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Improving ataxia symptoms in patients with monoallelic DHDDS-CDG using nicotinamide precursor supplements

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:


Congenital disorders of glycosylation are disorders of protein modification. In these disorders, decreased or aberrant surface glycosylation impair protein trafficking and function. Dehydrodolichol diphosphate synthase (encoded by DHDDS) works in complex in the NAD-dependent dolichol cycle to produce dolichol; its derivative dolichol phosphate is a lipid carrier and monosaccharide donor of N- & O-glycosylation/GPI anchor formation, respectively. Defective variants in DHDDS lead to typically severe early-onset multisystemic autosomal recessive disease; however, inheritance of a single defective variant causes isolated neurological manifestations (ataxia, developmental delay, speech apraxia, and seizures). Like other rare diseases, monoallelic DHDDS-CDG has been diagnosed in very few (<100) individuals; and, medical therapy remains elusive.

 

Methods:


In a model organism screen for modifiers of monoallelic DHDDS-CDG, several NAD precursors improve cell growth viability via ATP production. Among other nicotinamide precursors, one of the drugs that induced the largest response was the small-molecule nicotinamide mononucleotide (NMN). We describe four individuals with autosomal dominant DHDDS-CDG (ages 9-19; harboring known disease-associated p.R37H and p.R205Q variants) who were started on NMN for adjunctive therapy. Phenotypes associated with disease presentation were obtained on initial intake, and ataxic symptoms were monitored with the International Cooperative Ataxia Rating Scale (ICARS).

 

Results:


On intake, these individuals had varying levels of autism/intellectual disability requiring specialized education (2/4), speech delay with persistent impairment (2/4), and functionally impairing ataxia (ICARS range 12-25). Patients on NMN demonstrated subjective and objective improvements in movement and speech (standard video imaging and n = 1 on follow-up with an improvement of 10 in ICARS score).

Conclusion:


Taken together, these findings suggest that replenishment of NAD+ via precursor therapy partially rescues the metabolic defect of monoallelic DHDDS-CDG and may provide a viable therapy for this disease.

 

Agenda

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