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There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

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The Brazilian Policy of Comprehensive Care for People with Rare Diseases (BPCCPRD) was established by the Ministry of Health to reduce morbidity and mortality and improve the quality of life of people with rare diseases (RD). Several laboratory tests, most using molecular genetic technologies, have been incorporated by the Brazilian Public Health System, and 18 specialised centres have so far been established at university hospitals (UH) in the capitals of the Southern, Southeastern and Northeastern regions. However, whether the available human and technological resources in these services are appropriate and sufficient to achieve the goals of care established by the BPCCPRD is unknown. Despite great advances in diagnosis, especially due to new technologies and the recent structuring of clinical assessment of RD in Brazil, epidemiological data are lacking and when available, restricted to specific disorders. This position paper summarises the performance of a nationally representative survey on epidemiology, clinical status, and diagnostic and therapeutic resources employed for individuals with genetic and non-genetic RD in Brazil. The Brazilian Rare Disease Network (BRDN) is under development, comprising 40 institutions, including 18 UH, 17 Rare Diseases Reference Services and five Newborn Screening Reference Services. A retrospective study will be initially conducted, followed by a prospective study. The data collection instrument will use a standard protocol with sociodemographic data and clinical and diagnostic aspects according to international ontology. This great collaborative network is the first initiative of a large epidemiological data collection of RD in Latin America, and the results will increase the knowledge of RD in Brazil and help health managers to improve national public policy on RD in Brazil.

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BACKGROUND: We assessed the clinimetric properties of ataxia rating scales and functional tests, and made recommendations regarding their use. METHODS: A systematic literature search was conducted to identify the instruments used to rate ataxia symptoms. The identified rating scales and functional ability tests were reviewed and ranked by the panel as "recommended," "suggested," or "listed" for the assessment of patients with discrete cerebellar disorders, using previously established criteria. RESULTS: We reviewed 14 instruments (9 rating scales and 5 functional tests). "Recommended" rating scales for the assessment of symptoms severity were: for Friedreich's ataxia, the Friedreich's Ataxia Rating Scale, the International Cooperative Ataxia Rating Scale (ICARS), and the Scale for the Assessment and Rating of Ataxia (SARA); for spinocerebellar ataxias, ICARS and SARA; for ataxia telangiectasia: ICARS and SARA; for brain tumors, SARA; for congenital disorder of glycosylation-phosphomannomutase-2 deficiency, ICARS; for cerebellar symptoms in multiple sclerosis, ICARS; for cerebellar symptoms in multiple system atrophy: Unified Multiple System Atrophy Rating Scale and ICARS; and for fragile X-associated tremor ataxia syndrome, ICARS. "Recommended" functional tests were: for Friedreich's ataxia, Ataxia Functional Composite Score and Composite Cerebellar Functional Severity Score; and for spinocerebellar ataxias, Ataxia Functional Composite Score, Composite Cerebellar Functional Severity Score, and SCA Functional Index. CONCLUSIONS: We identified some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted. © 2020 International Parkinson and Movement Disorder Society.

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Xia-Gibbs syndrome (XGS) is a rare neurological disorder characterized by global developmental delay, hypotonia, intellectual disability, seizures, and sleep apnea. XGS is defined by monoallelic pathogenic variants in AHDC1. In this study, we identified a Brazilian patient carrying a likely de novo AHDC1 nonsense mutation (c.451C>T; p.Arg151*) which was absent in both parents. All disease-causative variants already associated with XGS have been reviewed and the mutation described here corresponds to the closest one to the N-terminal region. Our findings were discussed based on the suggested genotype-phenotype correlation of the disease.

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Limb-girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous disorders characterized by predominantly proximal muscle weakness. We aimed to characterize epidemiological, clinical and molecular data of patients with autosomal recessive LGMD2/LGMD-R in Brazil. A multicenter historical cohort study was performed at 13 centers, in which index cases and their affected relatives' data from consecutive families with genetic or pathological diagnosis of LGMD2/LGMD-R were reviewed from July 2017 to August 2018. Survival curves to major handicap for LGMD2A/LGMD-R1-calpain3-related, LGMD2B/LGMD-R2-dysferlin-related and sarcoglycanopathies were built and progressions according to sex and genotype were estimated. In 370 patients (305 families) with LGMD2/LGMD-R, most frequent subtypes were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related, each representing around 30% of families. Sarcoglycanopathies were the most frequent childhood-onset subtype, representing 21% of families. Five percent of families had LGMD2G/LGMD-R7-telethonin-related, an ultra-rare subtype worldwide. Females with LGMD2B/LGMD-R2-dysferlin-related had less severe progression to handicap than males and LGMD2A/LGMD-R1-calpain3-related patients with truncating variants had earlier disease onset and more severe progression to handicap than patients without truncating variants. We have provided paramount epidemiological data of LGMD2/LGMD-R in Brazil that might help on differential diagnosis, better patient care and guiding future collaborative clinical trials and natural history studies in the field.

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OBJECTIVE: ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. METHODS: A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. RESULTS: Thirty-seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss-of-function variants were not associated with specific phenotypes. INTERPRETATION: We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.

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Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado-Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado-Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado-Joseph disease. The main nonmotor manifestations of Machado-Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders. © 2013 Movement Disorder Society.

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