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NEUROLOGY BOARD REVIEW MANUAL

STATEMENT OF
EDITORIAL PURPOSE Neurogenetics Review
The Hospital Physician Neurology Board Review
Manual is a study guide for residents and Editor and Contributor:
practicing physicians preparing for board
examinations in neurology. Each quarterly Catherine L. Gallagher, MD
manual reviews a topic essential to the cur-
rent practice of neurology.
Assistant Professor of Neurology
University of Wisconsin Movement Disorders Program
PUBLISHING STAFF Staff Physician
PRESIDENT, GROUP PUBLISHER Middleton VA Hospital
Bruce M. White
Madison, WI
EDITORIAL DIRECTOR
Debra Dreger
ASSISTANT EDITOR
Rita E. Gould
EXECUTIVE VICE PRESIDENT
Barbara T. White
EXECUTIVE DIRECTOR
OF OPERATIONS
Jean M. Gaul
PRODUCTION DIRECTOR
Suzanne S. Banish
PRODUCTION ASSISTANT
Kathryn K. Johnson
ADVERTISING/PROJECT MANAGER
Patricia Payne Castle
Table of Contents
SALES & MARKETING MANAGER
Deborah D. Chavis Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

NOTE FROM THE PUBLISHER: Neurologic Disorders with Genetic

This publication has been developed without
involvement of or review by the American Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Board of Psychiatry and Neurology.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Endorsed by the
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 NEUROLOGY BOARD REVIEW MANUAL
Neurogenetics Review
Catherine L. Gallagher, MD
INTRODUCTION
In the past half century, an explosion of knowledge
in the field of molecular genetics has revolutionized our
understanding of human diseases. One third of known
single gene defects cause diseases that affect the ner-
vous system, so knowledge of the clinical approach to
genetic disorders is essential for the practicing neurolo-
gist. This manual provides a survey of single gene de-
fects that affect the nervous system, based on the most
prominently affected neuroanatomic region.
BASIC CONCEPTS
Genetic Basis of Inheritance
Humans have 22 pairs of autosomes and 1 pair of sex
chromosomes. Each chromosome is made up of 2 com-
plementary strands of DNA consisting of a double helical
structure surrounding matched nucleotide base pairs
(guanine with cytosine, adenine with thymine). Each set
of 3 DNA base pairs, or codon, codes for 1 amino acid.
DNA is transcribed into messenger RNA (mRNA) by RNA
polymerase and then translated into protein. Introns and
untranslated regions are portions of the DNA sequence
that are transcribed but not translated.
A gene is a portion of the DNA sequence that is the
basic unit of inheritance. Genotype is an individual’s
genetic makeup; phenotype is an individual’s physical
traits or morphology. Expressivity of a gene is the degree
to which a trait attributable to the gene is evident in the
phenotype. Gene expression is more frequently used to
describe the quantity and location of mRNA and pro-
tein transcribed and translated from the gene. Tran-
scription factors are proteins that bind to DNA to regulate
gene expression.
Alleles are variations in the sequence of nucleotides
that make up a gene. An individual inherits 2 alleles of
each gene, 1 from each parent. If the alleles are identi-
cal, the genotype is homozygous; if they are different, the
genotype is heterozygous. The penetrance of an allele is the
proportion of individuals that express its phenotypic
manifestations (ie, disease). Penetrance is frequently
variable, particularly in autosomal dominant disorders.
A proband is the first person within a family or kinship to
2 Hospital Physician Board Review Manual
be identified with a genetic disorder. Founder effect is
when a particular (especially recessive) mutation is
overrepresented in a population due to a small genetic
pool. An example would be the propagation of
X-linked hemophilia in European royalty in the nine-
teenth and twentieth centuries. A polymorphism is an
allele (DNA sequence variation) that occurs in at least
1% of the normal population.
Genomic imprinting is the preferential inactivation
(by methylation) of some regions of a chromosome
based on its parental origin. The most striking exam-
ples of imprinting are Prader-Willi syndrome and
Angelman’s syndrome, both caused by deletion of
genes on the proximal long arm of chromosome 15.
Prader-Willi syndrome (obesity, hypotonia, mild mental
retardation, small hands and feet) is caused by a defi-
ciency of paternal gene expression within this region,
whereas Angelman’s syndrome (severe mental retarda-
tion, epilepsy, facial abnormalities, jerky movements,
hypopigmentation, frequent laughter) is caused by a
deficiency of maternal gene expression.1
Patterns of Inheritance
Single gene disorders are traits produced by the
effects of a single gene or gene pair. Such traits are
inherited in patterns originally described by Mendel as
either dominant (transmitted virtually unchanged by
hybridization) or recessive (masked in the process). Four
inheritance patterns are seen in genetic disorders of the
nervous system: autosomal dominant, autosomal recessive,
X-linked, and mitochondrial. A patient presenting with a
genetic disease without a family history is said to be a
sporadic or isolated case; explanations that should be con-
sidered in such cases include new mutations (common
in certain conditions), false paternity, variable pene-
trance, and recessive inheritance.
Autosomal dominant. A dominant trait will manifest
in both the heterozygote and homozygote, meaning that
a single copy of the mutant allele is sufficient to produce
the trait. Characteristics of an autosomal dominant dis-
order include: multiple successive generations are affect-
ed, males and females are affected in similar proportions,
both males and females transmit disease, and at least 1
instance of male-to-male transmission is seen.
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 Neurogenetics Review
Autosomal recessive. A recessive trait will manifest
only in the homozygote, meaning that both copies of
the allele must be mutant to produce the trait. Charac-
teristics of an autosomal recessive disorder include: both
males and females are affected, the disorder frequently
occurs in only 1 generation (usually among siblings),
and the parents may be consanguineous. An individual
with 1 recessive allele is referred to as a carrier.
X-linked. Because men have only 1 X chromosome,
loss of function mutations in genes carried on this chro-
mosome will result in disease. Characteristics of
X-linked recessive inheritance include: males are affect-
ed almost exclusively, transmission occurs through un-
affected carrier females to their sons, daughters of
affected males become carriers, and male-to-male
transmission does not occur. Some X-linked disorders,
such as Duchenne muscular dystrophy, do produce a
mild phenotype in carrier females. X-linked dominant
disorders are rare and imply that females who harbor
the mutation are affected.2
Mitochondrial. Mitochondria are cytoplasmic orga-
nelles that are a critical source of ATP for cell function.
Each mitochondrion contains 2 to 15 copies of mito-
chondrial DNA (mtDNA), which contains 37 genes that
code for some of the polypeptides involved in oxidative
phosphorylation (OXPHOS), 22 mitochondrial trans-
fer RNAs (tRNAs), and 2 ribosomal RNAs. Aspects of
mitochondrial OXPHOS important for disease patho-
genesis include energy production, generation of reac-
tive oxygen species, and regulation of programmed cell
death (apoptosis).3 Because mitochondria are inherit-
ed from the oocyte cytoplasm, diseases caused by de-
fects in mtDNA follow a maternal inheritance pattern.
Thus, only mothers can transmit disease to male or
female offspring. Mutations in nuclear genes that code
for mitochondrial proteins may be inherited in an auto-
somal dominant, autosomal recessive, or X-linked fash-
ion.
Types of Mutations
The normal DNA sequence is referred to as wild-
type. A mutation is an alteration in the DNA sequence
that has the potential to cause disease. Mutations range
