Rare and very rare neurological diseases primarily or exclusively affect the nervous system with a prevalence of < 5 out of 10'000 and 100'000 people, respectively. Besides these, there are undiagnosed neurological diseases: neurological conditions without a diagnosis after completing a full diagnostic examination.

Rare, very rare, and undiagnosed neurological diseases are complicated and progressive and often cause variegated motor signs, impairments, and syndromes.

Balance and gait are frequently affected in these conditions, already at the clinical examination. These balance and gait impairments limit activities and cause an increased risk of falling. Falls can eventually result in injuries, even severe.

There are only a few studies about these diseases, likely because of their rarity. Hence, the clinical presentation and the course of rare and very rare diseases are poorly known or even unknown. Essential information for these conditions' diagnosis, prognosis, treatment and rehabilitation is missing.

MaNeNeND is an observational study underway at the Fondazione IRCCS Istituto Neurologico "Carlo Besta" (Milano) aimed at detailing the clinical and biological features of very rare and undiagnosed neurological diseases.

Research questions:

1. Do patients with rare (Ra), very rare (V) and undiagnosed (U) neurological diseases suffer a balance and gait impairment?
2. Is there a correlation between the clinical and instrumental severity of the balance and gait impairment in RaVU neurological diseases?
3. Are instrumental measures more sensitive in detecting balance and gait impairments in patients affected by a RaVU neurological disease than the clinical measures?
4. Do the balance and gait impairments in RaVU neurological diseases worsen in time?

The current project aims at diagnosing, quantifying and detailing the balance and gait impairment in rare, very rare and undiagnosed neurological diseases.

To this aim, questionnaires, clinical scales and instrumental tests will be administered to these patients to collect a wide range of balance and gait measures.

These measures will also integrate those collected with MaNeNeND to provide a more detailed description of patients with rare, very rare and diagnosed neurological diseases.

Participants will complete two questionnaires: the Dizziness Handicap Inventory - short form (DHI-sf, an ordinal score of self-perceived balance) and the Modified Fatigue Impact Scale (MFIS, an ordinal score of self-perceived fatigue).

Moreover, a clinician will administer the Mini Balance Evaluation Systems Test (Mini-BESTest, an ordinal score of balance), the 10 m walking test (for measuring the gait speed and other gait parameters) and the Timed Up and Go test (an instrumental measure of mobility and balance). Walking and the Timed Up and Go tests will be recorded with a trunk-worn inertial measurement unit.

Finally, participants will be asked to complete an instrumental upright stance and gait assessment, the first consisting of standing on posturographic plates and the second of walking on a treadmill equipped with force sensors. When walking on the treadmill, an optoelectronic system will also record the position in time of limbs and trunk.

The quantification of the severity of the balance and gait impairment of the patients suffering a rare, very rare or undiagnosed neurological disease will highlight these persons' therapeutic and rehabilitative needs.

Comparing the balance and gait impairment of rare, very rare and undiagnosed diseases with those of multiple sclerosis, Parkinson's disease and peripheral neuropathy will highlight if the formers' balance and gait impairment has unique characteristics that could help ease the diagnosis of these uncommon conditions.

The longitudinal measurements on rare, very rare and undiagnosed diseases will be paramount to identifying prognostic factors.

In addition, the data collected in the current study will be crucial for future studies, for example, for estimating the sample size in clinical trials.

Inclusion criteria

• Multiple sclerosis, Parkinson's disease, peripheral neuropathy of the lower limbs or rare or ultrarare neurological disease (e.g. la Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome - CANVAS, ORPHAcode: 504476; Wilson's disease, ORPHAcode: 905)
• undiagnosed neurological disease, i.e. a neurological disease that remains unknown after a full diagnostic assessment;
• age > 18 years;
• ability to stand upright with no assistance and no assistive device for > 30 seconds;
• ability to walk without assistance and with no assistive device for > 50 m;
• ability to give their informed consent.

Exclusion criteria

• pregnancy or breastfeeding
• any other medical conditions affecting by itself balance and gait (e.g. lower limb amputation, hemiparesis due to a stroke)
• major orthopaedic surgery (e.g. hip or knee replacement).

Patients with a balance and gait impairment secondary to multiple sclerosis, Parkinson's disease, peripheral neuropathy of the lower limbs, a rare, ultrarare or undiagnosed neurological disease.

A group of age-matched controls will also be recruited.

The database will be made available upon request on Zenodo.