2026 American Academy of Neurology Abstract Website

Sandra Azareli Garcia Velazquez¹, Paloma Parra Díaz², Burak Altintas³, Nawale Hadouri⁴, Emily Durham⁵, Shayanne Martin⁵, Arnaud Monteil⁶, Catherine Gooch³, Antonio Gil-Nagel⁷, Daniel Calame⁸, Jeremy Tanner¹
¹Neurology, University of Texas Health Science Center San Antonio, ²Neurology, Hospital Universitario Ramón y Cajal, Hospital Ruber Internacional, Fundación Iniciativa para las Neurociencias (FINCE), ³Pediatrics, Washington University in St. Louis, ⁴Physical Medicine and Rehabilitation, Dijon-Bourgogne University Hospital, ⁵Channeling Hope Foundation, ⁶Neuroscience, Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, ⁷Hospital Ruber Internacional, ⁸Baylor College of Medicine, Child Neurology

Objective:

Compile and analyze the clinical features associated with CLIFAHDD across reported cases.

Background:

Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the NALCN gene. While hallmark neurologic and musculoskeletal features are recognized, the broader multisystem clinical spectrum remains incompletely characterized.

Design/Methods:

Four individuals with CLIFAHDD were clinically characterized. A systematic review of molecularly confirmed cases was performed using different databases. Inclusion criteria required individuals with confirmed NALCN mutations. Data from 102 total individuals were extracted. Features were classified as primary (coverage ≥20 patients, frequency ≥70%) or supportive (coverage ≥10 patients, frequency ≥50%). Percentages reflect only patients in whom the feature was assessed.

Results:

Clinical evaluations of four unique patients revealed features of CLIFAHDD: global neurodevelopmental delay, hyperkinetic movements, ASD, irregular breathing, disrupted sleep, recurrent vomiting, and clinical regression with progressive ataxia. In the systematic review, findings included hypotonia (85%,n=44/52), global neurodevelopmental delay (100%,n=69/69), distinct craniofacial features—nasal abnormalities (98%,n=41/42), long philtrum (86%,n=24/28), micrognathia (87%,n=27/31), full cheeks (92%,n=22/24); and musculoskeletal contractures such as distal arthrogryposis (79%,n=37/47), camptodactyly (100%,n=36/36), ulnar deviation (100%,n=34/34), and clubfoot (67%,n=47/70). Neonatal complications included ventilatory support (42%,n=14/33), ICU care (53%,n=19/36), and feeding difficulties (81%,n=30/31). Neurologic features included movement disorders (75%,n=46/61), strabismus (65%,n=28/43), seizures (43%,n=23/53), autonomic dysfunction (90%,n=43/48), and ASD (34%,n=17/50). Gastrointestinal symptoms included feeding difficulties (92%,n=24/26), GERD (76%,n=41/54), constipation (76%,n=48/63), and recurrent vomiting (75%,n=27/36). Respiratory findings included irregular breathing (63%,n=24/38), respiratory insufficiency (47%,n=27/58), ventilatory support (24%,n=8/34), and central (38%,n=16/42) and obstructive (41%,n=17/42) apneas. Sleep disturbances included nocturnal arousals (54%,n=19/35) and other sleep issues (46%,n=26/56). Brain MRI was abnormal in 60% (n=30/50), with >90% showing cerebellar and cerebral atrophy.

Conclusions:

CLIFAHDD is a complex multisystem disorder. Broader recognition of non-neurologic manifestations is essential for comprehensive care and highlights the need for longitudinal, standardized phenotyping to guide future management and interventions.