from changes in a single base pair to large alterations in
a part of or an entire chromosome (eg, trisomy 21).
The main types of single gene mutations are:
• Deletions (removal of DNA material) or expansions
(insertion or duplication of DNA material)
• Single base pair substitutions (also called point muta-
tions), which include missense mutations (alteration
in an amino acid in the protein product) and non-
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sense mutations (truncation of the protein product
due to introduction of a stop codon)
• Frame shifts, which disrupt the reading frame of RNA
polymerase due to the excision or addition of base
pairs, resulting in the production of an incorrect
amino acid sequence
• Dynamic mutations (repeat sequences that can change
size on transmission [eg, trinucleotide repeat disor-
ders])
Although the consequences of mutations vary widely
depending on how cellular proteins are altered, in gener-
al, mutations produce their effect through a loss or gain
of protein function. The majority of mutations are loss of
function mutations. In most cases, protein synthesized
from the normal (wild-type) allele is sufficient to main-
tain cellular processes, so only individuals with 2 mutant
alleles will express disease (ie, recessive inheritance pat-
tern). In some cases, a reduction in protein quantity or
activity due to heterozygous mutation will result in less
severe disease than does the homozygous state; this con-
dition is termed haploinsuffiency. One generalization is that
autosomal recessive disorders often have a more severely
affected phenotype than do autosomal dominant disor-
ders because recessive disorders involve a complete rather
than partial alteration in protein function.
Gain of function mutations result in critical changes
in protein dosage; a simple example of this would be tri-
somy 21 (Down syndrome). Gain of function mutations
usually produce dominant phenotypes.
Molecular Genetics Testing
Discoveries in molecular genetics are making possi-
ble the development of tools for precise DNA-based
diagnosis, which have the potential to provide valuable
prognostic and genetic counseling information. Al-
though a discussion of genetic testing for heritable neu-
rologic disorders is beyond the scope of this review, a
few essential points are noted.
Techniques. Beginning with a family in which some
individuals are affected by a genetic trait or disease, mo-
lecular biologic techniques can be used to find the
chromosomal location of the gene that causes the trait.
Positional cloning uses linkage analysis (degree of associ-
ation during meiotic segregation) between the disease
trait and other traits of known location with the
genome to determine the chromosomal location of the
trait of interest. During this process, restriction endonucle-
ases can be used to cut DNA where specific sequences
occur; gel electrophoresis is used to separate fragments of
DNA, RNA, or protein by their size (molecular weight);
and polymerase chain reaction is invariably used to selec-
tively increase the copy number of segments of DNA for
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 Neurogenetics Review
Table 1. Examples of Mitochondrial Disorders
Mitochondrial genomic mutations
Kearns-Sayre syndrome/progressive external ophthalmoplegia
Leigh syndrome
Mitochondrial myopathy
Leber’s hereditary optic neuropathy
Myoclonic epilepsy with ragged red fibers
Mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes
Neurogenic weakness, ataxia, and retinitis pigmentosa
Diabetes mellitus
Cardiomyopathy
Pearson syndrome
Nuclear DNA mutations
Multiple mitochondrial DNA deletions (Leigh phenotype)
Progressive external ophthalmoplegia
Mitochondrial neurogastrointestinal encephalopathy syndrome
X-linked hereditary spastic paraplegia (paraplegin deficiency)
Friedreich’s ataxia
further analysis. DNA sequencing is used to determine
the specific sequence of nucleotides that make up a seg-
ment of DNA. Recognition of elements with typical
functions within a DNA sequence and comparison to
known genes in other organisms also helps determine
which portion of the sequence constitutes the gene.
Commercially available genetic tests may use various
techniques for mutation analysis (not always DNA
sequencing). Therefore, these tests may not detect all
possible mutations that give rise to a particular disease.
Ethical issues. Genetic tests are one of the few pre-
dictive tests available in medicine, and several ethical
issues accompany this fact. The disease that the test pre-
dicts may be untreatable and a positive result, therefore,
seen as a “death sentence.” Patients with a positive test
result may be at risk for suicide, whereas those with a
negative result may be at risk for “survivor guilt.” When
ordering a genetic test for a patient, the neurologist
must also consider implications of a positive result for
family members who are at risk for the disease. For
example, a positive test for an autosomal dominant mu-
tation in the patient and the patient’s maternal grand-
mother may unmask the patient’s mother as an “obli-
gate carrier” of the mutation.
Patients at risk for genetic conditions may be sympto-
matic or asymptomatic, adults or children, or cognitively
competent or cognitively impaired. Special considera-
tions must taken when testing vulnerable groups, par-
ticularly children, for presymptomatic disease. Test of
presymptomatic children prior to age 18 years is discour-
4 Hospital Physician Board Review Manual
aged unless treatment can be offered. Particularly in
asymptomatic individuals, genetic counseling is recom-
mended for the patient and family prior to DNA testing.
Online resources. Extensive neurogenetic informa-
tion to support the clinical neurologist is available in pub-
lic databases. One of the most useful online databases of
information for genetic diagnosis and testing is Online
Mendelian Inheritance in Man (OMIM), which can be
searched by disease name, symptom/sign, gene symbol,
or protein name. OMIM searches can be entered using
the Entrez system on PubMed (www.pubmed.gov).
NEUROLOGIC DISORDERS WITH GENETIC
ASSOCIATIONS
MITOCHONDRIAL, TRINUCLEOTIDE REPEAT, AND ION
CHANNEL DISORDERS
Genetic disorders that are frequently discussed
together due to thematic similarities include the mito-
chondrial disorders, trinucleotide repeat disorders, and
channelopathies.
Mitochondrial Disorders
Manifestations of mitochondrial disorders can vary
significantly between individuals; different mtDNA muta-
tions can cause similar phenotypes, and different pheno-
types can be seen in patients with identical mtDNA
defects. This variation has been explained partially by het-
eroplasmy (presence of wild-type and mutant mitochon-
drial genomes in the same cell), tissue mosaicism (dispro-
portionate distribution of mutant mtDNA to progenitor
cells during cell division), and threshold effects (a certain
proportion of mtDNA must carry the mutation to pro-
duce disease). Implications of mosaicism for the clinician
are that it is best to select affected tissues for genetic test-
ing because the mutation can sometimes be missed in
serologic tests. Long-lived tissues with high metabolic
demand have a lower threshold for the expression of
mitochondrial disease. In particular, brain, heart, skeletal
muscle, retina, renal tubules, and endocrine glands tend
to be affected.4 The classic manifestation in skeletal mus-
cle is the ragged red fiber, a contracted irregular muscle
fiber with a rim that is red on Gomori trichrome stain
due to proliferation and accumulation of mitochondria
inside the cell membrane.
General neurologists should be familiar with the clas-
sic mtDNA disorders that have primarily neurologic
manifestations (Table 1). Leigh syndrome (familial bilat-
eral striatal necrosis) presents in infancy or early child-
hood with encephalopathy, cranial nerve abnormalities,
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 Neurogenetics Review

