De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
Authors: Galosi Serena , Edani Ban H , Martinelli Simone , Hansikova Hana , Eklund Erik A , Caputi Caterina , Masuelli Laura , Corsten-Janssen Nicole , Srour Myriam , Oegema Renske , Bosch Daniëlle G M , Ellis Colin A , Amlie-Wolf Louise , Accogli Andrea , Atallah Isis , Averdunk Luisa , Barañano Kristin W , Bei Roberto , Bagnasco Irene , Brusco Alfredo , Demarest Scott , Alaix Anne-Sophie , Di Bonaventura Carlo , Distelmaier Felix , Elmslie Frances , Gan-Or Ziv , Good Jean-Marc , Gripp Karen , Kamsteeg Erik-Jan , Macnamara Ellen , Marcelis Carlo , Mercier Noëlle , Peeden Joseph , Pizzi Simone , Pannone Luca , Shinawi Marwan , Toro Camilo , Verbeek Nienke E , Venkateswaran Sunita , Wheeler Patricia G , Zdrazilova Lucie , Zhang Rong , Zorzi Giovanna , Guerrini Renzo , Sessa William C , Lefeber Dirk J , Tartaglia Marco , Hamdan Fadi F , Grabińska Kariona A , Leuzzi Vincenzo 
Published: August 2021

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 fibres 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.