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Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 1
GENETIC DISORDERS
Celia H. Chang, MD
Acting Chief of the Division of Child Neurology
Associate Health Sciences Clinical Professor of Neurology
Department of Neurology, MIND Institute
University of California, Davis, Health System
Question Based Learning
Lecture Modules
Chromosomopathies
Mitochondrial Disorders
Other Inborn Errors of Metabolism
Module: Chromosomopathies
Question: A 5 y.o. boy has mental retardation
and hyperactivity. His mother has anxiety and
mitral valve prolapse. Her father has difficulty
walking and a tremor that is not responsive to
levo-dopa. What is the most likely inheritance
pattern?
A. Autosomal dominant
B. Autosomal recessive
C. Maternal
D. X-linked
E. Sporadic
Question: An 11 m.o. girl is no longer reaching
for objects. She has intractable epilepsy and
now has microcephaly even though her head
circumference was normal at birth. She also
hyperventilates intermittently and has
respiratory pauses at other times. What is the
most likely diagnosis?
A. Angelman syndrome
B. Rett syndrome
C. William syndrome
D. Leigh syndrome
E. Canavan’s disease
Suspect a chromosomopathy if there are
characteristic
Dysmorphic features
Congenital malformations
Behavioral phenotypes
Neurological abnormalities
Can be diagnosed with specific genetic testing
If features not diagnostic for specific
chromosomopathy, request high resolution
chromosomes vs. chromosomal microarray
May also need parental testing
Fragile X syndrome
Down syndrome
Rett syndrome
Angelman syndrome
Prader-Willi syndrome
Williams syndrome
Klinefelter syndrome
Velocardiofacial (DiGeorge) syndrome
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 2
Source:
http://2.bp.blogspot.com/_nCLKbj44niI/SDG19TVleqI/
AAAAAAAAA9c/_NFVq5sxNYI/s400/fragile-x-syndrome.gif
Fragile X
X-linked dominant Xq27.3
FMR1 mutation with CGG repeat
Macrocephaly
Long thin face, prominent forehead and jaw,
large, protuberant ears
Mitral valve prolapse
Macro-orchidism
Joint laxity – dislocated hips
Mental retardation
Hyperactivity
Aversion of gaze
Stereotypies
Perseverative speech
Autism
Epilepsy
Trinucleotide Repeat Diseases
Polyglutamine (PolyQ) diseases: CAG triplet
repeat disorders
Dentatorubropallidoluysian atrophy
(DRPLA): Chr 12
Huntington’s disease: Chr 4
Spinobulbar muscular atrophy or
Kennedy disease: X
Spinocerebellar ataxia Type 1: Chr 6
Spinocerebellar ataxia Type 2: Chr 12
Spinocerebellar ataxia Type 3 or
Machado-Joseph disease: Chr 14
Spinocerebellar ataxia Type 6: Chr 19
Spinocerebellar ataxia Type 7: Chr 3
Spinocerebellar ataxia Type 17: Chr 6
Non-polyglutamine diseases
Fragile X syndrome: CGG on X
Fragile X-associated tremor/ataxia
syndrome: CGG on X
Fragile XE mental retardation: GCC on X
Friedreich’s ataxia: GAA on Chr 9 AR
Myotonic dystrophy (DM1): CTG on Chr 19
DM2 is CCTG repeat on Chr 3
Spinocerebellar ataxia Type 8: CTG on Chr 13
Spinocerebellar ataxia Type 12: CAG on Chr 5
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 3
Source: http://1.bp.blogspot.com/_s6wxjn4-5Jo/SSsi-yJEaNI/
AAAAAAAABkI/lMMRo4m1UVY/s320/down%27s.jpg
Down Syndrome Phenotype
Trisomy 21
Short stature
Brachycephaly
Epicanthal folds, upslanting palpebral fissures,
Brushfield spots
Small ears
Protruding tongue
Single transverse palmar crease, short & curved
5th finger
Wide space between 1st and 2
nd toes = “sandal foot”
Down Syndrome
Congenital heart disease 50%
Conductive hearing loss 75%
Otitis media 50%70%
Eye disease 60%
Cataract 15%
Severe refractive errors 50%
Thyroid disease 15%, 1% congenital
Leukemia <1%
Leukemoid reaction 18%
Hirschsprung disease <1%
Gastrointestinal atresia 12%
Down Syndrome cont’d
Hypotonia
Atlantoaxial instability
Obstructive sleep apnea 50%75%
Joint laxity
Acquired hip dislocation 6%
Mental retardation
Alzheimer’s disease with onset in 40s
Rett Syndrome
X-linked dominant Xq28
Acquired microcephaly
Intermittent hyperventilation
Cardiac conduction abnormalities
Mental retardation
Epilepsy
Autism
Loss of hand use (wring of hands) ~1 y.o.