Table 2. Trinucleotide Repeat Disorders

Disorder Inheritance Gene Chromosome Repeat Type

Fragile X syndrome XLD FMR1 X CGG
Kennedy’s disease XLD Androgen receptor X CAG
Huntington’s disease AD Huntingtin 04 CAG
Myotonic dystrophy 1 AD DMPK 19 CTG
Myotonic dystrophy 2/PROMM AD ZNF9 03 CCTG
Friedreich’s ataxia AR Frataxin 09 GAA
DRPLA AD DRPLA/Atrophin 1 12 CAG
SCA1 AD Ataxin 1 06 CAG
SCA2 AD Ataxin 2 12 CAG
SCA3 (MJD) AD Ataxin 3 (josephin) 14 CAG
SCA6 AD CACNA1A 19 CAG
SCA7 AD Ataxin 7 03 CAG
SCA8 AD Unknown 13 CTG
SCA10 AD Ataxin 10 22 ATTCT
SCA12 AD PP2A 05 CAG
SCA17 AD TATA box-binding protein 06 CAG
OPMD AD PABP2 14 GCG

AD = autosomal dominant; AR = autosomal recessive; CACNA1A = voltage-dependent calcium channel alpha-1A subunit; DMPK = dystrophia
myotonica protein kinase; DRPLA = dentatorubropallidoluysian atrophy; FMR1 = fragile X mental retardation 1; MJD = Machado-Joseph disease;
OPMD = oculopharyngeal muscular dystrophy; PABP2 = polyadenylate-binding protein 2; PME = progressive myoclonic epilepsy; PP2A = protein
phosphatase 2A; PROMM = proximal myotonic myopathy; SCA = spinocerebellar ataxia; XLD = X-linked dominant; ZNF9 = zinc finger protein 9.

and ataxia associated with hyperintensity or necrosis in
the basal nuclei, cerebellum, and brainstem on T2-
weighted magnetic resonance imaging (MRI). Muta-
tions in both nuclear and mitochondrial genes, most
notably nuclear-encoded OXPHOS subunits and the
gene encoding subunit 6 of mitochondrial ATPase
(ATPase 6), have been associated with this phenotype.
Kearns-Sayre syndrome (KSS) and chronic progressive
external ophthalmoplegia (CPEO) are characterized by
ptosis, ophthalmoplegia, and ragged red fiber myopathy
and are variably associated with other organ system in-
volvement and ataxia. KSS is a more severe syndrome,
whereas CPEO is less severe, with potentially an adult or
adolescent onset. Myoclonic epilepsy with ragged red
fibers (MERRF) and mitochondrial myopathy, enceph-
alopathy, and lactic acidosis with stroke-like episodes
(MELAS) are caused by mutations in mitochondrial
tRNA genes; both conditions have a variable age of on-
set. MERRF is characterized by myoclonic epilepsy, pro-
gressive ataxia, and mitochondrial myopathy; midline
lipomas may be associated. MELAS is a cause of evanes-
cent stroke-like events in children and young adults
and is frequently associated with migraine, ataxia, and
seizures. Leber’s hereditary optic neuropathy (LHON)
is caused by point mutations in 1 of 7 subunits of com-
plex I (the first step in the electron transport chain)
encoded by mitochondrial genes. LHON presents as
painless loss of central visual acuity in teenage or young
adult life, with higher penetrance in men. Neuropathy,
ataxia, and retinitis pigmentosa (NARP) syndrome is
also caused by a mutation in ATPase 6. Finally, mito-
chondrial dysfunction is thought to play a role in sever-
al neurodegenerative syndromes, including Alzheimer’s
disease and Parkinson’s disease.
Trinucleotide Repeat Disorders
Human genomic DNA contains numerous spans of
repeated trinucleotide elements. When these sequences
expand beyond the normal length, they can alter gene
expression such that disease results (Table 2). In most
cases, the disorders are autosomal dominant (toxic gain
of function). CAG expansions code for polyglutamine
tracts that accumulate in neuronal nuclear inclusions
thought to be the result of altered protein compartmen-
talization and degradation. In some conditions (eg, frag-
ile X syndrome, myotonic dystrophy, Friedreich’s ataxia,
spinocerebellar ataxia type 8 [SCA8], SCA12), the trinu-
cleotide element involves untranslated regions of DNA.5
Generally, the phenotypes of trinucleotide repeat disor-
ders correlate with the repeat length; larger expansions
cause more severe disease. The repeat length can change
(frequently expanding) during gametogenesis, leading
to earlier disease onset and more severe disease in suc-
cessive generations (anticipation). In some cases, parents

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Table 3. Channelopathies with Neurologic Manifestations gene families that probably evolved from a common
Ligand-gated channels
ancestral gene by gene duplication and divergence.
Nicotinic acetylcholine receptors
Disorders caused by mutations in ion channel genes are
Myasthenia congenita
typically autosomal dominant (cystic fibrosis is an
Autosomal dominant nocturnal frontal lobe epilepsy
exception) and are characterized by episodic attacks
GABAA receptors
that can be precipitated by particular stressors such as
Generalized epilepsy with febrile seizures
exercise, dietary factors, or neuromuscular blocking
Glycine receptors
agents. Classic examples of channelopathies are long
Familial hyperplexia
QT syndrome, periodic paralyses, paramyotonia con-
genita, and malignant hyperthermia. Several disorders
Calcium channels are caused by allelic defects in the P/Q type voltage-
Sarcoplasmic reticulum calcium release channel (ryanodine receptor 1) dependent calcium channel, including SCA6, episodic
Central core disease ataxia type 2, and familial hemiplegic migraine.6 – 8
Malignant hyperthermia susceptibility type 1
Neuronal P/Q type voltage-dependent calcium channel CEREBRAL CORTICAL DISORDERS
Spinocerebellar ataxia type 6 Developmental Delay
Familial hemiplegic migraine Encephalopathy and developmental delay can be
Episodic ataxia type 2 associated with one of many inborn errors of metabo-
Skeletal muscle L-type voltage-dependent calcium channel lism. These disorders will not be discussed in detail.
Hypokalemic periodic paralysis Most single gene defects that affect development are
Sodium channels
associated with dysmorphic features. Two common dis-
Skeletal muscle
orders are trisomy 21 (Down syndrome) and fragile X
Hyperkalemic periodic paralysis
syndrome. About half of live births with trisomy 21 sur-
Paramyotonia congenita
vive until age 50 years. Some morphologic features of
Brain
trisomy 21 include a third fontanelle, large tongue, sin-
Generalized epilepsy with febrile seizures
gle palmar crease, clinodactyly, epicanthic folds, and
Brushfield’s spots of the iris. Obesity, short stature, and
Potassium channels congenital heart defects are common.
Episodic ataxia with myokymia Fragile X syndrome is caused by an expansion of
Benign familial neonatal convulsions more than 200 CGG repeats in an untranslated region
Chloride channels
of the FMR1 gene on the distal long arm of the X chro-
Myotonia congenita
mosome. The expansion leads to transcriptional silenc-
ing of the FMR1 gene due to abnormal methylation.
Gap junction channels The expansion is visualized as a constriction in the chro-
X-linked Charcot-Marie-Tooth neuropathy mosome in folate-deficient media. Boys with fragile X
GABA = γ-aminobutyric acid.
syndrome have hyperextensible joints, a high-arched
palate and high-pitched voice, pectus excavatum, mac-
roorchidism, developmental delay, and frequently autis-
of patients affected by these disorders carry a premutation, tic features. Men who carry a premutation of about 80
a trinucleotide repeat expansion of insufficient length to to 100 repeats may develop action tremor with parkin-
cause disease in the parent. In fragile X syndrome, pre- sonism in the sixth decade.9
mutations are more likely to expand with maternal trans-
mission. In Huntington’s disease, allele expansion is Neurocutaneous Syndromes
more likely to occur with paternal transmission. Congenital syndromes with skin and nervous system
manifestations are listed in Table 4; tuberous sclerosis
Channelopathies and neurofibromatosis are most common. Although
Mutations in genes that code for protein subunits of genetically unrelated, many neurocutaneous syndromes
ion channels and for the elements of ligand-gated are caused by defects in tumor suppressor genes.
channels (eg, the nicotinic acetylcholine receptor) have Tuberous sclerosis is caused by a mutation in the
been termed channelopathies (Table 3). Although their TSC1 gene on chromosome 9, which codes for
gating characteristics and selectivity vary, many ion hamartin, or a mutation in the TSC2 gene on chromo-
channels have a similar structure and are grouped into some 16, which codes for tuberin; half to three quarters

