Name: SKY-0515 in Huntington's disease: Diagnosis
Published: 2026-09-16T18:00:43-04:00

Establishing the diagnosis: clinical findings and molecular genetic testing

“The diagnosis of HD is established in a proband with suggestive findings and a heterozygous CAG trinucleotide repeat expansion in HTT identified by molecular genetic testing (see Table 1).” (opens the source at this quote in a new tab)
“Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.” (opens the source at this quote in a new tab)

“The diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state.” (opens the source at this quote in a new tab)

Laboratory testing standards

“Assays used to diagnose Huntington disease must be optimized to ensure the accurate and unambiguous quantitation of CAG repeat length.” (opens the source at this quote in a new tab)

Clinical motor diagnosis: diagnostic confidence level

“Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset.” (opens the source at this quote in a new tab)

“with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale)” (opens the source at this quote in a new tab)

Staging: Huntington's Disease Integrated Staging System

“The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments.” (opens the source at this quote in a new tab)

“If there are signs of neurodegeneration, evidenced by atrophy of the caudate or putamen, individuals are assigned to stage 1. If disease signs are measurable by the TMS or Symbol Digit Modalities Test (SDMT), they are classified as stage 2. Finally, if there is an impact on daily functioning as assessed by the Total Functional Capacity (TFC) or the Independence Scale, individuals are assigned to stage 3.” (opens the source at this quote in a new tab)
“Clinical motor diagnosis, or a Diagnostic Confidence Level (DCL) of 4, corresponds to the latter part of HD-ISS stage 2.” (opens the source at this quote in a new tab)

Predictive genetic testing in at-risk individuals

“Testing of asymptomatic adults at risk for HD is possible but requires careful deliberation, as there is currently no cure for the disorder” (opens the source at this quote in a new tab)
“Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed.” (opens the source at this quote in a new tab)

“Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not.” (opens the source at this quote in a new tab)

Biomarkers: plasma neurofilament light protein

“Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next.” (opens the source at this quote in a new tab)
“In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48-7·34, p=0·0036).” (opens the source at this quote in a new tab)

Neuroimaging

“Regional atrophy of the caudate and putamen is among the earliest pathologic changes in HD” (opens the source at this quote in a new tab)