Huntington Disease

Huntington disease (HD) is an autosomal dominant,

progressive neurodegenerative disorder, typically

characterized by a movement disorder, affecting

middle-aged adults. It is the most frequent cause of

genetic chorea with reported prevalence rates in North

America and Europe ranging from 3 to 7 per 100,000

(Cardoso et al. 2006).

Synonyms and Related Disorders

Huntington chorea

Genetics/Basic Defects

1. Caused by a mutation in the IT15 gene, which

is a 210-kb gene located near the tip of the short

arm of chromosome 4 (4p16.3), resulting in the

N-terminal region of huntingtin protein (Htt) (The

Huntington’s Disease Collaborative Research

Group 1993; Cardoso 2009; Harris et al. 2009)

2. Patients with Huntington disease have an expanded

and unstable trinucleotide CAG (cytosine-adenine-

guanine) repeat in the IT15 gene within exon 1

(Rubinsztein et al. 1996). Huntington disease is,

therefore, considered one of the trinucleotide repeat

disorders.

a. Normal CAG repeat length in theHD gene: 35 or

lower

b. Expansions of 40 or more cause HD with com-

plete penetrance.

c. Individuals with 36–39 repeats may also

develop HD but penetrance is incomplete

(Rubinsztein et al. 1996).

d. A CAG repeat range between 27 and 35:

considered normal allele with particular risk for

expansion into the HD range in the paternal

germline (Ranen et al. 1995; Laccone et al. 1999)

e. The number of CAG repeats

i. Has significant implications for age at onset,

disease severity, and stability of the gene

between generations

ii. Presence of a robust inverse correlation

between the number of polyglutamine

repeats and the age at disease onset so that

longer repeat lengths are associated with

earlier onset of Huntington disease

(Shelbourne et al. 2007)

iii. The number of CAG repeats, however, is not

an absolute prediction of disease onset.

3. The nature of the genetic defect in the HD gene

(Myers et al. 1998) explains many of the genetic

features of the disorder, including:

a. The variability in age at onset

b. The tendency for juvenile disease to be inherited

from fathers

i. Merritt et al. (1969) first observed that

a disproportionate number of cases with

onset before the age of 21 had inherited the

HD gene from affected fathers.

ii. The observation of earlier ages at onset in

successive generations, termed “anticipa-

tion,” is seen in several of the trinucleotide

repeat disorders including HD.

iii. Meiotic instability of the HD repeat in pater-

nal transmission explains the observation of

anticipation in HD.

c. The sporadic appearance of new mutations

to HD

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_121,# Springer Science+Business Media, LLC 2012

1073

4. Pathophysiology (Roze et al. 2008)

a. The expanded polyglutamine repeat alters the

normal functions of Htt.

b. The mutated protein, Exp-Htt, is itself toxic.

c. Htt interacts with an array of proteins in neuronal

cells

d. One important characteristic of Huntington

disease is the particular vulnerability of

a particular brain region, the caudate–putamen,

despite similar expression of the mutated protein

in other brain areas.

Clinical Features

1. A triad of HD (Cardoso 2009; Harris et al. 2009)

a. Movement disorder (Leigh et al. 1983; Carella

et al. 1993; Jankovic and Ashizawa 1995; Reuter

et al. 2000; Tan et al. 2000)

i. Full spectrum of motor impairment

a) Eye movement abnormalities

b) Parkinsonian features

c) Dystonia (particularly in juvenile HD)

d) Myoclonus

e) Tics

f) Ataxia

g) Dysarthria

h) Dysphagia

i) Spasticity with hyperreflexia and

extensor plantar responses

ii. Chorea: often superseded by dystonia or

akineto-rigid parkinsonian features with

progressing illness

iii. Dystonia: found in more than 90% of

patients with HD in one study (Louis et al.

1999) although rarely it becomes as promi-

nent as in idiopathic dystonias

b. Cognitive decline

i. Universally go through cognitive decline,

mental slowing, impaired problem-solving

abilities, and other signs of a frontal

dysexecutive syndrome, and they eventually

become demented. These patients present

with the prototype of so-called subcortical

dementia (Lawrence et al. 1996; Kirkwood

et al. 2001; Ho et al. 2003).

ii. Cognitive decline also heralds the juvenile

onset of HD (Ribai et al. 2007).

iii. Asymptomatic carriers of the HD gene have

decreased phonemic fluency (Larsson et al.