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 Neurogenetics Review

Table 4. Neurocutaneous Disorders

Inheri-
Disorder tance Cutaneous Features Neurologic Features Gene Function
Ataxia-telangiectasia AR Conjunctival telangiectasia, skin Ataxia, intention tremor, ATM DNA repair
telangiectasis (late) decreased tendon reflex-
es, abnormal saccades
Fabry’s disease XLR Angiokeratomas Painful neuropathy, stroke GLA α-Galactosidase A
deficiency
Hypomelanosis of Ito AD Linear or swirling hypopigment- Mental retardation, epilepsy Mosaic of —
ed areas incontentia
pigmenti
Incontentia pigmenti XLD Neonatal: erythematous, macu- Mental retardation, epilepsy, X/autosome Transcription factor
(90% of lar, papular, vesicular lesions; microcephaly, spasticity translocation activator
females) later: pigmented macules,
whorls
Lesch-Nyhan XLR Self-mutilation, especially of Mental retardation, dystonia HPRT1 Defective purine
syndrome digits and lips metabolism
Linear sebaceous Sporadic Linear verrucous lesion near Epilepsy, mental retarda- Unknown Unknown
nevus syndrome midline of face or scalp tion, focal deficits
Menkes (kinky hair) XL Colorless, friable hair, pili torti Seizures, hypotonia, devel- MNK Gut copper-binding
disease (kinky hair), trichlorrhexis opmental delay and protein
nodosa (hair fractures) regression
Neurofibromatosis AD Café-au-lait spots, axillary Learning disability, cogni- NF1 Tumor suppressor
type 1 freckling, Lisch nodules of iris, tive impairment, neuro-
cutaneous neurofibromas, axis tumors
plexiform neurofibromas
Neurofibromatosis AD Skin tumors Neuro-axis tumors NF2 Tumor suppressor
type 2
Osler-Weber-Rendu AD Cutaneous and membrane Abscess, meningitis, embo- Endoglin TGF binding protein
disease telangiectasias lism, cerebral vascular (ENG)
abnormalities
Sturge-Weber Sporadic Facial port-wine stain, glaucoma Epilepsy, mental retarda- ?Somatic 4q Altered fibronectin
syndrome tion, focal deficits inversion expression
Tuberous sclerosis AD Hypomelanotic macules, ungual Epilepsy, mental retarda- TSC1, TSC2 Tumor suppressor
fibromas, shagreen patches, tion, autism, giant cell
facial angiofibromas astrocytoma
von Hippel-Lindau AD Retinal hemangioblastoma Cerebellar hemangioblas- VHL Tumor suppressor
disease toma

AD = autosomal dominant; AR = autosomal recessive; HPRT1 = hypoxanthine guanine phosphoribosyltransferase 1; TGF = transforming growth
factor; XL = X-linked; XLD = X-linked dominant; XLR = X-linked recessive. (Modified from Conneally M, Bird T, Engel AG, et al. Neurogenetics.
Continuum 2000;6[6]:36.)

of cases are sporadic. Both tuberin and hamartin have
tumor suppressor activity. Cutaneous manifestations of
tuberous sclerosis include hypomelanotic leaf-shaped
macules (ash-leaf spots), facial angiofibromas, periun-
gual fibromas, and shagreen patches. Ash-leaf spots are
the most frequent lesion present at the earliest age;
patients typically have 3 or more.10 Systemic manifesta-
tions include retinal lesions, cardiac rhabdomyomas,
renal angiomyolipomas, and pulmonary lymphangio-
matosis. Seizures, especially infantile spasms, occur in at
least 80% of diagnosed cases. Central nervous system
(CNS) lesions include calcified subependymal nodules,
cortical hamartomas, heterotopic grey matter, and sub-
ependymal giant cell astrocytomas (which may cause
acute hydrocephalus). Although cognitive and behav-
ioral problems are common, only about 50% of patients
have mental retardation.11
Neurofibromatosis. Neurofibromatosis type 1 (NF1;
von Recklinghausen’s disease) is caused by a mutation in
a gene on chromosome 17 that codes for neurofibromin;
NF2 is caused by a mutation in a gene on chromosome
22 that codes for neurofibromin-2 (also called merlin or
shwannomin). Both genes have tumor suppressor activi-
ty. NF1 is a predominantly a peripheral nervous system

