Management of Friedreich Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature.

A major manifestation of Friedreich ataxia (FRDA) is cardiomyopathy, caused by mitochondrial proliferation in myocytes. Because the lifespan for patients with FRDA improves with better treatment modalities, more patients are becoming pregnant, meaning that more medical providers must know how to care for this population. This report provides a review of the literature on multidisciplinary management of pregnant patients with FRDA and cardiomyopathy from preconception through lactation. A cardio-obstetrics team, including cardiology, anesthesiology, and obstetrics, should be involved for this entire period. All patients should be counseled on pregnancy risk using elements of existing stratification systems, and contraception should be discussed, highlighting the safety of intrauterine devices. Electrocardiogram should be obtained at baseline and each trimester, looking for atrial arrhythmias and ST-segment changes, as should transthoracic echocardiogram, with a focus on left ventricular ejection fraction-which is typically normal in FRDA cardiomyopathy-and relative wall thickness and global longitudinal strain-which tend to decrease as cardiomyopathy progresses. Brain natriuretic peptide is also a helpful marker to detect adverse events. If heart failure develops, it should be treated like any other etiology of heart failure during pregnancy. Atrial arrhythmias should be treated with ß blockers or electrical cardioversion and anticoagulation, as necessary. Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor because of the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications.

Manejo anestésico de una tormenta tiroidea en un paciente afecto de ataxia de Friederich. A propósito de un caso / Anaesthetic management of thyroid storm in a patient with Friederich's ataxia. A case report

Paciente de 26 años afecto de ataxia de Friederich con una miocardiopatía hipertrófica no obstructiva sometido a una tiroidectomía total por una tirotoxicosis secundaria a amiodarona persistente (a pesar de elevadas dosis de antitiroideos y corticoides), que intraoperatoriamente presentó un episodio sugestivo de tormenta tiroidea.La tormenta tiroidea es una urgencia endocrinológica que asocia una elevada morbimortalidad. Para mejorar la supervivencia es de vital importancia un diagnóstico temprano y un tratamiento precoz que incluya: un tratamiento sintomático, el tratamiento de las manifestaciones cardiovasculares, neurológicas y/o hepáticas y de la tirotoxicosis, así como suprimir o evitar estímulos desencadenantes y practicar un tratamiento definitivo.(AU)

A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing a total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm.Thyroid storm is an endocrine emergency that is associated with high morbimortality. Early diagnosis and treatment, which is of vital importance to improve survival. Treatment includes: symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment.(AU)

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA-TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA. METHODS: Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). RESULTS: The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 µm in FRDA; 98 ± 9 µm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 µm) was best predicted by disease burden (GAA-TR length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 µm. RNFL thickness decreased at a rate of -1.2 ± 1.4 µm/year and reached 68 µm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. INTERPRETATION: These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial.

BACKGROUND: Friedreich Ataxia is the most common recessive ataxia with only one therapeutic drug approved solely in the United States. OBJECTIVE: The aim of this work was to investigate whether anodal cerebellar transcranial direct current stimulation (ctDCS) reduces ataxic and cognitive symptoms in individuals with Friedreich's ataxia (FRDA) and to assess the effects of ctDCS on the activity of the secondary somatosensory (SII) cortex. METHODS: We performed a single-blind, randomized, sham-controlled, crossover trial with anodal ctDCS (5 days/week for 1 week, 20 min/day, density current: 0.057 mA/cm2 ) in 24 patients with FRDA. Each patient underwent a clinical evaluation (Scale for the Assessment and Rating of Ataxia, composite cerebellar functional severity score, cerebellar cognitive affective syndrome scale) before and after anodal and sham ctDCS. Activity of the SII cortex contralateral to a tactile oddball stimulation of the right index finger was evaluated with brain functional magnetic resonance imaging at baseline and after anodal/sham ctDCS. RESULTS: Anodal ctDCS led to a significant improvement in the Scale for the Assessment and Rating of Ataxia (-6.5%) and in the cerebellar cognitive affective syndrome scale (+11%) compared with sham ctDCS. It also led to a significant reduction in functional magnetic resonance imaging signal at the SII cortex contralateral to tactile stimulation (-26%) compared with sham ctDCS. CONCLUSIONS: One week of treatment with anodal ctDCS reduces motor and cognitive symptoms in individuals with FRDA, likely by restoring the neocortical inhibition normally exerted by cerebellar structures. This study provides class I evidence that ctDCS stimulation is effective and safe in FRDA. © 2023 International Parkinson and Movement Disorder Society.

Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia.

Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms. This narrative review summarizes the current knowledge on neuropsychiatric impairment in SCA and FRDA. We discuss the prevalence, clinical features and treatment approaches in the most commonly reported domains of depression, anxiety, apathy, agitation and impulse dyscontrol, and psychosis. Since these symptoms have a considerable impact on patients' quality of life, we argue that further research is mandated to improve the detection and treatment options of neuropsychiatric co-morbidities in ataxia patients.