http://www.dnatube.com/video/585/Rett-Syndrome-Mouse
Video of mouse with Rett syndrome gene vs.
normal mouse
Source: http://www.armyofangels.org/liam_school_1_sm.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 4
Angelman Syndrome
15q11-q13, Xq28
Deletion
Paternal disomy (missing maternal DNA)
Microcephaly
Epilepsy
Mental retardation
Prognathia, widely spaced teeth
Source: http://library.thinkquest.org/06aug/00440/images/
mpraderwillisymptomweb.jpg
Prader-Willi Syndrome
Chromosome 15q12, 15q11-q13
Deletion
Maternal disomy (missing paternal DNA)
Failure to thrive
Onset of obesity from 6 months to 6 years
Mental retardation
Treatment: growth hormone
Source:
http://images.google.com/imgres?imgurl=http://medgen.genet
ics.utah.edu/photographs/diseases/high/williams_syndrome_o
riginal1.gif&imgrefurl=http://medgen.genetics.utah.edu/photo
graphs/pages/williams.htm&usg=__V_DJjFnNNiCgdeXM76-
iJijvK-E=&h=911&w=607&sz=330&hl=en&start=1&itbs=
1&tbnid=8NUN5mwRQd_R_M:&tbnh=147&tbnw=98&prev
=/images%3Fq%3Dwilliam%2Bsyndrome%26hl%3Den%26
gbv%3D2%26tbs%3Disch:1
Source: http://odlarmed.com/wp-content/uploads/2009/01/
williamskid.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 5
Source:
http://images.google.com/imgres?imgurl=http://odlarmed.com
/wp-content/uploads/2009/01/williamskid.jpg&imgrefurl=
http://odlarmed.com/%3Fcat%3D25&usg=__DAB4K7lS2Pn
DwK-Mu4z_wBn57Qg=&h=215&w=183&sz=7&hl=en&
start=4&itbs=1&tbnid=tROI3VVf_m-_M:&tbnh=106&tbnw=
90&prev=/images%3Fq%3Dwilliam%2Bsyndrome%26hl%3
Den%26gbv%3D2%26tbs%3Disch:1
Williams (Beuren) Syndrome
Autosomal dominant, 7q11.123 deletion
Sensorineural hearing loss
Supravalvular stenosis (aortic and other valves)
ASD, VSD
Kidney abnormalities
Mental retardation (average IQ 56)
Relative sparing of language
ADD
Friendly, gregarious
Hypercalcemia
Source:http://1.bp.blogspot.com/_AL7GK_3BsMM/SIKzXusC0EI/A
AAAAAAAFHo/zt6AappSMcY/s400/Klinefelter%2Bsyndrome.jpg
Klinefelter Syndrome XXY
Developmental delay
Motor
Language
Infertility 95%99%
More breast disease, autoimmune disease and
osteoporosis than normal men
Question: A pregnant woman has an
amniocentesis. The amniocentesis shows a 22q
microdeletion. What is the most serious
complication of this condition?