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 Neurogenetics Review
disease, although it does have some CNS manifestations
including high signal lesions in the basal nuclei on T2-
weighted MRI. Mild cognitive abnormalities and psychi-
atric symptoms may occur. NF1 is a cause of moyamoya
disease. Diagnosis of NF1 requires the presence of 2 or
more of the following criteria: 6 or more café-au-lait
spots (> 5 mm in diameter before puberty or 15 mm in
diameter after), axillary or inguinal freckling, optic glio-
ma, 2 or more neurofibromas or 1 plexiform neurofi-
broma, a first-degree relative with NF1, and a charac-
teristic bone lesion (ie, sphenoid dysplasia). NF2 has
primarily CNS and cranial nerve manifestations, espe-
cially bilateral vestibular shwannomas.11 Both NF1 and
NF2 are associated with CNS neoplasms (eg, ependymo-
mas, meningiomas, astrocytomas).
Sturge-Weber syndrome typically presents as a facial
port-wine stain, most commonly involving the oph-
thalmic distribution of the trigeminal nerve. The facial
angioma is frequently associated with an ipsilateral lep-
tomeningeal angioma that is calcified on computed
tomography and enhances on MRI. Affected individu-
als often develop progressive neurologic problems, in-
cluding difficult to control seizures, migraines, stroke-
like episodes, mental retardation, and hemiparesis. The
syndrome is postulated to result from a somatic muta-
tion resulting in mosaic alteration in fibronectin gene
expression.12
von Hippel-Lindau disease consists of angiogenic
tumors in a variety of organs, especially hemangioblas-
toma of the CNS and retina, renal cell carcinoma,
pheochromocytoma, and pancreatic neuroendocrine
tumors. A variety of defects in the VHL gene (chromo-
some 11) impair its tumor suppressor activity.13
Neuronal Migration Disorders
During brain development, neurons migrate along
radial glial fibers from the ependymal zone (along the
cerebral ventricles) to the cerebral cortex. Disruption of
this process results in cerebral cortical malformations and
heterotopias. One such disorder is classic lissencephaly
(4-layered cortex lacking gyri or sulci), which is caused by
a mutation in the LIS1 gene on chromosome 17. LIS1
codes for a subunit of platelet-activating factor that,
when inhibited, suppresses neuronal migration. Classic
lissencephaly is characterized by profound mental retar-
dation and epilepsy; it may occur alone or in association
with facial dysmorphism as part of the Miller-Dieker
syndrome.
Another gene responsible for lissencephaly, the dou-
ble cortex (DC) gene, was identified on the X chromo-
some. DC mutations cause an X-linked dominant disor-
der characterized by classic lissencephaly in hemizygous
8 Hospital Physician Board Review Manual
males and milder mental retardation and seizures (sub-
cortical band heterotopia) in heterozygous females. It is
hypothesized that in females, X chromosome inacti-
vation leads to 2 distinct populations of migrating
neurons—normal neurons that form the cortex and
neurons in which the normal DC allele has been inacti-
vated, which fail to migrate normally, forming the sub-
cortical band heterotopia.14
Epilepsy
Several genes responsible for familial epilepsy syn-
dromes have been mapped. Many of these are muta-
tions in genes that code for ion channels (see Table 3).
Autosomal dominant nocturnal frontal lobe epilepsy is
caused by mutations that cause defects in the neuronal
nicotinic acetylcholine receptor. Patients experience
clusters of brief motor seizures (usually with conscious-
ness preserved) during non–rapid eye movement sleep.
Ictal findings on electroencephalogram (EEG) are
characteristically inconclusive, potentially leading to a
diagnosis of psychogenic seizures. Benign familial neo-
natal convulsions is a rare autosomal dominant disorder
caused by a mutation in a voltage-gated potassium
channel that is one of the major regulators of neuronal
excitability in the brain. Brief, multifocal or generalized
tonic clonic seizures typically begin at about 3 days of
life. The seizures are associated with suppression of
EEG background. Seizures resolve within the first few
months of life but may recur later in life. Generalized
epilepsy with febrile seizures is probably autosomal
dominant with variable penetrance and is the cause of
a prolonged course of febrile seizures (lasting beyond
age 6 years) and some more grave phenotypes. It is
caused by mutations in voltage-gated sodium channel
subunits. Alexander disease—a rare cause of childhood
epilepsy, macrocephaly, and progressive neurodegener-
ation with Rosenthal fibers—has recently been linked
to mutations in a gene encoding glial fibrillary acidic
protein (GFAP).15
Dementia
Alzheimer’s disease (AD), the most common late-
onset dementia, is characterized by early deficits in for-
mation of new memories. Having a first-degree relative
with AD doubles the risk of developing late-onset AD.
The apolipoprotein E4 polymorphism is a risk factor for
late-onset disease and a dose-dependent modifier of
age of onset.16 Autosomal dominant mutations in amy-
loid beta protein precursor (APP; chromosome 21),
presenilin 1 (PS1; chromosome 14), and presenilin 2
(PS2; chromosome 1) account for a significant propor-
tion of early-onset AD (onset before age 60 years).
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 Neurogenetics Review
Pathologically, brains of patients with AD bear neuro-
fibrillary tangles consisting of paired helical filaments
of hyperphosphorylated tau protein (microtubule-
associated protein tau [MAPT]; chromosome 17) and
senile plaques containing insoluble aggregates of
amyloid-beta (A-beta) protein. The protein product of
APP is cleaved by proteases (β secretase, γ secretase) to
form A-beta proteins of various lengths. Longer frag-
ments 42 to 42 amino acids in length (A-beta-42) are
prone to forming amyloid plaques. Mutations in PS1
and PS2 are thought to alter γ secretase activity such
that a higher proportion of amyloidogenic A-beta-42 is
produced.17
Frontotemporal dementia. Several neurodegenera-
tive disorders including frontotemporal dementia
(FTD) have been categorized as tauopathies on the
basis of neurofibrillary tangles pathology. Tau isoforms
present in the tangles differ somewhat among disor-
ders. FTD typically causes a presenile dementia charac-
terized by early executive and language dysfunction.
Autosomal dominant FTD with parkinsonism is associ-
ated with missense and splice site mutations in the tau
protein sequence on chromosome 17.18
Prion disease. A small proportion of diseases linked
to proteinaceous infectious particles (prions) are inher-
ited as autosomal dominant traits. All of these condi-
tions are caused by mutations in the human prion pro-
tein (PRNP) gene on chromosome 20. PRNP mutations
are associated with Creutzfeldt-Jakob disease (CJD),
Gerstmann-Sträussler disease (GSD), and familial fatal
insomnia (FFI). CJD is characterized by dementia, atax-
ia, and stimulus-sensitive myoclonus with spongiform
change in the neocortex; GSDS is characterized by atax-
ia and dementia associated with the accumulation of
multicentric prion protein–containing plaques in affect-
ed CNS regions; and FFI presents as insomnia and auto-
nomic symptoms followed by progressive dementia,
ataxia, dysarthria, myoclonus, and pyramidal signs asso-
ciated with degeneration of the thalamus.
Although several PRNP mutations have been associat-
ed with human disease, a glutamic acid to lysine change
at codon 200 (E200K mutation) is the most frequent
cause of inherited CJD, a proline to leucine substitution
at codon 102 (P102L mutation) is most commonly asso-
ciated with GSD, and a mutation at codon 178 (D178N
mutation) accounts for FFI. In the presence of the
D178N mutation, disease phenotype is determined by
the type of polymorphism present at codon 129; valine at
codon 129 plus the D178N mutation causes familial CJD,
while methionine at codon 129 plus D178N produces
FFI.19 The valine-methionine polymorphism at codon
129 also influences susceptibility to CJD; 100% of cases of
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new variant CJD were homozygous for methionine at
codon 129, and a high percentage of patients with spo-
radic and iatrogenic CJD are homozygous for either
methionine or valine at codon 129.20
CEREBROVASCULAR DISEASE
Cerebral autosomal dominant arteriopathy with sub-
cortical infarcts and leukoencephalopathy (CADASIL)
is a nonamyloid form of small-vessel disease caused by
mutations in the NOTCH3 gene on chromosome 19.
NOTCH3 is one of a family of transmembrane receptors
that have many roles in organismal development. Clin-
ical manifestations include migraine with aura and re-
current deep white matter infarcts, leading to cognitive
decline and pseudobulbar symptoms (worse in men);
average age of onset is 45 years.21,22
Cerebral cavernous malformations (CCMs) are dom-
inantly inherited vascular malformations that cause
seizures and cerebral hemorrhages, with associated focal
neurologic deficits. Three CCM loci have been mapped,
two to chromosome 7 (CCM1, CCM2) and one to chro-
mosome 3 (CCM3). Loss of function mutations have
been identified in the KRIT1 (CCM1) and malcavernin
(CCM2) genes. CCM3 is caused by a mutation in a pro-
grammed cell death gene (PDCD10).23
The vascular type of Ehlers-Danlos syndrome (EDS
IV), an autosomal dominant cause of structural defects
in type III collagen, is associated with dissection of intra-
cranial arteries, aneurysm, carotid-cavernous fistula,
and spontaneous rupture of bowel. Skin is thin, translu-
cent, and mildly extensible. The collagen defect can be
identified in cultured skin fibroblasts.
Marfan syndrome, caused by a defect in the connec-
tive tissue protein fibrillin 1, causes asthenic body and
facial type, mild to moderate joint laxity, vertebral col-
umn abnormalities, subluxation of the lenses (ectopia
lentis), dural ectasia, and spontaneous dissection of the
aortic and cerebral vessels.
BASAL GANGLIA DISORDERS
Huntington’s Disease
Huntington’s disease (HD) is an autosomal domi-
nant disorder characterized by chorea, cognitive de-
cline, and early degeneration of the caudate nucleus; it
is caused by expansion of a polymorphic trinucleotide
repeat (CAG) in the 5′ coding region of the huntingtin
gene on chromosome 4. Repeats range in number from
9 to 37 in normal individuals and from 37 to 86 in HD
patients; genes with 42 or more CAG repeats are 100%
penetrant. In the disease state, intranuclear inclusions
consisting of polyglutamine fragments and truncated
huntingtin protein are found. The mean age of onset is
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 Neurogenetics Review

