CMT4A
The SPARK Study
Schwann cell & Axonal Registry for Prospective study of CMT4A (GDAP1)
A prospective, genotype-defined natural history study of biallelic GDAP1-related Charcot-Marie-Tooth disease
Sponsored by the Hereditary Neuropathy Foundation, conducted through the GRIN Registry
SPARK, the CMT4A Natural History Study, is HNF’s dedicated natural history study for patients with biallelic (autosomal recessive) GDAP1 mutations causing CMT4A, the most severe subtype of GDAP1-related Charcot-Marie-Tooth disease. Mitochondria are the spark of cellular energy, and biallelic GDAP1 loss-of-function mutations extinguish it in both the axons that carry nerve signals and the Schwann cells that insulate them. It is the one CMT gene known to strike both cell types at once.
Why CMT4A needs its own study
CMT4A is early-onset, rapidly progressive, and disproportionately disabling relative to other GDAP1-related subtypes. In the first dedicated natural history data on GDAP1-related neuropathy, roughly half of CMT4A patients required a wheelchair and all required walking support, far exceeding the disease burden seen in dominant GDAP1 subtypes.
By prospectively capturing genotype-phenotype correlations, disease progression markers, and biomarker data specifically within this biallelic, demyelinating population, SPARK is building the evidence base needed to bring HNF’s two active therapeutic programs, AAV gene therapy and HDAC6 inhibition, to clinical trial readiness: genotype-matched cohorts, validated outcome measures, and longitudinal natural history data.
Built to reach patients where they are
Because CMT4A is rare and geographically scattered, concentrated in southern Spain, southern Italy, and northern Finland, with smaller cohorts identified in China and Brazil, patients are often far from the handful of specialists who understand this specific gene. SPARK is designed to be as decentralized as possible: bringing the study to patients wherever they live, rather than requiring them to travel to a small number of specialized centers.
How it works
Four phases, built so that each one adds to what came before.
- I Join and share your story Join GRIN, HNF’s Global Registry for Inherited Neuropathies, and complete your patient journey profile. Upload your genetic report confirming biallelic (two-copy) GDAP1 mutations if you have one. This is the foundation. Every phase after this builds on what you share here.
- II Biospecimen collection Once enrolled, an HNF/GRIN co-investigator will contact you to arrange a biospecimen collection. At-home collection is currently available for participants in the United States. International participants: we do not yet have a solution for at-home collection outside the U.S., but you can still donate samples in person at either of our upcoming Summits (see Phase III), and we are actively working on how to extend remote collection globally.
- III Join us at the annual CMT Clinical Trial Readiness Summit SPARK participants, including international participants unable to access at-home collection, are invited to attend HNF’s Annual CMT Clinical Trial Readiness Summit, where standardized outcome measures are collected in person: CMAP amplitude and nerve conduction velocity, validated functional composite scores (CMTNS2 / CMT-FOM), the 9-hole peg test, and timed walk / 6-minute walk testing. This includes pilot studies using FDA-registered wearable devices to objectively assess gait, balance, fall risk, mobility, and upper limb function, alongside blood and urine sample donation to the CMT Biobank. The upcoming Summits are April 2027 and April 2028.
- IV Longitudinal follow-up at the Summit Participants return to the Summit year over year for reassessment, combining in-person clinical measures with the ongoing real world data collected between visits, building the first longitudinal natural history dataset for CMT4A and the exact evidence industry needs to design and qualify future clinical trials.
Between Summits: remote monitoring and real world data
SPARK does not pause between annual Summit visits. Participants take part in continuous, at-home monitoring designed to capture quality of life as it is actually lived day to day, available to participants both in the United States and internationally.
Study design summary
- Population
- Genetically confirmed biallelic (autosomal recessive) GDAP1 loss-of-function mutations causing CMT4A, all ages, across the disease severity spectrum.
- Design
- Prospective, multi-site (hub-and-spoke), observational. Minimum 2-year follow-up with annual Summit visits and continuous remote monitoring between visits.
- Primary endpoints
- CMAP amplitude (peroneal / ulnar), motor and sensory nerve conduction velocity, and CMTNS2 / CMT-FOM or an equivalent validated functional composite score.
- Secondary endpoints
- The 9-hole peg test, timed 10-meter walk and 6-minute walk (ambulatory patients), wheelchair-use and walking-support status, pulmonary function (FVC) given diaphragmatic involvement in advanced disease, patient-reported quality-of-life measures, and wearable-derived digital endpoints.
- Biosamples
- Blood, PBMCs, urine, and iPSCs collected at each visit for the CMT Biobank.
- Use of data
- Defines trial eligibility and stratification for the biallelic GDAP1 / CMT4A population specifically, supports endpoint selection, and may serve as a historical or external comparator given the ultra-rare nature of CMT4A.
TRIAD partners
SPARK is conducted in partnership with the TRIAD consortium, together providing the clinical, genetic, and translational infrastructure to move CMT4A from a neglected subtype to an active area of treatment development.
- Weill Cornell Medicine
- Boston University
- Transcripta
- University of Miami
- Inotiv
- Miralinc Pharmaceuticals
Take part in SPARK
Everything starts with Phase I. Joining GRIN and completing your patient journey profile is what makes every later phase possible.
Join the GRIN Registry