A. Gastrointestinal atresia
B. Blindness
C. Liver failure
D. Congenital heart disease
E. Autonomic polyneuropathy
Source: http://www.netterimages.com/images/vpv/000/000
/011/11481-0550x0475.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 6
Velocardiofacial (DiGeorge) Syndrome
22q microdeletion 22q11.2DS, AD, about 93%
de novo
Congenital heart disease (conotruncal
malformations) 74%
Tetralogy of Fallot
Facial anomalies 69%
Velopharyngeal incompetence
Immune system abnormalities 77%
Immunodeficiency
Autoimmune disease: thrombocytopenia,
JRA, Grave’s disease, vitiligo, neutropenia,
hemolytic anemia
Velocardiofacial (DiGeorge) Syndrome cont’d
Hypocalcemia 50%
Learning disabilities 70%90%
Below average IQ, ADHD, autism
Renal anomalies 37%
Hearing loss (both conductive and sensorineural)
Laryngotracheoesophageal anomalies
Seizures
Skeletal abnormalities
Schizophrenia in 25%30%
Source: http://migale.jouy.inra.fr/psychrophilum/transport-and-metabolism/FpsyMetabTransp.png
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 7
Inborn Error of Metabolism
Suspect when patient has
Neurological or developmental deterioration
Episodes of severe illness with common
infections
Metabolic acidosis
Hypoglycemia
Person may be asymptomatic and laboratory
testing may be normal between episodes
Caution
In children with suspected inborn errors of
metabolism
AVOID valproic acid
Especially for disorders of fatty acid
metabolism or mitochondrial disease
Valproic acid may cause carnitine depletion
Be careful of ketogenic diet
Avoid in disorders of fatty acid metabolism
or mitochondrial disease
Source: http://www.noatak.com/images/carnitexpl.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 8
General Screening for Inborn Errors of Metabolism Lactate
Ammonia
Carnitine
Acylcarnitine
Serum amino acids
Urine organic acids
CSF lactate
CSF amino acids
Module: Mitochondrial Disorders
Electron Transport Chain
90 proteins
77 from nuclear DNA (all of complex II)
13 from mitochondrial DNA
Mitochondrial DNA
16.6 kB double stranded circular
210 copies per mitochondrial
13 genes for electron transport chain
2 genes for rRNA
22 genes for tRNA
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 9
Source: http://chemistry.umeche.maine.edu/CHY431/MitoDNA.jpg
Source: http://www.nature.com/nrg/journal/v6/n5/images/nrg1606-f3.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 10
Mitochondrial Disorders Leigh syndrome
MERRF
MELAS
Kearns-Sayre syndrome and chronic progressive
external ophthalmoplegia
POLG1 mutations
Leber hereditary optic neuropathy
Source:
http://www.ajnr.org/content/vol24/issue10/images/large/j4113
0822001.jpeg
Leigh Syndrome
Most autosomal recessive ETC proteins and
pyruvate dehydrogenase, some X-linked and
maternal
Brainstem and basal ganglia
Hypotonia
Ophthalmoplegia
Nystagmus
Psychomotor regression
Source: http://www.jmda.or.jp/6/hyakka/image/zu31.jpg
Myoclonic Epilepsy with Ragged Red
Fibers (MERRF) tRNA lysine point mutation in 90%
Ragged red fibers
Myoclonus
Epilepsy
Pseudolaminar necrosis
Basal ganglia mineralization
Source: http://www.neuropathologyweb.org/chapter10/images10/10-
melasx.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 11
Source:
http://www.ispub.com/ispub/ijn/volume_2_number_2_34/dia
gnostic_considerations_on_melas_syndrome/melas-fig1.jpg
Mitochondrial Encephalomyopathy with
Lactic Acidosis and Strokelike Episodes
(MELAS)
tRNA leucine in 80%
Dementia
Seizures
Recurrent strokelike events
Myopathy
Lactic acidosis
Ataxia
Deafness
Pigmentary retinopathy
Pigmentary retinopathy in mitochondrial
myopathy
(A) Granular (“salt and pepper”) retinopathy
(B) Bone spicule appearance
(C) Diffuse retinal atrophy
Source:
http://jnnp.bmj.com/content/75/suppl_4/iv12/F2.large.jpg
Kearns-Sayre Syndrome and Chronic
Progressive External Ophthalmoplegia
Large mtDNA deletions (up to 50% of DNA)
protein synthesis is affected, usually sporadic
Ophthalmoplegia and ptosis
Weakness
Ataxia
Pigmentary retinopathy
Hearing loss
Dementia
Seizures
Cardiomyopathy
Cardiac conduction abnormalities
Impaired GI motility
Diabetes mellitus
Endocrine
Renal dysfunction
POLG1 mutations
Polymerase, DNA, Gamma 1, 15q25 AR
Used in replication of mitochondrial DNA
May cause multiple mitochondrial DNA
deletions in patients
Mitochondrial DNA depletion syndromes
Alpers type
MNGIE type
Source: PubMed: 15702133
Source: http://content.lib.utah.edu/EHSL-WFH/image/353.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 12
Leber Hereditary Optic Neuropathy Maternally inherited, ETC complex I mutations
Loss of retinal ganglia cells in perifoveal region
(macula densa) and degeneration of
papillomacular bundle
Painless progressive central vision loss
Dystonia
Pseudobulbar palsy
Intellectual deterioration
Weakness
Wolff-Parkinson-White
Females may have multiple sclerosis like
symptoms
Module: Other Inborn Errors of
Metabolism
Question: A 42 y.o. man has lancinating pains
in his hands and feet. He also has cloudy
corneas and worsening proteinuria. What is the
most likely diagnosis?
