Autosomal Dominant Inheritance

2.1.1 Huntington's Disease

The most important cause of genetic chorea is Huntington's disease (HD), a neurodegenerative autosomal dominant disorder due to mutation of the huntingtin gene (htt; IT15) on chromosome 4 [1]. HD is due to expansion of a physiological poly-glutamine stretch which ranges from 27 to 35 in healthy individuals. Penetrance is incomplete with between 36 and 39 repeats, and individuals may or may not develop disease. Ranges of 40 or more repeats eventually cause HD, and the longer the stretch the more severe the clinical phenotype. Disease onset is inversely related to the number of repeats [46, 119].

HD prevalence has been found to be high in regions of Venezuela and Scotland, and relatively low in Japan, Finland and Norway [57, 123]. In Europe and North America the prevalence is about 4-8 per 100,000.

Onset of classic HD is around age 40 with a combination of personality changes, generalized chorea, and cognitive decline. However, in children or adolescents, HD

tends to present as an akinetic rigid variant (Westphal form), rather than with chorea. This young-onset variant is more commonly inherited from the father, due to meiotic instability with an increased risk of expansion. Other features in both adult and young onset forms include eye movement abnormalities (impersistence of gaze, difficulty initiating saccades), dysarthria, dysphagia, pyramidal signs, and ataxia resulting in imbalanced gait and reduced postural stability. Dystonia, myoclonus, tics and tremor can also occur as part of the clinical spectrum. Progression is inexorable with death after 15-20 years. Brain imaging reveals progressive atrophy of the caudate nuclei, present even before onset of symptoms. The diagnosis is based on genetic testing. Positive testing has major implications for the entire family and genetic counselling should be offered to explain the risk of inheriting the disease (50%) and penetrance (100% when the polyglutamine stretch exceeds 40 repeats) [75, 119].

The underlying mechanisms of HD are not fully understood. Aggregation of mutant protein fragments, interference with transcription factors and gene expression, abnormal levels of nerve growth factors and calcium, mitochondrial dysfunction, and reduction of synaptic transmission resulting in interference of signaling pathways all seem to play a role [35, 46, 93].

Therapy remains symptomatic. Tetrabenazine reduces chorea through presynaptic dopamine depletion and mild D2-receptor blockage. Typical and atypical neurolep-tics also reduce chorea. However, chorea is usually more bothersome for relatives and carers than for patients. Furthermore, if medication is excessive, motor abilities may markedly deteriorate as chorea becomes replaced by disabling hypokinesia, hence, the primary aim should be to lessen chorea rather than fully suppress it.

Depression can be treated with classical antidepressants. Deep brain stimulation of the globus pallidus internus has been performed experimentally, and has been reported to provide temporary benefit in single cases, but it cannot stop neurodegeneration [59]. Multiple drug trials are currently being carried out in the hope of finding neuroprotective agents.

2.1.2 Dentatorubral-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is in many respects similar to HD. It is an autosomal dominant neurodegenerative disorder [101] due to expansion of trinucleotide (CAG) repeats [67]. The mutated atrophin-1 gene was mapped to chromosome 12p13.31 [131]. The repeat size ranges from 8 to 25 repeats in healthy subjects and from 49 to 88 repeats in affected patients [71, 100]. Instability in transmission has been reported, with an average change in repeat length of 4 repeats for paternal transmission and a decrease of 1 during maternal transmission [71]. Similarly to HD, repeat size correlates with age of onset and disease severity. Three clinical phenotypes have been described; presentation with prominent chorea similar to HD; prominent ataxia; and prominent myoclonus. Usual age of onset is in the third decade with death in the forties. However, early onset disease with severe progressive myoclonic epilepsy and cognitive decline is reported. Late onset disease may present with mild cerebellar ataxia [5].

DRPLA is relatively prevalent in Japan. However, Caucasian cases have been reported [11, 78, 137]. Recently, four Portuguese families with DRPLA [92] were

Table 1 Summary of genetic causes of chorea

Chromosomal

Table 1 Summary of genetic causes of chorea

Chromosomal

Condition

Inheritance

location

Gene

Huntington's disease

AD

4pl5

IT 15/Hunt in gt in

DRPLA

AD

12pl3

Atrophia-1

HDL1

AD

20p 12

PRNP

HDL2

AD

16q24

JPH3

HDL3

AR

4pl5

n.k.

