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GENOMICS AND GENETIC
SYNDROMES AFFECTING
MOVEMENTS
Presented By: Himani Kaushik
★ Mendel’s work on inheritance in Pisum sativum was
first published in 1866 and gave the law of inheritance.
★ He described the concept of Modern Genetics.
★ While Mendel’s research was with pisum sativum, the
same principle of heredity that was discovered by
Mendelian also apply to the human and other animals
because of the mechanism of heredity same for all
complex forms of life.
BACKGROUND
★ Rosalind Franklin and Maurice
Wilkins contribute to the discovery
of the double-helix structure of DNA
and James Watson and Francis Crick
solved the structure of DNA, starting
the new branch of molecular
biology.
HUMAN GENOME PROJECT
★ This project is completed in 2003 and expanded knowledge about
the genetic basis for diseases and congenital malformation.
★ The impact of this project is just being realized, with new research
into diagnostic and treatment techniques for genetic disorders.
Genomes and genetic_syndromes_affecting_movements
★ Genetics and genomics can be applied to the study of both rare
and common multifactorial phenotypes {Bruce R. Korf; 2017}.
★ Human genetics research has a long history, dating from the study
of quantitative traits in the 19th century and the study of human
Mendelian traits in first decade of the 20th century.
★ Single gene traits are transmitted in accordance with Mendel’s
laws as dominant or recessive.
★ Common, complex traits may cluster in families according to the
principles of multifactorial inheritance.
★ Genetic information is stored in the form of the sequence of DNA
and encodes proteins as well as some noncoding RNAs.
★ The human genome sequence has been determined, and the
mechanisms of gene expression and regulation are now being
studied at the genomic level.
DIAGNOSIS OF A GENETIC DISEASE
1. History and Physical Examination
2. Pedigree Analysis
3. Red Flags for Genetic Disease
4. Cytogenetic, Biochemical and Molecular testing
5. Genome Wide Association Study
GENETIC DISORDERS
★ According to WHO it occurs due to a
defect in a single gene or set of genes.
★ According to degree of gene mutation,
diseases are categorized into:
a) Chromosomal disorders
b) Single gene disorders
c) Multifactorial disorders
d) Mitochondrial disorders
Chromosomal
disorders
E.g. a) Autosomal Trisomy
(21, 18, 13), b) Sex
Chromosome: Aneuploidy
Turner and Klinefelter
syndrome c) Partial
Deletion: Prader-Willi
syndrome, Angelman
Syndrome, Cri-du-chat
syndrome
Occurs when an
alteration occurs in
a gene causing one
gene to stop
working..
Single gene
disorders
E.g. a) Autosomal Dominant:
Neurofibromatosis type 1,
Tuberous sclerosis,
Osteogenesis imperfecta b)
Cystic fibrosis, Spinal muscle
atrophy,
Phenylketonuria,Hurler
syndrome c) Sex-Linked:
Duchenne muscular dystrophy
Occur as the result
of mutations in
multiple genes,
frequently coupled
with environmental
causes.
Multifactorial
disorders
E.g. Cleft lip with or without
cleft palate, Clubfoot (talipes
equinovarus) and Spina
bifida
are rare disorders
caused by
mutations in non-
chromosomal DNA
located within the
mitochondria.
Mitochondrial
disorders
E.g. Mitochondrial
myopathy and Kearns-Sayre
disease
Occurs when the
entire or large
segment of a
chromosome, is
missing, duplicated
or altered.
GENETIC
DISORDERS
Monogenic
inheritance
Polygenic
inheritance
Multifactorial
inheritance
LIST OF GENETIC
CONDITIONS
★ Genetic disorders in individuals can
result in a wide variety of a movement
impairments and disabilities as a result
of combined effect of alleles.
★ Modern genetic techniques allow
specific diagnoses to be secured in
many hereditary and “sporadic”
movement disorders {Steven J. Frucht
and Pichet Termsarasab; 2020}.
MOVEMENT IMPAIRMENTS
★ Movement disorders delineate a subdiscipline of neurology
and are caused by affections of the central nervous system
{Wojtecki L., Schnitzler A; 2013}.
★ Brain and spinal cord serve as the main “processing center”
for the entire nervous system, and control all the workings of
individual’s body.