A. Refsum disease
B. Krabbe disease
C. Alexander disease
D. Niemann-Pick disease
E. Fabry disease
Lysosomal Storage Disorders ICD
Lipid storage disorders, mainly sphingolipidoses
Gaucher’s
Niemann-Pick diseases
Gangliosidosis
Tay-Sachs disease
Leukodystrophies
Mucopolysaccharidoses
Hunter syndrome
Hurler disease
Glycoprotein storage disorders
Mucolipidoses
Lysosomal Storage Disorders
Suspect when patient has:
Coarse facial features
Hepatosplenomegaly
Neurological deterioration
Order lysosomal storage disease panel
Leukodystrophies
“Progressive degeneration of the white matter
of the brain due to imperfect growth or
development of the myelin sheath”
Adrenoleukodystrophy
Alexander disease
Metachromatic leukodystrophy
Krabbe’s disease or globoid cell leukodystrophy
Canavan disease
Childhood ataxia with central nervous system
hypomyelination or vanishing while matter
disease (CACH)
Pelizaeus-Merzbacjer disease
Refsum disease
Cerebrotendinous xanthomatosis
Source: http://www.ninds.nih.gov/disorders/leukodystrophy
/leukodystrophy.htm
Adrenoleukodystrophy
Source: http://www.ajnr.org/cgi/content-nw/full/22/4/773/F2
X-linked
Childhood cerebral form appears in mid-
childhood (at ages 4-8)
Adrenomyelopathy occurs in men in their 20s or
later in life
Impaired adrenal gland function
Diagnostic test: very long chain fatty acids
Treatment
Lorenzo’s oil = oleic acid and erucic acid
Docosahexanoic acid (DHA)
Bone marrow transplant
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 13
Alexander Disease
Source: http://www.ajnr.org/cgi/content-nw/full/22/3/541/F6
Source: http://www.ajnr.org/cgi/content-nw/full/22/3/541/F4
Mutations in glial fibrillary acidic protein
Often sporadic
Rosenthal fibers = abnormal clumps of protein
in astrocytes (not pathognomonic)
Usually infantile <2 y.o.
Developmental delay, seizures,
macrocephaly
Juvenile 3-13 y.o.
Loss of motor control
Adult rare
Rosenthal Fibers
Source: http://www.ajnr.org/cgi/content/full/27/5/958
Metachromatic Leukodystrophy
Source: http://radiographics.rsnajnls.org/cgi/content-nw/full/22/3/461/F1A
Autosomal recessive deficiency of arylsulfatase A
Accumulation of the myelin lipid sulfatide in
oligodendrocytes and Schwann cells
Late infantile: blindness, seizures, dementia
Juvenile: mental deterioration
Adult: psychiatric symptoms and dementia
Neuropathy
Treatment: bone marrow transplant
Source: http://www.neuropathologyweb.org/
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 14
Globoid Cell Leukodystrophy or
Krabbe’s Disease
Deficient galactocerebrosidase
Accumulation of galactocerebroside
Central and peripheral nervous system
Treatment
Intravascular injection of cord blood
Bone marrow transplant
Globoid Cell Leukodystrophy
Source: http://www.pathology.vcu.edu/WirSelfInst/
neuro_medStudents/leukodys.html
Source: http://images.the-
scientist.com/content/figures/images/yr2001/sep17/normal.jpg
Source:
http://radiographics.rsnajnls.org/content/vol22/issue3/images/l
arge/g02ma01g14b.jpeg
Canavan’s Disease or
Spongiform Leukodystrophy Deficient enzyme: aspartoacylase
Autosomal recessive
Ashkenazi Jews
Mental retardation
Loss of motor skills
Feeding difficulties
Abnormal muscle tone
Macrocephaly
Blindness
Hearing loss
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 15
Vanishing White Matter
Source:
http://www.ajronline.org/cgi/content/full/175/3/826/FIG1
Vanishing White Matter Disease
or Childhood Ataxia with Diffuse CNS
Hypomyelination (CACH) Autosomal recessive
Mutations of one of five genes for eIF2B
(eukaryotic initiation factor 2B)
Deterioration with trauma, fever or infection
