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Kim and Choi: The Author Reply: Genotypic and Phenotypic Heterogeneity of LGMD1D due to DNAJB6 Mutations
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Yonsei Medical Journal 2018; 59(8): 1010-1011.

Published online: 5 September 2018

DOI: https://doi.org/10.3349/ymj.2018.59.8.1010

The Author Reply: Genotypic and Phenotypic Heterogeneity of LGMD1D due to DNAJB6 Mutations

Kitae Kim, Young-Chul Choi

Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.

Corresponding author: Young-Chul Choi, MD, PhD, Department of Neurology, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. Tel: 82-2-2019-3323, Fax: 82-2-3462-5904, ycchoi@yuhs.ac

Received 1 August 2018

© Copyright: Yonsei University College of Medicine 2018

Yonsei University College of Medicine

(open-access, https://creativecommons.org/licenses/by-nc/4.0/):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dear Editor,
Limb-girdle muscular dystrophies type 1D (LGMD1D) is generally known as an adult-onset musculoskeletal disease. However, according to reports, there are cases of onset in children, including Nam, et al.'s study.1 Although most patients with LGMD1D are characterized by an onset in adulthood, some develop at an early age, and as noted, the age of disease onset can vary. Our patients also presented with various clinical manifestations. In our patients, there was no significant evidence of cardiac involvement based on past history, clinical symptoms and signs, findings on physical examination, laboratory data, and chest X-ray. The possibility of subclinical cardiac abnormality in our patients cannot be ruled out completely, however, alhough we believe that our patients did not have cardiac abnormalities at that time.
In addition, serum creatine kinase (CK) levels (our normal range: 35–232 IU/L) are a useful clinical biomarker, but fluctuate and vary, even at low levels in a muscle atrophy state. The serum CK levels of our patients were normal to mildly elevated. The first patient had a CK level of 175 IU/L, and the second patient had levels of 504 IU/L and 673 IU/L on two tests. The last patient had a level of 301 IU/L.
We also agree that the phenotype of LGMD1D may appear more heterogeneous than we thought. This has been confirmed from the paper published by Ruggieri, et al.2 According to the paper, patients with proximal G/F domain mutations (Phe89, Phe91, and Phe93) in DNAJB6 show proximal limbgirdle weakness, whereas patients with distal G/F domain mutations (Pro96 and Phe100) expereience distal leg weakness.
We stated more than nine mutations in the DNAJB6 gene have been reported, including p.Phe89Ile, p.Phe91Ile, pPhe-91Leu, p.Phe93Ile, p.Phe93Leu, p.Pro96Arg, p.Pro96Leu, p.Phe-100Val, and p.Phe100Ile. Recently, two mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) were reported.3 Thus, at least 11 different mutations have been identified so far (Table 1). As next generation sequencing becomes more wildly used, additional novel mutations will be identified.

Notes

The authors have no financial conflicts of interest.

References

1. Nam TS, Li W, Heo SH, Lee KH, Cho A, Shin JH, et al. A novel mutation in DNAJB6, p.(Phe91Leu), in childhood-onset LGMD1D with a severe phenotype. Neuromuscul Disord. 2015; 25:843–851. PMID: 26371419.
crossref
2. Ruggieri A, Brancati F, Zanotti S, Maggi L, Pasanisi MB, Saredi S, et al. Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. Acta Neuropathol Commun. 2015; 3:44. PMID: 26205529.
crossref
3. Jonson PH, Palmio J, Johari M, Penttilä S, Evilä A, Nelson I, et al. Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families. Eur J Neurol. 2018; 25:790–794. PMID: 29437287.
crossref
4. Kim K, Park HJ, Lee JH, Hong J, Ahn SW, Choi YC. Two Korean families with limb-girdle muscular dystrophy type 1D associated with DNAJB6 mutations. Yonsei Med J. 2018; 59:698–701. PMID: 29869469.
crossref
5. Couthouis J, Raphael AR, Siskind C, Findlay AR, Buenrostro JD, Greenleaf WJ, et al. Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscul Disord. 2014; 24:431–435. PMID: 24594375.
crossref
6. Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, et al. Mutations affecting the cytoplasmic functions of the co-chaper-one DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012; 44:450–455. PMID: 22366786.
crossref
7. Palmio J, Jonson PH, Evilä A, Auranen M, Straub V, Bushby K, et al. Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease. Neuromuscul Disord. 2015; 25:835–842. PMID: 26338452.
crossref
8. Sato T, Hayashi YK, Oya Y, Kondo T, Sugie K, Kaneda D, et al. DNAJB6 myopathy in an Asian cohort and cytoplasmic/nuclear inclusions. Neuromuscul Disord. 2013; 23:269–276. PMID: 23394708.
crossref
9. Harms MB, Sommerville RB, Allred P, Bell S, Ma D, Cooper P, et al. Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol. 2012; 71:407–416. PMID: 22334415.
crossref
10. Tsai PC, Tsai YS, Soong BW, Huang YH, Wu HT, Chen YH, et al. A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy and compromises DNAJB6 function. Clin Genet. 2017; 92:150–157. PMID: 28233300.
Table 1

Clinical Features and Genetic Findings for DNAJB6 Mutations

ymj-59-1010-i001
Genotype References Region of study Onset age Distribution of weakness Serum CK Muscle pathology Bulbar symptoms
p.Phe89Ile Kim, et al.4 Asia 30–40 Proximal NL N/A None
Couthouis, et al.5 America 8–18 Proximal NL RV -
Sarparanta, et al.6 America 20–55 Proximal NL–10× Myopathic, RV Yes
p.Phe91Ile Palmio, et al.7 Europe 6–13 Proximal NL–2× RV, fibrosis, atrophy, myofibrillar aggregations None
Ruggieri, et al.2 Europe 16 Proximal NL Dystrophic, RV None
p.Phe91Leu Nam, et al.1 Asia 8–11 Proximal NL–2× RV None
Palmio, et al.7 Europe 15 Proximal and distal NL RV, Fibrosis, atrophy, myofibrillar aggregations Yes
Ruggieri, et al.2 Europe 11 Proximal NL Myopathic, RV Yes
p.Phe93Ile Sato, et al.8 Asia 30s Proximal 1.5–5× Myopathic, RV None
p.Phe93Leu Harm, et al.9 America 30–40 Proximal 3–6× Myopathic, RV None
Ruggieri, et al.2 Europe 45 Proximal NL Myopathic, RV None
p.Ans95Ile Jonson, et al.3 Europe 36–55 Distal NL–2× RV Yes
p.Pro96Arg Harm, et al.9 African American 18–35 Distal 2× N/A None
p.Pro96Leu Tsai, et al.10 Asia 30–40 Proximal NL Fatty change Yes
p.Asp98del Jonson, et al.3 Europe 16, 20 Proximal and distal 2× RV None
p.Phe100Val Ruggieri, et al.2 Europe 10–50 Proximal and distal 1.5–4× RV Yes
p.Phe100Ile Kim, et al.4 Asia 17, 27 Proximal and distal 3× RV Yes

N/A, not available; NL, normal; RV, rimmed vacuole.

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