HDL4/SCA17

AD

6q27

TBP

SCA 1

AD

6p23

ATXN1

SCA 2

AD

12q24

ATXN2

SCA 3

AD

14q32.1

MJD-1

Neuroferritinopathy

AD

19ql3

FTL

Benign hereditary chorea

AD

14ql3

TITF-1

Chorea-acanthocytosis

AR

9q21

VPS13A

PKAN

AR

20p 13

PANK2

Karak syndrome

AR

22ql2-ql3

PLA2G6

Wilson's disease

AR

13ql4

ATP7B

Aceruloplasminemia

AR

3q23

CP

Friedreich's ataxia

AR

9pl3

FXN

Ataxia-telangiectasia

AR

llq22.3

ATM

Ataxia with oculomotor

AR

9pl3.3

APTX

apraxia I

Ataxia with oculomotor

AR

9q34

apraxia 2

Age of onset Clinical characteristics

2CM10 Chorea, personality changes, dementia

20-30s Ataxia, chorea, myoclonus

2CM10 HD phenocopy with prominent psychiatric features

35 HD phenocopy, in black Africans

Childhood Extrapyramidal, pyramidal, ataxia, dementia (single family) 25^4-0 Ataxia or HD phenocopy

3CM10 Ataxia, extrapyramidal features including chorea

5-45 Ataxia, extrapyramidal features, neuropathy, dementia

25—45 Ataxia, chorea, dystonia, parkinsonism

40 Chorea, dystonia, oromandibular involvement, parkinsonism, dysarthria

Childhood Non-progressive chorea, thyroid, pulmonary abnormalities 30 Chorea, dystonia, oromandibular involvement, self-mutilation, neuropathy Childhood Dystonia, oromandibular involvement, parkinsonism, chorea, dementia Childhood Ataxia, chorea

20-30 Extrapyramidal, psychiatric, Kayser-Fleischer ring; hepatic involvement

20-50 Ataxia, spasticity, dystonia, retinal degeneration, diabetes mellitus

Childhood Ataxia, spasticity, chorea, dystonia, myoclonus Childhood Ataxia, oculomotor apraxia, chorea, dysarthria Childhood Ataxia, oculomotor apraxia, chorea, neuropathy

Childhood

Ataxia, oculomotor apraxia, chorea, neuropathy

McLeod

X-linked

Xp21

XK

Lesch-Nyhan

X-linked

Xq26

HPRT

Lubag

X-linked

Xql3.3

DYT3

PKD

-

Hetereogenous

n.k.

PNKD

AD

2q33

MR-1

PED

-

Heterogeneous

n.k.

Paroxysmal choreoathetosis

AD

lp21

n.k.

with spasticity

Episodic ataxia 1

AD

12p3

KC.NAl

AD autosomal dominant, AR autosomal recessive, n.k. not known. Dyskinesias; PED Paroxysmal Exercise-induced Dyskinesias;

40-50 Chorea, dystonia, parkinsonism, tremor, psychiatric features, neuropathy

Childhood Dystonia, spasticity, mental retardation, self -mutilation 10^40 Dystonia, parkinsonism, chorea, tremor

7-15 Paroxysmal dyskinesias triggered by movement

2-79 Paroxysmal dyskinesias triggered by alcohol or coffee

2-30 Paroxysmal dyskinesias triggered by exercise

Childhood Dystonia, choreoatherosis, dysarthria, spasticity triggered by stress etc

Childhood Episodic ataxia, myokymia, dysarthria

PKD Paroxysmal Kinesigenic Dyskinesias; PNKD Paroxysmal Non-Kinesigenic

Table 2 Non-genetic causes of chorea

Immune-mediated Sydenham's chorea

Systemic lupus erythematosis Antiphospholipid syndrome Paraneoplastic syndromes Drug-induced Dopamine-blocking agents