Table 5. Loci and Genes Linked to Familial Parkinson’s tonia, DYT3 dystonia, and the autosomal recessive form
Disease
of dopa-responsive dystonia, the disorders are autoso-
Chromosomal Mode of mal dominant with variable penetrance.26 The follow-
Locus Location Gene Inheritance ing dystonias are the most clinically relevant to the neu-
PARK1 4q21.3 α-Synuclein AD rologist.
PARK2 6q25.2-27 Parkin AR DYT1 dystonia is strongly represented in Ashkenazi
PARK3 2p13 Unknown AD Jewish populations and typically causes early-onset
PARK4 4p15 Unknown AD generalized dystonia that initially involves 1 foot (also
PARK5 4p14 UCH-L1 AD known as primary or idiopathic torsion dystonia). The
PARK6 1p35-p36 PINK1 AR genetic defect is deletion of 1 of a pair of CAG repeats
PARK7 1p36 DJ1 AR in the gene encoding torsinA, leading to aggregation of
PARK8 12p11.2-q13.1 LRRK2 AD the protein in perinuclear inclusions.27
PARK9 1p36 Unknown AR* Dopa-responsive dystonia (DRD; Segawa syndrome)
PARK10 1p32 Unknown Late-onset sus- can result from any of several genetic defects that im-
ceptibility gene pair dopamine synthesis. DRD is an early-onset gener-
alized dystonia associated with diurnal fluctuations,
AD = autosomal dominant; AR = autosomal recessive; LRRK2 =
leucine-rich repeat kinase 2; PINK1 = PTEN-induced putative kinase 1;
parkinsonism, dramatic response to levodopa, and low
UCH-L1 = ubiquitin carboxyl-terminal esterase L1. (Adapted with per- levels of the dopamine metabolite homovanillic acid in
mission from Dawson TM, Dawson VL. Rare genetic mutations shed cerebrospinal fluid. The condition may be confused
light on the pathogenesis of Parkinson disease. J Clin Invest 2003; with AR-JP and cerebral palsy. A dominant form of DRD
111:146.) is caused by a mutation in the gene encoding GTP
*Kufor-Rakeb syndrome. cyclohydrolase 1 (GCH1; chromosome 14), which im-
pairs biosynthesis of tetrahydrobiopterin, a cofactor for
tyrosine hydroxylase. A defect in the tyrosine hydroxy-
between 35 and 44 years, leading to death after about lase gene (chromosome 11), which codes for the rate-
15 years. Onset earlier than age 20 years (Westphal vari- limiting enzyme in dopamine synthesis, causes a reces-
ant) is frequently associated with akinetic/rigid clinical sive form of DRD.28
signs and 60 or more CAG repeats.24 Dentatorubropal-
lidoluysian atrophy (DRPLA) is in the differential diag- Wilson’s Disease
nosis of these cases. Wilson’s disease is a recessively inherited form of
hepatolenticular degeneration that can present with an
Parkinson’s Disease ataxic, extrapyramidal, psychiatric, or mixed pheno-
Although Parkinson’s disease (PD) usually is sporadic, type. In Wilson’s disease, inadequate function of a cop-
10 genetic loci (PARK1–10) have been linked to PD per transporting ATPase (ATP7B) on chromosome 13
(Table 5). Several of these mutations affect proteins results in excessive free serum copper that accumulates
involved in or degraded by the ubiquitin-proteasomal in tissues, especially the liver, brain, and cornea (Kayser-
pathway. The most extensively studied and most common Fleischer ring seen on slit-lamp examination).
mutation in cases of early-onset PD (autosomal recessive
juvenile parkinsonism [AR-JP]) are mutations in the Pantothenate Kinase-associated Neurodegeneration
parkin gene (PARK2) on chromosome 6, which codes for Since it was described by Hallervorden and Spatz in
a ubiquitin-protein ligase. Features of this disease include 1922, this diagnosis has been applied to children and
early psychiatric symptoms, dystonia, excellent response young adults who develop progressive and inevitably
to levodopa, susceptibility to medication-induced dyski- fatal dystonia, dysarthria, and rigidity associated with
nesias, and relatively slow progression. PARK2 mutations iron deposition in the basal nuclei (“eye of the tiger”
are found in as many as 77% of sporadic cases when onset sign on T2-weighted MRI). Classic cases and one third
occurs earlier than age 20 but in only 3% when onset of atypical cases are correlated with mutations in the
occurs later than age 30 years.25 Most cases of genetic PANK2 gene, which encodes a pantothenatekinase that
parkinsonism do not have Lewy bodies. regulates coenzyme A synthesis.29

Dystonia SPINOCEREBELLAR ATAXIA

At least 14 genetic loci (DYT1–14) have been linked Genetic causes of SCA come in autosomal recessive,
to dystonia (Table 6). With the exception of DYT2 dys- autosomal dominant, and X-linked varieties. The

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 Neurogenetics Review

Table 6. Dystonia Genetic Loci

Gene Locus Inheritance Phenotype Gene Product

DYT1 9q34 AD Early limb onset TorsinA
DYT2 Not mapped AR Early onset —
DYT3 Xq13.1 XR Filipino dystonia/parkinsonism Not identified
DYT4 Not mapped AD Whispering dysphonia —
DYT5 14q22.1 AD DRD/parkinsonism GCH1
TH 11p15.5 AR DRD TH
DYT6 8p AD Mixed Not identified
DYT7 18p AD Adult cervical Not identified
DYT8 2q33-35 AD PDC/PNKD Not identified
DYT9 1p21 AD Episodic choreoathetosis/ataxia/spasticity Not identified
DYT10 16 AD PKC/PKD Not identified
DYT11 7q21 AD Myoclonus dystonia Epsilon-sarcoglycan
DYT12 19q AD Rapid-onset dystonia/parkinsonism Not identified
DYT13 1p36.13-p36.32 AD Cervical/cranial/brachial Not identified
DYT14 14q13 AD DRD Not identified

AD = autosomal dominant; AR = autosomal recessive; DRD = dopa-responsive dystonia; GCH1 = GTP cyclohydrolase 1; PDC = paroxysmal
dystonic choreoathetosis; PKC = paroxysmal kinesigenic choreoathetosis or dyskinesia; PKD = paroxysmal kinesogenic dystonia; PNKD = parox-
ysmal non-kinesigenic dyskinesia; TH = tyrosine hydroxylase; XR = X-linked recessive. (Adapted with permission from Bressman SB. Dystonia
genotypes, phenotypes, and classification. In: Fahn S, Hallett M, DeLong MR, editors. Dystonia 4: advances in neurology. Vol. 94. Philadelphia:
Lippincott Williams & Wilkins; 2004:103.)

autosomal recessive forms are typically of earlier onset
(< 20 years of age), whereas autosomal dominant
SCAs generally are of later onset (> 25 years of age),
although some have onset in childhood. X-linked
SCAs are rare.
Autosomal Recessive Forms
Friedreich’s ataxia is the most common hereditary
form of spinocerebellar degeneration, characterized by
progressive limb and gait ataxia, neuropathy, areflexia,
dysarthria, and pyramidal signs. A trinucleotide repeat
expansion on chromosome 9 causes diminished expres-
sion of frataxin, a mitochondrial protein encoded in
the nucleus, which plays a role in iron homeostasis.30
Although rare, ataxia caused by vitamin E deficiency
(due to a defect in the α-tocopherol transfer protein)
has a similar phenotype to Friedreich’s ataxia and
responds to vitamin E. Ataxia-telangiectasia presents in
childhood with progressive ataxia, ocular and cuta-
neous telangiectasia, extrapyramidal signs, and cogni-
tive decline; it is caused by a defect in DNA repair (ATM
gene). The disease is associated with a high risk of
hematologic malignancies and low serum IgA levels.
Autosomal Dominant Forms
As medical genetics advances, the autosomal domi-
nant cerebellar ataxias (ADCAs) continue to grow into a
bewildering number of genetically defined conditions.
Although it may be of limited utility to memorize these
conditions, it is important to recognize particular phe-
notypes. These disorders were initially classified by
Harding31 according to 3 clinical phenotypes: ADCA
type I (associated with varying degrees of dementia and
pyramidal, extrapyramidal, peripheral neuropathic, and
ophthalmologic signs), ADCA type II (cerebellar and
retinal degeneration), and ADCA type III (pure cere-
bellar syndrome). The prototype of ADCA type I is
Machado-Joseph disease (SCA3), the most common
form of SCA. This condition was initially described in
Azorean Greek families but is now known to affect pa-
tients in many ethnic groups; expanded alleles may be
quite large (up to 200 CAG repeats). SCA1 and SCA2
are phenotypically similar to SCA3, although SCA2 is
characterized by early slow saccades. The prototype for
ADCA type II is SCA7, which causes optic atrophy and
pigmented retinopathy. The ADCA type III phenotype is
characteristic of SCAs 5, 6, 10, 11, 14, 15, 16, and 22.
Many ADCAs have onset in the third or fourth decade.
The earliest is SCA13, which presents in early childhood
with ataxia associated with motor and cognitive delay. The
latest is typically SCA6, a pure cerebellar late-onset syn-
drome associated with ophthalmoplegia. Episodic ataxia
type 1 (EA1) and episodic ataxia type 2 (EA2) typically
have onset in childhood to adolescence. EA1 causes facial
myokymia and very brief episodes of ataxia that are
responsive to acetazolamide. EA2 causes attacks of ataxia