★ It is characterized by problems with movement either
unwanted movements or slowness and poverty of
voluntary movement which are a subject of diagnosis,
therapy, and research.
CHROMOSOMAL DISORDERS
★ Cytogenetics is the study of chromosomal abnormalities.
★ A karyotype is prepared that displays the 46 chromosomes: 22 pairs
of autosomes arranged according to length, and then the two sex
chromosomes that determine male or female sex.
★ Modern methods of staining karyotypes enable analysis of the various
numerical (monosomy and trisomies) and structural abnormalities
(mosaic and translocation) that can occur.
AUTOSOMAL TRISOMIES
★ Trisomy is the condition of a single extranuclear chromosome and can
occur in autosomal or sex cells.
★ Trisomies occur frequently among live births, usually as a result of
the failure of the parental chromosomes to disjoin during meiosis.
★ Trisomies 21, 18, and 13 are the most frequently occurring trisomies;
however, few children with trisomy 18 and 13 survive beyond 1 year
of age.
DOWN SYNDROME (Trisomy 21)
★ Trisomy 21 are caused by an overexpression of gene on human
chromosome 21.
★ 95% of individuals have an extra copy in all of
their body cells, 3-4% have the translocation
and remaining 1% have the mosaic forms.
★ Whichever the type, DS typically have poorer overall health, mobility
and increased secondary complications with the age.
★ Down syndrome is detected with various prenatal
tests, and confirmed by the presence of
characteristic features in the infant at birth.
★ Although DS itself is not a medical condition but is
simply a common variation in the human form,
there are many medical conditions that people with
DS frequently experience.
★ Characteristic features:
1. Learning difficulties
2. Poor cardiac and respiratory health
3. Thyroid dysfunction
4. Diabetes
5. Obesity
6. Digestive problems
7. Low bone density
8. Hearing and Vision loss
9. Dementia and Alzheimer’s disease
10. Depression
11. Leukaemia
12. sleep apnea.
Genomes and genetic_syndromes_affecting_movements
Genomes and genetic_syndromes_affecting_movements
EDWARDS SYNDROME (Trisomy 18)
★ Trisomy 18 are caused by random events during
the formation of reproductive cells and fewer
cases occur as errors in cell division during early
fetal development; and inherited, translocation
forms rarely occur.
★ Trisomy 18 typically have malformations affect
the cardiovascular, gastrointestinal, urogenital,
and skeletal systems.
★ Muscle tone is initially hypotonic, but it becomes hypertonic in
children with longer than typical life span. The period of
hypertonicity in the early years may change to low tone and joint
hyperextensibility by preschool and school age.
★ Microcephaly, abnormal gyri, cerebellar anomalies,
myelomeningocele, hydrocephaly, and corpus callosum defects
have been reported in individuals with trisomy 18.
★ Infants with trisomy 18 may also have:
1. scoliosis,
2. limited hip abduction,
3. flexion contractures of the fingers,
4. rocker-bottom feet,
5. talipes equinovarus,
6. feeding difficulties as a result of a poor suck,
7. profound intellectual disability is another clinical factor that will affect
the developmental therapy programs for children with trisomy 18.
PATAU SYNDROME (Trisomy 13)
★ Trisomy 13 are caused by random events during the
formation of eggs and sperm, such as nondisjunction
errors during cell division.
★ Reported central nervous system (CNS)
malformations include arhinencephalia, cerebellar
anomalies, defects of the corpus callosum, and
hydrocephaly.
SEX CHROMOSOME ANEUPLOIDY
★ The human X chromosome is large, containing approximately 5% of a
humans nuclear DNA. The Y chromosome, much smaller, contains
few known genes.
★ Females, with genotype XX, are mosaic for the X chromosome,
meaning that one copy of their X chromosome is inactive in a given
cell; some cell types will have a paternally derived active
chromosome, and others a maternally derived X chromosome.
★ Males, genotype XY, have only one copy of the X chromosome;
therefore diseases caused by genes on the X chromosome, called
X-linked diseases (see section on sex-linked disorders), can be
devastating to males and less severe in females.
★ In the presence of abnormal numbers of sex chromosomes, neither
male nor female individuals will be phenotypically normal.
TURNER’S SYNDROME (Gonadal Dysgenesis)
★ Turner syndrome affects females with monosomy
of the X chromosome.
★ Turner syndrome is the most common
chromosomal anomaly among spontaneous
abortions.
