Huntington Disease, Hereditary Choreas and Dyskinesias

Literature and regulatory information updated: 1 November 2026.

Huntington disease (HTT), juvenile form, phenocopies (HDL1–HDL4, C9orf72), benign hereditary chorea / brain–lung–thyroid syndrome (NKX2-1) and ADCY5-related dyskinesia

0. Initial Reference Table

1. Introduction

Huntington disease (HD), formerly termed Huntington chorea, is a progressive neurodegenerative disease with autosomal dominant inheritance, defined by a triad of involuntary movement disorder, psychiatric abnormalities and cognitive decline progressing to dementia [3, 4]. Its classical description is attributed to George Huntington, a physician from Long Island who, in 1872 at the age of 22, published “On chorea” in the Medical and Surgical Reporter, distinguishing hereditary chorea from other choreas and identifying three features that remain valid: hereditary transmission without skipped generations when the parent is unaffected, a tendency towards “insanity” and suicide, and adult onset with progressive deterioration [5]. Before the molecular era, “St Vitus's dance” and “Sydenham chorea” were used indiscriminately for any chorea, and “Westphal variant” came to denote the rare akinetic-rigid form [4].

The molecular history of HD is a milestone in human genetics. In 1983, Gusella and colleagues, working with American families and extensive pedigrees from the Lake Maracaibo region of Venezuela, demonstrated genetic linkage of the disease to a polymorphic DNA marker on the short arm of chromosome 4 — the first human disease mapped through DNA polymorphisms without prior knowledge of the protein [6]. Ten years later, the Huntington's Disease Collaborative Research Group identified IT15 (now HTT) and the unstable expansion of a CAG triplet on disease-bearing chromosomes [7]. The Venezuelan families, which constitute the largest known founder cluster, continued to contribute to knowledge of genetic and environmental factors modifying age at onset [8]. HD also became the model on which predictive testing protocols for late-onset diseases without preventive treatment were built, from the 1994 recommendations of the International Huntington Association and World Federation of Neurology (IHA/WFN) to the 2013 recommendations of the European Huntington's Disease Network (EHDN) [3, 9, 10].

The scope of this article includes, alongside classical adult HD, the juvenile form, genetic phenocopies — diseases with a similar phenotype and negative HTT testing, particularly Huntington-like syndromes 1 to 4 (HDL1 due to octapeptide expansion in PRNP, HDL2 due to CTG/CAG expansion in JPH3, autosomal recessive HDL3 linked to 4p15.3, HDL4 corresponding to spinocerebellar ataxia type 17 due to expansion in TBP) and the C9orf72 hexanucleotide expansion — and, as a contrasting entity, benign hereditary chorea (BHC) caused by NKX2-1 haploinsufficiency, which falls within the brain–lung–thyroid syndrome spectrum [4, 11, 12]. BHC was described in 1967 by Haerer, Currier and Jackson in a five-generation family with early-onset non-progressive chorea [13]; the gene was identified in 2002 [14, 15], and Willemsen and colleagues coined “brain–lung–thyroid syndrome” in 2005 when describing a patient with a de novo variant and severe multisystem involvement [16]. Distinguishing these entities has direct implications for prognosis, genetic counselling and surveillance: HD is neurodegenerative and fatal, whereas NKX2-1 chorea has a developmental basis, with an expected normal life expectancy but specific thyroid and pulmonary risks [12]. ADCY5-related dyskinesia also falls within this scope; it was recognised in 2001 by Fernandez and colleagues as “familial dyskinesia with facial myokymia” in a family with childhood-onset chorea and facial twitches, a designation that a later electromyographic study corrected, because the movements were chorea and myoclonus rather than myokymia [17, 18]. The gene was identified in 2014, when Chen and colleagues showed that ADCY5 missense variants increased cyclic adenosine monophosphate production, the first established link between an adenylyl cyclase and a human disease [19]. The entity belongs in this article because it shares childhood-onset chorea with benign hereditary chorea and because it is the second gene that Orphanet associates with that designation; the International Parkinson and Movement Disorder Society classification renamed it mixed movement disorder MxMD-ADCY5 in its 2022 update, and GeneReviews recommends abandoning the term “benign hereditary chorea” for these patients, because the disease can be disabling and, with certain variants, progressive [20–22].

2. Molecular Genetics and Pathophysiology

2.1 The HTT gene and huntingtin

HTT is located at 4p16.3 and encodes huntingtin, a large, ubiquitously expressed protein with a polyglutamine (polyQ) tract at the amino-terminal end [4]. Huntingtin is indispensable for early embryonic development and neurogenesis and functions as a scaffold for multiple cellular processes: cytoskeletal dynamics, autophagy, endocytosis, vesicular transport (including transport of brain-derived neurotrophic factor, BDNF), synaptic transmission, energy metabolism, calcium transport, RNA processing, transcription and translation, chromatin remodelling and DNA repair [4]. In cortical and striatal neurons, huntingtin is distributed mainly in the cytoplasm, although some fragments occur in the nucleus [23].

In Human Genome Variation Society (HGVS) nomenclature, the repeat is described against reference sequence NM_002111.8 as c.52CAG[n], translating to p.Gln18[n]: c.52CAG[9_26] corresponds to normal alleles, c.52CAG[27_35] to intermediate alleles, c.52CAG[36_39] to reduced-penetrance alleles and c.52CAG[40_?] to full-penetrance alleles [4]. The current MANE Select transcript is NM_001388492.1 (ENST00000355072.11; protein NP_001375421.1), differing from NM_002111.8 only in the number of CAGs in the reference sequence (19 rather than 21); the repeat likewise begins at c.52, so c.52CAG[n] and p.Gln18[n] notation is retained, but the report should specify the transcript and version used [24]. The canonical regional sequence is interrupted, [(CAG)n-CAA-CAG], followed by a polymorphic proline tract encoded by CCG; this structure is present in more than 95% of alleles [4].

2.2 Allelic classes and penetrance

The allelic classification, shared by the Oxford Desk Reference, Síndromes Genéticas: Reconhecer para Tratar and GeneReviews, is summarised in Table 1 [3, 4, 23]. In table 3.21 of the Oxford Desk Reference, the full-penetrance allele row is printed as “≤39 repeats”; the correct value, consistent with the text of the same work and the other sources, is ≥40 repeats [3, 4].

Table 1. Classification of HTT alleles (CAG repeat)

Intermediate alleles are rare in the general population but may be found in the parent — usually the father — of an apparently sporadic case; they are generally not associated with clinical manifestations but are unstable during transmission, with a mutation rate of 10% per generation suggested [3]. Risk estimates specific to each intermediate allele size, derived from repeat instability in sperm, show that all intermediate sizes may expand in the male germline, but that the probability of reaching the pathogenic range increases markedly with the number of CAGs [4, 25]. Maternal expansions of intermediate alleles into the pathogenic range are extremely rare [4]. Approximately 8% of patients with HD have no known family history [3].

Alleles with 36 or more CAGs occur in up to 1 in 400 individuals of European ancestry; most lie within the 36–39 range, and lifetime penetrance of 36–38 CAG alleles over a typical lifespan has been estimated at 0.2% to 2% in the general population, much lower than that observed in clinically identified families [4, 26]. This discrepancy is partly explained by cis genetic modifiers, particularly loss-of-interruption (LOI) variants. The pure [(CAG)n] allele, without the CAA interruption, occurs in approximately 1% of alleles but is present in approximately one third of symptomatic patients with 36–39 CAGs and in most symptomatic patients with 36–37 CAGs [4]. The CAG-CCG LOI variant is identified in ~1% of symptomatic patients overall, but in 32% of symptomatic patients with 36–39 CAGs, with frequencies of 66.7%, 45% and 20% for 37, 38 and 39 CAGs, respectively [4, 27]. LOI variants advance onset by up to ~13 years, whereas duplication-of-interruption (DOI) variants delay it [4, 28].

There is a direct laboratory implication: fragment analysis assays measure repeat length only up to the penultimate CAA of the canonical sequence, so, in the absence of the CAA interruption, the number of CAGs is underestimated by two units. Individuals reported with 34–35 CAGs may actually have 36–37 and manifest disease, and individuals with 38–39 CAGs may be classified in a penetrance range lower than the true one [4, 27].

2.3 Genotype–phenotype correlation and modifiers

There is a significant inverse correlation between CAG number and age at onset. Patients with adult onset usually have 36 to 55 CAGs, and those with the juvenile form usually have more than 55 CAGs [4]. Repeat length explains up to 70% of variation in age at onset; 10% to 20% of residual variation is heritable [4]. Table 2, derived from Brinkman and colleagues and reproduced in the Oxford Desk Reference, illustrates median age at onset by expansion size; both the authors and the book emphasise that these values describe groups and should not be used to predict age at onset in an individual [3, 29].

Table 2. Effect of expansion size on age at onset (age at which 50% of carriers are affected)

Age-at-onset variation is greater for shorter alleles, suggesting that non-CAG modifiers have a greater influence in that range [4]. Repeat length predicts age at death but not disease duration; progression of behavioural symptoms appears independent of CAG number [4]. Homozygotes for full-penetrance alleles have an age at onset similar to that of heterozygotes but may progress more rapidly [4].

Genome-wide association studies by the GeM-HD consortium identified modifiers in DNA mismatch repair genes (MSH3, MLH1, PMS1, PMS2, LIG1) and in FAN1; their effect on age at onset is approximately 0.1 to 5 years, smaller than that of cis modifiers. These findings demonstrated that DNA repeat length, rather than polyglutamine length, determines the timing of onset, and placed somatic expansion at the centre of pathogenesis [4, 28].

2.4 Pathogenic mechanisms

The CAG expansion translates into an uninterrupted polyQ tract conferring a toxic gain of function on mutant huntingtin (mHTT), with dysregulation of vital cellular processes, protein aggregation and cell death; a contribution from loss of function cannot be excluded, because HTT deletion or inactivation also causes neurodegeneration [4]. Amino-terminal fragments containing exon 1 and the expanded polyQ tract, generated through aberrant splicing or proteolytic cleavage, are more toxic than the full protein [4]. Huntingtin has three caspase cleavage sites; nuclear and cytoplasmic aggregation induces this cleavage, and normal huntingtin inhibits caspases 9 and 3, a function ineffective in the mutant form [23]. Interaction of mHTT with nuclear proteins disrupts mitochondrial activity and transcriptional pathways, contributing to progressive neurodegeneration [23].

The current model gives a central role to somatic instability: in the striatum, the repeat continues expanding throughout life, and this expansion correlates with earlier onset. Longer repeats are proposed to have a greater propensity to expand until they exceed a toxic threshold, beyond which gain of function triggers neuronal dysfunction and death [4]. Tissue mosaicism is demonstrable: the highest repeat numbers have been detected in the brain (basal ganglia, putamen and caudate) and sperm [23]. RNA-level mechanisms — incorrect exon 1 splicing, RNA foci, repeat-associated non-AUG (RAN) translation and ribosomal stalling — have been proposed, although their contribution to adult disease remains uncertain [4]. Intraneuronal huntingtin inclusions are a neuropathological hallmark, but their chronology and distribution do not correlate with selective degeneration and they are not considered primary determinants of pathology [4].

2.5 Neuropathology and basal ganglia physiology

The fundamental lesion is progressive bilateral atrophy of the caudate nucleus and putamen, with global loss of cortical white and grey matter in advanced stages; on gross brain examination in advanced disease, the caudate is the most atrophied structure, although the putamen and globus pallidus are also involved, and the brain is globally smaller, particularly in the frontal lobes [3, 4]. Neuronal loss selectively affects striatal GABAergic medium spiny neurons and selected cortical excitatory neurons. Preferential degeneration of enkephalinergic medium spiny neurons in the indirect pathway precedes that of substance P-containing direct-pathway neurons, providing the neurobiological basis of chorea: loss of indirect-pathway inhibition disinhibits the thalamus and facilitates involuntary movements [4]. Neuronal loss also occurs in the globus pallidus, subthalamic nucleus, thalamus, hypothalamus, substantia nigra and hippocampus, with abnormalities in peripheral tissues such as skeletal muscle and testes [4]. The basal ganglia, a group of structures facilitating motor, cognitive and emotional behaviours determined by the cerebral cortex, account for the pattern of disease signs and symptoms [23].

2.6 Anticipation and effect of parental origin

The repeat is unstable in meiosis, accounting for the term “dynamic mutation” [3]. Expansions and contractions occur in both germlines, but expansion is much more frequent in paternal transmission and contraction in maternal transmission; large expansions (an increase of more than 7 CAGs) occur almost exclusively through the paternal line, as a result of instability during spermatogenesis [4]. Expansions exceeding 60 repeats are usually paternally inherited and almost always associated with juvenile presentation [3]. Most children with juvenile HD inherit the allele from their father, although occasionally from their mother [4]. Síndromes Genéticas: Reconhecer para Tratar describes this parental transmission bias as “imprinting”; strictly, it is an effect of parental origin on germline repeat instability, rather than genomic imprinting in the epigenetic sense [4, 23].

2.7 Allelic disorder: Lopes-Maciel-Rodan syndrome

Biallelic missense variants in HTT cause Lopes-Maciel-Rodan syndrome (LOMARS; OMIM 617435), an autosomal recessive neurodevelopmental disease with a Rett-like phenotype, intellectual impairment, dystonia, bradykinesia and seizures, without chorea and with onset in early childhood [4].

2.8 Molecular genetics of phenocopies

HDL1 (PRNP, 20p13). HDL1 is an autosomal dominant familial prion disease caused by repeated octapeptide insertions in the prion protein; the original family had a 192-nucleotide insertion, corresponding to eight additional octapeptides [30]. A new eight-octapeptide insertion was recently described in a Chinese family with chorea and negative HD testing [31]. GeneReviews notes that the neuropathological findings in these patients would classify them as Gerstmann-Sträussler-Scheinker syndrome [4]. The mechanism is a toxic gain of function through conversion of cellular prion protein into a self-propagating misfolded isoform [4].

HDL2 (JPH3, 16q24.2). HDL2 results from a CTG/CAG expansion in JPH3, identified by Holmes and colleagues in 2001 [32]. The repeat is located in JPH3 exon 2A (CTG orientation) and the antisense transcript JPH3-AS (CAG orientation). Alleles with 6 to 28 CTGs are normal, 29 to 39 are of uncertain significance and ≥40 are pathogenic with full penetrance; the largest described allele has 63 CTGs [33]. Three mechanisms that are not mutually exclusive have been proposed: loss of junctophilin-3 expression (a brain protein linking the plasma membrane to the endoplasmic reticulum and coupling voltage-dependent calcium channels to calcium-release channels), toxicity of transcripts containing the expanded repeat, and toxic gain of function of a polyglutamine protein encoded by JPH3-AS [33, 34]. Neuropathologically, neuronal loss predominates in the striatum and cortex, follows the same dorsoventral gradient as HD and is accompanied by intranuclear inclusions immunoreactive for polyglutamine, ubiquitin, torsin A and TATA-binding protein (TBP) [33].

HDL3 (4p15.3). Autosomal recessive Huntington-like neurodegenerative disease with childhood onset, mapped to 4p15.3 in a consanguineous Saudi Arabian family; the gene has not been identified [11, 35].

