DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Neurodevelopmental outcomes in a cohort of Australian families with self-limited familial epilepsy of neonatal/infantile onset.

OBJECTIVES: To determine: i) seizure recurrence; ii) developmental disability; iii) co-morbidities and risk factors in self-limited familial neonatal and/or infantile epilepsy (SeLFE) in a multigenerational study. METHODS: Families were retrospectively recruited from epilepsy databases (2021-2022) in 2 paediatric hospitals, Sydney, Australia. Eligible families had 2 first degree relatives with seizures and underwent genetic testing. Demographics/clinical data were collected from interviews and medical records. Vineland Adaptive Behaviour Scales-Third Edition measured adaptive function. RESULTS: Fifteen families participated. Fourteen had a genetic diagnosis (93%): 11 pathogenic; PRRT2 (n=4), KCNQ2 (n=3), SCN2A (n=4), 3 likely pathogenic; KCNQ2 (n=1), SCN8A (n=2). Seizures affected 73 individuals (ages 1-76 years); 30 children and 20 adults had in-depth phenotyping. Ten of 50 individuals (20%) had seizure recurrence, aged 8-65 years. Median time from last neonatal/infantile seizure was 11.8/12.8 years. Predictors of recurrence were high seizure number (p=0.05) and longer treatment duration (p=0.03). Seven children had global developmental delay (GDD): mild (n=4), moderate (n=1) and severe (n=2). Vineland-3 identified 3 had low-average and 3 had mild-moderately impaired functioning. The majority (82%) were average. GDD was associated with older age at last seizure (p=0.03), longer epilepsy duration (p=0.02), and higher number of anti-seizure medications (p=0.05). Four children had speech delay, 5 (10%) had Autism Spectrum Disorder. Paroxysmal kinesiogenic dyskinesia (n=5) occurred in 4 families and hemiplegic migraine (n=8) in 3 families. CONCLUSIONS: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative.

Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids.

BACKGROUND: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. METHODS: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs). FINDINGS: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively). INTERPRETATION: This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

SPG11 presenting with dystonic tremor in childhood.

This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor.

Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.

BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.

Biceps skin-fold thickness may detect and predict early lipoatrophy in HIV-infected children.

BACKGROUND: The prevalence of potentially stigmatizing lipoatrophy in children receiving antiretroviral therapy in Southern Africa is high, affecting around a third of children. Early diagnosis of lipoatrophy is essential for effective intervention to arrest progression. METHODS: Prepubertal children receiving antiretroviral therapy were recruited from a hospital-based family HIV clinic in Cape Town and followed up prospectively. Lipoatrophy was identified and graded by consensus between 2 HIV pediatricians. A dietician performed anthropometric measurements of trunk and limb fat. Anthropometric measurements in children with and without lipoatrophy were compared using multivariable linear regression adjusting for age and gender. The most discerning anthropometric indicators of lipoatrophy underwent receiver operating characteristic curve analysis. The precision of anthropometric measurements performed by an inexperienced healthcare worker was compared with that of a research dietician. RESULTS: Of 100 recruits, 36 had lipoatrophy at baseline and a further 9 developed lipoatrophy by 15-month follow-up. Annual incidence of lipoatrophy was 12% (confidence interval [CI]: 5-20%) per person-year of follow-up. A biceps skin-fold thickness <5 mm at baseline had a sensitivity of 89% (CI: 67-100%) and a specificity of 60% (CI: 46-75%) for predicting development of lipoatrophy by 15-month follow-up. Negative and positive predictive values were 97% (CI: 91-100%) and 32% (CI: 14-50%). CONCLUSION: Biceps skin-fold thickness <5 mm in prepubertal children exposed to thymidine analogue-based antiretroviral therapy may be a useful screening tool to identify children who are likely to develop lipoatrophy. The variation in precision of measurements performed by an inexperienced healthcare worker only marginally impacted performance.