★ Most infants who survive to term have the mosaic
form of this syndrome, with a mix of cell
karyotypes, 45,X and 46,XX.
★ The SHOX gene, found on both the X and Y chromosomes, codes
for proteins essential to skeletal development.
★ Deficiency of the SHOX gene in females accounts for most of the
characteristic abnormalities of this disorder.
★ Three characteristic impairments of the syndrome are sexual
infantilism, a congenital webbed neck, and cubitus valgus.
★ Noonan syndrome, once thought to be a variant of Turner
syndrome, has several common clinical characteristics; however,
advancements in genetics research have shown that the syndromes
have different genetic causes
KLINEFELTER SYNDROME
★ Klinefelter syndrome is an example of aneuploidy with
an excessive number of chromosomes that occurs in
males.
★ The most common type, 47,XXY, is usually not
clinically apparent until puberty, when the testes fail to
enlarge and gynecomastia occurs.
★ The extra X chromosome(s) can be derived from either
the mother or the father, with nearly equal occurrence.
★ Advanced maternal age is widely
accepted as a causal factor.
★ FISH analysis of spermatozoa from
fathers of boys with Klinefelter syndrome
suggests that advanced paternal age
increases the frequency of aneuploid
offspring.68-70
SINGLE GENE DISORDERS
★ The inheritance patterns of single-gene traits were described by
Gregor Mendel in the nineteenth century.
★ These patterns, autosomal dominant, autosomal recessive, and sex
linked, are discussed separately, and specific examples of syndromes
or disorders associated with each type are presented.
AUTOSOMAL DOMINANT DISORDERS
★ Mutations on one of the 22 numbered pairs of autosomes may
result in isolated anomalies that occur in otherwise normal
individuals, such as extra digits or short fingers.
★ Each child of a parent with an autosomal dominant trait has a 50:50
chance of inheriting that trait.
★ Other autosomal dominant disorders include syndromes
characterized by profound musculoskeletal and neurological
impairments.
★ Examples: osteogenesis imperfecta (OI), tuberous sclerosis, and
neurofibromatosis (NFM).
AUTOSOMAL RECESSIVE DISORDERS
★ An unaffected carrier of a disease-causing trait is heterozygous for
the abnormal gene (possessing one normal and one mutated copy of
the gene).
★ If both parents are unaffected carriers of the gene, each of their
offspring has a 25% risk of exhibiting the disorder.
★ Consanguinity involving close relatives increases the chance of
passing on autosomal recessive traits.
★ Certain types of limb defects, familial microcephaly, and a variety
of syndromes are passed on through autosomal recessive genes.
★ Examples: cystic fibrosis (CF), Hurler syndrome, phenylketonuria
(PKU), and spinal muscle atrophy (SMA).
SPINAL MUSCLE ATROPHY
★ Autosomal recessive genetic disorder
★ Degeneration of motor neurons in the
spinal cord caused by mutations of the
SMN1 gene
★ Brain has a difficult time
communicating with muscles due to
loss of connection between motor
neurons.
★ Cognition usually not impacted
★ 5 types that determine the severity and prognosis of the disorder:
Type I (Werdnig-Hoffman Disease): Age of onset 0-6 months with profound
hypotonia, never sit unsupported (highest function achieved), weak
intercostal muscles, paradoxical breathing, aspiration PNA, poor
suck/swallow
Type II (Intermediate): Age of onset: 7-18 months, sit and never stand
(highest function achieved), fine tremors, kyphoscoliosis, respiratory failure
requiring mechanical ventilation
Type III (Kugelberg-Welander Disease): Age of onset: > 18 months, stand
and walk during adulthood (highest function achieved), reach all major
milestones, occasional wheelchair assistance, risk of obesity, osteoporosis
Type IV (adult): walk unaided (highest function achieved), minimal to no
impact on motor function
SEX LINKED DISORDERS
★ In most sex-linked disorders, the abnormal gene is carried on the X
chromosome. Female individuals carrying one abnormal gene usually
do not display the trait because of the presence of a normal copy on
the other X chromosome.
★ Each son born to a carrier mother, however, has a 50:50 chance of
inheriting the abnormal gene and thus exhibiting the disorder.
★ Examples: hemophilia, fragile X syndrome (FXS), Lesch-Nyhan
syndrome (LNS), and Rett syndrome (RS).