HDL4 / SCA17 (TBP, 6q27). Spinocerebellar ataxia type 17 (SCA17) results from expansion of a mixed CAG/CAA repeat in the TATA-binding protein gene, a central subunit of transcription factor TFIID [36, 37]. Allele size corresponds to the sum of CAG and CAA triplets; according to GeneReviews, 25–40 repeats are normal, 41–48 have reduced penetrance (~50% at 41 and 44) and ≥49 have full penetrance (maximum described, 66), whereas the EMQN consensus considers up to 42 normal and 43 to 48 uncertain — so a result of 41 or 42 should be reported as uncertain rather than normal [37, 38]. A digenic form, in which a TBP allele with 41–46 repeats combines with a heterozygous pathogenic STUB1 variant, explains some of the incomplete penetrance of short expansions [39].

Expansion of C9orf72 (9p21.2). Expansion of the GGGGCC hexanucleotide (from 2–22 to hundreds or thousands of copies) in a C9orf72 intron, the principal cause of familial frontotemporal dementia and amyotrophic lateral sclerosis, is the most frequently identified genetic cause of an HD phenocopy: 10 of 514 patients (1.95%) in a British cohort [40].

2.9 NKX2-1 and benign hereditary chorea

NKX2-1 encodes the Nkx-2.1 homeobox protein, also termed thyroid transcription factor 1 (TTF-1), essential for basal ganglia, lung and thyroid organogenesis [12]. In the brain it participates in development of the globus pallidus and striatal cholinergic neurons; in the lung, in bronchial branching and surfactant production and homeostasis; in the thyroid, in early development and maintenance of gland architecture and function, activating the thyroglobulin, thyroperoxidase and thyrotropin receptor promoters [12, 15]. The mechanism is loss of function through haploinsufficiency: a single functional copy is insufficient [12, 15]. Chorea has a developmental rather than degenerative basis: autopsies of two patients showed no gross macroscopic or microscopic abnormalities, but a reduction in striatal and neocortical interneuron numbers, consistent with a neuronal migration defect [12]. There are several transcripts; the longest (NM_001079668.2, three exons) contains most described variants, and a shorter transcript exists (NM_003317.3) [12]. The current MANE Select transcript is NM_001079668.3; because the short transcript omits 30 initial codons, the same variant is numbered differently depending on the reference (for example, NM_001079668.3:c.671T>G p.Leu224Arg corresponds to NM_003317.4:c.581T>G p.Leu194Arg) [24]. Partial and complete gene deletions, extensive contiguous 14q deletions, a 3.5 Mb deletion adjacent to the gene without disrupting it, and a deletion of a non-coding region downstream of NKX2-1 in three unrelated BHC families have been described [12]. Missense variants were associated with milder phenotypes, but a systematic analysis showed no clear correlation between variant type and protein function [12, 41]. Somatic NKX2-1 variants occur in sporadic papillary thyroid carcinomas and lung adenocarcinomas, without a hereditary basis [12].

2.10 ADCY5 and related dyskinesia

ADCY5 is located at 3q21.1 and encodes adenylyl cyclase 5, an enzyme that converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP), a second messenger for multiple intracellular pathways [21]. It is the predominant adenylyl cyclase isoform in striatal medium spiny neurons, where it integrates dopaminergic and adenosinergic signalling: it is inhibited by dopamine through D2 receptors and activated by adenosine through A2A receptors, so that the striatal cAMP level regulates the initiation of voluntary movement and the suppression of involuntary movements [42, 43].

In the autosomal dominant form, the variants are gain-of-function and raise intracellular cAMP, as shown by cAMP accumulation assays under β-adrenergic agonist stimulation in cells expressing the mutant proteins [19, 43]. Excess cAMP reduces inhibitory control of cortical and thalamic motor pathways and results in chorea, dystonia and myoclonus [21]. In the autosomal recessive form, described in eight individuals from five families, the biallelic variants are loss-of-function, cluster in the C1 catalytic domain and reduce or abolish functional enzyme, with a phenotype that tends to be more severe and to include intellectual disability [21, 44, 45]. The coexistence of two opposing mechanisms in the same gene has a practical consequence: pharmacological modulation of cAMP cannot be extrapolated from one form to the other, and the identification of functional markers of striatal cAMP is considered a prerequisite for targeted therapies [46].

Sequencing detects all the pathogenic variants described, which are missense or nonsense and located in the coding region; no intragenic deletions or duplications have been published [21]. The recurrent variant NM_183357.3:c.1252C>T p.(Arg418Trp) (NC_000003.12:g.123352464G>A) is the most frequent, and residue 418 is a hotspot, with the alternatives p.(Arg418Gln) and p.(Arg418Gly) also described [19, 47, 48]. The variant NM_183357.3:c.2176G>A p.(Ala726Thr) (NC_000003.12:g.123319754C>T), in the C1b domain, was the first identified, in a family with dyskinesia and facial twitches, and is associated with the mildest phenotype [19, 49]. A C2 domain variant, p.(Met1029Lys), caused severe dystonia, hypotonia and chorea in one family, and the transmitting parent, who was mosaic, had had an episodic disorder in childhood that almost disappeared in adulthood [47].

Table 2A. Protein domain–phenotype correlation in ADCY5

Sources: [21, 46, 47, 49].

Somatic mosaicism has been demonstrated in 43% of individuals with a de novo variant and is a major determinant of phenotypic variability: mosaic patients usually have milder disease, sometimes limited to nocturnal paroxysmal episodes with a normal interictal examination [47, 50, 51]. One individual mosaic for p.(Arg418Trp) had only mild chorea with infrequent facial twitches and no dysarthria, whereas non-mosaic heterozygotes for the same variant may have marked dyskinesia and speech impairment [52]. In two families, the mosaic parent was mildly affected and the heterozygous children, carrying the variant constitutionally, were much more severely affected [47]. Penetrance of the dominant form is, to date, 100% in both sexes, but may be overestimated, because undetected mosaicism and mild phenotypes escape identification [21]. No other germline phenotypes have been attributed to ADCY5 [21].

The neuropathology is subtle and non-degenerative. In one patient with a confirmed molecular diagnosis, gross examination was normal and there was no neuronal loss, but increased immunoreactivity for adenylyl cyclase 5 was found in several brain regions, together with hyperphosphorylated tau deposits in the depths of cortical sulci, the midbrain and the hippocampus, without Lewy bodies or amyloid pathology [53]. Brain magnetic resonance imaging and electroencephalography are normal, which separates this entity from choreas with striatal lesions and from epileptic encephalopathies [21, 46].

3. Clinical Spectrum and Manifestations by System

3.1 Stages of Huntington disease

HD is divided into a premanifest period, comprising a presymptomatic phase and a prodromal phase, and a manifest period (early, moderate, advanced) [4]. Carriers are asymptomatic at birth and, in the vast majority, have no manifestations during childhood or adolescence. Subtle motor, cognitive and psychiatric abnormalities emerge in the prodromal phase and may precede diagnosis by 15 to 20 years; disease is considered manifest when the motor diagnosis is established [3, 4]. The criteria of Reilmann and colleagues, based on natural history, combine the diagnostic confidence level (DCL) of the UHDRS (Unified Huntington's Disease Rating Scale) with cognitive and functional abnormalities (Table 3) [4, 54].

Table 3. Classification and clinical stages (adapted from Reilmann et al. 2014)

The HD-ISS (Huntington's Disease Integrated Staging System), proposed in 2022, defines four stages from birth: stage 0, carriers without pathological abnormalities; stage 1, measurable pathophysiological abnormalities (caudate and putamen volume); stage 2, detectable clinical phenotype; stage 3, functional decline (TFC and independence scale) [55]. It is primarily a research tool, useful in designing trials targeting premanifest phases [4].

3.2 Adult onset and course

Mean age at onset is approximately 45 years, peaking between 40 and 45 years; in the South Wales study, 4.5% of patients developed disease before 20 years and 8% after 60 years [3, 4]. Approximately two thirds present with neurological manifestations and the remainder with psychiatric abnormalities [4]. In ~25% of patients, onset occurs after 50 years, sometimes after 70; these patients have chorea, gait abnormalities and dysphagia, but usually a more prolonged course [4]. Initially, motor abnormalities are subtle — restless movements of the fingers and toes — and associated with difficulty solving problems and depression; with progression, coordination is lost, involuntary movements intensify, and the patient progressively loses the ability to communicate and move [23]. Table 4 summarises the chronology of manifestations.

Table 4. Chronology of clinical manifestations of HD

Source: GeneReviews [4].

3.3 Motor manifestations

Chorea — involuntary, non-repetitive and non-periodic movement of the limbs, face or trunk — is the major sign of HD, present in approximately 90% of patients with adult onset [4, 23]. Movements are flowing, arrhythmic and brief, begin in one segment and abruptly move to another, and predominantly affect distal regions [23]. They are present during wakefulness, disappear during sleep, cannot be voluntarily suppressed and worsen with stress; chorea tends to increase during the first ten years and, as disease progresses, diminishes and gives way to bradykinesia, rigidity and dystonia [3, 4]. Dystonia — simultaneous contraction of agonist and antagonist muscles producing slow movements and abnormal postures of the head, hands, trunk or feet — may be present from symptom onset [23]. Voluntary motor impairment occurs early: relatives describe clumsiness in daily activities, with involvement of motor speed, fine motor skills and gait. Oculomotor abnormalities (difficulty initiating saccades, slow and hypometric saccades, fixation abnormalities) occur in up to 75% of symptomatic patients. Dysarthria is early and frequent, dysphagia is late, hyperreflexia occurs early in 90%, and clonus and the Babinski sign occur late and are less frequent [4]. Myoclonus and spasticity may occur in advanced phases [4]. The 2021 French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS) quantifies dystonia in about 90% of patients, often associated with rigidity, and myoclonus in fewer than 2%, mainly in the akinetic-rigid phenotype and the juvenile form, where it may coexist with epilepsy; it adds that juvenile and late-onset patients frequently have a predominantly bradykinetic phenotype, with little or no chorea, which may be mistaken for atypical parkinsonism or psychiatric disease, and that in late stages most progress to an akinetic-rigid syndrome with generalised hypertonia [2]. The same document describes bruxism, linked to dystonia or chorea of the jaw, and gait abnormalities (irregular cadence, greater variability of step width and length, widened base of support), a cause of falls and loss of autonomy [2].

3.4 Cognitive manifestations

All patients have global, progressive cognitive decline, with forgetfulness, slowing of thought, visuospatial deficits and difficulty manipulating acquired knowledge; initial abnormalities involve loss of mental flexibility and executive dysfunction (planning and organising sequences) [4]. Memory is affected primarily in recall, which improves with verbal cues and time; initially, impairment is much less severe than in Alzheimer disease, and the cognitive and behavioural profile more closely resembles frontotemporal dementia. Attention and concentration are affected early; language is relatively preserved, with reduced syntactic complexity, paraphasias and word-finding difficulty in late phases. Lack of awareness of one's own deficits (anosognosia) is frequent [4]. In adults, chorea, rather than dementia, is the usual presenting manifestation [3]. The HAS PNDS adds details of the cognitive profile. Cognitive deficits frequently appear before motor signs, although disease onset is conventionally defined by the appearance of the latter, and, together with psychiatric symptoms, they are the main cause of family disruption and social withdrawal. Language difficulties are present subclinically from the presymptomatic phase (phonological and syntactic changes); changes in syntax and morphology (conjugation, affixation) precede reduction of the lexicon, and speech becomes slurred and slow, with pauses or vocal outbursts and progressive loss of fluency. Bradyphrenia — slowing of information processing, with an increase in reaction time proportional to task complexity — becomes more marked with progression. Temporal disorientation precedes spatial disorientation, which is rare before advanced stages; visuospatial and visual perception deficits are present before motor signs but have clinical expression only late. In memory, learning and recall are affected, rather than storage, unlike Alzheimer disease. Social cognition is also altered (recognition and expression of emotions, theory of mind), and a motor-origin “facial mask” is often interpreted by those close to the patient as indifference or self-centredness [2].

3.5 Psychiatric manifestations

Before motor onset, carriers score higher on scales of depression, hostility, obsession–compulsion, anxiety and psychoticism [4]. Depression is the most frequent psychiatric manifestation (40%), followed by anxiety, and its incidence is more than twice that in the general population, even in the preclinical phase [4]. Suicide and suicidal ideation are frequent; critical periods are immediately before diagnosis and, later, when independence is lost — a relevant consideration when communicating predictive test results [4]. Suicide accounts for 5% to 10% of causes of death [23]. Apathy — loss of interest, difficulty taking initiative, passivity — worsens with progression. Irritability, intermittent explosiveness, aggression, alcohol misuse, sexual dysfunction and deviations, and increased appetite are frequent; delusions, often paranoid, are common and hallucinations less frequent. Unlike motor and cognitive disorders, psychiatric abnormalities do not necessarily parallel disease severity [4]. HD has often been misdiagnosed as schizophrenia or paranoid psychosis, but these disorders are also more frequent in patients with HD [3].

The HAS PNDS brings together the frequencies described in European and clinical cohorts, which vary considerably with the instrument and the stage (Table 4A). Perseverations — repetition of a thought, behaviour or emotion beyond the context in which it arose, often without insight — are very frequent in the moderate and advanced stages and must be distinguished from true obsessions, which are rare and recognised by the patient as abnormal, because treatment differs; repetitive hypersexual behaviours are frequently linked to perseveration. Apathy and irritability coexist, sometimes on the same day, and motor agitation or increased chorea is mistaken by families for irritability [2]. Suicide may occur at any stage, with the highest risk around the time of diagnosis (in symptomatic or presymptomatic patients) and when the disease begins to affect daily life; it is associated with a family history of suicide, previous attempts and depression, especially in the prodromal phase, but impulsive suicides without identified depression have been described, and the Columbia scale (C-SSRS) has become the reference instrument [2].

Table 4A. Frequency of motor, neuropsychiatric and general manifestations in HD

Source: HAS PNDS, which compiles the original series [2]. The frequencies come from selected cohorts and series and are not population estimates; the 40% frequency of depression given above comes from another compilation [4].

3.6 Systemic manifestations

Patients lose weight, muscle mass and body mass index; these changes reflect metabolic and mitochondrial abnormalities, aggravated by the energy expenditure of chorea, and may begin in the prodromal phase, progressing to a systemic wasting syndrome with very high caloric requirements [4]. Reduced cerebral cholesterol biosynthesis may contribute to cognitive and synaptic deficits [4]. Dysarthria may progress to complete anarthria; dysphagia due to oropharyngeal incoordination causes choking and aspiration pneumonia, a frequent cause of death [4]. Sleep and circadian rhythms are disturbed, possibly through hypothalamic dysfunction and altered melatonin secretion [4]. According to the HAS PNDS, a higher baseline body mass index (BMI) is associated with slower decline, independently of CAG number and stage, and weight loss may occur with normal or high caloric intake, even in presymptomatic carriers; lung function and respiratory muscle strength decline from the presymptomatic stages (upper airway changes, less effective cough, reduced lung volume), which, together with postural changes and reduced exercise capacity, increases vulnerability to respiratory infections [2]. The same document describes dysautonomia (digestive, bladder, cardiac), hyperhidrosis, sialorrhoea due to poor mouth closure or defective swallowing, urinary incontinence due to an overactive bladder of frontal origin or to sudden complete voiding without urgency, frequent constipation with overflow diarrhoea, poor oral health (difficult brushing, reduced motivation, drugs that reduce saliva, trauma and bruxism), a raised pain threshold that delays complaints, and a higher frequency of subdural haematoma in this population [2].

