Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B.

Current clinical scales that track disease progression are more tailored to spasticity or ataxia, with limited sensitivity to change. The aim was to develop a sensitive and valid scale specifically geared towards optimized sensitivity to change and adapted to patients presenting with both spasticity and ataxia. Longitudinal data from 127 spastic paraplegia type 7 (SPG7) and 112 autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) patients were collected within the multicenter PROSPAX study. Sensitivity to change over 2 years of 30 items from the Scale for the Rating and Assessment of Ataxias (SARA), Spastic Paraplegia Rating Scale (SPRS), and the Activities of Daily Living subscale of the Friedreich's Ataxia Rating Scale (FARS-ADL) was evaluated. Items that demonstrated the highest sensitivity to change were used to build the Spastic Ataxia Composite scale (SPAXCOM). With seven items, the SPAXCOM showed an effect size of 0.71, higher than reference scales (SARA: 0.43, SPRS: 0.42, FARS-ADL: 0.27). The SPAXCOM had a similar sensitivity to change for both genotypes and was more sensitive in participants with a SARA lower than 10 and within the intermediate disease stage (FARS-Disease Staging: 2-3.5). The SPAXCOM showed a high correlation with disease duration (r = 0.67 [0.60; 0.72]) and disease stage (r = 0.86 [0.83; 0.89]). Perception of improvement, stagnation, and worsening were associated with a mean yearly SPAXCOM change of 0.44 (-0.14; 1.01), 0.61 (0.19; 1.03), and 1.22 (0.96; 1.49), respectively. The SPAXCOM is more sensitive to change and homogeneous across genotypes than the reference scales, allowing a reduction of the required sample size in future clinical trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype of autosomal recessive hereditary spastic paraplegia (HSP), to date, there are more than 181 different KIAA1840 gene mutations detected, and yet the genetic landscape of SPG11 is far from complete. To find the clinical and genetic characteristics of SPG11, we performed a reanalysis of the clinical features and genotype-phenotype correlations in all reported studies exhibiting SPG11 mutations. A total of 339 patients were collected, their mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and mental retardation (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%). The most common brain MRI abnormality is thinning of the corpus callosum (TCC) (173/190, 91.05%), followed by periventricular white matter changes (130/158, 82.28%), cerebral or cerebellar cortical atrophy (55/107, 51.40%). The mutational spectrum associated with KIAA1840 gene is wide, and frameshift mutations are the most common type followed by nonsense mutations. Our reanalysis demonstrated that SPG11 exhibited significant clinical and genetic heterogeneity, and no clear genotype-phenotype correlation was observed. There is no mutational hot spot in the KIAA1840 gene, which emphasizes the need to analyse the whole gene in clinical practice. In addition to conventional genetic testing methods, further mRNA analysis should be conducted on some cases to yield a definitive diagnosis.

Pyruvate carboxylase (PC) is a biotin-containing enzyme that is responsible for the adenosine triphosphate-dependent carboxylation of pyruvate to oxaloacetate, a key intermediate in the tricarboxylic acid cycle. PC deficiency (OMIM 266150) is a rare autosomal recessive metabolic disease, causing elevation of pyruvate, lactate, and alanine. Three types of PC deficiency have been described in the literature; A, B, and C. Type A PC deficiency, also called infantile or North American type, is characterized by infantile onset acidosis, failure to thrive, and developmental delay. The second subtype or type B, the neonatal or French form, presents usually in the neonatal period, mostly in the first 72 hours of life with severe lactic acidosis, truncal hypotonia, and seizures. The third type is called type C, is extremely rare with few cases published in the literature. In this case report, we present an 11-month-old girl who presented with acute flaccid paralysis, lethargy, and constipation with elevated ketones and lactate. She was confirmed genetically and biochemically to have PC deficiency type C. The patient's unusual presentation expands the clinical phenotype of this extremely rare disease.

Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.