DUCHENNE MUSCULAR DYSTROPHY
★ DMD is an X-linked recessive
disorder that affects 1 in 3,500
males and is caused by mutations in
the dystrophin gene.
★ The vast majority of DMD patients
lack the dystrophin protein.
Genomes and genetic_syndromes_affecting_movements
HUNTINGTON’s DISEASE
★ HD is a dominantly transmitted neurodegenerative
disorder involving the basal ganglia and cerebral cortex
that typically strikes in midlife but can occur as young
as age 2 or 3 and as old as age 80 or more.
★ Children of HD gene carriers have a 50% chance of
inheriting the gene, and because penetrance is full,
those who inherit the gene eventually develop the
disease, given that they do not die of other causes
before onset.
★ Because most persons at risk for HD will have known an affected
parent, they often have personal experiences which shape their
views and influence major life choices.
★ HD is a “trinucleotide repeat” disorder, which is caused by an
increase in the number of CAG repeats in the HD gene.
★ The characteristic symptoms of HD
are:
involuntary choreiform
movements,
cognitive impairment,
mood disorders,
and behavioral changes which are
chronic and progressive over the
course of the illness.
PARKINSON’S
DISEASE
SUMMARY OF THE CHARACTERISTIC FEATURES OF THE GENETIC CONDITIONS
Genomes and genetic_syndromes_affecting_movements
“Discovery of genomes and genetics
in neurological and movement
disorders and its influence requires
the physical therapist to encounter in
therapy programs.”
“All diseases involve some changes in gene
structure or expression”
REFERENCES
1. Bruce R. Introduction to Human Genetics, Principles of Human
Research; 2017, Pages 281-311.
2. Ezquerra, M., Compta, Y., & Marti, M. J. (2011). Identifying the
genetic components underlying the pathophysiology of movement
disorders. The application of clinical genetics, 4, 81–92.
https://doi.org/10.2147/TACG.S7333.
3. https://www.who.int/genomics/public/geneticdiseases/en/
4. Cordeiro, D., Bullivant, G., Siriwardena, K., Evans, A., Kobayashi,
J., Cohn, R. D., & Mercimek-Andrews, S. (2018). Genetic landscape
of pediatric movement disorders and management implications.
Neurology. Genetics, 4(5), e265.
https://doi.org/10.1212/NXG.0000000000000265
Genomes and genetic_syndromes_affecting_movements

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Genomes and genetic_syndromes_affecting_movements

  • 1. GENOMICS AND GENETIC SYNDROMES AFFECTING MOVEMENTS Presented By: Himani Kaushik
  • 2. ★ Mendel’s work on inheritance in Pisum sativum was first published in 1866 and gave the law of inheritance. ★ He described the concept of Modern Genetics. ★ While Mendel’s research was with pisum sativum, the same principle of heredity that was discovered by Mendelian also apply to the human and other animals because of the mechanism of heredity same for all complex forms of life. BACKGROUND
  • 3. ★ Rosalind Franklin and Maurice Wilkins contribute to the discovery of the double-helix structure of DNA and James Watson and Francis Crick solved the structure of DNA, starting the new branch of molecular biology.
  • 4. HUMAN GENOME PROJECT ★ This project is completed in 2003 and expanded knowledge about the genetic basis for diseases and congenital malformation. ★ The impact of this project is just being realized, with new research into diagnostic and treatment techniques for genetic disorders.
  • 6. ★ Genetics and genomics can be applied to the study of both rare and common multifactorial phenotypes {Bruce R. Korf; 2017}. ★ Human genetics research has a long history, dating from the study of quantitative traits in the 19th century and the study of human Mendelian traits in first decade of the 20th century.
  • 7. ★ Single gene traits are transmitted in accordance with Mendel’s laws as dominant or recessive. ★ Common, complex traits may cluster in families according to the principles of multifactorial inheritance.
  • 8. ★ Genetic information is stored in the form of the sequence of DNA and encodes proteins as well as some noncoding RNAs. ★ The human genome sequence has been determined, and the mechanisms of gene expression and regulation are now being studied at the genomic level.