3.7 Juvenile Huntington disease

Juvenile HD is historically defined by onset before 20 years and accounts for 1% to 15% of cases; the term “paediatric HD” denotes currently affected patients younger than 18 years [4, 56]. It is usually associated with more than 55–60 CAGs, acquired through anticipation in paternal transmission [3, 56]. In the first decade, it presents with behavioural disturbance and declining school performance, followed by dysarthria, seizures, rigidity, gait abnormalities, bradykinesia and dystonia; chorea is less frequent [4]. With onset in the second decade, motor manifestations may resemble those in adults, with a high frequency of depression, suicidal ideation, obsessive behaviour and perseveration; cerebellar ataxia, spasticity, tremor and blinking and sniffing tics are more characteristic of the juvenile form [4]. Rigidity, rather than chorea, dominates the juvenile form and the Westphal variant; reduced facial expression is characteristic [3]. In adolescents, the Westphal variant combines cognitive dysfunction, bradykinesia and rigidity [23]. Progression is faster, with disease duration of 8 to 12 years [4]. The review by the EHDN paediatric group adds epilepsy, ataxia, spasticity, pain, pruritus and possibly hepatic steatosis as features characteristic of the juvenile form, and warns that behavioural abnormalities may be confused with autism spectrum disorder or ADHD, causing diagnostic delay; there are no specific pharmacological or multidisciplinary guidelines for the juvenile form [56]. Many patients are diagnosed only in young adulthood because of atypical presentation and diagnostic errors [4].

3.8 Intermediate alleles and reduced penetrance

Most carriers of 27–35 CAGs remain unaffected; subtle cognitive, behavioural or motor abnormalities have occasionally been described, and some individuals with an estimated 34–35 CAGs are symptomatic because of sequence variation that leads to underestimation of the actual length [4]. Carriers of 36–39 CAGs may never develop disease [4].

3.9 Clinical spectrum of phenocopies

HDL2. Clinically indistinguishable from HD: onset in middle age (mean 41 years, SD 11.1; range 12–66), a progressive triad of motor, emotional and cognitive abnormalities, and death 10 to 20 years after onset [33]. Chorea and oculomotor abnormalities are the most frequent initial motor manifestations, followed by rigidity, bradykinesia, dysarthria and dystonia; dysarthria and dystonia may be more marked than in HD at the same disease duration, and some patients, particularly those with 58–63 CTGs, have a rigid-dystonic form with cognitive deficits more severe than motor deficits [33]. Dementia is universal; psychomotor speed and dexterity are the most affected domains [33]. A five-generation African American family with 47–53 CTGs presented with an akinetic-rigid syndrome unresponsive to levodopa, severe dementia, clinically insignificant chorea and putaminal rim hyperintensity, demonstrating that absence of chorea does not exclude the diagnosis [34]. Each additional CTG advances onset by 1.2 to 2.9 years [33]. Penetrance is unknown; a carrier of 44 CTGs had no signs at 65 years [33]. Anticipation is possible but limited, without major changes in allele size during transmission [33].

HDL1. An HD phenocopy with early onset and slow progression; progressive involuntary movements, bradykinesia and cognitive decline [3, 4]. In octapeptide insertions the phenotype is heterogeneous: in a review of 25 patients from 14 families with a five-repeat insertion, onset ranged from 26 to 63 years and duration from 4 to 192 months, with dementia in all, cerebellar signs in 68%, extrapyramidal signs in 60% and myoclonus in 44% [57].

HDL3. Childhood onset (3–4 years), autosomal recessive, with chorea, dystonia, ataxia, gait abnormalities, spasticity, seizures, mutism and dementia, associated with caudate and frontal atrophy [35].

HDL4 / SCA17. A triad of ataxia (~95%), dementia (~90%) and involuntary movements (~70%: chorea and dystonia — blepharospasm, torticollis, writer's cramp, foot dystonia), with psychiatric symptoms, pyramidal signs, rigidity, parkinsonism and seizures. Onset ranges from 3 to 75 years (mean ~34.6), usually with ataxia and psychiatric abnormalities; all carriers of full-penetrance alleles have symptoms by 50 years. Magnetic resonance imaging (MRI) shows cerebral, brainstem and particularly cerebellar atrophy [37]. SCA17 has been identified in patients of European ancestry with a Huntington-like phenotype and negative HTT testing [58].

Expansion of C9orf72. In patients with an HD phenocopy, it is associated with dystonia, chorea, myoclonus, tremor and rigidity, with younger age at onset than in other presentations, including a paediatric case; dementia and psychiatric manifestations are the features overlapping with HD [4, 40].

3.10 Benign hereditary chorea and brain–lung–thyroid syndrome (NKX2-1)

Patients may have any combination of brain, lung and thyroid involvement; in a review of 46 patients, 50% had the complete syndrome, 30% brain and thyroid involvement and 13% isolated chorea [12, 59].

Neurological manifestations. Chorea — involuntary, random, irregular, continuous, jerky — is the cardinal manifestation; it usually begins in the first year of life or, less frequently, in late childhood or adolescence, progresses until the second decade and then stabilises or, rarely, remits [12, 60]. It affects the face, tongue, neck, trunk and limbs, worsens with stress and disappears during sleep [12]. In a series of 28 patients from 13 families with mean follow-up of 24.5 years, all had chorea and hypotonia; hypotonia appeared in the first year, with or without motor delay, and chorea, generally mild, improved until puberty or early adulthood, stabilising and sometimes disappearing [41]. Despite the designation “benign”, manifestations may be disabling, particularly because of gait and balance abnormalities and frequent falls; two patients had falls without loss of consciousness before chorea [12]. Less frequent manifestations include myoclonus, dystonia, ataxia, intention tremor, dysarthria, restless legs syndrome, seizures, learning difficulties with reduced working memory and attention, and attention deficit hyperactivity disorder (ADHD); schizophrenia, postpartum psychosis and obsessive-compulsive disorder have been described in isolated cases [12]. Two siblings initially diagnosed with ataxic-dyskinetic cerebral palsy had a pathogenic NKX2-1 variant [12]. Neuroimaging is usually normal; rare abnormalities have been described (abnormal sella turcica, agenesis of the corpus callosum, cavum septi pellucidi, microcephaly, hypoplastic pallidum, pituitary cyst, Chiari I malformation), as have reduced caudate nucleus blood flow on SPECT and subtle presynaptic dopamine transporter abnormalities on PET [12].

Pulmonary manifestations. These constitute the second most frequent involvement, present in up to 49% (61/124) in a meta-analysis [12, 41]. Respiratory distress syndrome predominates in the neonatal period, with or without pulmonary hypertension, often requiring mechanical ventilation; three neonatal deaths from respiratory failure were recorded, but respiratory function improves in most patients [12]. Neuroendocrine cell hyperplasia of infancy and interstitial lung disease may appear between 4 months and 7 years, and pulmonary fibrosis at older ages; recurrent respiratory infections and asthma persist throughout life. High-resolution computed tomography (CT) showed ground-glass opacities and consolidation; histology showed interstitial widening, pneumocyte hyperplasia, desquamative interstitial pneumonia, foamy alveolar macrophages and alveolar proteinosis [12]. The risk of lung carcinoma is increased in young adults, from the beginning of the third decade [12].

Thyroid manifestations. Thyroid dysfunction results from dysgenesis (hypoplasia or hemiagenesis in 11/31; agenesis in 3/31) and manifests as congenital or compensated hypothyroidism (elevated TSH with low-normal free T4); among 46 patients, 40 had clinical or subclinical hypothyroidism [12, 59]. Congenital hypothyroidism may be the only manifestation [12]. The Oxford Desk Reference adds that iodide uptake may be reduced, with a positive perchlorate discharge test suggesting dyshormonogenesis [61].

Other manifestations described in isolated patients include hypodontia or oligodontia, vesicoureteric reflux, megabladder, hypogonadotropic hypogonadism, growth hormone deficiency, short stature, webbed neck, cardiac septal defects, patent foramen ovale, joint hypermobility, pes cavus and kyphosis [12]. Life expectancy is considered normal [12].

3.11 Clinical spectrum of ADCY5-related dyskinesia

The disorder consists of continuous and/or paroxysmal hyperkinetic involuntary movements, combined in most patients: generalised chorea, generalised dystonia and segmental or generalised myoclonus [21, 46]. Onset is in infancy or early childhood, usually as an infantile hyperkinetic disorder, and against a continuous background of choreiform and dystonic movements there are episodic exacerbations triggered by voluntary movement, sleep–wake transitions, emotional stress, excitement, fatigue, gastrointestinal discomfort and intercurrent illness [21]. Episodes last from seconds to hours and recur from a few to dozens of times a day; chorea and dystonia of the face, neck, trunk and limbs are usually uncomfortable or painful [21, 46].

Three findings are particularly suggestive: facial involvement, especially perioral and periorbital chorea and myoclonus; nocturnal paroxysmal dyskinesias; and persistence of dyskinesia during sleep, with worsening at sleep–wake transitions, which fragments sleep and causes prolonged awakenings [21, 46]. The last two separate this entity from the other paroxysmal dyskinesias, in which movements cease during sleep [46]. Needle electromyography of the facial twitches showed a pattern compatible with chorea and myoclonus, without fibrillations, fasciculations, myokymia or myotonia, which invalidated the historical designation of facial myokymia [18]. In addition to well-delimited episodes, some patients describe fluctuations in severity without a defined beginning or end [46].

Axial hypotonia and generalised weakness may be marked at onset, especially in forms presenting in infancy, and contribute to delayed head control, sitting and walking, frequently requiring mobility aids [21]. Dysarthria is common and ranges from mildly slurred speech to a disorder that compromises intelligibility, partly due to oral motor dysfunction and orofacial and lingual dyskinesia; language development may be delayed in severe forms [21]. A distinctive oculomotor apraxia has been described in several adults, with difficulty initiating voluntary eye movements, limitation of vertical and horizontal gaze, hypometric saccades and abnormal smooth pursuit [21]. Lower limb spasticity with pyramidal signs is part of the spectrum and dominates the picture in transmembrane domain variants [21, 46]. Epilepsy occurs in a minority, mainly in the most severe phenotypes, and is not characteristic of the disease; intellectual capacity is preserved in most patients with the dominant form, and global developmental delay with intellectual disability is typical, though not exclusive, of the recessive form [21, 44, 46].

Anxiety and depression are the most frequent psychiatric manifestations and usually appear in adolescence or adulthood; the extent to which they belong to the phenotype or reflect the social and functional impact of a disabling disease is not established, although there is evidence favouring a primary component [21, 46]. Obsessive-compulsive behaviour, psychosis with delusions and auditory hallucinations, and autism spectrum-like traits have also been described [21]. Gastrointestinal manifestations — gastro-oesophageal reflux, constipation and altered gastric motility — are clinically relevant in their own right because they are among the triggers of exacerbations [21]. Dilated cardiomyopathy has been described in only one multigenerational family, in which several members developed congestive heart failure, presumably in adulthood, and it is rare among published patients [21, 47].

The disease is considered non-progressive, but its natural history is not established: some patients have increasing frequency and severity of dyskinesias in childhood and adolescence, followed by stabilisation or partial improvement in adulthood [21, 46]. In the paediatric cohort of five patients with identified variants, the course ranged from stability to spontaneous improvement in adolescence, and in two of them episodic attacks preceded the baseline movement disorder [62]. The exception to the non-progressive character is the spastic-dystonic phenotype of M1 and M2 domain variants, which worsens slowly [46]. Pregnancy was associated with a reduction in manifestations [46]. Life expectancy is normal [21, 46].

4. Clinical Recognition and Warning Signs

4.1 When to suspect Huntington disease

HD should be suspected in the presence of a combination of a progressive motor disorder with chorea (voluntary motor function may also be affected), cognitive decline and personality or psychiatric abnormalities, particularly depression; on imaging, in the presence of progressive caudate and putamen atrophy, dilatation of the lateral ventricles and progressive grey and white matter atrophy; and in the presence of a family history compatible with autosomal dominant inheritance, although absence of a family history does not exclude the diagnosis [4]. History-taking should include a three-generation pedigree, extended whenever possible to all affected relatives, recording women's maiden names and places of prolonged institutionalisation, ages at onset and death, and any psychiatric illness, suicide or dementia in apparently unaffected relatives, who may have been unrecognised cases of HD [3].

At the first consultation of an asymptomatic at-risk individual, neurological examination is not routinely performed unless explicitly requested; this consultation aims to provide information about the disease and the geneticist's role. Careful observation during the consultation may be informative — restless leg movements or facial grimacing increase suspicion — but anxiety, frequent at these consultations, may manifest as restlessness or facial contractions and should not be overinterpreted [3]. The subtlest early signs are restless finger movements, difficulty solving problems and depression [23]; abnormalities of eye saccades and coordination frequently accompany early chorea [4].

The HAS PNDS highlights three situations. Without a family history, the complete triad (motor, cognitive and psychiatric) is sufficient to suggest HD. In isolated chorea without a known family context, it is legitimate to look first for non-genetic causes (iatrogenic, infectious, immunological, vascular, metabolic, toxic). Choreas beginning at an advanced age, formerly called “senile choreas” and attributed to drugs or vascular disease, should raise the possibility of a late-onset form of HD, almost always without a family history [2]. Because patients rarely voice complaints spontaneously, professionals should actively seek symptoms, life events and their functional consequences [2].

4.2 Specific warning signs

Table 5. Warning signs and interpretation

Sources: [3, 4, 12, 21, 33, 46, 61].

4.3 Particular considerations in children and adolescents

In a child from a family with HD, the disease itself and progression in the parent may explain school difficulties, making assessment difficult. The Oxford Desk Reference recommends assessment by a paediatric neurologist, formal psychometric testing repeated at intervals of 4 to 6 months to document progression and an organic basis, and brain MRI to look for basal ganglia abnormalities, in order to establish the clinical diagnosis before molecular testing; otherwise, if the child does not have juvenile HD, there is a 50% probability of inadvertently performing a predictive test [3]. The diagnosis of HD in a child is evident in a family in which the father is the transmitting parent; without a family history and with a normal CAG result, ataxia-telangiectasia, pantothenate kinase-associated neurodegeneration, Lesch-Nyhan disease, Wilson disease, progressive myoclonic epilepsies and other metabolic diseases must be excluded [4].

In BHC, the warning sign is generalised chorea with onset in the first year of life, associated with axial hypotonia, motor delay, ataxia, frequent falls and, possibly, a history of congenital hypothyroidism (with or without diagnosis through newborn screening) or neonatal respiratory distress; an autosomal dominant family history with stable chorea in adults strengthens suspicion [12, 61].

In ADCY5 dyskinesia, the most frequent misdiagnosis in early childhood is dyskinetic cerebral palsy, because of the overlap of global developmental delay, hypotonia, dystonia and early-onset spasticity; the hyperkinetic jerks are sometimes interpreted as epileptic seizures, a hypothesis excluded by the normal electroencephalogram, preserved consciousness during episodes and lack of response to antiseizure medications [21]. The combination of dyskinesia persisting during sleep, perioral myoclonus and exacerbations on awakening justifies sequencing, including in children previously diagnosed with cerebral palsy, and the absence of a family history does not exclude the diagnosis, because most variants are de novo [21, 46, 49].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria for Huntington disease

Diagnosis is established in a proband with suggestive findings and a heterozygous expansion of the CAG repeat in HTT identified by molecular testing [4]. The clinical diagnosis of manifest HD is based on unequivocal motor signs (UHDRS DCL 4) in an individual with a confirmed expansion or a family history, and the 2014 criteria allow recognition of the prodromal phase and predominantly cognitive manifest HD [54]. Brain MRI and neuropsychological assessment support diagnosis and staging but do not establish the diagnosis [4]. In France, diagnostic testing in a symptomatic patient requires detailed information, including the legal obligation to inform relatives (Decree No. 2013-527, implementing the 2011 bioethics law), and written consent before a physician; in adults unable to consent (dementia, severe psychiatric illness, guardianship) and in symptomatic minors, the legal representative signs. The result is communicated in a dedicated consultation by the prescribing physician, with a clinical psychologist if necessary, together with the care plan, the multidisciplinary team and the contact details of patient associations [2].

