Changrui Xiao

Background: The hereditary cerebellar ataxias are a clinically and genetically heterogeneous group of disorders characterized by progressive cerebellar degeneration leading to incoordination of gait, speech, limb, and eye movements. Hundreds of genes encoding diverse proteins underlie this family of degenerative disorders that may exhibit autosomal dominant, recessive, mitochondrial, or X-linked inheritance. Variations in clinical presentation, such as age of onset and severity, are typical of these disorders and are attributed to other genetic effects, notably repeat expansion instability. Methods: In this observational study, we evaluated 45 individuals in a 5-generation kindred exhibiting features of progressive ataxia and cognitive impairment with wide-ranging ages of onset, intergenerational anticipation, diverse clinical features, and male infertility. Results: The variant (m.9035 T > C) in the gene MT-ATP6 was detected in all affected individuals, and the age of onset from early childhood to the 8th decade was inversely correlated with heteroplasmy levels. Neuropsychological evaluation of affected individuals demonstrated low average/borderline overall intellectual ability and weaknesses in working memory, executive function, memory, and fine motor skills. Affected males had testicular atrophy and azoospermia. Postmortem examination revealed widespread cerebellar Purkinje cell loss. Testicular biopsy from one sterile male demonstrated a complete absence of germ cells and progenitors. Discussion: This study expands the phenotypic spectrum of MT-ATP6 to include azoospermia in affected males with cerebellar ataxia. Those with low levels of heteroplasmy had mild adult-onset ataxia reminiscent of many forms of SCA. Those with high levels of heteroplasmy had early onset and suffered from the full complement of ataxia, mild cognitive impairment, and in males’ azoospermia.

Background/Objectives: Neurofibromatosis Type 1 (NF1) plexiform neurofibroma (PN) can cause morbidity, including disfigurement that can negatively impact social functioning. Historically, the mainstay treatment is surgical resection. However, complete resection is often prohibitive due to multiple nerve involvement. Moreover, post-operative recurrence is common. MEK inhibitors, including selumetinib and mirdametinib, have recently changed the treatment paradigm for these tumors. In 2020, selumetinib was FDA-approved for pediatric NF1 patients with inoperable symptomatic PNs, but selumetinib remains under investigation for their adult counterparts. In 2025, mirdametinib was FDA-approved for use in adults with symptomatic incompletely resectable NF1 PNs. Lower partial response rates have been reported with mirdametinib compared to selumetinib, but direct comparative analyses have not been conducted to establish the superiority of one agent over the other. Results: We present a case of a 38-year-old male with a right facial PN successfully treated with selumetinib, resulting in a 16.77% tumor volumetric reduction over 7 months. Selumetinib was well tolerated in our patient, with an asymptomatic Grade 3 CPK elevation that subsequently improved with a dose reduction. Conclusion: Our case adds to the growing body of evidence suggesting that selumetinib is effective and well tolerated in adult patients with NF1-associated PNs.

Background and Objectives Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown. Methods This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup. Results In total, 15 of 44 patients received a diagnosis through genomic testing explaining their calcifications, and 2 more received a diagnosis that has not been previously associated with EICs. Six of the 15 were found to have one of the 4 genes (PDGFB, PDGFRB, SLC20A2, and XPR1) conventionally associated with the phenotypic term “idiopathic basal ganglia calcifications.” Discussion These findings support the use of genomic testing for symptomatic patients with EICs.