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 Neurogenetics Review
Table 7. Selected Examples of Hereditary Spastic Paraplegia Syndromes
Locus Protein/Function
SPG1 L1 adhesion molecule
SPG2 Proteolipid protein
SPG4 Spastin/binds microtubules
SPG7 Paraplegin/mitochondrial protein
SPG10 Kinesin heavy chain/axonal transport
SPG20 Spartin
SPG21 Unknown
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; SPG = spastic gait; XL = X= linked.
and signs of vestibulocerebellar dysfunction lasting min-
utes to days, which are acetazolamide-unresponsive.
SCA12 presents with upper extremity and head tremor.
DRPLA, which is most common in Japanese populations,
is associated with myoclonus, chorea, dementia, parkin-
sonism, and epilepsy; the genetic defect is a CAG repeat
expansion in atrophin 1 on chromosome 12. DRPLA,
SCA10, and SCA7 may be associated with epilepsy.5,32,33
SPINAL CORD DISORDERS
The hereditary spastic paraplegias (HSPs) are disor-
ders characterized by insidiously progressive lower limb
weakness and spasticity that produce progressive diffi-
culty walking.34 At least 21 loci have been linked to HSP.
Some HSPs are uncomplicated syndromes character-
ized only by progressive paraparesis; others are associat-
ed with additional neurologic abnormalities. The most
notable forms for which genes have been mapped are
listed in Table 7. Some of the mutations that cause HSP
code for proteins that may be involved in axonal trans-
port (spastin, kinesin heavy chain, proteolipid protein).
Some are mitochondrial proteins (paraplegin, chaper-
onin [heat shock protein] 60). Some are X-linked (pro-
teolipid protein, L1 cell adhesion molecule). Pelizaeus-
Merzbacher disease, a progressive leukodystrophy
associated with “tigroid” dysmyelination, is allelic with
an X-linked form of HSP.
ANTERIOR HORN CELL DISORDERS
The spinal muscular atrophies (SMAs) cause geneti-
cally predetermined degeneration of spinal and bulbar
motor neurons. SMAs have been classified on the basis
of age of onset and severity into 5 types (Table 8). Most
are the result of recessive (loss of function) mutations.
The most important mutation associated with SMA is in
the gene encoding the survival motor neuron (SMN)
protein. Several other genetic factors are phenotypic
modifiers of SMN deletions, thought to produce dis-
ease phenotypes of varying severity. Kennedy’s disease
(X-linked spinal-bulbar muscular atrophy) is an
12 Hospital Physician Board Review Manual
Inheritance Clinical Syndrome
XL Mental retardation, congenital abnormalities
XL CNS white matter abnormality
AD Uncomplicated
AR Mitochondrial myopathy
AD Uncomplicated
AR Distal muscle wasting (Troyer syndrome)
AR Childhood onset
X-linked recessively inherited disease caused by a CAG
repeat expansion in the androgen receptor gene. The
androgen receptor is a ligand-dependent transcription
factor that may play a role in apoptosis. This disease,
like many polyglutamine repeat disorders, is associated
with intracellular aggregates.
Amyotrophic lateral sclerosis (ALS) is the most com-
mon sporadic cause of motor neuron degeneration. In
a minority of patients with familial ALS, a mutation in
the gene that codes for superoxide dismutase 1 (SOD1;
copper-zinc superoxide dismutase) causes an autoso-
mal dominant form of the disease. SOD1 is a cytoplas-
mic protein that catalyzes detoxification of oxygen free
radicals generated by mitochondrial electron transport
and the cytochrome P-450 system.35
PERIPHERAL NERVE DISORDERS
A clinical classification was created in 1975 for the
hereditary motor and sensory neuropathies (HMSN),
designating these disorders as HMSN I–VII. Once the
genetic defects responsible for some of these disorders
were mapped, this classification made less sense from a
genetic point of view. HMSN I (demyelinating type) is
the same as Charcot-Marie-Tooth disease type 1 (CMT1),
and HSM II (axonal type) is the same as CMT2, but
HMSN III (Dejerine-Sottas disease) can be caused by
point mutations in the same genes that contain deletions
in CMT1. A more current classification of CMT neu-
ropathies is shown in Table 9.36
CMT Type 1 (CMT1)
CMT1A–D are autosomal dominant disorders (spo-
radic in 20%) with onset in childhood or early adult-
hood. These disorders are characterized by demyelinat-
ing and re-myelinating neuropathy leading to nerve
hypertrophy (onion bulbs on pathologic nerve sec-
tion), distal weakness, pes cavus, loss of stretch reflexes,
and postural (Roussy-Levy) tremor in one third of pa-
tients. Median nerve conduction velocities are less than
38 m/sec. CMT1A is caused by a duplication or point
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 Neurogenetics Review

Table 8. Clinical Classification of Spinal Muscular Atrophies (SMAs)

Main Mode of Age of Pathologic
Type Inheritance Onset Features Hallmark Prognosis
SMA type I AR or XL (rare) In utero to Hypotonia and weakness; Never able to sit Avg life expectancy is
(Werdnig-Hoffmann 6 mo problems with sucking, swal- without sup- 8 mo; 95% dead before
disease) lowing, and breathing port age 1 y
SMA type II AR 3–15 mo Proximal leg weakness, fasci- Death usually occurs
(Dubowiz disease, culations, fine hand tremor after age 2 y
intermediate form)
SMA type III AD, AR 15 mo to teen Proximal leg weakness, Can sit but never Varies depending on
(Wohlfart-Kugelberg- years delayed motor milestones able to stand; extent and timing of
Welander disease, facial muscles respiratory complica-
chronic SMA) spared tions
SMA type IV (adult- AD, AR 37 y (avg) Proximal weakness variable Life expectancy not
onset SMA) and more severe in AD form markedly reduced
Distal SMA type V AD, AR AR: birth or Distal weakness Very slow clinical pro-
(progressive SMA, infancy gression; does not alter
Charcot-Marie- AD: adulthood life span
Tooth type-SMA)

AD = autosomal dominant; AR = autosomal recessive; XL = X-linked. (Adapted with permission from Cole N. Genetic disorders of motor neu-
rons. Semin Neurol 1999;19:408.)

mutation in the peripheral myelin protein-22 (PMP22) Table 9. Charcot-Marie-Tooth (CMT) Neuropathies and
gene on chromosome 17. The protein product is local- Related Disorders
ized to the compact portion of peripheral myelin, Chromosome
contains 4 transmembrane domains, and is highly con- Disorder Locus Gene
served in evolution. The interesting aspect of PMP22 CMT type 1 (CMT1)*
mutations is that a duplication of this genetic material CMT1A 17p11.2-12 PMP22
causes early-onset demyelinating neuropathy, but a de- CMT1B 1q22-23 Po
letion in this gene causes the less severe phenotype, CMT1C Unknown Unknown
hereditary neuropathy with liability to pressure palsies CMT type 2 (CMT2)
(HNPP). CMT1B is caused by point mutations or small CMT2A 1p36 Unknown
deletions in the myelin protein zero (P0) gene, linked CMT2B 3q13-22 Unknown
to the Duffy blood group on chromosome 1q. CMT1D CMT2C Unknown Unknown
has been linked to mutations in early growth response CMT2D 7p14 Unknown
gene 2 (EGR2), a zinc finger protein that has homolo- Dejerine-Sottas disease (DSD)*
gy to a mouse transcription factor. DSDA 17p11.2-12 PMP22
DSDB 1q22-23 Po
CMT Type 2 (CMT2) CMT type 4 (CMT4)
CMT2 is an axonal neuropathy (median nerve con- CMT4A 8q13-21.1 Unknown
duction velocities > 38 m/sec) that is inherited as an CMT4B 11q23 MTMR2
autosomal dominant, autosomal recessive, or X-linked CMT4C 5q23-33 Unknown
trait. The recessive and X-linked forms are rare. The CMTX Xq13.1 Connexin 32
disorder typically presents later than CMT1 with distal HNPPA 17p11.2-12 PMP22
sensory loss and muscle weakness and atrophy. CMT2B HNPPB Unknown Unknown
is associated with poorly healing ulcers. CMT2C is asso-
CMTX = X-linked dominant Charcot-Marie-Tooth disease; HNPP =
ciated with distal spinal muscular atrophy and vocal hereditary neuropathy with liability to pressure palsies; MTMR2 =
cord paralysis. CMT2A and CMT2B have now been myotubularin-related protein-2. (Adapted with permission from
linked to more than 1 gene each, and CMT2D–K have Mendell JR, Kissel JT, Cornblath DR. Diagnosis and management of
been described based on genetic linkage.37 peripheral nerve disorders. New York: Oxford University Press;
2001:430. Copyright © 2001.)
Dejerine-Sottas Disease *Early growth response gene mutations on chromosome 10q21.1-22.2
Dejerine-Sottas disease (DSD) is a severe (usually cause CMT1 and DSD.