2008).

c. Behavioral changes

i. Universal and may occasionally antedate

motor manifestations

ii. Major depression is common, diagnosed

in more than 40% of subjects, and res-

ponsible for increased suicide rates

in HD

iii. Broad spectrum of behavioral abnormalities

(Caine and Shoulson 1983; Mendez 1994;

Schoenfeld et al. 1984; Shiwach 1994;

Rosenblatt and Leroi 2000; Rosenblatt

et al. 2003; Guttman et al. 2003)

a) Anxiety or panic attacks

b) Obsessive compulsive symptoms

c) Manic features

d) Psychosis

e) Irritability and aggressive behavior

f) Sexual disinhibition

g) Apathy

h) In presymptomatic HD, significantly

more psychiatric symptoms (specially

depression, anxiety, and obsessive-com-

pulsiveness) were reported than for the

controls (Duffin et al. 2007)

i) Similarly, psychiatric difficulties are

indicators of juvenile HD onset (Ribai

et al. 2007).

2. End-stage HD

a. Relentlessly progressive course with death

occurring 15–20 years after symptom onset

with particularly rapid progression in the juve-

nile Westphal variant

b. Typically rigid and akinetic, demented, and

mute

c. Immobility and dysphagia often lead to aspira-

tion pneumonia, the most common cause of

death in these patients (Marshall 2004; Sorensen

and Fenger 1992; Lanska et al. 1988).

3. Differential diagnosis

a. Choreoacanthocytosis: the most likely disorder

to be confused

i. Dementia

ii. Involuntary movements

iii. Caudate atrophy

iv. Abnormal red blood cell morphology

1074 Huntington Disease

v. Neuropathy

vi. Seizures

vii. Myopathy

viii. Elevated creatine phosphokinase

ix. Self-mutilation

x. An unusual eating dystonia

b. Different causes of chorea

i. Genetic causes

a) Huntington disease

b) Huntington disease–like illnesses

c) Neuroacanthocytosis

d) McLeod syndrome

e) Wilson disease

f) Benign hereditary chorea

g) Spinocerebellar atrophy types 2, 3, 17

h) Dentatorubropallidoluysian

degeneration

i) Ataxia-telangiectasia

j) Ataxia associated with oculomotor

apraxia

k) Neuroferritinopathy

l) Pantothenate kinase associated

degeneration

m) Leigh disease and other mitochondrio-

pathies

n) Lesch–Nyhan disease

o) Creutzfeldt–Jakob disease

p) Neuronal ceroid lipofuscinosis

q) Glutaric aciduria

r) Polycythemia vera

s) Celiac disease

t) Benign familial chorea

ii. Immunologic causes

a) Sydenham chorea

b) Systemic lupus erythematosus

c) Antiphospholipid antibody syndrome

iii. Drug-induced chorea

a) Amantadine

b) CNS stimulants (amphetamines, methyl-

phenidate, cyproheptadine)

c) Anticholinergics

d) Anticonvulsants (carbamazepine,

phenytoin)

e) Carbon monoxide

f) Cocaine

g) Dopamine agonists

h) Dopamine-receptor blockers

i) Estrogens

j) Ethanol

k) Levodopa

l) Levofloxacin

m) Lithium

n) Sympathomimetics

o) Theophylline

p) Tricyclic antidepressants

q) Carbamazepine

r) Drugs that cause tardive dyskinesia

s) Withdrawal emergent syndrome

iv. Infections

a) AIDS-related (toxoplasmosis, progres-

sive multifocal leukoencephalopathy,

HIV encephalitis)

b) Bacteria (diphtheria, scarlet fever,

whooping cough)

c) Encephalities (B19 parvovirus, Japanese

encephalitis, measles, mumps, West

Nile river encephalitis, others)

d) Parasites (neurocysticercosis)

e) Protozoan (malaria, syphilis)

v. Endocrine-metabolic dysfunction

a) Adrenal insufficiency

b) Hyper/hypocalcemia

c) Hyper/hypoglycemia

d) Hypomagnesemia

e) Hypernatremia

f) Liver failure

vi. Vascular

a) Postpump chorea (cardiac surgery)

b) Stroke

c) Subdural hematoma

vii. Miscellaneous

a) Anoxic encephalopathy

b) Cerebral palsy

c) Kernicterus

d) Multiple sclerosis

e) Normal maturation (less than 12months

old)

f) Nutritional (e.g., B12 deficiency)

g) Posttraumatic (brain injury)

h) Chorea gravidarum hyperthyroidism

i) External pallidal atrophy

j) Pick disease

k) Paraneoplastic syndromes

l) Acute disseminated encephalo

myelopathy

m) Multiple system atrophy

Huntington Disease 1075

Diagnostic Investigations

1. A confirmed family history of Huntington disease

combined with clinical manifestations: sufficient

for diagnosis (Harris et al. 2009)

2. Neuroimaging (MRI and CT)

a. Severe atrophy of the caudate nucleus in moder-

ately disabled patients

b. May be relatively normal in patients in the early

stages

3. Pet scan: Atrophy of the caudate nucleus can be

detected in a presymptomatic state by the finding

of head of caudate hypometabolism

4. Neuropathological features

a. Neuronal loss and gliosis in the cortex and stria-

tum, particularly the caudate nucleus: the most

prominent neuropathologic features (Roth et al.

