De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Abstract

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants

“…Variable glycosylation of the different lysosomal enzymes could also explain some of the neurological manifestations such as movement disorders and seizures. Furthermore, abnormalities in the dolichol pathway can result in low dolichol levels underlying some of the clinical features in DHDDS related disorders [ 10 ].…”

“…Multisystem presentation in association with DHDDS variants have been linked to various genetic mechanisms. Hamdan et al (2017) and Galosi et al (2021) identified de novo pathogenic variants (R37H and R211Q) in DHDDS which have been reported in multiple families with developmental delay, seizures, myoclonus, and adult-onset ataxia (MIM 617836 ) [ [10] , [11] , [12] ]. Sabry et al (2016) identified biallelic loss of function pathogenic variants (c.192G > A; p.W64X and the splicing variant c.441-24A > G) in DHDDS in a young male with hypotonia and lethal epileptic encephalopathy (13).…”

“…As p.F304S has been considered as a modifier that exacerbates the expression in individuals carrying pathogenic variants in other CDG genes, the authors suggested that the ALG6 variant might have had a role in enhancing phenotypic severity in this case (MIM 613861 ). This patient (with DHDDS-CDG) had an early onset and exhibited very severe multisystem organ involvement such as bradycardia, axial hypotonia, peripheral hypertonia, an enlarged liver with high transaminases levels, renal failure, and status epilepticus resulting in death at 8 months of age [ 10 , 11 , 13 ].…”

Structural basis for long-chain isoprenoid synthesis by cis -prenyltransferases

“…1A) (15). In line with its important biological roles, mutations in both subunits of hcis-PT were identified as causing several human diseases with ocular (16,17) and neurological (18)(19)(20)(21) manifestations, among others (22,23). Physiologically, hcis-PT is localized to the endoplasmic reticulum (ER) membrane via an N-terminal transmembrane domain of NgBR, where it synthesizes the precursor for dolichol-phosphate (Dol-P) by consecutive condensations of IPP onto the allylic diphosphate primer farnesyl diphosphate (FPP, C 15 ) (Fig.…”

Structural basis for long-chain isoprenoids synthesis by cis-prenyltransferases

“…14 This heteromeric enzyme is composed of two types of subunits: a catalytic subunit termed dehydrodolichyl diphosphate synthase (DHDDS) and an auxiliary quiescent subunit termed Nogo B-receptor (NgBR) (Figure 1A). 15 In line with its important biological roles, mutations in both subunits of hcis-PT were identified as causing several human diseases with ocular 16,17 and neurological [18][19][20][21] manifestations, among others. 22,23 Physiologically, hcis-PT is localized to the endoplasmic reticulum (ER) membrane via an N-terminal transmembrane domain of NgBR, where it synthesizes the precursor for dolichol-phosphate (Dol-P) by consecutive condensations of IPP onto the allylic diphosphate primer farnesyl diphosphate (FPP, C 15 ) (Figure 1B).…”