The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders
Authors: Saffari Afshin , Lau Tracy , Tajsharghi Homa , Karimiani Ehsan Ghayoor , Kariminejad Ariana , Efthymiou Stephanie , Zifarelli Giovanni , Sultan Tipu , Toosi Mehran Beiraghi , Sedighzadeh Sahar , Siu Victoria Mok , Ortigoza-Escobar Juan Darío , AlShamsi Aisha M , Ibrahim Shahnaz , Al-Sannaa Nouriya Abbas , Al-Hertani Walla , Sandra Whalen , Tarnopolsky Mark , Alavi Shahryar , Li Chumei , Day-Salvatore Debra-Lynn , Martínez-González Maria Jesús , Levandoski Kristin M , Bedoukian Emma , Madan-Khetarpal Suneeta , Idleburg Michaela J , Menezes Minal Juliet , Siddharth Aishwarya , Platzer Konrad , Oppermann Henry , Smitka Martin , Collins Felicity , Lek Monkol , Shahrooei Mohmmad , Ghavideldarestani Maryam , Herman Isabella , Rendu John , Faure Julien , Baker Janice , Bhambhani Vikas , Calderwood Laurel , Akhondian Javad , Imannezhad Shima , Mirzadeh Hanieh Sadat , Hashemi Narges , Doosti Mohammad , Safi Mojtaba , Ahangari Najmeh , Torbati Paria Najarzadeh , Abedini Soheila , Salpietro Vincenzo , Gulec Elif Yilmaz , Eshaghian Safieh , Ghazavi Mohammadreza , Pascher Michael T , Vogel Marina , Abicht Angela , Moutton Sébastien , Bruel Ange-Line , Rieubland Claudine , Gallati Sabina , Strom Tim M , Lochmüller Hanns , Mohammadi Mohammad Hasan , Alvi Javeria Raza , Zackai Elaine H , Keena Beth A , Skraban Cara M , Berger Seth I , Andrew Erin H , Rahimian Elham , Morrow Michelle M , Wentzensen Ingrid M , Millan Francisca , Henderson Lindsay B , Dafsari Hormos Salimi , Jungbluth Heinz , Gomez-Ospina Natalia , McRae Anne , Peter Merlene , Veltra Danai , Marinakis Nikolaos M , Sofocleous Christalena , Ashrafzadeh Farah , Pehlivan Davut , Lemke Johannes R , Melki Judith , Benezit Audrey , Bauer Peter , Weis Denisa , Lupski James R , Senderek Jan , Christodoulou John , Chung Wendy K , Goodchild Rose , Offiah Amaka C , Moreno-De-Luca Andres , Suri Mohnish , Ebrahimi-Fakhari Darius , Houlden Henry , Maroofian Reza 
Published: February 2023

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted.

Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0–24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week–9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death.

In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.