Adrenoleukodystrophy (ALD) is a rare X-linked genetic metabolic disorder characterized by the accumulation of very long chain fatty acids (VLCFA) within the adrenal glands, as well as the central and peripheral nervous systems. Adult-onset ALD is particularly uncommon and easily misdiagnosed. The objective of this study is to facilitate the early diagnosis and treatment of adult-onset ALD. Seven adult-onset ALD patients of Chinese descent were enrolled in the study. Detailed clinical characteristics, laboratory results, imaging findings and genetic testing of the patients were collected and analyzed. All seven patients diagnosed with adult-onset ALD were male, including two with adult cerebral ALD (ACALD), one with adrenomyeloneuropathy (AMN), and four presenting with the spinocerebellar variant. The primary clinical manifestations of the two ACALD patients were progressive cognitive dysfunction and psychiatric symptoms. The AMN patient showed chronic progressive spastic paraplegia and displayed non-specific thoracic spinal cord atrophy on MRI. Symptoms observed in the four patients with spinocerebellar variant included cerebellar ataxia, dysarthria, spastic paraplegia, peripheral neuropathy, sphincter dysfunction, and alopecia. These four patients all demonstrated symmetrical white matter hyperintensity (WMH) in the cerebellum on brain magnetic resonance imaging (MRI). Additionally, two of these patients exhibited abnormal MRI signals in the pyramidal tract. All the patients had an elevation of VLCFAs, which is diagnostic for ALD. One patient exhibited elevated adrenocorticotropic hormone (ACTH) and decreased cortisol levels, while six patients displayed slightly elevated ACTH levels and normal cortisol levels without any clinical signs of adrenal insufficiency. Genetic testing identified four known ABCD1 pathogenic variants as well as two novel pathogenic variants. Progressive cognitive impairment and behavioral abnormalities are common clinical manifestations of ACALD. AMN and the spinocerebellar variant are prevalent phenotypes of adult-onset ALD. Patients with adult-onset ALD may present with isolated WMH in the cerebellum on brain MRI. Routine screening for ALD should be conducted in male patients diagnosed with Addison's disease. Subclinical adrenal cortex insufficiency is a common finding in adult-onset ALD. Elevated levels of VLCFA function as a reliable clinical biomarker for ALD. The identification of novel pathogenic variants in ABCD1 broadens the genetic spectrum of ALD.

Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca2+) concentration. Here, we characterize an X-linked syndrome, its underlying genotype, and a functional evaluation of the identified candidate genetic variant. Evaluation of motor features, neuroimaging studies, neurophysiological, and cognitive tests. Whole exome sequencing (WES) was applied, a plasmid encoding BCAP31 with and without a candidate variant was transfected into SH-SY5Y cells to assess subcellular location and to measure Ca2+ levels in the cytoplasm. Adult-onset ataxia, cognitive impairment, and hearing loss leading to deafness are the predominant features. Reduced penetrance, slow progression with preserved ability to walk in advance age, and universal cerebellar atrophy are other features for this syndrome. This condition is associated with the new variant c.22G>A (V8I) in BCAP31 at Xq28. The subcellular location of the V8I BCAP31 protein was not altered but caused significant elevation of cytosolic Ca2+. Our findings expand the spectrum of variants in BCAP31 from neurodevelopmental syndromes to include a progressive neurodegenerative disease with variable expressivity. This is the first time ataxia is described in association with a BCAP31 variant and functional evidence of pathogenicity is provided. Additional BCAP31 cases featuring ataxia are needed to establish an association. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Apoptosis-inducing factor mitochondria-associated 1 (AIFM1) gene encodes a mitochondrial flavoprotein that mediates caspase-independent programmed cell death. We report a novel AIFM1 variant in 2 siblings with early-onset hearing loss and progressive cerebellar ataxia. We evaluated the clinical features, brain MRI scans, EMG studies, and whole genome sequencing (WGS). Sibling A is a 19-year-old man with auditory neuropathy at age 15 years, who subsequently developed optic atrophy, progressive gait and limb ataxia, peripheral neuropathy, and ambulation with cane by age 17 years. Brain MRI was normal. Sibling B is a 13-year-old boy with auditory neuropathy diagnosed at 7 and gait instability at 13, with rapid development of peripheral neuropathy, cerebellar ataxia, muscle weakness and atrophy needing wheelchair for mobility, and neuromuscular respiratory failure requiring noninvasive ventilation. Brain MRI showed mild cerebellar atrophy. Initial EMGs showed axonal neuropathy in both and diffuse chronic and active anterior horn cell disorder later in Sibling B. WGS revealed an X-linked, maternally inherited novel AIFM1 variant (c.1299C>G p. Ile433Met). AIFM1 variants should be considered in patients with hereditary cerebellar ataxia and auditory neuropathy. We highlight a novel AIFM1 variant and its phenotypic intrafamilial variability expanding the knowledge of the genetic spectrum of AIFM1-related diseases.

Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood. Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. 44 individuals with 31 unique NHE6 mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history. We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study. In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.

X-linked adrenoleukodystrophy (X-ALD) caused by ATP-binding cassette subfamily D member 1 (ABCD1) gene defects is the most common inherited peroxisomal disorder.The female cerebello-brainstem dominant type in which cerebellum and brainstem are mainly involved is very rare. We report a 40-year-old female who was diagnosed as the rare disorder with magnetic resonance imaging (MRI) and genetic analysis mainly. Her initial symptoms were progressive slurred speech and writing disturbance. Her brain MRI showed obvious atrophy of brainstem and cerebellum. She did not have adrenal insufficiency. Genetic analysis showed a heterozygous missense mutation in exon 4 of the coding region of ABCD1 (c.1252C > T, p.Arg418Trp).This is the first report of this particular mutation being associated with the cerebello-brainstem dominant phenotype of X-ALD, as well as the first description of this X-ALD variant in a (heterozygous) female patient.X-ALD should be considered in young and middle-aged patients with slow-progressing ataxia and dysarthria.