5.2 Laboratory methods for the CAG repeat

Testing is based on targeted analysis of CAG number, which detects 100% of causal variants; multigene panel, exome or genome sequencing can detect the expansion but is not routinely used in diagnosis, and approaches using amplicon, exome, genome or long-read sequencing are primarily research tools [4]. Table 6 summarises the performance of the methods.

Table 6. Methods for characterising the HTT CAG repeat

Source: GeneReviews [4].

The critical points are: an apparently homozygous result for a normal allele requires TP-PCR or Southern blot to exclude a very large expansion, which may fail to amplify because of competition with the normal allele; TP-PCR indicates the presence of an expansion without sizing it; somatic and germline instability must be considered in interpretation; and underestimation by two units in alleles with LOI particularly affects the 34–35 and 38–39 ranges [4]. The laboratory guidelines of the American College of Medical Genetics and the American Society of Human Genetics (ACMG/ASHG) define technical and reporting requirements for HD testing [63]. In the absence of a family history, the Oxford Desk Reference recommends, in addition to HD testing, a fresh blood film for acanthocytes, molecular testing for dentatorubral-pallidoluysian atrophy (DRPLA) and hereditary spinocerebellar ataxias, copper studies in juvenile or rigid presentations, and DNA storage for future studies [3].

5.3 Neuroimaging and complementary investigations

Regional atrophy of the caudate and putamen is one of the earliest pathological abnormalities, correlates with CAG number and age at onset, and serves as a sensitive biomarker; cortical thinning (occipital, motor, dorsomedial prefrontal, parietal) and global grey and white matter atrophy emerge years before predicted onset, whereas the hippocampus and cerebellum are relatively spared [4]. Table 7 incorporates the imaging findings described in Síndromes Genéticas: Reconhecer para Tratar.

Table 7. Complementary investigations in HD and expected results

Source: [23].

Fluid biomarkers now have a central role in research: NfL in cerebrospinal fluid (CSF) and plasma increases with progression and correlates with motor, cognitive and atrophy measures; plasma glial fibrillary acidic protein (GFAP) parallels NfL; proenkephalin and prodynorphin are reduced in CSF and reflect the integrity of medium spiny neurons; and CSF mHTT, measured using clinically validated assays, is the pharmacodynamic biomarker of target engagement in huntingtin-lowering trials [4]. In the HD-YAS studies, young adult carriers remained clinically and cognitively stable for 4.5 years but already had elevated NfL, reduced proenkephalin, striatal atrophy and increased somatic expansion in blood cells [4].

5.4 Assessment scales

The UHDRS comprises six sections (motor, cognitive, behavioural, functional assessment, independence scale and total functional capacity, TFC). The cUHDRS, comprising TFC, total motor score (TMS), the Symbol Digit Modalities Test (SDMT) and the Stroop Color and Word Test (SCWT), is the most sensitive measure of progression and the primary endpoint of several trials [4]. The HAS PNDS adds that use of the UHDRS in trials requires annual certification of raters, that the UHDRS-FAP (for Advanced Patients), validated in 2013, replaces it in advanced forms, and that stages are defined by total functional capacity — work, finances, domestic activities, autonomy and place of care — and not by the intensity of an isolated symptom such as chorea; the heterogeneity of presentations precludes an individual prognosis of progression [2].

5.5 Diagnosis of phenocopies

For HDL2, diagnosis requires a heterozygous expansion of ≥40 CTGs in JPH3; alleles of 29–39 are of uncertain significance, and PCR has an accuracy of approximately ±1 triplet, which makes borderline alleles difficult to assess. In the presence of strong suspicion and apparent homozygosity, testing should be repeated with another pair of primers, because a polymorphism at the binding site may prevent amplification [33]. For SCA17, targeted sizing of the TBP CAG/CAA repeat detects 100% of probands; exome, genome interpreted as a sequence test, and sequencing panels do not size this expansion, so a normal exome does not exclude it [37, 38]. HDL1 is confirmed by identification of the octapeptide insertion in PRNP [30]; C9orf72 expansion requires repeat-primed PCR and, for sizing, Southern blot [40].

5.6 Diagnosis of benign hereditary chorea (NKX2-1)

Diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic variant in NKX2-1; a variant of uncertain significance neither establishes nor excludes the diagnosis [12]. Suggestive findings are: non-progressive childhood-onset chorea, with or without mild neurological symptoms (axial hypotonia, ataxia, developmental delay), congenital hypothyroidism or respiratory distress syndrome; or a history of congenital hypothyroidism associated with hypotonia, developmental delay, seizures or respiratory dysfunction (including interstitial lung disease in children). Laboratory findings are congenital hypothyroidism (low thyroid hormone and elevated TSH) or compensated hypothyroidism (low-normal hormone and elevated TSH) [12].

Table 8. Molecular tests in NKX2-1

Source: GeneReviews [12].

The approach may be targeted (gene sequencing followed by deletion/duplication analysis, or a multigene panel) or genomic (exome, genome, CMA). CMA is recommended in childhood-onset chorea when the panel and exome are negative, because deletions downstream of the gene, outside the coding region, cause the phenotype [12]. Non-molecular investigations define the extent of involvement: thyroid function (TSH, T4, T3), thyroid ultrasound or scintigraphy when palpation is abnormal, respiratory function tests, chest radiography and CT and, in selected cases, lung biopsy; brain MRI is recommended in the initial assessment but is usually normal and serves primarily to exclude other causes of chorea [12]. In the context of congenital hypothyroidism, the Oxford Desk Reference recommends reviewing the original thyroid results from newborn screening, testing the mother for TSH receptor antibodies in transient cases, thyroglobulin measurement, scintigraphy, the perchlorate discharge test and neck ultrasound, and genomic investigation when syndromic signs are present [61].

5.7 Diagnosis of ADCY5-related dyskinesia

No published consensus diagnostic criteria exist; diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic variant, in the dominant form, or two variants in ADCY5, in the recessive form, in a patient with compatible findings [21]. Suggestive findings are axial hypotonia with weakness, a mixed hyperkinetic disorder of variable severity with paroxysmal exacerbations, persistence of dyskinesia during sleep with worsening at sleep–wake transitions, perioral and periorbital chorea or myoclonus, lower limb spasticity with pyramidal signs, mild to moderate dysarthria and motor and language delay, in the context of normal brain magnetic resonance imaging and electroencephalography [21].

Single-gene sequencing is not useful and is not recommended, and a movement disorder panel may be too restrictive given the rarity of the disease, so the preferred approach is genomic, with exome or genome, in which almost all the variants described are detectable because they lie in the coding region [21]. The main limitation of testing is mosaicism: a considerable proportion of variants are postzygotic and may escape detection in peripheral blood DNA, so that, when clinical suspicion is strong and the result is negative, high-depth sequencing, allele-specific PCR and study of other tissues, such as buccal mucosa or skin biopsy, are used [21, 46, 51]. No intragenic deletions or duplications have been described, which makes targeted gene dosage analysis unnecessary as a routine step [21]. A variant of uncertain significance neither confirms nor excludes the diagnosis [21]. The report follows the rules in section 5.9, with the MANE ADCY5 transcript NM_183357.3 and the five-tier ACMG/AMP classification; when mosaicism is documented, the allele fraction should be stated in the report, because it has prognostic value and guides the study of the parents [21, 50, 51].

After diagnosis, the recommended initial evaluation includes neurological examination by a movement disorder specialist, characterising nocturnal dyskinesias and sleep disturbance and recording the response to drugs already tried; complete ophthalmological examination, with attention to saccades, smooth pursuit, gaze limitation and ptosis; orthopaedic, physical medicine and rehabilitation, physiotherapy and occupational therapy assessment of gross and fine motor function, mobility and the need for adaptive devices; developmental assessment in children and, in adults, assessment of spatial, working and episodic memory; speech and swallowing assessment, with study of aspiration risk and nutritional status; gastroenterological assessment of reflux, constipation and gastric motility; neuropsychiatric assessment; electrocardiogram and echocardiogram, given the rare possibility of dilated cardiomyopathy; and genetic counselling with construction of the pedigree [21].

5.8 Integrated diagnostic algorithm

Table 9. Algorithm for chorea of presumed genetic origin

Sources: [3, 4, 12, 21, 33, 40].

5.9 Limitations of genetic tests and report content

HD testing is a targeted repeat-sizing assay, rather than a sequence readout, and its limitations are specific to that technology. Fragment analysis measures length up to the penultimate CAA in the canonical sequence; it does not read the tract composition and therefore does not identify loss-of-interruption (LOI) variants, which cause CAG number to be underestimated by two units, or duplication-of-interruption variants (DOI, with repeated CAACAG), associated with later onset — both are recognised only by targeted sequencing of the repeat region, currently primarily in research settings [4, 27]. Sizing accuracy decreases with allele size, amplification of very large alleles may fail because of competition with the normal allele, and TP-PCR confirms the presence of an expansion without sizing it; ACMG technical standards require assays optimised for exact and unequivocal quantification of CAG number and provide examples of reports placing the result in its corresponding allelic class [4, 64]. The repeat is unstable across tissues: the number measured in leucocytes does not reflect striatal somatic expansion, and expanded alleles may show somatic instability; the highest repeat numbers have been found in the brain and sperm, limiting prediction of the transmitted repeat [4, 23]. Panels, exome and genome can flag the expansion but are not used to size it in diagnosis, and a negative exome does not exclude HD — as illustrated by the case in section 10.1, in which exome, the spinocerebellar ataxia panel and microarray were normal before HTT testing [4, 65]. The same restrictions apply to phenocopies: the JPH3 repeat has an accuracy of approximately ±1 triplet, the TBP repeat combines CAG and CAA and is not sized by exome, and C9orf72 expansion requires repeat-primed PCR and Southern blot to estimate its size [33, 37, 40].

The report should specify the gene, transcript with version (MANE Select: HTT NM_001388492.1; JPH3 NM_020655.4; TBP NM_003194.5; C9orf72 NM_018325.5; PRNP NM_000311.5; NKX2-1 NM_001079668.3; VPS13A NM_033305.3; XK NM_021083.4; ATN1 NM_001940.4; ADCY5 NM_183357.3), HGVS notation (for example, NM_001388492.1:c.52CAG[17];[42]) with the repeat number of each allele and its class, zygosity, the method and its detection limit, and, when the cited literature uses another reference (NM_002111.8 in GeneReviews; NM_001079668.2 or NM_003317 in NKX2-1), the correspondence between numbering systems [24, 64]. For sequence variants, as in NKX2-1, VPS13A or XK, the five-class ACMG/AMP classification applies; a variant of uncertain significance does not become pathogenic through a response to a drug or partial segregation in a small family, and segregation analysis is described as research [12, 66]. Repeats are classified by range: results of 27–35 CAGs require counselling about intergenerational instability, those of 34–35 and 38–39 CAGs should mention possible underestimation due to LOI, and those of 36–39 CAGs should explicitly state reduced penetrance; in SCA17, alleles of 41–42 repeats should be reported as of uncertain significance rather than normal [4, 37, 38].

6. Differential Diagnosis

6.1 Differential diagnosis of Huntington disease in adults

Diseases with a phenotype overlapping with HD and no HTT expansion are termed phenocopies. Collectively, phenocopies account for a small proportion of cases tested; C9orf72 expansion is the most frequent identified cause in European cohorts (1.95%) and HDL2 the most frequent in populations of African ancestry [33, 40]. Table 10 incorporates the differential diagnoses presented in the Oxford Desk Reference, Síndromes Genéticas: Reconhecer para Tratar and GeneReviews.

Table 10. Genetic differential diagnosis of adult HD

Sources: [3, 4, 23, 33, 35, 40].

The differential diagnosis table in Síndromes Genéticas: Reconhecer para Tratar additionally includes amyotrophic lateral sclerosis (movement disorder, dementia and psychiatric abnormality; distinguished by torticollis, tremor and myoclonus), frontotemporal dementia with parkinsonism (without chorea), early-onset familial Alzheimer disease (without a movement disorder) and familial Creutzfeldt-Jakob disease (with myoclonus) [23].

Among non-genetic causes, the Oxford Desk Reference highlights drug-induced chorea (amiodarone, dopaminergic agents, neuroleptics, carbamazepine, anticholinergics), tardive dyskinesia in at-risk patients treated with phenothiazines, Parkinson disease (possible confusion only with the rigid juvenile form; some patients with HD were misdiagnosed with Parkinson disease), Wilson disease in juvenile and rigid forms, and primary psychiatric illnesses [3]. Other acquired causes include thyrotoxicosis, cerebrovascular disease, cerebral lupus, polycythaemia, metabolic diseases, post-infectious autoimmune diseases, paraneoplastic syndromes and infections [4].

6.2 Differential diagnosis of juvenile HD

Ataxia with oculomotor apraxia types 1 and 2 (APTX, SETX), ataxia-telangiectasia (ATM), Wilson disease (ATP7B), aceruloplasminaemia (CP), Huntington-like chorea-dementia syndrome due to FRRS1L (AR, with seizures), Friedreich ataxia (FXN), Lesch-Nyhan disease (HPRT1, with hyperuricaemia and self-injury), Lopes-Maciel-Rodan syndrome (biallelic HTT, without chorea), Niemann-Pick type C (NPC1, NPC2, with vertical supranuclear gaze palsy), pantothenate kinase-associated neurodegeneration (PANK2) and PLA2G6 dystonia-parkinsonism [4].

6.3 Differential diagnosis of benign hereditary chorea

Table 11. Differential diagnosis of NKX2-1

Sources: [12, 61].

Some patients initially diagnosed with BHC subsequently received another diagnosis, such as myoclonus-dystonia or HD [12]. ADCY5 is the second gene listed by Orphanet for BHC, which has implications for panel interpretation [67]. Mencacci and colleagues showed that ADCY5 variants are a cause of benign hereditary chorea and that, in a child with non-progressive chorea and negative NKX2-1 testing, ADCY5 is the next gene to consider; hypothyroidism or lung disease points to NKX2-1, whereas perioral myoclonus, nocturnal dyskinesia and persistence of movements during sleep point to ADCY5 [21, 52].

6.4 Differential diagnosis of ADCY5-related dyskinesia

The difficulty lies in distinguishing ADCY5 dyskinesia from the other early-onset hyperkinetic disorders with paroxysmal exacerbations. The most useful cross-cutting criterion is behaviour during sleep: ADCY5 movements persist or worsen during sleep and at sleep–wake transitions, unlike PRRT2 paroxysmal kinesigenic dyskinesia, GNAO1-related disorder and alternating hemiplegia of childhood, in which they improve or disappear [21, 46]. The second criterion is the presence of epilepsy and severe delay or regression, which point to developmental encephalopathies; the third is striatal lesions on magnetic resonance imaging, which exclude ADCY5, in which imaging is normal [21].

Table 11A. Differential diagnosis of ADCY5-related dyskinesia

Sources: [21, 46].

