The expanding clinical and genetic spectrum of DYNC1H1-related disorders

Abstract

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Keywords: autophagy; intracellular trafficking; neurodevelopmental disorders; viral immunity.

Figure 1

Demographic findings. The demographic data of our cohort in relation to (A) ethnicity, (B) country of residence, (C) sex and (D) age distribution at the last clinical examination and divided by sex.

Figure 2

Genetic findings. DYNC1H1 protein structure, subdivided into different domains and with specified amino acid sequence length: beginning tail region (purple), including the dimerization domain (light green) and the overlapping dynein intermediate and light intermediate chain (DIC/DLIC) binding sites (dark green and blue), linker region (pink), motor region (light red) including AAA1-6 (dark red), stalk region (orange) consisting of CC6 and 7, MTBD region (yellow), as well as end tail region (purple). Below mutations are marked on protein level. The truncating variants p.Phe1169Serfs*8, p.Arg2179*, p.Arg3870*, as well as the splice site variant c.11595+3A>G are highlighted in red.

Figure 3

Protein modelling reveals pathogenic effects of patient mutations on protein level. (A) Tyr1019Cys with a predicted destabilizing effect (ΔΔGStability of −2.48 kcal/mol) modelled in PDB structure 7Z9J; mutant Cys1019 (right) with loss of hydrogen bonds to the illustrated surrounding residues in comparison to wild-type Tyr1019 (left). (B) Val1705Ala with a predicted destabilizing effect (ΔΔGStability of −2.26 kcal/mol) modelled in PDB structure 7Z8G; mutant Ala1705 with loss of hydrogen bonds to Phe1686 and Val1673 when compared to wild-type Val1705. (C) Leu2137Pro with a predicted destabilizing effect (ΔΔGStability of −1.27 kcal/mol) modelled in PDB structure 7Z8G; mutant Pro2137 with loss of hydrogen bonds to the illustrated surrounding residues when compared to wild-type Leu2137. (D) Glu2294Leu with a predicted destabilizing effect (ΔΔGStability of −0.71 kcal/mol) modelled in PDB structure 7Z8G; mutant Leu2294 with loss of hydrogen bonds to Ile2287 when compared to wild-type Glu2294. (E) Gly2598Val with a predicted destabilizing effect (ΔΔGStability of −1.33 kcal/mol) modelled in PDB structure 7Z8G; mutant Val2598 with a gain in clash to Arg2797 when compared to wild-type Gly2598. (F) Arg2694Cys with a predicted destabilizing effect (ΔΔGStability of −1.43 kcal/mol) modelled in PDB structure 7Z8G; mutant Cys2694 with gain of several hydrogen bonds to the illustrated surrounding residues when compared to wild-type Arg2694. Protein modelling with DynaMut2, red = hydrogen bonds; orange = polar bonds; bright blue = van der Waals bonds; violet = clash.

Figure 4

Clinical features of DYNC1H1-related disorders. (A) Photographs of patients in our cohort with pathogenic heterozygous DYNC1H1 variants. Patient P1 age-related progressing pes cavus. Patient P12 bilateral talipes equinovarus. Patient P16 bilateral talipes equinovarus with predominant left-sided expression. Patient P17 left-sided talipes equinovarus and right vertical talus with hyperflexibility. Patient P18 clinodactyly. Patient P20 brachycephaly, plagiocephaly, face bones anomaly, bilateral developmental dysplasia of the hip and congenital bilateral talipes equinovarus. Patient P26 muscle weakness and atrophy of the lower limbs. Patient P27 muscle weakness and atrophy of the lower limbs. Slight pes caves and clinodactyly. Patient P29 pes valgus and planus. (B) Brain MRI studies indicated small pituitary gland in a T₁-weighted image of Patient P16 (white arrow), corpus callosum dysgenesis in T₂-weighted images of Patients P19 and P28 (red arrows), and a cerebellar hypoplasia in Patient P28 (yellow arrow). Brain MRI of Patient P47 showed a thinned mesencephalon as well as a simplified and thickened cortex of the temporal and insular regions, associated with deep sylvian valleys, suggestive of bi-opercular dysplasia. (C) X-ray of Patient P17 with a congenital femur fracture and bone density <10%. (D) Muscle biopsy histology in Patient P9 indicates type 1 fibre predominance in ATPase (pH 10.3) (right) and internalized nuclei haematoxylin and eosin (left), as well as few non-specific myopathic changes with only few internalized nuclei in haematoxylin and eosin, trichrome Gomorri and succinate dehydrogenase stainings in Patient P41.

Figure 5

Evolution of DYNC1H1-related disorders over a life-long continuum. The age-related key findings of the patients in our cohort are shown as illustrative examples. We observed an occurrence of hypotonia, femur fracture, congenital foot deformities and contractures at infancy. Developmental delay and (speech) regression, muscle weakness and atrophy, abnormal gait, seizures and constipation occurred mainly at early childhood. We observed an age-related progression of hypo-/areflexia, muscle weakness and atrophy, cognition and memory disturbances, brain malformations and sensory axonal neuropathy at late adolescence and early adulthood. ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; DTR = deep tendon reflexes; LL = lower limb; UL = upper limb. Created with BioRender.com.