Spasticity
Lethargy
Optic atrophy
Epilepsy
Peroxisomal Disorders
Zellweger syndrome
Enlarged liver
Facial dysmorphology – high forehead,
deformed ears
Hypotonia
Glaucoma
Infantile Refsum disease
Neonatal adrenoleukodystrophy
Rhizomelic chondrodysplasia
Infantile Refsum Disease
Source: http://www.ajnr.org/cgi/content/figsonly/24/10/2082
Refsum Disease
Phytanic acid accumulation
Neuropathy
Retinitis pigmentosa
Ichthyosis
Cardiac arrhythmias
Treatment
Restrict intake of phytanic acid (dairy, beef
and lamb, fatty fish – tuna, cod, haddock
Plasmapheresis
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 16
Source: http://en.wikipedia.org/wiki/File:Sphingolipidoses.svg
Sphingolipidoses
Sphingomyelins have a phosphorylcholine or
phosphoroethanolamine molecule with an ester
linkage to the 1-hydroxy group of a ceramide
Glycosphingolipids, which differ in the
substituents on their head group (see image).
Glycosphingolipids are ceramides with one or
more sugar residues joined in a β-glycosidic
linkage at the 1-hydroxyl position
Cerebrosides have a single glucose or
galactose at the 1-hydroxy position
Sulfatides are sulfated cerebrosides
Gangliosides have at least three sugars, one of
which must be sialic acid
Sphingolipidoses cont’d
Gangliosides: gangliosidosis
GM1 gangliosidoses
GM2 gangliosidoses
Tay-Sachs disease
Sandhoff disease
Glycolipids
Fabry’s disease
Krabbe disease
Metachromatic leukodystrophy
Sphingomyelin
Niemann-Pick disease
Glucocerebrosides
Gaucher’s disease
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 17
Source: http://www.snof.org/maladies/imagesmaladie/taysachs.jpg
Tay-Sachs Disease
Hexosaminidase A deficiency, AR
Ashkenazi Jewish heritage
Onset 3-6 months of age, usually death before
4 years
Storage of glycosphingolipid GM2 ganglioside
Progressive weakness
Loss of motor skills
Decreased attentiveness
Increased startle response
Seizures
Blindness, cherry red spot of fovea centralis
of macula
Normal size spleen and liver
Spasticity
Source: http://img.medscape.com/pi/emed/ckb/pediatrics_genetics
/941088-941089-951451-1333973.jpg
Source: http://www.google.com/imgres?imgurl=http://img.medscape.co
m/pi/emed/ckb/pediatrics_genetics/941088-941089-951451-
1333973.jpg&imgrefurl=http://emedicine.medscape.com/
article/951451-media&usg=__Nzka-c8aC84Hk29w7dKcVVtJxUQ=
&h=407&w=678&sz=269&hl=en&start=4&um=1&itbs=1&t
bnid=DrCQfUT74QI6NM:&tbnh=83&tbnw=139&prev=/ima
ges%3Fq%3Dfabry%2Bdisease%2Bpictures%26um%3D1%2
6hl%3Den%26tbs%3Disch:1
Fabry Disease
Deficiency of α-galactosidase (α-Gal A), X
linked
<1% classic
>1% variants: LV hypertrophy or renal
Lysosomal deposition of globotriaosylceramide
(GL-3)
Neuropathy with acroparesthesias and
lancinating pains
Angiokeratomas
Hypohidrosis
Corneal and lenticular opacities
Proteinuria
ESRD in 3rd
to 5th decade
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 18
Source: http://jnnp.bmj.com/content/74/4/528/F1.large.jpg
Niemann-Pick Disease Type C Autosomal recessive, NCP1 and NCP2
Cannot esterify cholesterol
Hypotonia, developmental delay
Ataxia
Supranuclear vertical gaze palsy
Dementia
Dystonia
Seizures
Ascites, liver disease
MRI: late findings
Thin corpus callosum, cerebral and
cerebellar vermis atrophy
Increased signal periatrial white matter
Source: http://www.webpathology.com/slides/slides/
Spleen_NiemannPick4.jpg
Source: http://www.childrensmemorial.org/depts/genetics/images/
KMoran_cr.jpg
Mucolipidoses
Sialidosis II (ML I)
Deficiency of sialidase
Sialidosis I milder
Mucolipidosis types II and III
Deficiency of the enzyme