Beyond the genetic entities, dyskinetic cerebral palsy and primary mitochondrial diseases enter the differential diagnosis, the former as a frequent misdiagnosis in early childhood and the latter because they can present with dystonia and other abnormal movements [21]. When there is global developmental delay and intellectual disability, the whole group of movement disorders with developmental delay is considered, because the cognitive features of the recessive form of ADCY5 are not sufficient to identify it clinically [21].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no cure for HD; pharmacological therapy is symptomatic, and supportive care aims to improve quality of life, maximise function and reduce complications [4]. International treatment guidelines have been developed by the EHDN and collaborating groups [68]. Management is multidisciplinary — neurology, neuropsychiatry, physiotherapy, speech and language therapy and occupational therapy — in collaboration with community teams and patient organisations [3]. Initial assessment should include a complete neurological examination with the UHDRS, genetic counselling and assessment of family and social structure (community resources, social work, home nursing), with attention to children and adolescents living with an affected parent, sometimes in conditions of deprivation [4].

7.2 Treatment of chorea: VMAT2 inhibitors

Vesicular monoamine transporter type 2 (VMAT2) inhibitors deplete presynaptic dopamine, noradrenaline and serotonin, reducing chorea [23, 69]. They are effective, but must be weighed against adverse effects, which may outweigh the benefit and be confused with disease progression; patients with mild to moderate chorea may benefit more from non-pharmacological measures [4].

Table 12. VMAT2 inhibitors in HD chorea

Sources: [69–75].

All three drugs have a boxed warning for depression and suicidal ideation or behaviour in HD: the risk must be weighed against the need to control chorea, the emergence or worsening of depression monitored, and patients, carers and relatives informed [69–71]. The most frequent adverse effects of tetrabenazine (>10% and at least 5% above placebo) are sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety and nausea; those of deutetrabenazine in HD (>8%) are somnolence, diarrhoea, dry mouth and fatigue; those of valbenazine in HD (≥5% and twice placebo) are somnolence/lethargy/sedation, urticaria, rash and insomnia [69–71]. All may cause parkinsonism, akathisia, QTc interval prolongation, neuroleptic malignant syndrome and hyperprolactinaemia; if adverse effects occur, titration should be stopped and the dose reduced, and, if they do not resolve, discontinuation or specific treatment (for example, an antidepressant) considered [69]. Deutetrabenazine is a deuterated analogue of tetrabenazine; substitution with deuterium attenuates CYP2D6 metabolism and prolongs the half-life of active metabolites, allowing fewer doses and fewer adverse effects [4, 73]. Síndromes Genéticas: Reconhecer para Tratar also mentions benzodiazepines, with a mild antichoreic effect, useful in anxious patients [23].

7.3 Other motor treatments

Table 13. Symptomatic treatment by manifestation

Sources: [4, 68].

Agents to avoid. Levodopa-containing compounds may worsen chorea; monoamine oxidase inhibitors should be avoided (contraindicated with tetrabenazine); alcohol and tobacco are discouraged [4]. The PNDS also considers regular or excessive alcohol consumption harmful to psychiatric disorders [2].

Recommendations of the French PNDS by manifestation. The 2021 HAS PNDS, drawn up by the national reference centre using the HAS formal consensus method on the basis of 401 of the 761 publications retrieved (January 1965 to February 2020) and the 2019 international guidelines, with two rounds of external rating (only two proposals in the motor section were not accepted), retained 237 therapeutic and 139 medico-social recommendations, graded A (established evidence), B (scientific presumption), C (low level of evidence) or professional agreement [2, 68]. Two general rules apply to all manifestations: any symptom may be aggravated by stress, fatigue or intercurrent events (anxiety, digestive disorders, infections, pain), which are treated in parallel; and, at each therapeutic adjustment, only one drug is changed at a time, so that the effect can be attributed unambiguously. An effective and well-tolerated treatment should not be switched, and sedatives (benzodiazepines), neuroleptics and tetrabenazine can worsen apathy, memory, executive functions, gait and bradykinesia, which requires regular reassessment of the dose [2]. Table 13A summarises the pharmacological recommendations and Table 13B the dosages of drugs with a French national indication.

Table 13A. Pharmacological recommendations of the HAS PNDS (2021) by manifestation

Source: HAS PNDS [2]. The recommendations rest mainly on grade C and professional agreement; most drugs are used outside the approved indication.

Table 13B. Dosage of drugs with a French national indication or a dose given in the PNDS

Sources: HAS PNDS and French summaries of product characteristics (SmPCs) [2, 76–79].

Divergences between the PNDS, the other sources and the labels. (1) Allelic classes: the PNDS describes the “wild-type” gene as having 10 to 35 CAG (mean 18), without separating the 27–35 intermediate range that GeneReviews and the ACMG standards distinguish because of the risk of expansion in offspring; this article follows the four-class classification [2, 4, 64]. (2) Homozygosity: the PNDS states that homozygous forms are not more severe than heterozygous forms, citing a 2003 study by Squitieri and colleagues whose title concludes the opposite (a more severe clinical course); GeneReviews describes a similar age at onset with possibly faster progression, the wording this article retains [2, 4]. (3) Fraction of the variance in age at onset explained by CAG number: 56% in the PNDS introduction and about 60% in the genetic counselling section of the same document. (4) Tetrabenazine: in adults, the French SmPC, like the Irish one, allows up to 200 mg/day without CYP2D6 genotyping, whereas the FDA label limits it to 50 mg/day without genotyping and 100 mg/day in adult normal metabolisers; the PNDS does not set doses and adds persistent suicidal ideation as a contraindication [69, 76]. (5) Deutetrabenazine: the 2021 PNDS refers to it as an alternative not authorised in France; the European authorisation of January 2026 covers only tardive dyskinesia, so use for HD chorea remains off-label in the EU (Section 7.9). (6) Piracetam: the PNDS proposes it for cortical myoclonus, but the French SmPC contraindicates it in Huntington chorea; this is use against a label contraindication, not merely off-label use, and requires a specialist decision and information for the patient [2, 79]. (7) Myoclonus: the PNDS includes clonazepam and its combination with valproate, whereas Table 13 (GeneReviews) refers to valproate or levetiracetam [4]. (8) Apathy: Table 13 lists amantadine, atomoxetine, methylphenidate, modafinil, bromocriptine and bupropion with limited evidence; the PNDS recommends no drug for isolated apathy, limits SSRIs to suspected underlying depression and advises against amantadine for chorea and rigidity [2, 4]. (9) Levodopa: Section 7.3 notes that it may worsen chorea; the PNDS accepts it, at a low dose, in the akinetic-rigid phenotype, especially juvenile — the two positions apply to different phenotypes [2, 4]. (10) Spasticity and rigidity: tizanidine and baclofen in Table 13 do not appear in the PNDS, which favours physiotherapy, positioning orthoses and botulinum toxin.

Non-pharmacological measures in the PNDS. Regular adapted physical activity and daily walking are recommended from the presymptomatic stages; in symptomatic patients, physiotherapy should begin as early as possible and continue throughout the course, with a frequency that may exceed one session per week, and gait, balance and trunk stability rehabilitation programmes reduce falls (grades B and C); a wheeled walker (rollator) helps some patients (B) but increases the risk of falling in others, so its introduction should be assessed by a physiotherapist or occupational therapist; there was no consensus to recommend an electric wheelchair, which is useful in selected cases after cognitive assessment [2]. Low-impact exercise (yoga, hydrotherapy, swimming with protection, dance, tai chi, qi gong) and therapeutic horse riding may transiently attenuate chorea. In disabling chorea, protective equipment and technical aids are recommended for meals, bathing, bed and transfers, mouthguards for recurrent biting (weighing the risk of choking) and adaptation of the home against falls and impacts [2]. Swallowing should be assessed regularly (C): speech and language therapy from the first difficulties, breaking down the swallowing sequence, cough and pneumophonic coordination exercises, adaptation of textures, mouthful size and head posture, meals without distractions and training of carers; videofluoroscopy guides compensatory techniques (C). Percutaneous endoscopic gastrostomy (PEG) is discussed case by case, ideally before the advanced stages and crisis situations, with the patient and the trusted person, who may revise the decision at any time; it does not prevent aspiration of saliva or reflux and allows some oral feeding to be maintained for pleasure and socialisation [2]. In nutrition, maintaining a normal BMI, repeated screening for malnutrition with the MUST tool and early assessment by a dietitian are recommended; medical or social intervention is required for involuntary weight loss >10% in 3–6 months, or >5% in 3–6 months with BMI <20 kg/m²; high-calorie, high-protein supplements (C) complement, without replacing, food, and requirements may reach 5000 kcal/day in advanced stages; when choosing antidepressants and neuroleptics, those that increase weight are preferred in underweight patients (C) [2]. Speech and language therapy also addresses communication (gestures, closed questions, rephrasing, letter boards and augmentative and alternative communication systems, introduced while the patient can still learn them), and cognitive rehabilitation (speech and language therapy, occupational therapy, neuropsychology, psychomotor therapy) improves planning and task initiation (C); driving ability correlates with global cognitive performance and with TFC (C) and, when questioned, requires direct assessment [2]. Oral health requires high-fluoride toothpaste, adapted (preferably electric) toothbrushes, scaling at least annually, more often in advanced stages in dedicated disability clinics, radiopaque prostheses because of the risk of ingestion and, when necessary, conscious sedation (midazolam, diazepam), nitrous oxide, hypnosis or general anaesthesia (C). Respiratory physiotherapy improves ventilatory function (B), with little effect on swallowing and dyspnoea [2]. Therapeutic patient education, with programmes under development in rare disease centres, and objective information that counters alarmist or outdated data complete the plan [2].

For cognitive deficits, the PNDS proposes compensation strategies: helping the patient to organise and initiate activities (lists, diary, calendar, reminders) without taking over, as long as the patient is not endangered; allowing time to process information and avoiding time-pressured situations (bradyphrenia); daily routines, a diary and task lists for memory, with reduction of sedatives, neuroleptics or tetrabenazine when they worsen recall; alarms and external reminders for time management, which in some patients reinforce obsessive behaviours; padding furniture against impacts linked to visuospatial deficits; and explaining social cognition deficits to the family, professionals and colleagues. A confusional state requires a complete aetiological work-up. Speech and language therapy may exceed one weekly session, and relatives should learn to support verbal communication, which patients prefer even when speech becomes poorly intelligible [2]. In the motor domain, early referral to physiotherapy is recommended, establishing the therapeutic relationship and introducing compensation methods; targeted, personalised physiotherapy or exercise programmes, combined with pharmacological treatment, improve overall functional capacity and autonomy (B), and are complemented by adapted group physical activities, chairs designed for HD and fall alert devices; for gait, attention should be paid to sources of distraction, footwear and removal of obstacles [2]. Digestive disorders are not specific to HD and are investigated as in the general population; faecal impaction is systematically sought in constipation, overflow diarrhoea or vomiting, and gluten intolerance is only investigated as part of the usual work-up of unexplained prolonged diarrhoea. A Mediterranean diet improved quality of life in one study (C), but is difficult to maintain given the caloric demands of late stages. For hyperhidrosis, plastic-backed pads are avoided and clothing and pads are changed frequently to prevent maceration. Psychological support for relatives (individual, couple or discussion groups), professional help at home and respite stays strengthen the family's capacity to cope with all the behavioural symptoms [2].

7.4 Surveillance

At every visit, chorea, rigidity, gait, fine motor function, cognitive decline, functional capacity, mood and behaviour (depression, irritability, anxiety, apathy), sleep and social and family needs should be assessed using the UHDRS (motor, cognitive, behavioural, TFC) and complementary instruments: MoCA for severity of cognitive impairment, MMSE in moderate to severe disease, PHQ-9, GAD-7, Dimensional Apathy Scale, Insomnia Severity Index, Columbia scale for suicide risk and Brøset Violence Checklist; the BOSH scale is used for assessment in nursing homes, and digital tools (Q-Motor) reduce rater bias in trials [4]. The counsellor has a duty to inform the individual if the disease makes them unsafe to drive or dangerous to themselves or others [3]. The HAS PNDS organises follow-up as visits to the reference or competence centre once or twice a year (neurological, neuropsychological and psychiatric assessment and screening for adverse effects), a brief assessment admission (day or week hospital) every one or two years, and more frequent visits in the event of decompensation; before attributing rapid worsening to the natural history, a comorbidity and an iatrogenic cause should be sought (Table 18) [2].

7.5 Investigational therapies and regulatory status (October 2026)

A systematic review of trial registries between 2014 and November 2025 identified 165 clinical studies in HD, 69 of them pharmacological, with 50 agents tested and 21 under evaluation; disease-modifying therapies account for 90.5% of phase 1 trials, 61.8% of phase 2 and 55.6% of phase 3, with a shift towards populations at earlier stages [80]. Table 14 summarises the most relevant programmes.

Table 14. Disease-modifying therapies in clinical development

Sources: [4, 80–88].

AMT-130. In the American phase I/II trial, 26 patients with early manifest HD were randomised to AMT-130 (6 at low dose, 10 at high dose) or a sham procedure; a European study included additional patients [89]. GeneReviews emphasises that the high dose showed no benefit at one year compared with the sham procedure, that the benefit at three years is based on 12 patients compared with external rather than within-trial controls, and that target engagement (HTT reduction) was not reported [4]. In the September 2025 analysis (data cut-off 30 June 2025), the high dose was associated with 75% slowing of progression on the cUHDRS (p=0.003; change −0.38 vs. −1.52 in the propensity-score-matched external Enroll-HD control, n=940) and 60% on the TFC (p=0.033), with a safety profile considered manageable and adverse events mainly related to the procedure [90]. The regulatory course was irregular: in December 2025 and March 2026, the FDA considered that phase I/II data compared with an external control were insufficient as primary evidence and recommended a randomised, double-blind, sham-surgery-controlled study; in June 2026, at a type B meeting, the FDA accepted the 36-month analysis as the basis for an accelerated approval application, with a confirmatory study to be agreed [89, 90]. The BLA was submitted on 2 September 2026, with a request for priority review [81]. On 29 September 2026, the company released 36-month data for 15 high-dose patients (80% slowing on the cUHDRS, nominal p 0.005; 67% on the TFC, nominal p 0.011; CSF NfL 6% below baseline) and 48-month data for 12 patients (44% on the cUHDRS, not statistically significant, p=0.144; 61% on the TFC, nominal p 0.008), with 53% missing data in matched controls at 48 months [91]. These results derive from a company communication rather than a peer-reviewed publication; at this date, AMT-130 is not approved in any jurisdiction.

Tominersen. In the phase I/II trial, tominersen reduced CSF mHTT in a dose-dependent manner [92]. The phase 3 GENERATION HD1 trial was stopped in early 2021 because of an unfavourable benefit–risk profile; post hoc analysis suggested benefit in a subgroup of younger patients with a lower disease burden [4, 93]. Results published in the registry show that, at week 69, mean cUHDRS change was −1.17 with 120 mg every 8 weeks, −0.79 with 120 mg every 16 weeks and −0.63 with placebo (approximately 260 participants per arm), meaning that the more frequent regimen was associated with a worse course than placebo [94]. The phase 2 GENERATION HD2 trial (NCT05686551), with 100 mg in prodromal and early manifest disease, completed primary outcome data collection in May 2026 [83]; in July 2026, Roche announced that, despite reductions in mHTT and NfL in CSF and plasma and no new safety signals, progression on the cUHDRS and TFC at 16 months did not differ from placebo, discontinuing the programme together with that of the allele-selective ASO RG6496 (POINT-HD) [82].

Pridopidine. In the phase 3 PROOF-HD trial in early manifest disease, the drug was well tolerated but the primary endpoint was not met; the favourable signal emerged in a sensitivity analysis restricted to participants without antidopaminergic medication [85]. The EMA issued a negative opinion on 24 July 2025 because of a lack of evidence of efficacy and concerns about the validity of subgroup analyses, and the application was withdrawn on 7 November 2025 [84].