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 Neurogenetics Review
sporadic but also autosomal dominant) hypertrophic,
demyelinating neuropathy with severe slowing of
conduction velocities and onset in infancy or early
childhood. DSD is frequently caused by point muta-
tions in PMP22, P0, and others.
CMT Type 4
CMT4 neuropathies are autosomal recessive demyeli-
nating disorders. CMT4A and CMT4B have very early
onset (before age 3 years) and delayed motor mile-
stones. CMT4C is characterized by severe scoliosis and
mild distal neuropathy, presenting prior to age 10 years.
X-Linked Dominant CMT
X-linked dominant CMT (CMTX) has a more
severe phenotype and earlier onset in males. The phe-
notype is similar to CMT1, although in contrast to
CMT1, affected males may have delayed central con-
duction on brain stem auditory evoked responses.
CMTX is the result of a point mutation in a gap junc-
tion protein (connexin 32) and, thus, is also a chan-
nelopathy, but it does not have episodic features.36
NEUROMUSCULAR JUNCTION DISORDERS
The congenital myasthenic syndromes (CMS) are dis-
orders of the neuromuscular junction classified by the
site of the transmission defect (ie, presynaptic, synaptic,
postsynaptic). The majority of these syndromes are
caused by recessive mutations in genes encoding sub-
units of the muscle nicotinic acetylcholine receptor.11
Slow channel postsynaptic syndromes are caused by
autosomal dominant gain-of-function mutations. CMS
is characterized by significant fatigable weakness with
onset in childhood, decremental response to 2-Hz stim-
ulation on electromyelography, and negative acetylcho-
line receptor antibodies.
MUSCLE DISORDERS
Periodic Paralyses
Hypokalemic periodic paralysis is in most cases caused
by point mutations in the alpha 1 subunit of the L-type
(dihydropyridine-sensitive) calcium channel. Onset is
most common in the second decade and consists of
attacks of generalized weakness lasting hours to 1 day. Res-
piration is not compromised. Attacks are precipitated by
exercise, heavy carbohydrate load, or other conditions
that increase insulin (thus lowering serum potassium).
Hyperkalemic periodic paralysis is characterized by
attacks of muscle stiffness and ache followed by diffuse
muscle weakness lasting 15 minutes to 1 hour, begin-
ning in the first decade of life. The attacks tend to occur
in the morning, can be precipitated by potassium in-
14 Hospital Physician Board Review Manual
take or exercise, and are improved by oral glucose
intake. In this condition, single amino acid substitutions
in the alpha subunit of the skeletal muscle voltage-
gated sodium channel cause defective inactivation of
the open channel. Different point mutations in the
same channel cause paramyotonia congenita or overlap
syndromes. Paramyotonia congenita causes muscle stiff-
ness, particularly involving the neck, face, and hands
and provoked by cold exposure of exercise. Some forms
are responsive to acetazolamide.38
Malignant Hyperthermia
In skeletal muscle, excitation-contraction coupling
is accomplished by an interaction between voltage-
dependent L-type calcium channels in the T tubule
membrane and calcium release channels along the sar-
coplasmic reticulum.39 Both L-type channel and sar-
coplasmic reticulum calcium release channel complex-
es are named for their ligands, dihydropyridine (a
calcium channel blocker) and ryanodine (a plant alka-
loid), respectively. Malignant hyperthermia is an auto-
somal dominant condition caused by mutations in the
ryanodine receptor, which result in excessive calcium
release from the sarcoplasmic reticulum in response to
halothane and succinylcholine. Affected individuals
who have been given these agents develop masseter
spasm, rigidity, hyperpyrexia, hemodynamic instability,
and rhabdomyolysis.40
Muscular Dystrophies
Dystrophin deficiency disorders. Duchenne muscu-
lar dystrophy is an X-linked disorder characterized by
early onset progressive proximal muscle weakness, calf
pseudohypertrophy, cardiomyopathy, massively elevat-
ed creatine kinase, and limited life span. In Duchenne
muscular dystrophy, muscle immunocytochemistry
reveals almost complete loss of dystrophin protein. Dys-
trophin, syntrophins, sarcoglycans, and dystroglycans
are structural elements of the dystrophin-glycoprotein
complex that links the muscle cell cytoskeleton with the
extracellular matrix.41 A milder variant, Becker muscu-
lar dystrophy, is associated with a milder reduction in
dystrophin staining. About one third of cases of
Duchenne and Becker muscular dystrophy result from
new mutations, probably in part due to the dystrophin
gene (locus, Xp21) being one of the largest known
genes. Most of the mutations that produce complete
loss of functional dystrophin cause a frame shift. About
8% of female carriers are affected. In about 60% of
cases the diagnosis can be made by DNA analysis. In the
remainder (point mutations), diagnosis must be made
by muscle immunocytochemistry.
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 Neurogenetics Review
Limb-girdle muscular dystrophy (LGMD) refers to
genetic conditions that cause gradually progressive
proximal weakness, often beginning in the hip girdle,
then shoulder girdle, and then distal muscles. Trapezius
atrophy may be striking. Age of onset varies from child-
hood to adulthood, depending on the genetic defect.
LGMD occurs in both autosomal dominant and auto-
somal recessive forms, with the latter more common.
Many of the recessive LGMDs are caused by mutations
in genes that code for sarcoglycans of the dystrophin-
glycoprotein complex.
Myotonic dystrophy is an autosomal dominant disor-
der caused by a CTG repeat in an untranslated region
of chromosome 19. Clinical findings include myotonia,
progressive proximal muscle weakness, cataracts, hypo-
gonadism, frontal balding, cardiac conduction abnor-
malities, respiratory insufficiency, insulin resistance,
mild cognitive disorder, and other systemic symptoms.
In classic myotonic dystrophy (type 1), the number of
CTG repeats in leukocytes may be 100 to 750, but the
number of CTG repeats in skeletal muscle may be as
many as 5000, suggesting that the repeat expands dur-
ing mitosis or even in postmitotic tissues. Maternal in-
heritance of an allele that has expanded beyond 750
CTG repeats may result in a severe congenital form of
myotonic dystrophy associated with cardiomyopathy
and mental retardation.
Proximal myotonic myopathy (PROMM; myotonic
dystrophy type 2) is an autosomal dominant disorder
with clinical features similar to but milder than those of
myotonic dystrophy; it is caused by expansion of a
CCTG repeat in intron 1 of the zinc finger protein-9
gene.42 In contrast to myotonic dystrophy, patients with
PROMM present with predominant weakness and atro-
phy in proximal muscles.
Oculopharyngeal muscular dystrophy, which pre-
sents with progressive dysphagia, ptosis, and proximal
weakness, usually in the fifth or sixth decade, is caused
by small GCG expansions in the polyadenylate-binding
protein 2 (PABP2) gene.43
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