From the Guidelines
DYNC1H1 genetic disorders are associated with a range of neurological conditions, including peripheral nerve disease, spinal muscular atrophy with lower extremity predominance, and malformations of cortical development, as reported in a 2020 consensus statement 1. These disorders are characterized by interactions between collagen IV proteins, resulting in large caudate and vermian hypoplasia. The DYNC1H1 gene encodes a protein essential for motor neuron function and axonal transport, and mutations in this gene can lead to:
- Spinal muscular atrophy with lower extremity predominance (SMA-LED)
- Peripheral nerve disease ranging from fetal akinesia
- Malformations of cortical development, such as dysgyria Patients with DYNC1H1 disorders often present with:
- Muscle weakness, particularly in the legs
- Delayed motor milestones
- Intellectual disability Diagnosis requires genetic testing to identify DYNC1H1 mutations, and management is primarily supportive and multidisciplinary, including:
- Physical therapy to maintain muscle strength and range of motion
- Occupational therapy for daily living activities
- Orthotic devices or mobility aids as needed Regular monitoring by neurologists and other specialists is essential to address complications, and genetic counseling is important for affected families due to the autosomal dominant inheritance pattern. The underlying pathology involves disruption of dynein function, which impairs cellular transport mechanisms critical for neuronal development and maintenance, as noted in the 2020 study 1.
From the Research
Genetic Disorders Associated with DYNC1H1
The DYNC1H1 gene is associated with a range of genetic disorders, including:
- Spinal muscular atrophy with lower extremity dominance (SMALED) 2
- Autosomal dominant mental retardation syndrome 13 (MRD13) 2
- Peripheral neuromuscular disorders (NMD) 2, 3
- Neurodevelopmental disorders (NDD) 2, 3
- Charcot-Marie-Tooth disease type 2O 4, 5
- Infantile spasms 4
- Epilepsy 4
- Intellectual disability 4, 6
- Malformations in cortical development (MCD) 5, 6
- Hereditary motor and sensory neuropathy (HMSN) 5
- Axonal HMSN 5
- Cortical malformations 5
Clinical Features
The clinical features of DYNC1H1-related disorders can vary widely, but may include:
- Neuromuscular disease 2, 3, 6
- Intellectual disability 2, 4, 6
- Seizures 4
- Sensory neuropathy 3
- Autonomic features 3
- Behavioral disorders 3
- Movement disorders 3
- Periventricular lesions 3
- Primary immunodeficiency 3
- Bilateral sensorineural hearing loss 3
- Organ anomalies 3
- Skeletal manifestations 3
Genotype-Phenotype Correlations
There is evidence of genotype-phenotype correlations in DYNC1H1-related disorders, with certain domains of the gene associated with specific clinical features, such as:
- Mutations in the dimerization domain associated with reductions in lower limb strength in DYNC1H1-NMD 2
- Mutations in the motor domain associated with cerebral malformations in DYNC1H1-NDD 2
- Variants in the tail domain associated with axonal HMSN 5
- Variants in the stem domain associated with neuromuscular disease 6
- Variants in the motor domain associated with ID with MCD 6