Patients may be referred to trials through the Enroll-HD registry, the Huntington Study Group and US and EU clinical trial registries [4].

7.6 Treatment of phenocopies

In HDL2, treatment is symptomatic and presumed to resemble HD treatment, which must be regarded as speculative: tetrabenazine and derivatives or low-dose neuroleptics (fluphenazine, haloperidol) for movements; fall prevention (remove rugs and obstacles, avoid stairs), physiotherapy, speech and language therapy and communication devices, adapted feeding to prevent choking, driving restrictions, financial and legal planning; antidepressants, antipsychotics, mood stabilisers (lithium, valproic acid, carbamazepine, lamotrigine), electroconvulsive therapy and, occasionally, stimulants; surveillance at least annually; caution with drugs worsening ataxia, initiation of psychotropic drugs at low doses and minimisation of polypharmacy because of the risk of delirium [33]. Use of VMAT2 inhibitors outside HD is off-label. In SCA17, treatment is likewise symptomatic: psychotropic drugs, antiepileptics, botulinum toxin for dystonia, environmental adaptation for dementia, MRI and neuropsychological assessment at diagnosis, annual or six-monthly neurological surveillance, and avoidance of sedatives and alcohol, which worsen incoordination [37]. In genetic prion diseases, no disease-modifying treatment is approved; management is supportive, by a multidisciplinary team, with reassessment of needs approximately every 14 days because of rapid progression [95], and the intrathecal ASO ION717, which reduces prion protein, is in a phase 1/2 trial (PrProfile, NCT06153966) [96].

7.7 Treatment and surveillance in benign hereditary chorea (NKX2-1)

There are no published guidelines; GeneReviews recommendations are based on case series [12]. Table 15 summarises the approach.

Table 15. Management of NKX2-1-related disorders

Sources: [12, 69–71].

At-risk relatives should be tested prenatally or immediately after birth to identify congenital hypothyroidism and pulmonary disease early and prevent the neurological consequences of untreated hypothyroidism; where newborn screening is not routine, at-risk newborns should undergo specific screening [12]. No specific clinical trials are registered [12]. A Japanese case report described drop attacks in BHC responding to levothyroxine [97].

7.8 Pivotal trials and limits of comparison

Table 15A. Trials supporting authorisations and principal negative trials cited

These trials do not permit ranking drugs against one another. The three VMAT2 inhibitors were compared only with placebo, in populations and using instruments that were similar but not identical (chorea score in TETRA-HD; total maximal chorea, measured as the mean of two visits, in First-HD and KINECT-HD), with different titrations and 12-week durations; differences of 2.5 to 3.5 units on a scale from 0 to 28 concern chorea and do not demonstrate functional improvement, as shown by the absence of an effect on balance in First-HD [72–74]. There are no head-to-head trials or long-term controlled data on suicide or depression, which justify the boxed warnings [69–71]. In disease-modifying therapy, large randomised trials were negative (GENERATION HD1, PROOF-HD), and one showed harm with the more frequent dose; subsequent subgroup analyses (younger patients for tominersen, absence of antidopaminergics for pridopidine) generate hypotheses and were precisely the reason for the negative European opinion [84, 85, 93]. AMT-130 results are percentages of relative slowing compared with an external control, neither randomised nor blinded, in a small number of patients and with missing comparator data; an 80% relative reduction in a small cUHDRS change does not equate to absence of progression, and a controlled confirmatory trial remains necessary [4, 90, 91].

7.9 Comparative regulatory status, evidence hierarchy and off-label use

The evidence hierarchy should be explicit: a peer-reviewed article (TETRA-HD, First-HD, KINECT-HD, PROOF-HD), a sponsor communication or document submitted to the SEC (AMT-130 results at 36 and 48 months; discontinuation of tominersen), an opinion from the EMA Committee for Medicinal Products for Human Use (CHMP), and an authorisation decision (European Commission, national authority or FDA) are different levels. Submission of an authorisation application is neither acceptance nor approval, a favourable opinion is not authorisation, and authorisation does not guarantee marketing, reimbursement or access in each country — in Portugal these depend on marketing and funding assessment by INFARMED and, in Brazil, on ANVISA registration and incorporation into SUS following CONITEC assessment. No disease-modifying medicine is authorised; the table summarises the position on 6 October 2026.

Extrapolation and off-label use. Off-label use depends on the label text, age and jurisdiction rather than the quality of evidence. Deutetrabenazine in HD chorea is within its indication in the USA and outside it in the EU; valbenazine has no European authorisation; and all three VMAT2 inhibitors are labelled for adults (tetrabenazine without established efficacy in children), so their use in juvenile HD, NKX2-1 chorea, HDL2, SCA17 or other choreas is off-label, even when supported by reasonable pharmacological extrapolation [12, 33, 69–71]. The neuroleptics, antidepressants and mood stabilisers recommended by EHDN guidelines for HD manifestations are also mostly used outside the approved indication for the disease [68]. In pregnancy, the decision requires review of each label's data, because none of these drugs has been studied in pregnant women with HD [12, 69–71]. In France, the PNDS points out that prescribing outside the marketing authorisation is possible in the absence of an appropriate alternative, with information for the patient on the off-label nature, the risks and the reimbursement conditions, the statement “prescription hors AMM” on the prescription and justification in the medical record; the medicines agency (ANSM) may rely on the PNDS to issue a temporary recommendation for use (RTU), a prerequisite for derogatory reimbursement [2]. Tetrabenazine, haloperidol and tiapride have a French indication for HD chorea, whereas piracetam has Huntington chorea among the contraindications in its SmPC (Table 13B) [76–79].

7.10 Treatment of ADCY5-related dyskinesia

There are no guidelines or randomised trials; the evidence comes from case reports and case series, and GeneReviews states explicitly that its recommendations rest on the authors' experience [21]. The 2023 scoping review, which gathered 87 articles, mostly case reports and case series, identified caffeine, benzodiazepines and deep brain stimulation as the interventions consistently reported as useful, and stressed that drugs beneficial in some patients were useless or harmful in others — a result consistent with the heterogeneity of a gene in which gain- and loss-of-function mechanisms coexist [46]. Treatment is symptomatic and multidisciplinary: speech and language therapy for dysarthria, with augmentative and alternative communication when necessary; occupational therapy, speech and language therapy and nutritional support for feeding difficulties, considering gastrostomy when the swallowing study is abnormal or nutrition is not assured; treatment of reflux and constipation, which are among the triggers of exacerbations; orthopaedics, physical medicine and rehabilitation, physiotherapy and occupational therapy to maintain mobility and function, with walking aids, wheelchairs, orthoses and home adaptation; an individualised education plan when there is cognitive impairment; cognitive behavioural therapy and medication by mental health professionals for psychiatric manifestations; and a plan for transition from paediatric to adult care from 16 to 18 years of age [21].

Targeted treatment rests on antagonism of the adenosine A2A receptor, which is highly expressed in the striatum; this reduces cAMP production and counteracts the effect of gain-of-function variants [21, 43]. None of the drugs used is authorised for this indication in any jurisdiction, so any pharmacological treatment of this disease is off-label [21, 46].

Table 15B. Pharmacological and surgical treatment of ADCY5-related dyskinesia

The sources diverge on acetazolamide: the chapter on disorders of purine and pyrimidine metabolism in Inborn Metabolic Diseases presents it as the most effective means of controlling chorea and dyskinesia, whereas the scoping review recorded success in some series but inefficacy or worsening of episodes in eight patients, and the patient described by Shetty and colleagues worsened with the drug [42, 46, 51]. Because there is no guideline or trial for the disease, neither statement has the status of a recommendation: the defensible sequence is to try an A2A antagonist first and reserve acetazolamide for refractory cases, stopping it if worsening occurs. Levodopa improved axial hypotonia, dystonic spasms, hypophonia and speech in isolated reports, but was ineffective or worsened episodes in fifteen patients and, in one case, was considered a cause of hypotonia [46]. Methylphenidate improved chorea, paroxysmal episodes of weakness, dysarthria, attention and dexterity in one patient, and carbamazepine and oxcarbazepine improved dyskinesia in case reports [46]. Among the 30 patients in the caffeine series, 114 therapeutic trials with 30 different drugs were undertaken, which gives a measure of the frequency of unsuccessful attempts and justifies a sequential trial strategy with outcomes defined before starting each drug [46, 100].

Bilateral globus pallidus internus deep brain stimulation markedly reduces permanent hyperkinetic movements and paroxysmal episodes, including nocturnal exacerbations, and was used as an emergency for a dyskinetic storm in a 46-year-old man [102–104]. Improvement is usually partial: patients retain significant disability, the benefit does not always translate into improvement in activities of daily living, axial hypotonia and dystonia respond less, and the results are inferior to those obtained in DYT-TOR1A dystonia and SGCE myoclonus-dystonia [46, 103]. The response may be maximal immediately after stimulation begins, with gradual re-emergence of movements in the following weeks, but stopping stimulation worsens symptoms regardless of the time elapsed since surgery [46, 103]. Given the non-progressive nature of the disease, the benefit is expected to be maintained in the long term, and the indication lies in patients with disabling dyskinesia unresponsive to pharmacological treatment [21].

A reduction in manifestations has been described in pregnancy, and the potential teratogenic effects of the drugs in use should be discussed with women of childbearing potential, preferably before conception [21, 46]. Investigational therapies remain focused on modulation of the cAMP pathway through A2A receptor antagonism; at the time of the scoping review, two studies of these drugs were registered, one with caffeine (NCT04469283) and one with theophylline (DRKS00029154), and the retrospective theophylline study published in 2025 is registered as DRKS00034720 [46, 101]. There is no disease-modifying therapy in clinical development and no regulatory process under way for this indication [21, 46].

8. Reproductive Options and Family Counselling

8.1 Recurrence risk in Huntington disease

HD is inherited in an autosomal dominant manner: at conception, each child of an expansion carrier has a 50% probability of inheriting it [4]. Because the disease results from an unstable repeat, anticipation and parental origin influence age at onset and presentation [3]. Most patients have an affected parent; an apparent absence of family history may reflect failure to recognise the disease, early parental death before onset, an intermediate or reduced-penetrance allele in an asymptomatic parent, late onset in the transmitting parent or incorrectly attributed parentage [4]. In isolated cases, the parents can be tested; when neither has an intermediate or pathogenic allele, non-medical explanations should be considered, such as alternative paternity or maternity (including in assisted reproduction) or undisclosed adoption [4].

Table 16. Risk to siblings and offspring

Sources: [4, 25].

Table 17 recalls that the risk in a healthy individual with an a priori risk of 50% remains high at advanced ages; the Oxford Desk Reference itself cautions that it should not be used for individual counselling, because risk depends on age at onset in the family, maternal or paternal origin of the mutation and expansion size [3, 105].

Table 17. Risk that a healthy individual with an a priori risk of 50% carries an expansion, by age

Source: Harper and Newcombe, 1992, reproduced in the Oxford Desk Reference [3, 105].

8.2 Predictive testing protocol

CAG testing in an individual without definite symptoms is predictive testing [4]. HD was the model for all predictive testing programmes, and the 1994 international IHA/WFN guidelines and 2013 EHDN recommendations establish the current framework [3, 9, 10]. In the USA, the 2016 Huntington's Disease Society of America (HDSA) protocol is the reference; in 2026, an update was proposed to incorporate teleconsultation, legislation on immediate access to medical records and the possibility that carrier status may be incidentally disclosed by genomic sequencing [4, 106].

The essential elements, common to the sources, are as follows. Testing is intended for adults capable of informed decision-making and is voluntary. Diagnosis should first be confirmed in an affected relative, preferably molecularly [3, 4]. The programme involves several sessions — usually three or more meetings with the geneticist or genetic counsellor over several months — to explore motivations, knowledge of the disease, the possible impact of a positive or negative result, neurological status and future management; the process is longer when the family's knowledge of the diagnosis is recent [3, 107]. Implications for health, life and disability insurance, employment and education, social and family relationships, and other relatives' risk status are discussed [4, 107]. Depression and suicidal ideation must be assessed; testing should not be performed if psychiatric issues are uncontrolled or the professional considers that testing would be harmful [4]. Written informed consent is obtained, records are confidential, the result is communicated in person by a team member known to the patient (unless otherwise agreed), a support companion is recommended, and post-test follow-up and, for carriers, long-term follow-up are ensured [3, 4, 107].

Fewer than 20% of first-degree relatives choose predictive testing, and women use it more frequently [3, 4]. In the Canadian programme, testing maintained or improved the psychological well-being of most, but approximately 10% of individuals with a reduced-risk result had serious difficulty adapting because they faced a future they had not planned [4]. One study showed that perceived discrimination is related more to family history than to the test result [4].

Special situations. Testing an individual with a 25% risk amounts to predictive testing of the intervening parent if the result is positive, so it should be undertaken only after exhausting efforts to counsel the relative with a 50% risk [3, 107]. In asymptomatic minors, testing for an adult-onset disease without preventive intervention should be deferred until they can decide for themselves; when considered, it should be preceded by complete neurological and neuropsychological assessment [4, 107]. Síndromes Genéticas: Reconhecer para Tratar regards testing in asymptomatic individuals under 21 as ethically unacceptable [23]. In families with an established diagnosis, testing symptomatic individuals is appropriate at any age [4]. Individuals with results of 34–35 or 38–39 CAGs should be counselled about possible underestimation due to LOI [4]. Asymptomatic at-risk individuals may also seek testing to participate in clinical trials [4].

French framework. The HAS PNDS reserves presymptomatic diagnosis for adults belonging to a family with genetically confirmed HD, in multidisciplinary consultations whose composition and functioning are declared to the Agence de la Biomédecine, under the Public Health Code (articles L1130, L1131 and R1131-5), and based on four principles: autonomy, the right to know or not to know, confidentiality and informed consent. The obligation to inform relatives must be addressed before testing, and the arrangements for that information are recorded in the file [2]. With regard to insurance, a person without symptoms who knows their family risk is not obliged to declare it, but may not omit medical tests performed during the period covered by the questionnaire; therefore, anyone intending to undergo presymptomatic testing and take out a loan or insurance in the same period should seek prior advice from the social service of a reference centre or from patient associations. Once symptoms are present, the PNDS advises validation of the driving licence by the prefecture medical commission, to avoid challenge by the insurer [2]. The difference in minimum age between sources (age of majority in the PNDS and GeneReviews; 21 years in Síndromes Genéticas: Reconhecer para Tratar) reflects different legal and ethical frameworks [2, 4, 23].

8.3 Prenatal and preimplantation diagnosis

Once the expansion has been identified in an affected relative, prenatal diagnosis and preimplantation genetic testing (PGT) are possible [4]. The Oxford Desk Reference describes direct analysis and exclusion testing [3]. In prenatal exclusion testing, an at-risk individual who does not wish to know their status uses linked markers to define the haplotype around HTT: if the fetus inherited chromosome 4 from the affected grandparent, its risk is 50%; if it inherited that of the unaffected grandparent, it has the population risk. The couple must consider termination of a pregnancy with a 50% probability of being unaffected [3]. Exclusion PGT and non-disclosure PGT allow testing of the embryo without revealing the at-risk parent's status [3, 4]. HD is among the diseases for which PGT is most frequently requested, both by known carriers and for exclusion in individuals with a 50% risk [108]. PGT has pregnancy rates comparable to assisted reproduction in general (approximately 29% per transfer in ESHRE consortium data), risks of ovarian hyperstimulation syndrome (mild in 8–23%, severe in 0.1–2%) and a residual risk of diagnostic error from mosaicism, allele dropout or contamination, justifying the use of multiple informative markers [108]. Non-invasive prenatal diagnosis may become available, and updated information should be sought before counselling [3]. Risk determination and testing decisions should ideally take place before pregnancy [4].