Omaveloxolone: First Approval.

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

Remember Friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy. Revisited.

Friedreich ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy. We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5 years-old. RESULTS: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells. We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of HT as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.

Patient-Reported Impact of Symptoms in Friedreich Ataxia.

BACKGROUND AND OBJECTIVES: To determine the prevalence and relative importance of symptoms experienced by children and adults with Friedreich ataxia (FA) and to identify factors associated with a higher burden of disease. METHODS: We conducted qualitative interviews with individuals with FA and caregivers of pediatric individuals with FA to identify potential symptoms of importance to those living with FA. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in FA and to determine which factors are associated with a higher burden of disease. RESULTS: Thirty-nine participants provided 2,527 quotes regarding the symptomatic burden of FA. Two hundred two individuals (153 individuals with FA and 49 caregivers) participated in a subsequent cross-sectional study. Individuals with FA and caregivers identified impaired coordination, limitations with mobility and walking, inability to do activities, fatigue, and lower extremity weakness as the most prevalent and life-altering symptomatic themes in FA. Muscle stiffness and functional staging for ataxia were associated with the prevalence of symptomatic themes in FA. In addition, the length of smaller GAA expansion and the mean length of both GAA expansions were strongly associated with the onset of symptoms in FA. DISCUSSION: There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence]. / Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia.

Friedreich's ataxia is an autosomal recessive disease caused by trinucleotide repeat expansion, presenting among other systemic complications, diabetes mellitus. The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis, it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair, which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

La ataxia de Friedreich, de herencia autosómica recesiva causada por una expansión repetida de trinucleótidos se asocia, entre otras complicaciones sistémicas, con diabetes mellitus. La aparición de torpeza motriz, con dificultad en la carrera y el salto en un varón de 6 años motivaron el estudio genético para ataxia de Friedrich y permitieron confirmar el diagnóstico. Tres años más tarde, se diagnosticó diabetes mellitus y se inició el tratamiento con insulina. Durante el seguimiento, presentó un importante deterioro neurológico, con necesidad de usar silla de ruedas, lo que dificultó un adecuado control metabólico. Se presenta el manejo y la evolución de un paciente con ataxia de Friedreich y diabetes mellitus.

Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia / Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence

La ataxia de Friedreich, de herencia autosómica recesiva causada por una expansión repetida de trinucleótidos se asocia, entre otras complicaciones sistémicas, con diabetes mellitus. La aparición de torpeza motriz, con dificultad en la carrera y el salto en un varón de 6 años motivaron el estudio genético para ataxia de Friedrich y permitieron confirmar el diagnóstico. Tres años más tarde, se diagnosticó diabetes mellitus y se inició el tratamiento con insulina. Durante el seguimiento, presentó un importante deterioro neurológico, con necesidad de usar silla de ruedas, lo que dificultó un adecuado control metabólico. Se presenta el manejo y la evolución de un paciente con ataxia de Friedreich y diabetes mellitus

Friedreich's ataxia is an autosomal recessive disease caused by trinucleotide repeat expansion, presenting among other systemic complications, diabetes mellitus. The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis,it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair,which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages.

OBJECTIVES: Friedreich's ataxia (FA) is the most common hereditary ataxia, characterized by multisystemic manifestations including neurological, cardiological, and skeletal abnormalities. In this study, we aimed to analyze the incidences of disease-related and unrelated comorbidities occurring in different stages of the disease progression. METHODS: We analyzed longitudinal data from a 10-year prospective observational study in a cohort of 175 FA patients with disease onset < 25 years. We analyzed the time of diagnosis for the most frequently reported medical conditions, with respect to age and disease duration of each patient. RESULTS: In the early stage of the disease, scoliosis (53.3%), hypertrophic cardiomyopathy (46.7%), and pes cavus (33.3%) were the most frequently diagnosed conditions, sometimes occurring even before the onset of ataxia. Diabetes, bone fractures, and depression have the same incidence at all disease stages. In patients with > 20 years of disease duration, the most frequent complications were hearing and visual loss (20% and 26%), arrhythmias (16%), and psychosis (18%). Thirteen patients presented hallucinations/delusions in the absence of neurological acute events or mental illness predisposing to psychotic manifestations. Six of these patients fulfill the diagnostic criteria for Charles Bonnet syndrome. CONCLUSIONS: Incidence of FA-related medical conditions varies according to disease duration. In patients with very long disease duration, we observed an unexpectedly high incidence of visual and auditory pseudo-hallucinations that were not previously reported in FA patients. We hypothesized that these late complications may be possibly related to the severe sensory deafferentation syndrome observed in the advanced stages of FA disease.

Importance of an echocardiogram in the evaluation of ataxia.

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich's ataxia was confirmed.

Neurological Recovery with Interferon-gamma Treatment in Friedreich's Ataxia.

