencing.
• simplifies clinical reporting, because the significance of variants in exons is easier
to interpret in most cases.
• Disadvantage
exome sequencing could potentially miss a pathogenic variant(s) in a non-coding
region of the genome.
52. Whole genome sequencing
• if initial exome sequencing is not diagnostic
• is costlier than more limited sequencing
• may become preferable to exome sequencing
as cost decreases (Rs-30000)
more information about the role of non-coding DNA in human
disease becomes available.
53. Indications for NGS
• Diagnosis of complex diseases — sequencing of a single gene is
unlikely to provide a diagnosis.
• many different genes cause the same phenotype (eg, due to genetic
heterogeneity).
It would be less costly and more efficient to sequence the entire
genome, exome, or gene panel than to sequence individual candidate
genes sequentially.
54. FISH and high resolution chromosome
analysis
• used to determine genetic changes at the level of an entire chromosome or chromosome
segment
• Examples
• detection of aneuploidies
• gene translocations
• deletions of chromosomal regions.
• uses for
• prenatal diagnosis of aneuploidies
• unexplained congenital anomalies in children.
55.
56. Pre symptomatic testing
• Determine whether an at risk individual, who at the time of the test is
asymptomatic, carries a mutant gene , will therefore develop the disease at
some point in the future.
• Standard practice-to see the patient and discuss the issues around such
presymptomatic testing on at least two separate occasions, usually
separated by about three months.
• psychiatric assessment is part of the presymptomatic testing work up.
57. Prenatal genetic testing
• determines whether a parental variant is present in a fetus.
• used for genes that are inherited in Mendelian inheritance patterns,
• Specimens for analysis traditionally have been obtained either by
chorionic villus sampling or amniocentesis.
• Non-invasive prenatal diagnosis (NIPD), which uses DNA sequencing
of cell-free fetal DNA from maternal plasma samples, is expanding
58. Outcomes of testing
●The causative mutation is identified.
●No mutation is identified.
●A variant of uncertain significance (VUS) is identified.
Failure to identify a mutation does not eliminate the possibility of an
inherited risk.
59. Treatment of neurogenetics disease
• Drugs and neurosurgical procedures - not proven effective
• owing to the complexity and limited understanding of the
pathophysiology involved.
60. Treatment strategies
• novel uses of traditional medications
• targeted therapies for biochemical deficiencies
• nucleic acid derived therapies-modify gene expression
-antisense oligonucleotides
- RNA interference
- gene transfer
- stem cell transplantation
61. Traditional Medical Therapies with New Uses
• Minocycline-Fragile X syndrome
• Vitamin E- AD
• Lithium and baclofen- Down syndrome
62. Targeted Therapies to Metabolic Disequilibrium
• Dietary manipulations -alter the levels of deficient or excessive metabolites
• Examples-PKU
• Protein Replacement-(Enzyme Replacement Therapy)
• Gaucher disease
• Fabry disease
• mucopolysaccharidosis
• Limitations
-limited access across the blood–brain barrier
-Cost remains high
63. • Enhancement of Normal Activity-
• Molecular chaperones are small proteins that naturally act to
stabilize unfolded proteins for cellular translocation
• Chemical chaperones are used to correct protein conformational
defects
• Example-neurodegenerative LSD
64. Gene-Targeted Therapies
• the use of medications will at best ameliorate the symptoms
• it is necessary to treat at a genetic level, via activation, inactivation,
or modification of the target genes.
• Increasing Gene Expression
• Blocking Gene Expression
65. Gene-blocking therapies
• Effective in correcting abnormal gain-of-function mutations,
• Antisense oligonucleotides (AONs), single-stranded DNA oligonucleotides complementary to
mRNA transcripts, which can target the mRna resulting from gain-of-function mutations.
• The AON binds to the abnormal mRNA, preventing its translation into a harmful protein.
• Examples
• DMD
• spinal muscular atrophy
• ataxia telangiectasia.
66.
67. Gene Replacement Therapy
• the ultimate therapeutic goal is the permanent repair of the affected genes
• Transplantation Gene Therapy-Somatic cell gene therapy can be carried out via
transplantation, to introduce wild-type copies of a gene into patients requiring
functional gene copies.
These methods suited to the correction of a loss-of-function mutation .
Examples
• Canavan disease,
• Leber congenital amaurosis
• X-linked adrenoleukodystrophy
68. • Transductive Gene Therapy
• Transduction is the introduction of foreign DNA into a host cell via a
viral vector
• The foreign DNA can be used to replace a missing gene product by
inserting a normal gene into somatic cells.
69. Future Therapies
• Nonviral Vectors
• risks inherent with the use of viral vectors
• interest in gene therapy using nonviral vectors
• non-viral gene delivery -cationic lipid/DNA complexes
• Gene Repair
• Homologous recombination
• AAV vectors or induction of DNA double-strand breaks used to increase the
rate of homologous recombination for potential therapeutic use.
• Example-Zinc-finger nucleases
70. Ethics in neurogenetics
• The decision to take the test is the sole choice of the person concerned.
• It is recommended that the minimum age of testing be 18 years.
• Testing for the purpose of adoption should not be permitted
• Evidence of serious psychiatric condition, it may be advisable that testing
is delayed and support services put into
• The results of the test should be given personally by the counselor to the
person and his/her companion.
71. Conclusions
• Neurogenetics has developed enormously in recent years
• Due to high costs ,genetic tests have normally been performed late
• Proper genetic counselling is important , and in developing countries like
ours neuro physician has to shoulder this responsibilities
• Many of the treatment modalities are in various stages of development ,
but future seems to be bright
72. References
• D.H. Geschwind, H.L. Paulson, and C. Klein,Handbook of clinical neurology, Neurogenetics
Part-1,January 2018
• Farrah Rajabi ,New Innovations: Therapies for Genetic Conditions,Curr Genet Med Rep
(2014) 2:113–123
• Saskia Biskup ,Genetic testing in neurological diseases, Neurol (2012) 259:1249–1254
• Suman Jayadev, Neurology: Clinical Practice, December 2011
• WWW.UPTODATE.COM