2005)

b. Neuronal injury occurs initially in the caudate

tail, in the medial paraventricular caudate, and in

the dorsal part of the putamen.

c. Further neuronal loss and an increase in astro-

cytes can be observed in widespread cortical and

subcortical regions as the neurodegenerative

process progresses.

d. Pathologic observation of affected striatum

shows loss of GABAergic spiny projection neu-

rons with preservation of the aspiny interneurons

and large aspiny acetylcholinesterase-positive

neurons.

e. A decrease of important neurotransmitters and

neuropeptides, such as g-aminobutyric acid

(GABA), calbindin, enkephalin, and substance

P, as a result of selective loss of the medium

spiny neurons

5. Three main types of genetic testing of HD

a. To confirm or rule out disease

b. Presymptomatic testing to determine the carrier

status of an individual at genetic risk for

inheriting the disease

i. To assist in making decisions about mar-

riage, procreation, or career

ii. The emotional impact of the result can be

difficult to anticipate and can evoke substan-

tial adverse emotional reactions (Taylor and

Myers 1997; Almqvist et al. 1999).

iii. Appropriate pretest counseling is important

to assist the at-risk individual in considering

the risks and benefits of genetic testing for

diseases such as HD for which available

treatment does not justify testing

c. Prenatal testing to determine the carrier status of

a fetus

Genetic Counseling

1. Recurrence risk (Warby et al. 2010)

a. Patient’s sib

i. A 50% risk if a parent is affected or has

a CAG size of 40 or greater.

ii. An estimated risk as high as 5% (50% �10%) of inheriting a mutant allele (�36

CAG repeats) if the father has an

intermediated allele (Chong et al. 1997)

iii. A sib who inherits anHD allele with reduced

penetrance may or may not develop symp-

toms of HD.

b. Patient’s offspring

i. A 50% risk of inheriting the disease-causing

mutation from a parent with heterozygosity

for the HD allele

ii. A 100% risk of inheriting the disease-causing

allele from a parent with homozygosity for

CAG repeat expansion in the HD gene

2. Prenatal diagnosis (Warby et al. 2010)

a. Prenatal diagnosis is possible for pregnancies at

50% risk by analyzing DNA extracted from fetal

cells obtained by amniocentesis or CVS, pro-

vided the disease-causing allele in the affected

parent or in an affected relative has been

confirmed.

b. Preimplantation genetic diagnosis may be avail-

able for families in which the disease-causing

mutations have been identified in an affected

family member.

3. Management (Harris et al. 2009)

a. No definitive cure

b. Limited therapeutic options currently

c. Multidisciplinary team approach

i. Medical

ii. Social work

iii. Physical therapy

d. Selective serotonin reuptake inhibitors: effective

in treating depression symptoms:

i. Depression

ii. Mania

1076 Huntington Disease

iii. Delusions

iv. Paranoia

v. Chorea

vi. Other symptoms related to depression

a) Rumination

b) Perseveration

c) Obsessive-compulsive disorder

d) Suicide

vii. Mood stabilizers (valproate, carbamaze-

pine, lamotrigine, or lithium) for bipolar

disorders

e. Neuroleptic for delusions and paranoia symp-

toms as well as chorea

f. Atypical antipsychotics (risperidone, clozapine,

olanzapine, and quetiapine): provide sufficient

control of psychotic symptoms with a lower risk

for extrapyramidal adverse effects and tardive

dyskinesia.

g. Nutritional management

h. Palliative care in managing the latter stage of the

disease

i. Bedridden

ii. Mute

iii. Rigid

iv. Dysphagia

v. Aspiration

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1078 Huntington Disease

Fig. 1 The patient, a 42-year-

old lady, was evaluated for

increasing weakness of her

legs over the past 1 year,

dropping things out of her

hands and increased balance

difficulties. She was

ambulatory but had difficulty

going upstairs and on uneven

surfaces. She later developed

typical movement disorders,

chorea, dystonia, cognitive

decline, and behavioral

changes. The family history

was significant for affected

family members (mother and

two brothers). The diagnosis

of Huntington disease was

confirmed by the presence of

over 40 CAG repeats

Huntington Disease 1079