  • 9. DIAGNOSIS OF A GENETIC DISEASE 1. History and Physical Examination 2. Pedigree Analysis 3. Red Flags for Genetic Disease 4. Cytogenetic, Biochemical and Molecular testing 5. Genome Wide Association Study
  • 10. GENETIC DISORDERS ★ According to WHO it occurs due to a defect in a single gene or set of genes. ★ According to degree of gene mutation, diseases are categorized into: a) Chromosomal disorders b) Single gene disorders c) Multifactorial disorders d) Mitochondrial disorders
  • 11. Chromosomal disorders E.g. a) Autosomal Trisomy (21, 18, 13), b) Sex Chromosome: Aneuploidy Turner and Klinefelter syndrome c) Partial Deletion: Prader-Willi syndrome, Angelman Syndrome, Cri-du-chat syndrome Occurs when an alteration occurs in a gene causing one gene to stop working.. Single gene disorders E.g. a) Autosomal Dominant: Neurofibromatosis type 1, Tuberous sclerosis, Osteogenesis imperfecta b) Cystic fibrosis, Spinal muscle atrophy, Phenylketonuria,Hurler syndrome c) Sex-Linked: Duchenne muscular dystrophy Occur as the result of mutations in multiple genes, frequently coupled with environmental causes. Multifactorial disorders E.g. Cleft lip with or without cleft palate, Clubfoot (talipes equinovarus) and Spina bifida are rare disorders caused by mutations in non- chromosomal DNA located within the mitochondria. Mitochondrial disorders E.g. Mitochondrial myopathy and Kearns-Sayre disease Occurs when the entire or large segment of a chromosome, is missing, duplicated or altered.
  • 14. ★ Genetic disorders in individuals can result in a wide variety of a movement impairments and disabilities as a result of combined effect of alleles. ★ Modern genetic techniques allow specific diagnoses to be secured in many hereditary and “sporadic” movement disorders {Steven J. Frucht and Pichet Termsarasab; 2020}.
  • 15. MOVEMENT IMPAIRMENTS ★ Movement disorders delineate a subdiscipline of neurology and are caused by affections of the central nervous system {Wojtecki L., Schnitzler A; 2013}. ★ Brain and spinal cord serve as the main “processing center” for the entire nervous system, and control all the workings of individual’s body. ★ It is characterized by problems with movement either unwanted movements or slowness and poverty of voluntary movement which are a subject of diagnosis, therapy, and research.
  • 16. CHROMOSOMAL DISORDERS ★ Cytogenetics is the study of chromosomal abnormalities. ★ A karyotype is prepared that displays the 46 chromosomes: 22 pairs of autosomes arranged according to length, and then the two sex chromosomes that determine male or female sex. ★ Modern methods of staining karyotypes enable analysis of the various numerical (monosomy and trisomies) and structural abnormalities (mosaic and translocation) that can occur.
  • 17. AUTOSOMAL TRISOMIES ★ Trisomy is the condition of a single extranuclear chromosome and can occur in autosomal or sex cells. ★ Trisomies occur frequently among live births, usually as a result of the failure of the parental chromosomes to disjoin during meiosis. ★ Trisomies 21, 18, and 13 are the most frequently occurring trisomies; however, few children with trisomy 18 and 13 survive beyond 1 year of age.
  • 18. DOWN SYNDROME (Trisomy 21) ★ Trisomy 21 are caused by an overexpression of gene on human chromosome 21. ★ 95% of individuals have an extra copy in all of their body cells, 3-4% have the translocation and remaining 1% have the mosaic forms. ★ Whichever the type, DS typically have poorer overall health, mobility and increased secondary complications with the age.
  • 19. ★ Down syndrome is detected with various prenatal tests, and confirmed by the presence of characteristic features in the infant at birth. ★ Although DS itself is not a medical condition but is simply a common variation in the human form, there are many medical conditions that people with DS frequently experience.
  • 20. ★ Characteristic features: 1. Learning difficulties 2. Poor cardiac and respiratory health 3. Thyroid dysfunction 4. Diabetes 5. Obesity 6. Digestive problems 7. Low bone density 8. Hearing and Vision loss 9. Dementia and Alzheimer’s disease 10. Depression 11. Leukaemia 12. sleep apnea.
  • 23. EDWARDS SYNDROME (Trisomy 18) ★ Trisomy 18 are caused by random events during the formation of reproductive cells and fewer cases occur as errors in cell division during early fetal development; and inherited, translocation forms rarely occur. ★ Trisomy 18 typically have malformations affect the cardiovascular, gastrointestinal, urogenital, and skeletal systems.