L-dopa

Dopamine agonists Psychostimulants including cocaine

Antiepileptic drugs including carbamazepine, valproic acid

Tricyclic antidepressants

Baclofen

Calcium channel blockers Lithium

Steroids including oral contraceptives, estrogen replacement therapy Theophylline Digoxin Cyclosporine Infections HIV

Creutzfeld-Jakob disease

Tuberculosis

Measles

Mycoplasma pneumoniae Parvovirus Metabolic/Hormonal Hyperthyroidism

Hypo- and hyperglycemia Pregnancy Vascular Ischemia

Haemorrhagic stroke

Vasculitis including moyamoya disease

Post-pump chorea found to have two intragenic SNPs in introns 1 and 3, in addition to the CAG repeat, of the DRPLA gene. Notably, all four Portuguese families shared the same haplotype, which was also identical to Japanese DRPLA chromosomes. The fact that this haplotype is the most frequent in Japanese normal alleles, but rare in Portuguese controls, may explain the relatively frequency of DRPLA in Japan compared to Europe.

2.1.3 Huntington's Disease-like (HDL) Syndromes

Recently, it has been recognized that clinically diagnosed HD is genetically heterogeneous, as demonstrated by a report of 618 patients [126]. Only 93% of those with a clinical phenotype of HD were found to have the HD-causing 1T15 gene expansion. For the remaining cases, with a clinical picture of HD in the absence of an 1T15 mutation, the term "Huntington's disease-like" (HDL) syndromes was coined. Mutations in unrelated genes have recently been identified [10, 66, 89, 142]. Among HDL phenocopies, HDL 1 and HDL 4 seem to be most common. HDL 3 is autosomal recessive, and has only been reported in one family to date. HDL 3 is discussed in Sect. 2.2.5 under the recessive disorders.

HDL 1

HDL 1 is an autosomal dominant adult-onset progressive neurodegenerative disorder with prominent psychiatric features, now known to be a prion disease [76]. Similar to HD, the clinical picture is that of abnormal movements, difficulty in coordination, dementia, personality changes and psychiatric symptoms. Seizures have been also described [142]. In a French family the clinical picture resembled Gerstmann-Straussler-Schenker disease [76]. Mean age at onset is 20-45 years. Atrophy of the basal ganglia, the frontal and temporal lobes [142], and the cerebellum with kuru and multicentric plaques labeled with anti-prion antibodies [76] was demonstrated by neuropathological exam. Despite the clinical suggestion of spongiform encephalopathy, spongiosis was not prominent. Linkage to chromosome 20p12 was reported [142]. A 192-nucleotide insertion in the region of the prion protein gene (PRNP) encoding an octapeptide repeat in the prion protein was detected [97, 127].

HDL 2

HDL 2 is a rare cause of HD phenocopies, representing only about 2% of patients without the IT15 mutation [126, 127]. The frequency of HDL 2 is relatively high in black South Africans [9, 90]. North American and Mexican families with African origins have been described [88]. However, so far it has not been reported in Japanese or Caucasians.

Onset is in the fourth decade with a clinical picture resembling classic HD but similarities to the juvenile-onset variant have also been described (pedigree W), but with the absence of seizures and often normal eye movements [89].

Pathological examination showed a picture indistinguishable from classic HD [90]. The causal mutation is a CTG/CAG expansion on chromosome 16q24.3 in the junc-tophilin-3 gene [61]. Similar to HD, there is a correlation between age of onset and repeat length. The function of junctophilin is not fully understood but a role in junc-tional membrane structures and in the regulation of calcium has been suggested [70]. In the normal population, the repeat length ranges from 6 to 27 CTG/CAG triplets [70]. Pathological repeat expansions range from 43 to 57 triplets, with length instability in maternal transmission [90]. To date, the impact of alleles with 36-39 triplets is uncertain [90]. Approximately 10% of HDL2 patient have acanthocytosis on peripheral blood smear [136]. HDL2 is discussed in more detail in the chapter by Margolis.