N-acetylglucosamine-1-phosphotransferase
Type 2 more severe, type 3 milder
Mucolipidosis type IV
Deficiency of mucolipin-1
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
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Source: http://deti.msk.ru/plaxin_egor.jpg
Mucopolysaccharidoses
Normal intellect to profoundly retarded
Developmental delay
Severe behavioral problems
Coarse or rough facial features
Thick lips
Enlarged mouth and tongue
Short stature with a disproportionately short
trunk (dwarfism)
Abnormal bone size or shape (and other skeletal
irregularities)
Thickened skin
Enlarged organs such as the liver or spleen
Hernias
Excessive body hair growth
Recurrent upper respiratory tract and ear
infections
Cloudy corneas
Treatment
Alpha-L-iduronidase for MPS I (Scheie
syndrome and Hurler-Scheie syndrome: AR)
Idursulfase for MPS II (Hunter syndrome: X
linked recessive)
Arylsulfatase B for MPS VI
(Maroteaux-Lamy syndrome)
Neuronal Ceroid Lipofuscinosis
(NCL or CLN) or Batten Disease
Abnormal apoptosis of neurons
Dysregulated sphingolipid metabolism
Lysosomal enzymes
Lysosomal membrane proteins
Proteins in endoplasmic reticulum
Neurological symptoms
Epilepsy
Ataxia
Cognitive decline
Loss of vision
Diagnosis: DNA testing, EM of lymphocytes
Batten Disease (NCL or CLN) CLN1 infantile
CLN2 late infantile
CLN3 adult
CLN4 adult
CLN5 Finnish VLINCL
CLN6
CLN7 Turkish (Northern epilepsy)
CLN9
Santavuori-Haltia
Jansky-Bielschowsky
Spielmeyer-Sjögren
Kufs disease
Source:
http://www.neuropathologyweb.org/chapter10/images10/10-
curvil.jpg
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 20
Source: http://www.mdconsult.com/das/article/body/0/jorg=journal&source=&sp=20304244&sid=0/N/625024/1.html?issn=0028-
3878 Neurology - Volume 70, Issue 1 (January 2008) - Copyright © 2008 American Academy of Neurology
Source: http://www.ncbi.nlm.nih.gov/books/NBK1428/
Notes:
Neurology Certification Exam Prep Course: Genetic Disorders
Celia H. Chang © 2010-2012 BeatTheBoards.com 877-225-8384 21
Answer Key
Question: A 5 y.o. boy has mental retardation
and hyperactivity. His mother has anxiety and
mitral valve prolapse. Her father has difficulty
walking and a tremor that is not responsive to
levo-dopa. What is the most likely inheritance
pattern?
A. Autosomal dominant
B. Autosomal recessive
C. Maternal
D. X-linked
E. Sporadic
Question: An 11 m.o. girl is no longer reaching
for objects. She has intractable epilepsy and
now has microcephaly even though her head
circumference was normal at birth. She also
hyperventilates intermittently and has
respiratory pauses at other times. What is the
most likely diagnosis?
A. Angelman syndrome
B. Rett syndrome
C. William syndrome
D. Leigh syndrome
E. Canavan’s disease
Question: A pregnant woman has an
amniocentesis. The amniocentesis shows a 22q
microdeletion. What is the most serious
complication of this condition?
A. Gastrointestinal atresia
B. Blindness
C. Liver failure
D. Congenital heart disease
E. Autonomic polyneuropathy
Question: A 42 y.o. man has lancinating pains
in his hands and feet. He also has cloudy
corneas and worsening proteinuria. What is the
most likely diagnosis?
A. Refsum disease
B. Krabbe disease
C. Alexander disease
D. Niemann-Pick disease
E. Fabry disease
Resources
NIH site for neurological disorders
http://www.ninds.nih.gov/index.htm
Leukodystrophies
http://www.ninds.nih.gov/disorders/leukody
strophy/leukodystrophy.htm
Neuropathology pictures
http://www.neuropathologyweb.org/
Genetic or metabolic testing
http://www.genetests.org/
Clinical trials
http://www.clinicaltrials.gov/