Motor outcome measures in patients with
            <i>FKRP</i>
            mutations

Gedlinske, Amber M.; Stephan, Carrie M.; Mockler, Shelley R.H.; Laubscher, Katie M.; Laubenthal, K.; Crockett, Cameron D.; Zimmerman, M. Bridget; Mathews, Katherine D.

doi:10.1212/wnl.0000000000010604

Cited by 6 publications

(2 citation statements)

References 30 publications

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“…A founder mutation in Mexico (c.1387A>G) is associated with a more severe disease phenotype 30 . In general, homozygous mutations result in a less severe disease course than compound heterozygous mutations ( case 7-3 ) 31 . Weakness often develops in adolescence, although this is variable and somewhat related to the mutation.…”

Section: Common Subtypes Of the Limb-girdle Muscular Dystrophiesmentioning

confidence: 99%

The Limb-Girdle Muscular Dystrophies

Johnson¹,

Statland²

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEW: The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD.RECENT FINDINGS: Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessiveLGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches. SUMMARY: International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.

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Section: Common Subtypes Of the Limb-girdle Muscular Dystrophiesmentioning

confidence: 99%

The Limb-Girdle Muscular Dystrophies

Johnson¹,

Statland²

2022

CONTINUUM: Lifelong Learning in Neurology

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“…This idea is supported by numerous studies including efforts by the Clinical Outcome Study for dysferlin (COS) which analyzed many COAs, the University of Iowa which studied longitudinal effects of FKRP mutations, the Jain Clinical Outcomes Study of Dysferlinopathy for NSAD utilization and validation, and natural history multicenter studies on LGMDR1 in France. Data has shown small yet consistent changes in COAs during their 2-year time period, with data being statistically significant as early as 6 months for most mutations but earlier for FKRP (LGMDR9) and CAPN3 (LGMDR1) mutations [ 38 , 39 ]. We will determine the responsiveness of our COAs at 3, 6, and 12 months.…”

Section: Introductionmentioning

confidence: 99%

Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy: A GRASP-LGMD study

Doody,

Alfano,

Diaz-Manera

et al. 2023

Preprint

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Background The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. Methods/design: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). Discussion To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. Trial registration: clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019

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Prospective observational study of FKRP‐related limb‐girdle muscular dystrophy R9: A GRASP consortium study

Alfano,

James,

Grosfjeld Petersen

et al. 2024

Ann Clin Transl Neurol

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ObjectiveLimb‐girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin‐related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb‐girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross‐sectional validity and reliability of clinical outcome assessments in patients with FKRP‐related LGMDR9 participating in the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP) natural history study.MethodsEnrolled patients completed a battery of COA on two consecutive days, including the North Star Assessment for limb girdle‐type dystrophies (NSAD), the 100‐m timed test (100 m), and the Performance of Upper Limb 2.0 (PUL).ResultsA total of 101 patients with FKRP‐related LGMDR9 completed COA evaluations. All functional COA were highly and significantly correlated even across constructs, except for the 9‐hole peg test. Similarly, all tests demonstrated excellent test–retest reliability across 2‐day visits. The NSAD and PUL demonstrate robust psychometrics with good targeting, ordered response thresholds, fit and stability, and limited dependency of items across the scales.ConclusionsThis study has determined the suitability of several functional COA, cross‐sectionally, in LGMDR9 to inform future trial design and clinical care.

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Motor outcome measures in patients with FKRP mutations

Cited by 6 publications

References 30 publications

The Limb-Girdle Muscular Dystrophies

The Limb-Girdle Muscular Dystrophies

Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy: A GRASP-LGMD study

Prospective observational study of FKRP‐related limb‐girdle muscular dystrophy R9: A GRASP consortium study

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