RESUMEN
Pathogenic variants in DHDDS have been associated with either autosomal recessive retinitis pigmentosa or DHDDS-CDG. Heterozygous variants in DHDDS have been described in patients with a progressive neurodegenerative disease. Here we report on an individual presenting with a multisystem CDG phenotype who was diagnosed with known homozygous pathogenic DHDDS variants, previously associated with isolated retinitis pigmentosa. An adult Ashkenazi Jewish female developed multiple symptoms of late onset type 1 CDG including seizures, ataxia, protein losing enteropathy, tremor, and titubation in association with elevated mono-oligo/di-oligo transferrin ratio in blood, and classic retinitis pigmentosa. She was diagnosed by whole exome sequencing with the common Ashkenazi Jewish, homozygous p.K42E variants in DHDDS. She was started on Acetazolamide and responded well to the treatment which improved her titubation, tremor, and generalized edema. Reviewing the literature, families with DHDDS variants and multisystem presentation were different from our patient's presentation in terms of clinical manifestations, severity, genetic defect, and mode of inheritance. In previously reported patients with neurologic symptoms including seizures, movement abnormalities, and global development delay, the phenotype was caused by heterozygous pathogenic variants in DHDDS. The infant who was reported with a multisystem phenotype and fatal type 1 CDG had compound heterozygosity for a nonsense and a splice site variant in DHDDS, resulting in DHDDS-CDG. The discovery of the novel phenotype associated with the common p.K42E pathogenic variant in DHDDS expands the spectrum of CDG and further enhances our understanding on the role of DHDDS in glycosylation beyond the retina.
RESUMEN
Patient-reported outcomes (PROs) measure important aspects of disease burden, however they have received limited attention in the care of patients with Congenital Disorders of Glycosylation (CDG). We evaluated the PROs and correlation between clinical disease severity scoring and reported quality of life (QoL) in a PMM2-CDG patient cohort. Twenty-five patients with diagnosis of PMM2-CDG were enrolled as part of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study. Patient- Reported Outcomes Measurement Information System (PROMIS) was completed by caregivers to assess health-related QoL. Clinical disease severity was scored by medical providers using the Nijmegen Progression CDG Rating Scale (NPCRS). The domains such as physical activity, strength impact, upper extremity, physical mobility, and a satisfaction in social roles (peer relationships) were found to be the most affected in the PMM2-CDG population compared to US general population. We found a strong correlation between NPCRS 1 (current functional ability) and three out of ten PROMIS subscales. NPCRS 2 (laboratory and organ function) and NPCRS 3 (neurological involvement) did not correlate with PROMIS. Mental health domains, such as anxiety, were positively correlated with depressive symptoms (r = 0.76, p = 0.004), fatigue (r = 0.67, p = 0.04). Surprisingly, patients with severely affected physical mobility showed low anxiety scores according to PROMIS (inverse correlation, r = -0.74, p = 0.005). Additionally, there was a positive correlation between upper extremity and physical mobility (r = 0.75, p = 002). Here, we found that PROMIS is an informative additional tool to measure CDG disease burden, which could be used as clinical trial outcome measures. The addition of PROMIS to clinical follow-up could help improve the quality of care for PMM2-CDG by facilitating a holistic approach for clinical decision-making. SYNOPSIS: We recommend PROMIS as an informative tool to measure disease burden in PMM2-CDG in addition to traditional CDG disease severity scores.
