Laing(-like) distal myopathies are caused by mutations in the myosin gene MYH7. Patients present with clinically varied phenotypes and face no currently available targeted therapeutics.
Introduction
While there is no generally accepted definition of “ultra-rare diseases,” we know there is a wide range of prevalence of each rare disease, all the way down to the ominous N of 1. One such ultra-rare disease is Laing distal myopathy (also called Laing early-onset distal myopathy), which is caused by mutations in the type II myosin gene MYH7. Myosin is a critical protein for muscle contraction throughout the body. Type II or beta myosin is used in slow skeletal muscles and cardiac muscle. Laing distal myopathy patients have muscle weakness that begins in childhood at the feet and ankles. It can progress to other skeletal muscle groups, but, interestingly, less often involves cardiomyopathy.
Due to the perseverance of one patient, Daniel, La Jolla Labs has begun developing an oligo drug for his unique Laing-like distal myopathy. Daniel’s personal story of having a MYH7 myopathy is moving– we hope you get a chance to read about it (Daniel's story). Here, we document the genetics, research, and clinical details of his disease, and more broadly, of Laing distal myopathy.
Tell me about this rare disease.
Genetic basis: Laing distal myopathy is caused by mutations in the MYH7 gene inherited in an autosomal dominant fashion. However, 30-35% of mutations in MYH7 are de novo [1].
In Daniel’s family, the mutation in MYH7 is a single base pair change (G>C) (G4309C) that leads to an alanine to proline missense substitution. The mutation occurs in exon 31, which means it affects the rod domains of the type II myosin heavy chain [2]. Interestingly, in Daniel’s family, their mutation is partially penetrant leading to differing or no clinical presentations with the same mutation.
Clinical presentation: Laing distal myopathy often initially presents with ankle and foot weakness by 5 years of age, but symptom onset can be delayed until a patient’s 30’s. The progression continues to include finger weakness, tightening of the achilles’ heel
and a high stepping gait, weakening of the neck flexor muscles and facial muscles. In severe cases, patients must use a wheelchair [1]. Other concurrent complications can include cardiomyopathy, spinal malformations, neurological involvement, and respiratory issues.
For Daniel’s mutation, and another family with a very similar mutation at position 4301, symptoms include severe neck extensor contracture, inability to passively flex the neck, weak distal muscles, spinal complications, toe then heel placement while walking, and no cardiac symptoms.
Incidence: The incidence of Laing distal myopathy is unknown, but thought to be ultra rare. However, over 350 mutations in MYH7 have been documented, and these myosinopathies present with varying clinical phenotypes [2]. There are only two documented families (seven individuals) with the 4301/4309 MYH7 proline substitution mutations.
Geographical locale of patients: In line with 30-35% of causative mutations being de novo, Laing distal myopathy has been reported in countries all over the world [2]. The two families studied with the 4301/4309 MYH7 mutations are of Jewish Moroccan descent, but are unrelated [2].
Brief history:
The state of the disease today: There are few patients with Laing distal myopathy worldwide, but even fewer (no) targeted therapeutic options. Earlier this year, La Jolla Labs began working to develop an oligo for the A4309P mutation, but it is still in early phases of pre-clinical development.
What is it like to be a patient with this disease?
Who are the patients? As mentioned, the onset of Laing(-like) distal myopathy symptoms can vary tremendously from affecting learning to walk to first developing in adulthood. The autosomal dominant genetic inheritance and frequent de novo mutations explains why these myosinopathies are found equally in males and females. Symptoms progress slowly for the most part and are not thought to affect life span, but most definitely affect quality of life.
What do current treatment options look like? There are limited options. Exercise can help maintain muscle mass for a time. Physical and occupational therapies can relieve tightness, work on muscle strength and improve qualities of life. Other complications can be treated by specialists with typical standards of care.
Are there advocacy groups? I could not find any advocacy groups for Laing distal myopathy nor for these two mutations, although Daniel has most certainly been an advocate for his family and their mutation. The Patient Association for Distal Myopathies is a Japanese-based group for general distal myopathies. There are advocacy groups for muscular dystrophies, which have some similar clinical presentations, but different genetic causes.
Are there genetic tests? For Laing distal myopathy, sequencing is the best way to identify a causative mutation– either whole genome or whole exome work, or a gene panel that includes MYH7 has been described [5]. For these two MYH7 mutations, whole exome sequencing followed by genetic analysis of variants and Sanger sequencing confirmation of mutations identified the causative mutations [2].
How do scientists and clinicians study this disease?
Are there any (good) model systems for drug development? Daniel is actively doing what he can to supply DNA, cells and biopsies to study for drug development. Due to the rarity of his mutation model systems likely won’t be established for wide use. There are a number of mouse studies relating MYH7 and hypertrophic cardiomyopathy, but none to my knowledge for distal myopathies.