The HAS PNDS describes French practice. Prenatal diagnosis requires the anomaly to have been identified in a parent and takes place in a multidisciplinary prenatal diagnosis centre; it is preferably performed by chorionic villus sampling at 11–13 weeks of gestation, with a miscarriage risk of about 1% and, if the result is unfavourable, termination of pregnancy for medical reasons if possible before 14 weeks, or by amniocentesis from 15–16 weeks, with a lower miscarriage risk (0.5%) but later termination; termination for medical reasons requires the opinion of the multidisciplinary team and certification by two physicians that there is a strong probability of a particularly serious disease that is incurable at the time of diagnosis (article L2213-1). Preimplantation diagnosis is authorised (article L2131-4) when the variant has been identified in a parent or their direct ascendants; as described in the PNDS, biopsy of one to two cells is performed on day 3 (8-cell stage), one to two non-carrier embryos are transferred, only five French centres perform preimplantation diagnosis and not all offer it for HD, and the probability of pregnancy is about 30% over 2 years. Exclusion preimplantation diagnosis preserves the at-risk parent's right not to know and requires blood samples from both parents of that parent [2]. The pregnancy figures are not directly comparable with those of the ESHRE consortium (about 29% per transfer), because the PNDS denominator is the couple over 2 years rather than the transfer [2, 108]. The PNDS also requires that the existence and arrangements of prenatal and preimplantation diagnosis be communicated, at any point in the pathway, to anyone who wishes [2]. Prenatal diagnosis follows the same four principles as presymptomatic testing (autonomy, the right to know or not to know, confidentiality and free and informed consent) and falls within the bioethics laws of 1994, revised in 2004, 2011 and 2021, and the order (arrêté) of 25 January 2018 on the prescription, performance and communication of prenatal medical laboratory tests; exclusion preimplantation diagnosis is treated as an exceptional procedure [2].

8.4 Family counselling

Families value help in discussing the disease and deciding how and when to tell their children; contact with patient organisations (HDSA, Huntington's Disease Association, Huntington's Disease Youth Organization, HDBuzz, EHDN, Huntington Disease Africa, Huntington Society of Canada) is useful [3, 4]. In Europe, HD, phenocopies and hereditary choreas fall within the European Reference Network for Rare Neurological Diseases (ERN-RND), which brings together specialist centres and disease-specific clinical information [1]; national organisations collaborate through the European Huntington Association [109], and in Brazil the Associação Brasil Huntington provides information and family support [110]. Follow-up is offered to all carriers and at-risk individuals who declined testing, to keep them informed and, if they wish, assess signs of disease; registry participation (Enroll-HD) may be useful to some [3, 4].

The PNDS defines genetic counselling as the process that informs the patient or at-risk relative about the nature and consequences of the disease, the probability of developing or transmitting it and the options for life and family planning, with accurate information, without imposed direction and with confirmation that it has been understood; first-degree relatives (offspring and siblings) have a 50% risk of being carriers, and it should be explained that age at onset cannot be predicted individually [2]. In presymptomatic or at-risk people, the social assessment also serves to advise on loans, insurance and company arrangements in the event of prolonged illness [2].

Organisation of care in France. The national HD reference centre has its coordinating site in the neurology department of Hôpital Henri Mondor (Créteil) and constituent sites in Angers (neurogenetic diseases), Hendaye (neurological rehabilitation), Lille (neurology and movement disorders), Pitié-Salpêtrière (genetics) and Armand Trousseau (paediatric neurology), and 15 competence centres: Amiens, Bordeaux, Clermont-Ferrand, Grenoble, Lyon-Bron, Marseille, Montpellier, Nancy, Nantes, Poitiers, Rouen, Strasbourg and Toulouse in metropolitan France, Fort-de-France in Martinique, and Saint-Pierre in Réunion. Shared coordination between the centre physician and the attending physician, with care pathway coordinators, aims to avoid the disruptions of care that are frequent in this disease [2]. Once symptoms are present, the attending physician requests exemption from co-payment as a long-term condition (ALD 30). The PNDS recommends identifying local resources (équipes relais handicap rare, mobile teams and specialised psychiatry, neurology and palliative care teams) and home-based medico-social support services (SAMSAH, SAVS), training home care professionals in HD and maintaining stable teams, because interventions by unfamiliar people disturb patients [2]. It lists the associations Huntington France, Union Huntington Espoir (Grand-Est and Hauts-de-France branches), Huntington Avenir, Dingdingdong, Kachashi (dance project), Arc-en-Ciel, Huntington Bocage-Mauges-Choletais and the preparatory association of the Fondation Denise Picard, and the practical guide “Huntington et alors ?”, published with the reference centre and hosted by ERN-RND [1, 2].

8.5 Phenocopies

In HDL2, each child of an affected individual has a 50% risk; alleles with 29–39 CTGs may or may not cause disease. Predictive testing is possible once the expansion has been identified in an affected relative and should follow the same rules as HD, including prior counselling, a trusted person for support and follow-up after the result [33]. In SCA17, counselling is complicated by the ~50% penetrance of alleles with 41–48 repeats and possible digenic interaction with STUB1 [37, 39]. In genetic prion diseases, predictive testing of adults is possible after formal counselling, and testing minors is considered inappropriate [95].

8.6 Benign hereditary chorea

Inheritance is autosomal dominant; most patients have an affected parent, but the proportion of de novo variants is unknown [12]. If the variant is not detected in either parent, the risk to siblings is estimated at ~1% because of possible germline mosaicism; if the parents have not been tested but are clinically unaffected, the risk is low but not zero because of intrafamilial variability and possible reduced penetrance [12]. Each child of an affected individual has a 50% risk [12]. Unlike HD, testing at-risk relatives is recommended prenatally or neonatally because early hypothyroidism treatment and respiratory surveillance alter prognosis [12]. Prenatal diagnosis and PGT are possible after identification of the familial variant [12].

8.7 ADCY5-related dyskinesia

Inheritance is usually autosomal dominant, and most patients have a de novo variant, constitutional or postzygotic mosaic; a minority inherit it from a parent who may or may not have manifestations [21, 49]. In an apparently isolated case, testing of the parents is recommended to clarify the recurrence risk: a patient may appear to be the only one affected because the disease has not been recognised in relatives or because of mild, late onset in a carrier parent, and de novo origin is confirmed only when neither parent is shown to carry the variant constitutionally [21].

Recurrence risks are 50% for each child of a carrier of a constitutional variant; up to 50% for each child of a mosaic patient, with the caveat that a child who inherits the variant will carry it constitutionally and may be more severely affected than the parent; 50% for siblings when a parent is a carrier or affected; and higher than in the general population, although not quantified, when the variant is not detectable in leucocyte DNA from either parent, because of the possibility of gonadal or somatic and gonadal mosaicism [21, 47]. Testing of parental leucocyte DNA does not detect all somatic mosaicism and does not detect a variant present only in germ cells [21]. A parent with somatic and gonadal mosaicism may be minimally or mildly affected, so examination directed at facial twitches and nocturnal dyskinesia is part of the assessment of the parents [47, 50].

In the autosomal recessive form, both parents are presumed to be heterozygous and confirmation is recommended; each sibling has, at conception, a 25% chance of being affected, 50% of being heterozygous and 25% of inheriting neither variant, and the heterozygotes described are asymptomatic and are not at risk of developing the disease [21]. If only one parent is a carrier and biological parentage is confirmed, a de novo variant in the proband, a postzygotic event in a mosaic parent, a deletion of one or more exons undetected by sequencing that mimics homozygosity, or uniparental isodisomy of the chromosome containing the variant are considered [21]. Each sibling of the parents has a 50% chance of being heterozygous, and testing of relatives requires prior identification of the variants in the family [21].

Prenatal diagnosis and preimplantation genetic testing are possible once the variants have been identified in an affected relative, and the ideal time to assess risk and discuss these options is before pregnancy; counselling, including discussion of risks to offspring and reproductive options, should be offered to affected or at-risk young adults [21]. Unlike HD, this is not a late-onset disease, so the predictive testing protocol for asymptomatic adults does not apply; the practical problem is the reverse, that of identifying a parent minimally affected because of mosaicism, which may require high-depth sequencing of parental DNA [21, 50].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Global prevalence of Huntington disease

Mean prevalence in populations of European ancestry is 9.71 per 100,000, reaching 17 per 100,000 when multiple sources of ascertainment are used [4, 111]. In the United Kingdom, prevalence is approximately 1 in 10,000, and birth incidence is approximately 2.5 times higher, meaning that there are several asymptomatic carriers for each patient [3]. The meta-analysis by Pringsheim and colleagues, cited in Síndromes Genéticas: Reconhecer para Tratar, estimated 5.7 cases per 100,000 in Western Europe, North America and Australia and 0.40 per 100,000 in Asian countries, with an incidence of 0.38 per 100,000 person-years in populations of European origin [23, 112]. In East Asian (Japan, China, Korea) and African ancestry populations, estimates range from 0.1 to 2 per 100,000, but case ascertainment in these regions needs improvement before these values are accepted [4]. Finland has low prevalence for a European country, probably because of a population bottleneck, and prevalence is increasing in parts of Europe, North America and Asia because of increased life expectancy [4]. Orphanet records an annual incidence of 0.35 per 100,000 for Spain [113]. The HAS PNDS estimates prevalence at between 4 and 10 per 100,000 in Western populations, reports juvenile forms in about 10% of patients, usually through paternal transmission and with more than 60 CAG in about half, and does not present its own French estimate [2].

The unequal distribution is explained, at least partly, by differences in mean CAG number and the frequency of intermediate alleles and associated haplotypes between ancestry groups [4]. Alleles with ≥36 CAGs occur in up to 1 in 400 individuals of European ancestry [26].

9.2 Founder effects and clusters

The Lake Maracaibo region in Venezuela constitutes a founder cluster with the highest prevalence in the world, reported in Síndromes Genéticas: Reconhecer para Tratar as 7000 cases per 1,000,000 [4, 8, 23]. Venezuelan pedigrees enabled gene mapping and study of genetic and environmental factors modulating age at onset [6, 8].

9.3 Populations of African ancestry and HDL2

HDL2 has been described only in individuals with confirmed or probable African ancestry, sharing a common haplotype of African origin [33, 114]. It is the most frequent phenocopy in these populations and, globally, the most prevalent Huntington-like disease [33]. In South Africa, among patients with an HD phenotype referred for testing, 15% of Black patients and none of the White patients had HDL2, whereas 62% of White patients and 36% of Black patients had HD — approximately one HDL2 case for every two HD cases in Black patients [114]. The combined minimum frequencies of HD and HDL2 in South Africa were 5.1, 2.1 and 0.25 per 100,000 in White, mixed-ancestry and Black groups, respectively [115]. In Brazil, where approximately 44% of the population has African ancestry, up to 10% of patients with a Huntington-like phenotype may have HDL2; in Venezuela, 11 of 260 referred patients (4.2%) had a JPH3 expansion; cases have been described in France, the Caribbean, Botswana and Mali, and no cases were found among 1600 patients tested in Germany and Austria [33]. A Latin American review confirmed the presence of several non-HD genetic choreas in the region and the higher frequency of HDL2 in countries with populations of African ancestry [116]. In practice, a patient with African ancestry, even distant, an HD phenotype and negative HTT testing should undergo JPH3 testing [33].

9.4 Other phenocopies

DRPLA is more frequent in Japan and increasingly recognised in other regions since molecular testing became widespread [3]. SCA17 has a minimum prevalence of 0.16 per 100,000 in north-east England and an estimated prevalence of 0.047 per 100,000 in Japan, where it accounts for ~0.3% of autosomal dominant ataxias; fewer than 100 families have been described, and prevalence is probably underestimated because patients with a Huntington-like phenotype are not always tested for TBP [37, 117]. Chorea-acanthocytosis has been described predominantly in Japanese patients [3]. HDL3 was described in a consanguineous Saudi family [35].

9.5 Benign hereditary chorea

More than 120 patients with NKX2-1 variants have been described, and prevalence is unknown; Orphanet assigns BHC (an entity including NKX2-1 and ADCY5) a worldwide point prevalence of 0.02 per 100,000 and records approximately 100 cases or families with brain–lung–thyroid syndrome [12, 60, 67]. There are no regional prevalence data [12].

9.6 ADCY5-related dyskinesia

Prevalence is unknown. By 2023 about 100 individuals had been published, the number gathered in the scoping review that selected 87 articles, mostly case reports and case series [21, 46]. The only estimate of relative frequency comes from a multicentre paediatric cohort: on screening of the entire ADCY5 coding sequence in 44 unrelated children with genetically unexplained childhood-onset hyperkinetic disorders (isolated chorea or chorea associated with myoclonus and dystonia, with normal cerebrospinal fluid studies and neuroimaging, followed in tertiary centres), five patients with pathogenic variants were identified, that is 11% of the cohort: three with p.(Arg418Trp), one with p.(Arg418Gln) and one with p.(Arg418Gly), four de novo and one inherited from an equally affected father [62]. This figure measures the proportion in an already selected and extensively investigated group and is not a population prevalence. The autosomal recessive form has been described in eight individuals from five families, with published cases from Saudi Arabia and Japan [21, 44, 45]. The sources consulted contain no regional prevalence data or studies in Portugal or Brazil, and the literature assumes that the disease remains underdiagnosed, partly because of undetected mosaicism and partly because of confusion with dyskinetic cerebral palsy and with epilepsy [46, 49]. Resources for patients and families include the organisation ADCY5.ORG, which funded the scoping review and through whose portal the questionnaire of the theophylline study was distributed, and the Dystonia Medical Research Foundation [21, 46, 101].

9.7 Data gaps

The sources consulted did not identify population prevalence studies of HD in Portugal or national population-based estimates in Brazil, which does not prove they do not exist; African and East Asian data are considered underestimated by the literature itself; and no regional prevalence data were found for BHC, SCA17 outside the United Kingdom and Japan, HDL1 or ADCY5-related dyskinesia, whose literature consists almost exclusively of case reports and case series, with the reporting bias inherent to them [46]. These absences should be acknowledged as gaps and not extrapolated from other populations [4, 12, 116].

10. Illustrative Clinical Case

10.1 Very early-onset juvenile Huntington disease with paternal transmission

Moeller and colleagues described a boy with paternally inherited juvenile HD and onset between 18 and 24 months [65]. Initial presentation comprised an ataxic gait, truncal titubation and language delay, and MRI showed cerebellar atrophy. The course was one of continuous regression: he stopped speaking, became dependent on a wheelchair and gastrostomy and developed increasing rigidity. Molecular testing revealed 250 to 350 CAG repeats, one of the largest published expansions. The authors emphasise that the very early age and ethical reservations about HD testing in minors delayed diagnosis [65]. The report details the chronology: normal development on formal assessment at 17 months; first consultation at 2 years and 9 months for an unsteady gait; at 4 years, absence of verbal language and loss of walking; at 5 years, gastrostomy and progression from hypotonia to severe rigidity. MRI at 3 years showed moderate atrophy of the cerebellar hemispheres and vermis, which was severe at 5 years and accompanied by mild diffuse white matter loss, without caudate atrophy (figure 1 of the original article, available open access at https://pmc.ncbi.nlm.nih.gov/articles/PMC8371413/). Family history indicated HD in the paternal grandmother; the asymptomatic father had never been tested, and a genetic counsellor initially advised against testing on ethical grounds, considering the presentation atypical for the age and because testing might reveal HD unrelated to the symptoms, functioning as predictive testing. Metabolic investigations, microarray, alpha-fetoprotein, testing for the FXN expansion, the spinocerebellar ataxia repeat panel, exome and mitochondrial DNA sequencing were normal; only at 7 years, at an Undiagnosed Diseases Network unit, did the family choose HTT testing, repeated by the laboratory to confirm the size. His 9-year-old brother, with seizures and behavioural abnormalities and, in the last year, dysarthria, gait instability and more seizures, had 98 CAGs [65].