  • 24. ★ Muscle tone is initially hypotonic, but it becomes hypertonic in children with longer than typical life span. The period of hypertonicity in the early years may change to low tone and joint hyperextensibility by preschool and school age. ★ Microcephaly, abnormal gyri, cerebellar anomalies, myelomeningocele, hydrocephaly, and corpus callosum defects have been reported in individuals with trisomy 18.
  • 25. ★ Infants with trisomy 18 may also have: 1. scoliosis, 2. limited hip abduction, 3. flexion contractures of the fingers, 4. rocker-bottom feet, 5. talipes equinovarus, 6. feeding difficulties as a result of a poor suck, 7. profound intellectual disability is another clinical factor that will affect the developmental therapy programs for children with trisomy 18.
  • 26. PATAU SYNDROME (Trisomy 13) ★ Trisomy 13 are caused by random events during the formation of eggs and sperm, such as nondisjunction errors during cell division. ★ Reported central nervous system (CNS) malformations include arhinencephalia, cerebellar anomalies, defects of the corpus callosum, and hydrocephaly.
  • 27. SEX CHROMOSOME ANEUPLOIDY ★ The human X chromosome is large, containing approximately 5% of a humans nuclear DNA. The Y chromosome, much smaller, contains few known genes. ★ Females, with genotype XX, are mosaic for the X chromosome, meaning that one copy of their X chromosome is inactive in a given cell; some cell types will have a paternally derived active chromosome, and others a maternally derived X chromosome.
  • 28. ★ Males, genotype XY, have only one copy of the X chromosome; therefore diseases caused by genes on the X chromosome, called X-linked diseases (see section on sex-linked disorders), can be devastating to males and less severe in females. ★ In the presence of abnormal numbers of sex chromosomes, neither male nor female individuals will be phenotypically normal.
  • 29. TURNER’S SYNDROME (Gonadal Dysgenesis) ★ Turner syndrome affects females with monosomy of the X chromosome. ★ Turner syndrome is the most common chromosomal anomaly among spontaneous abortions. ★ Most infants who survive to term have the mosaic form of this syndrome, with a mix of cell karyotypes, 45,X and 46,XX.
  • 30. ★ The SHOX gene, found on both the X and Y chromosomes, codes for proteins essential to skeletal development. ★ Deficiency of the SHOX gene in females accounts for most of the characteristic abnormalities of this disorder. ★ Three characteristic impairments of the syndrome are sexual infantilism, a congenital webbed neck, and cubitus valgus.
  • 31. ★ Noonan syndrome, once thought to be a variant of Turner syndrome, has several common clinical characteristics; however, advancements in genetics research have shown that the syndromes have different genetic causes
  • 32. KLINEFELTER SYNDROME ★ Klinefelter syndrome is an example of aneuploidy with an excessive number of chromosomes that occurs in males. ★ The most common type, 47,XXY, is usually not clinically apparent until puberty, when the testes fail to enlarge and gynecomastia occurs. ★ The extra X chromosome(s) can be derived from either the mother or the father, with nearly equal occurrence.
  • 33. ★ Advanced maternal age is widely accepted as a causal factor. ★ FISH analysis of spermatozoa from fathers of boys with Klinefelter syndrome suggests that advanced paternal age increases the frequency of aneuploid offspring.68-70
  • 34. SINGLE GENE DISORDERS ★ The inheritance patterns of single-gene traits were described by Gregor Mendel in the nineteenth century. ★ These patterns, autosomal dominant, autosomal recessive, and sex linked, are discussed separately, and specific examples of syndromes or disorders associated with each type are presented.
  • 35. AUTOSOMAL DOMINANT DISORDERS ★ Mutations on one of the 22 numbered pairs of autosomes may result in isolated anomalies that occur in otherwise normal individuals, such as extra digits or short fingers. ★ Each child of a parent with an autosomal dominant trait has a 50:50 chance of inheriting that trait. ★ Other autosomal dominant disorders include syndromes characterized by profound musculoskeletal and neurological impairments. ★ Examples: osteogenesis imperfecta (OI), tuberous sclerosis, and neurofibromatosis (NFM).
