KLHL40-Related Myopathy: A Systematic Review and Insight into a Follow-up Biomarker via a New Case Report

Figures

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  Figure 1. PRISMA flowchart of review.

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  Figure 2. The KLHL40 gene maps to chromosome 3q22.1 (A)-blue arrow). KLHL40 transcript contains 6 exons (B) and encodes the 621-amino acid KLHL40 protein, which has an N-terminal BTB and BACK domains (blue box and red box) and 5 C-terminal Kelch repeats (green boxes) that are predicted to form a β-propeller structure (C). The corresponding protein domains are represented according to the Protein Families (PFAM) database (C). Schematic view of the KLHL40 mutations of patients described in the present work with related position according to UNIPROT (https://www.uniprot.org/uniprotkb/Q5EB39/entry, accessed on 23 January 2024).

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  Figure 3. Sequential imaging studies show slow progression over time. (A–D). The axial T1 weighted image at 18 months shows: marked fat infiltration and hypotrophy of the gluteus muscles (maximum(GM), medius (Gmed) and minimus gluteus(Gmin)) (A); at thigh level (A1) is evident the prevalent involvement of the posterior compartment (biceps femoris muscle (BF), semitendinosus (SM), semimembranosus (SM)) and of medial muscles (adductor longus muscle (ADL), adductor magnus muscle (ADM) and gracilis muscle (Gr)) with complete fat replacement of the sartorius. A modest fibro-adipose infiltration of the mid-distal sections of the rectus femoris muscle is evident too (A1). At leg level (A2) complete fat replacement of the gastrocnemius muscles and the peripheral portion of the soleus muscle can be seen, with relative sparing of anterior compartment. This pattern remained stable in two consecutive examinations (7 years (B,B1,B2) and 10 years (C,C1,C2)) and it showed only minimal variations at 13 years (D,D1,D2), with increased involvement of the vastus intermedius (D1) and the soleus (D2).

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  Figure 4. Overview of the muscle MRI pattern of NEM (Mod. by Perry et al. 2023 [7]). Gray scale where dark gray corresponds to the maximum degree of fibroadipose replacement. Note the different pattern present in NEM with prevalent involvement of soleus and tibialis anterior in NEB-NEM (Panel (a)) and in ACTA1-NEM (Panel (b)) and the prevalent involvement of the hamstring muscles in the thigh and comparative sparing of the rectus femori in TPM3-NEM (Panel (c)), while in KLHL40-NEM (Panel (d)), there is the prevalent involvement of hamstring muscles in the thigh but also of the rectus femori and the involvement of soleus and gastrocnemi with sparing of tibialis anterior.