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Objective To expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD). Methods We performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional rating scales. We performed ophthalmologic examinations and metabolic testing. Results A 41-year-old patient presented with slowly progressive lower limb spasticity combined with optic atrophy. He was clinically diagnosed with complex hereditary spastic paraparesis. The initial panel diagnostics did not reveal the disease-causing variant; therefore, ES was performed. ES revealed biallelic pathogenic variants in the BTD gene leading to the genetic diagnosis of BD. BD is an autosomal recessive metabolic disorder causing a broad spectrum of neurologic symptoms, optic atrophy, and dermatologic abnormalities. When treatment is initiated in time, symptoms can be prevented or reversed by biotin supplementation. After diagnosis in our patient, biotin supplementation was started. One year after the onset of therapy, symptoms remained stable with slight improvement of sensory deficits. Conclusions These findings expand the genetic spectrum of the clinical diagnosis of complex hereditary spastic paraparesis by a treatable disease. Today, most children with BD should have been identified via newborn screening to start biotin supplementation before the onset of symptoms. However, adult patients and those born in countries without newborn screening programs for BD are at risk of being missed. Therapeutic success depends on early diagnosis and presymptomatic treatment.

Objective To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia. Methods Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length. Results Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62). Conclusion Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects-we found NfL levels to be stable.

Journal of neurology -, - (2020). doi:10.1007/s00415-020-09722-6, Published by Springer37620, Berlin