Have natural history studies been done? No, the patient population for either Laing distal myopathy or the 4301/4309 mutations are too small for formal natural history studies. Daniel’s family could likely tell you how the disease progresses in their family though– who is looking for a publication to write?
Certain physicians or centers that are experts? The current experts on the MYH7 4301/4309 mutations are the families who have the mutations and the authors of the paper detailing them– the authors are in Israel. Nigel G Laing, PhD, after whom Laing distal myopathy is named, is an active researcher in the field based out of Western Australia.
What are the major challenges for studying and curing this disease? Small population size is extremely limiting for drug development in N of 1 (or N of 7) diseases. Groups like n-Lorem and La Jolla Labs are making drug development for N of 1 patients easier.
The Cure Corner: What is needed for a cure?
What does an ideal therapeutic look like? For either Laing distal myopathy or the MYH7 4301/4309 mutations, an ideal therapeutic will be effective in muscle and have sustained efficacy and/or a high tolerability and minimal side effects for lifelong use.
Are there companies already developing drugs? If so, what kind of molecules and what stage in development are they? La Jolla Labs is developing a gapmer oligo to decrease the expression of the mutated MYH7 allele, but it is in early design phases.
What are current therapies and treatments lacking? There are no therapies available to treat the molecular basis of the disease. Current treatments include physical therapy to loosen and strengthen muscles, bracing of the ankles and evaluation for complications such as cardiomyopathy and scoliosis by specialists and subsequent treatment as necessary.
Could an RNA therapeutic fit the need? An RNA therapeutic could be helpful with either the 4301 or 4309 mutation because of their specific effect on myosin and sarcomere assembly and function. The paper that described these two mutations included in vitro work that demonstrated that these mutations interfere with the ability of myosin to self-assemble in non-muscle cells. However, the presence of the wild-type allele
somewhat corrected the phenotype towards a more normal myosin filament assembly (see Figure 5). Further, in rat neonatal muscle cells, the mutant alleles could still assemble into sarcomeres [2]. Therefore, an oligo or siRNA that decreases the function of only the mutant allele has the potential to be an effective molecularly targeted therapeutic. Allele specific drug development and validation are technically quite challenging, but proof of concept has been established with three MYH7 SNPs [6].
mRNA replacement therapy or gene editing techniques could also be considered to replace the mutant allele. However, a major challenge for any (RNA) therapeutic for this disease is effective and sustained muscle delivery [7].
Delivery to distal muscles could be achieved by local administration, although the literature lacks substantial knowledge regarding local delivery of RNA based therapeutics to muscle cells. Antisense oligonucleotides are effective in neuromuscular diseases, but these drugs are generally delivered intrathecally [7] [8].
RNA therapeutics have been tested in other muscle diseases like muscular dystrophies. For example, an exon skipping morpholino was administered through IV infusion and alleviated muscle degeneration in some Duchenne muscular dystrophy patients [9]. Yet, an antisense oligonucleotide for myotonic dystrophy was discontinued from further development due to the lack of necessary drug concentration achieved in muscle through systemic administration [10].
Therefore, conjugating RNA based drugs to moieties that improve their uptake and potency in muscle are being developed. A study from Ionis Pharmaceuticals recently showed that fatty acid conjugation improved muscle targeting by 3- to 7-fold in mouse tissues [11] and more modestly in monkeys [12]. Further development and testing are required to improve the delivery of RNA based therapeutics for muscle diseases.
Conclusion
Laing(-like) distal myopathies are a complicated set of diseases that present with varying clinical phenotypes depending on their mutation in MYH7. The exact function of the MYH7 mutation on myosin and sarcomere function suggest different types of potential molecularly targeted therapeutics. Overall, more research and development are needed to understand the molecular impact of each mutation, to improve allele specific targeting strategies and to enhance delivery of therapeutics to the muscle before a promising drug is in the pipeline.
A very big and sincere thank you to Daniel for allowing us to share and include his story and disease through this avenue.
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[2] Feinstein-Linial M, Buvoli M, Buvoli A, et al. Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture. BMC Med Genet. 2016;17(1):57. Published 2016 Aug 12. doi:10.1186/s12881-016-0315-1
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[8] Abati E, Manini A, Comi GP, Corti S. Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases. Cell Mol Life Sci. 2022;79(7):374. Published 2022 Jun 21. doi:10.1007/s00018-022-04408-w
[9] Scaglioni D, Catapano F, Ellis M, et al. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun. 2021;9(1):7. Published 2021 Jan 6. doi:10.1186/s40478-020-01106-1
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