The case illustrates several principles of this article: very large expansions arise almost exclusively through paternal transmission; the juvenile form presents with rigidity, ataxia, delay or regression and, frequently, epilepsy rather than chorea; and expansions of this size require methods capable of detecting very large alleles (TP-PCR, Southern blot), because conventional PCR may show only the normal allele [4, 56]. Another report described a 6-year-old boy with myoclonic seizures and 140 CAGs [118]. It also demonstrates the tension between the rule against testing asymptomatic minors and the need to confirm a diagnosis in a symptomatic child: in the presence of objective neurological signs, testing is diagnostic rather than predictive, and the Oxford Desk Reference recommends documenting an organic basis beforehand (paediatric neurological assessment, serial psychometry, MRI) [3, 4].

10.2 Benign hereditary chorea in a four-generation Norwegian family

Koht and colleagues described a four-generation Norwegian family with eight affected individuals, all with a movement disorder beginning before the first year of life, motor delay and chorea [119]. Learning difficulties were frequent from the first school years. In addition to chorea at rest, myoclonus, dystonia, ataxia, stuttering and tic-like movements were observed; all reported unsteadiness, and two had an ataxic gait. Most had asthma and clinical or subclinical hypothyroidism. All affected individuals carried NKX2-1 c.671T>G (p.Leu224Arg), and the authors provided videos as supplementary material [119]. The article, available open access (https://pmc.ncbi.nlm.nih.gov/articles/PMC4736661/), includes the BHC clinical spectrum (figure 1), the family pedigree (figure 2), a clinical table of the affected individuals and an Archimedes spiral from one patient (figure 3). The variant, described on the long transcript, is normalised as NM_001079668.3:c.671T>G p.(Leu224Arg) on the MANE transcript (NC_000014.9:g.36517813A>C), equivalent to NM_003317.4:c.581T>G p.(Leu194Arg) on the short transcript [24].

The family demonstrates that “benign hereditary chorea” is not limited to chorea, that the combination with asthma and thyroid dysfunction guides diagnosis even without the complete brain–lung–thyroid presentation, and that recognising the diagnosis has practical consequences: annual thyroid and pulmonary surveillance (including malignancy screening from ages 5 and 13, respectively), avoidance of neuroleptics and tobacco exposure, and neonatal testing of at-risk offspring [12].

10.3 Teaching scenario: request for predictive testing with a borderline result

Scenario constructed for teaching purposes, without correspondence to a real patient. A 28-year-old woman, whose father was diagnosed with HD at 52 (44 confirmed CAGs), requests predictive testing because she plans to become pregnant. Over three counselling consultations, with time for reflection and her partner present as a companion, motivations, the possible impact of results, depression screening and the alternative of exclusion PGT, which would allow her to have children without knowing her status, are discussed [3, 4, 10]. She chooses testing; the result is 17 and 39 CAGs. In-person disclosure explains that this is a reduced-penetrance allele, that the lifetime probability of manifesting the disease is uncertain, that median onset for 39 CAGs is ~66 years, with wide variability, and that possible absence of the CAA interruption may underestimate the true size by two units — so sequencing analysis of the repeat region may be discussed [4, 27, 29]. For offspring, the risk of transmitting a pathogenic allele is 50%, with possible expansion, less likely in maternal transmission; prenatal diagnosis and PGT by direct analysis are discussed, and long-term follow-up is offered [3, 4].

10.4 Nocturnal paroxysmal dyskinesia due to a mosaic ADCY5 variant

Shetty and colleagues described a 32-year-old man, born to non-consanguineous parents and with no history of perinatal injury, with paroxysmal involuntary movements during sleep since the age of 4 years [51]. On video-electroencephalography, each episode was preceded by arousal, marked by the appearance of posterior alpha rhythm, followed by generalised non-patterned choreiform movements with a dystonic component, described as generalised dyskinesia or “ballistic bursts”, lasting about three minutes with preserved consciousness. Episodes recurred 20 to 30 times a night, totalling 60 to 90 minutes of involuntary movements, predominated in the early morning hours and in winter, and also occurred during daytime naps. The interictal examination, brain magnetic resonance imaging and metabolic work-up were normal. The exome identified the recurrent ADCY5 variant c.1252C>T p.(Arg418Trp) in the mosaic state, with 13 mutant reads out of 85 (about 15%), confirmed by Sanger sequencing in the proband and absent in both parents, who were homozygous for the normal allele (figure 1 of the original article, open access at https://pmc.ncbi.nlm.nih.gov/articles/PMC7502297/) [51]. The variant is normalised as NM_183357.3:c.1252C>T p.(Arg418Trp) on the MANE transcript, corresponding to NC_000003.12:g.123352464G>A.

Clonazepam gave slight benefit, estimated at about 25%; carbamazepine, tetrabenazine, propranolol and trihexyphenidyl gave no benefit, and acetazolamide worsened the condition. With coffee at a dose equivalent to about 100 mg of caffeine, divided into two to three daytime doses plus one at bedtime, the patient reported resolution of 50 to 70% of nocturnal attacks, and video-electroencephalography recorded 20 episodes per night. Because of gastric discomfort associated with the volume of coffee, he was switched to 100 mg caffeine capsules at bedtime, continuing clonazepam 0.5 mg: from the first day there was a reported 90% reduction and, two months later, video-electroencephalography documented three episodes per night, each lasting about one minute, compared with thirty three-minute episodes before treatment; the response was maintained at three months, without adverse effects [51].

The case illustrates three points. Somatic mosaicism can produce a phenotype limited to nocturnal paroxysmal dyskinesias with a normal interictal examination, a situation in which a low allele fraction requires careful reading of the sequencing data and confirmation by a second method. Video-electroencephalographic recording quantifies the number and duration of episodes and allows objective measurement of response, which is valuable in a disease without a validated scale or controlled trials. And the effective caffeine dose in this patient was far below the upper limit of the range described in the retrospective series, which supports titration from low doses [51, 100]. The management described is that of an isolated report and does not constitute a protocol; in particular, worsening with acetazolamide is an individual finding and not an established contraindication [46, 51].

11. Prognosis and Long-Term Follow-up

11.1 Huntington disease

With progression, chorea becomes more marked, voluntary activity increasingly difficult, and dysarthria and dysphagia worsen; most patients stop working and become progressively dependent, retaining some personal independence for a time. In late stages, motor disability is severe and the patient is frequently completely dependent, mute and incontinent [4]. Median survival after onset is 15 to 18 years (range 5 to more than 25), and mean age at death is 54 to 58 years [4]; Síndromes Genéticas: Reconhecer para Tratar reports mean survival of 15 years, potentially reaching 40 years [23]. Causes of death include bronchopneumonia (frequently from aspiration), heart failure and suicide (5–10%) [4, 23]. The juvenile form lasts 8 to 12 years, shorter with larger expansions [4, 56]; the late-onset form, after age 50, tends to have a more prolonged course [4].

Potential long-term complications for carriers and at-risk individuals include symptom onset and the psychological, social and family problems arising from that knowledge [3]. Follow-up of symptomatic carriers, summarised in Section 7.4, includes UHDRS and cUHDRS at every visit, suicide screening, nutritional and swallowing assessment, sleep, driving and future planning (legal, financial and employment issues, with support from patient organisations) [4, 68]. Transition to home or institutional care is organised by social services when the patient can no longer care for themselves [4]. The HAS PNDS reports a median survival of 18 years after motor onset and death on average about 20 years after symptom onset [2].

The PNDS devotes a chapter to the medico-social dimension, based entirely on professional agreement for lack of publications. Aids should be introduced as soon as a need arises, progressively and starting with those the patient requests spontaneously, because anosognosia, fear of losing freedom and a sense of intrusion hinder acceptance; early professional help protects family carers from exhaustion, a frequent cause of breakdown in the care pathway [2]. In France, it is recommended to open a file with the Maison Départementale des Personnes Handicapées (MDPH) from the first functional impact — for example with the mobility inclusion card or recognition of disabled worker status (RQTH), which is confidential with respect to the employer —, to request human assistance before 60 years of age and the first opening of rights before 75 years, ages after which assessment passes to services for older people [2]. The advance arrangements to propose include the future protection mandate, designation of a trusted person, advance directives and, when the patient can no longer defend their own interests, family authorisation, safeguard of justice, curatorship or guardianship [2]. Remaining in employment, with workstation adaptation by the occupational physician and redeployment, or sheltered work (ESAT) in young patients, preserves income and activity. Day care and respite stays (up to 90 days a year in medico-social facilities) support staying at home; for permanent accommodation, before 60 years foyers de vie, FAM or MAS are sought and after 60 years residential homes and EHPAD, with temporary preparatory stays. Psychiatric services are sometimes the only emergency response in behavioural crises, and the PNDS calls for coordination between these services and the centres to organise the return home or to an adapted place of living [2].

Table 17A. French medico-social arrangements referred to in the PNDS

Source: HAS PNDS [2]. The thresholds and ages are those in force at the date of the PNDS (2021).

11.2 Phenocopies

In HDL2, death usually occurs 10 to 20 years after onset, presumably from starvation, immobility and dysphagia, as in HD; surveillance is at least annual (motor function, falls, cognition and driving, weight and swallowing, mood and suicide, sleep, family needs) [33]. In SCA17, progression leads to dependence, and neurological surveillance is annual or six-monthly [37]. In prion diseases, the course ranges from months (familial CJD and fatal familial insomnia) to a few years (Gerstmann-Sträussler-Scheinker syndrome) [95].

11.3 Benign hereditary chorea

Life expectancy is considered normal [12]. Chorea improves until puberty or early adulthood and then stabilises, potentially disappearing [41]. Long-term pulmonary and thyroid prognosis is less well described: progression is rare and manifestations may improve in adulthood, but patients with pulmonary involvement have a risk of respiratory failure early in life and infections and asthma throughout life, and compensated hypothyroidism is usually well controlled [12]. Lung carcinoma risk in young adults and the possibility of thyroid cancer justify lifelong annual surveillance, even in patients without manifestations in these organs [12].

11.4 ADCY5-related dyskinesia

Life expectancy is normal and, despite the breadth of the clinical spectrum, the disease is considered non-progressive, with stabilisation after adolescence; systematic longitudinal data are lacking, and both worsening in childhood and adolescence followed by stabilisation or partial improvement in adulthood and spontaneous improvement have been described [21, 46, 62]. The exception is the spastic-dystonic phenotype of M1 and M2 domain variants, which worsens slowly over time [46]. Disability ranges from mild to severe: the allele fraction of mosaicism, the mode of inheritance and the location of the variant in the protein explain part of this variation, with mosaicism and C1b domain variants associated with the mildest presentations and biallelic forms with the most severe [46, 47]. Recommended follow-up rests on scheduled visits monitoring existing manifestations, response to supportive care and the emergence of new manifestations, with periodic reassessment of the need for social support, palliative care or home nursing and for further genetic counselling when reproductive questions arise [21].

Table 18. Long-term follow-up

Sources: [2–4, 12, 21, 33, 37]. The “every visit” frequency in the American sources and the 1–2 annual visits to the centre in the PNDS do not contradict each other: the latter sets the minimum pace of specialist assessment.

12. Summary and Final Considerations

Huntington disease is caused by expansion of a CAG repeat in HTT exon 1, with four allelic classes of distinct clinical significance — normal (≤26), intermediate (27–35), pathogenic with reduced penetrance (36–39) and pathogenic with full penetrance (≥40) — and an inverse relationship between repeat number and age at onset that, although strong in groups, does not permit prediction of onset in an individual. Germline instability, greater in spermatogenesis, explains paternal anticipation and the juvenile form, usually with more than 55–60 CAGs, manifesting with rigidity, dystonia, epilepsy and school decline rather than chorea. Somatic instability and DNA repair modifiers (MSH3, FAN1 and others), together with loss-of-interruption variants causing allele size to be underestimated by two units, have shifted the focus of pathogenesis towards the DNA repeat itself and changed interpretation of borderline alleles.

Diagnosis relies on targeted repeat sizing, with methods detecting very large expansions, and predictive testing follows a multisession protocol established since 1994, with informed consent, psychological assessment, in-person disclosure and follow-up. Reproductive options include direct or exclusion prenatal diagnosis and PGT, including exclusion and non-disclosure protocols. Treatment remains symptomatic: VMAT2 inhibitors — tetrabenazine, deutetrabenazine and valbenazine — reduce chorea, but require titration, attention to CYP2D6 genotyping and depression and suicide surveillance. In disease modification, 2025–2026 brought discontinuation of the tominersen programme, the negative European opinion on pridopidine and submission, in September 2026, of an accelerated approval application for AMT-130 gene therapy, supported by phase I/II data compared with external controls; no disease-modifying therapy is approved at this date. The 2021 French PNDS adds a graded set of recommendations by symptom, rehabilitation, nutrition and oral health measures, a follow-up pace of 1–2 annual visits to the reference centre and a medico-social framework; it diverges from the other sources in the definition of the normal allele, the severity attributed to homozygosity and the recommendation of piracetam, which the French label contraindicates in Huntington chorea. The VMAT2 inhibitor regulatory framework also differs: in the USA, all three are authorised for HD chorea; in the EU, tetrabenazine has only national authorisations (in adults, with a maximum dose of 200 mg/day and no mandatory genotyping), deutetrabenazine is authorised only for tardive dyskinesia and valbenazine is not authorised.

In a Huntington-like phenotype with negative HTT testing, investigation should include C9orf72, JPH3 (mandatory in patients of African ancestry), TBP, ATN1, PRNP and treatable causes, such as Wilson disease. NKX2-1-related benign hereditary chorea occupies the opposite end of the spectrum: childhood-onset, non-progressive chorea with a developmental basis, forming part of a brain–lung–thyroid syndrome with variable expression, whose recognition requires early hypothyroidism treatment, lifelong pulmonary and thyroid surveillance and avoidance of dopamine blockers and tobacco. The lack, in the sources consulted, of population data from Portugal, Brazil, Africa and much of Asia is a gap that should be acknowledged without confusing it with the absence of studies.

ADCY5-related dyskinesia completes the spectrum at the opposite end from HD: a mixed hyperkinetic disorder beginning in infancy or early childhood, non-degenerative and with normal life expectancy, recognisable by perioral myoclonus, dyskinesia persisting during sleep and exacerbations at sleep–wake transitions, with normal magnetic resonance imaging and electroencephalography. In most cases it results from gain-of-function missense variants, with residue 418 as a hotspot, and in a minority from biallelic loss-of-function variants with a more severe phenotype; somatic mosaicism, present in 43% of de novo cases, causes mild presentations, complicates testing — which may require deep sequencing and other tissues — and raises the recurrence risk above that of the general population when the parents are apparently negative. No medicine is authorised for the disease, and the best available evidence, from retrospective series of 30 and 12 patients, supports adenosine A2A receptor antagonism with caffeine or modified-release theophylline, with bilateral pallidal stimulation reserved for disabling refractory dyskinesia.

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