  • 36. AUTOSOMAL RECESSIVE DISORDERS ★ An unaffected carrier of a disease-causing trait is heterozygous for the abnormal gene (possessing one normal and one mutated copy of the gene). ★ If both parents are unaffected carriers of the gene, each of their offspring has a 25% risk of exhibiting the disorder. ★ Consanguinity involving close relatives increases the chance of passing on autosomal recessive traits. ★ Certain types of limb defects, familial microcephaly, and a variety of syndromes are passed on through autosomal recessive genes. ★ Examples: cystic fibrosis (CF), Hurler syndrome, phenylketonuria (PKU), and spinal muscle atrophy (SMA).
  • 37. SPINAL MUSCLE ATROPHY ★ Autosomal recessive genetic disorder ★ Degeneration of motor neurons in the spinal cord caused by mutations of the SMN1 gene ★ Brain has a difficult time communicating with muscles due to loss of connection between motor neurons. ★ Cognition usually not impacted
  • 38. ★ 5 types that determine the severity and prognosis of the disorder: Type I (Werdnig-Hoffman Disease): Age of onset 0-6 months with profound hypotonia, never sit unsupported (highest function achieved), weak intercostal muscles, paradoxical breathing, aspiration PNA, poor suck/swallow Type II (Intermediate): Age of onset: 7-18 months, sit and never stand (highest function achieved), fine tremors, kyphoscoliosis, respiratory failure requiring mechanical ventilation Type III (Kugelberg-Welander Disease): Age of onset: > 18 months, stand and walk during adulthood (highest function achieved), reach all major milestones, occasional wheelchair assistance, risk of obesity, osteoporosis Type IV (adult): walk unaided (highest function achieved), minimal to no impact on motor function
  • 39. SEX LINKED DISORDERS ★ In most sex-linked disorders, the abnormal gene is carried on the X chromosome. Female individuals carrying one abnormal gene usually do not display the trait because of the presence of a normal copy on the other X chromosome. ★ Each son born to a carrier mother, however, has a 50:50 chance of inheriting the abnormal gene and thus exhibiting the disorder. ★ Examples: hemophilia, fragile X syndrome (FXS), Lesch-Nyhan syndrome (LNS), and Rett syndrome (RS).
  • 40. DUCHENNE MUSCULAR DYSTROPHY ★ DMD is an X-linked recessive disorder that affects 1 in 3,500 males and is caused by mutations in the dystrophin gene. ★ The vast majority of DMD patients lack the dystrophin protein.
  • 42. HUNTINGTON’s DISEASE ★ HD is a dominantly transmitted neurodegenerative disorder involving the basal ganglia and cerebral cortex that typically strikes in midlife but can occur as young as age 2 or 3 and as old as age 80 or more. ★ Children of HD gene carriers have a 50% chance of inheriting the gene, and because penetrance is full, those who inherit the gene eventually develop the disease, given that they do not die of other causes before onset.
  • 43. ★ Because most persons at risk for HD will have known an affected parent, they often have personal experiences which shape their views and influence major life choices. ★ HD is a “trinucleotide repeat” disorder, which is caused by an increase in the number of CAG repeats in the HD gene.
  • 44. ★ The characteristic symptoms of HD are: involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness.
  • 46. SUMMARY OF THE CHARACTERISTIC FEATURES OF THE GENETIC CONDITIONS
  • 48. “Discovery of genomes and genetics in neurological and movement disorders and its influence requires the physical therapist to encounter in therapy programs.”
  • 49. “All diseases involve some changes in gene structure or expression”
  • 50. REFERENCES 1. Bruce R. Introduction to Human Genetics, Principles of Human Research; 2017, Pages 281-311. 2. Ezquerra, M., Compta, Y., & Marti, M. J. (2011). Identifying the genetic components underlying the pathophysiology of movement disorders. The application of clinical genetics, 4, 81–92. https://doi.org/10.2147/TACG.S7333. 3. https://www.who.int/genomics/public/geneticdiseases/en/ 4. Cordeiro, D., Bullivant, G., Siriwardena, K., Evans, A., Kobayashi, J., Cohn, R. D., & Mercimek-Andrews, S. (2018). Genetic landscape of pediatric movement disorders and management implications. Neurology. Genetics, 4(5), e265. https://doi.org/10.1212/NXG.0000000000000265