HDL 4/SCA17

HDL 4 or SCA17 is an autosomal dominant triplet repeat disorder. The mutated gene on chromosome 6q27, TBP, encodes for the TATA box-binding protein, an important general transcription initiation factor. Normal CAG repeat stretches range from 25 to 42 in Caucasians, with larger repeats considered pathological. Onset age is between 19 and 48 years with rare childhood onset [87]. Although cerebellar ataxia is the most common feature, the phenotype is markedly heterogeneous and extrapyramidal, pyramidal, epilepsy, dementia, or psychiatric disturbances may be prominent. A clinical picture indistinguishable from classical HD has been reported in both heterozygous and homozygous mutation carriers [10, 72]. Although within most families HD-like presentation is observed only sporadically or in solitary individuals, HDL phenotypic homogeneity in all members of a SCA17 family has also been described [117]. The broad spectrum of clinical manifestations correlates with the neuropathological findings of the cerebellar pathology, involvement of the cerebral cortex, basal ganglia, and hippocampus [113].

2.1.5 Spinocerebellar Ataxias

Chorea may be seen in other autosomal dominant cerebellar ataxias including SCA 1 [102], SCA 2 [50], and SCA 3 (Machado-Joseph disease).

2.1.6 Neuroferritinopathy

This autosomal dominant condition due to mutation of the FTL gene on chromosome on 19q13, coding for ferritin light chain, presents with extrapyramidal features including chorea, dystonia with prominent oromandibular dyskinesias and parkinsonism (without tremor). Abnormal aggregates of ferritin and iron in the brain can be detected by imaging. Other features include dysarthria, spasticity, cerebellar signs, frontal lobe syndrome and dementia which are variably present [24, 27]. Average age of onset is 40 years. The condition is more common in the Cumbrian region of England due to a founder effect. A French family, possibly sharing a common ancestor, with exactly the same mutation, has also been described [24].

Patients have low serum ferritin levels. MRI may reveal cystic changes in the basal ganglia and bilateral pallidal necrosis [24, 85]. Abnormalities of the mitochondrial respiratory chain were demonstrated in skeletal muscle biopsy [24].

2.1.7 Benign Hereditary Chorea (BHC)

Following the first description of benign hereditary chorea in 1967 [53] of two brothers from Mississippi with early-onset non-progressive chorea, a number of cases have been reported [17, 24, 118, 139]. For several years there was debate about whether BHC is a syndrome [118] or a true entity. However, recently BHC was linked to chromosome 14q encoding for the T1TF-1 gene (NKX2-1 gene), a homeodomain-containing transcription factor essential for the organogenesis of the lung, thyroid and the basal ganglia [14, 33, 74].

Onset of disease is in early infancy with focal or generalized chorea with both intra- and interfamilial variability. Pulmonary and thyroid dysfunction may be present. Atypical additional features include intention tremor [109], dysarthria and gait disturbances [25] and mental impairment [80]. However, as many reports date back to the era before genetic testing, the diagnosis is questionable.

Pathological study of a genetically-proven case revealed no significant abnormalities using standard methods [70]. However, immunohistochemical staining showed loss of most TITF-1-immunoreactive striatal interneurons as compared to four matched control brains [69, 70].

Treatment is not needed in most cases, but favorable responses to levodopa [6], haloperidol, chlorpromazine, and prednisone [139] has been reported.

2.1.8 Idiopathic Basal Ganglia Calcification

Idiopathic basal ganglia calcification (IBGC; Fahr's disease) is a heterogeneous group of disorders in which there is deposition of calcium in the basal ganglia and other cerebral regions, particularly the deep cerebellar nuclei. The clinical picture may include dystonia, parkinsonism, chorea, ataxia, cognitive impairment and behavioural changes. IBGC is genetically heterogeneous, and may occur sporadically. In one family, linkage was demonstrated to 14q (IBC1) [49] although in other families with autosomal dominant inheritance, linkage to this locus was excluded [15, 106, 141]. In some families, the pattern of inheritance and additional clinical features suggest mitochondrial inheritance [112, 145].

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Responses

  • fulgenzio
    How to diagnose huntington's disease autosomal dominant?
    1 month ago
  • awet
    Is the huntingtons gene dominant or recessive?
    1 month ago

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