Friedreich's ataxia (FA) is a rare, progressive, and degenerative hereditary disorder caused by a deficiency of frataxin protein. This disease is characterised by severe neurological dysfunction and life-threatening cardiomyopathy. Various drugs are used to slow down / stop the neurodegenerative progress. However, recent clinical trials and animal experiments demonstrate that interferon-gamma (IFN-É£) treatment might improve signs of FA as well. A 9-year-old girl was admitted to our hospital with gait instability, mild dysarthria, and sensorimotor polyneuropathy. Her genetic examination was consistent with FA. IFN-É£ treatment was started 3 times a week. The treatment was evaluated by physical examination and side effects assessment. Friedreich Ataxia Rating Scale (FARS), 9-hole peg test (9HPT), and time of 25-foot walk (T25FW) were measured. Ataxia and cerebellar findings improved within 9 months. Although clinical neurological improvement was achieved, there was no improvement in cardiomyopathy. Key Words: Interferon-gamma, Friedreich ataxia, FARS, Children, Cardiomyopathy.

The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis.

BACKGROUND: Study the cognitive profile of individuals with Friedreich ataxia (FRDA) and seek evidence for correlations between clinical, genetic and imaging characteristics and neuropsychological impairments. METHODS: Based on PRISMA guidelines, a meta-analysis was realized using the Pubmed and Scopus databases to identify studies (1950-2021) reporting neuropsychological test results in genetically confirmed FRDA and control participants in at least one of the following cognitive domains: attention/executive, language, memory and visuo-spatial functions as well as emotion. Studies using identical outcomes in a minimum of two studies were pooled. Pooled effect sizes were calculated with Cohen's d. RESULTS: Eighteen studies were included. Individuals with FRDA displayed significantly lower performance than individuals without FRDA in most language, attention, executive function, memory visuospatial function, emotion regulation and social cognitive tasks. Among the included studies, thirteen studies examined the relationship between neuropsychological test results and clinical parameters and reported significant association with disease severity and six studies reviewed the relationship between neuroimaging measures and cognitive performance and mainly reported links between reduced cognitive performance and changes in cerebellar structure. CONCLUSIONS: Individuals with FRDA display significantly lower performances in many cognitive domains compared to control participants. The spectrum of the cognitive profile alterations in FRDA and its correlation with disease severity and cerebellar structural parameters suggest a cerebellar role in the pathophysiology of FRDA cognitive impairments.

Friedreich's Ataxia related Diabetes: Epidemiology and management practices.

AIMS: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. METHODS: FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. RESULTS: FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely. CONCLUSIONS: Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease.

SARS-CoV-2 attacks the weakest point - COVID-19 course in a pediatric patient with Friedreich's ataxia.

COVID-19 pandemic is the biggest epidemiologic problem of the 21st century. A severe course of SARS-CoV-2 infection in children is rare. Sometimes, especially in patients with chronic disease, COVID-19 may be insidious and life-threatening. This article presents the course of COVID-19 in a 17-year-old boy with Friedreich's ataxia-induced hypertrophic cardiomyopathy. Although, the main symptoms of COVID-19 (i.e., fever, cough) were moderate at the beginning of the illness, the patient's condition deteriorated rapidly due to cardiac problems, atrial fibrillation, and heart failure. The patient required antiarrhythmic treatment and pharmacological and electrical cardioversion. Moreover, because of pneumonia requiring supplemental oxygen, remdesivir and convalescent plasma therapy was given to the patient., The administration of the antiviral treatment was crucial to the patient's recovery.

A Standardized Pipeline for Examining Human Cerebellar Grey Matter Morphometry using Structural Magnetic Resonance Imaging.

Multiple lines of research provide compelling evidence for a role of the cerebellum in a wide array of cognitive and affective functions, going far beyond its historical association with motor control. Structural and functional neuroimaging studies have further refined understanding of the functional neuroanatomy of the cerebellum beyond its anatomical divisions, highlighting the need for the examination of individual cerebellar subunits in healthy variability and neurological diseases. This paper presents a standardized pipeline for examining cerebellum grey matter morphometry that combines high-resolution, state-of-the-art approaches for optimized and automated cerebellum parcellation (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization; ACAPULCO) and voxel-based registration of the cerebellum (Spatially Unbiased Infra-tentorial Template; SUIT) for volumetric quantification. The pipeline has broad applicability to a range of neurological diseases and is fully automated, with manual intervention only required for quality control of the outputs. The pipeline is freely available, with substantial accompanying documentation, and can be run on Mac, Windows, and Linux operating systems. The pipeline is applied in a cohort of individuals with Friedreich ataxia (FRDA), and representative results, as well as recommendations on group-level inferential statistical analyses, are provided. This pipeline could facilitate reliability and reproducibility across the field, ultimately providing a powerful methodological approach for characterizing and tracking cerebellar structural changes in neurological diseases.