Laing et al. (1995) described a family with an autosomal dominant distal myopathy closely resembling that described in the original report of Gowers (1902).
Scoppetta et al. (1995) and Voit et al. (2001) reported 2 families ... Laing et al. (1995) described a family with an autosomal dominant distal myopathy closely resembling that described in the original report of Gowers (1902). Scoppetta et al. (1995) and Voit et al. (2001) reported 2 families with autosomal dominant distal myopathy with clinical features similar to those reported by Laing et al. (1995). Characteristics common to both families included onset in the second or third year of life, selective wasting and weakness of the anterior tibial and extensor digitorum longus muscles, a slowly progressive course, and, at later stages, involvement of hand extensors, neck flexor, and abdominal muscles. Some patients developed tremor. Zimprich et al. (2000) described an Austrian family with a similar phenotype. In a family with 9 affected members spanning 3 generations, Mastaglia et al. (2002) described selective weakness of the ankle dorsiflexors and toe extensors, in particular the extensor hallucis longus. Ankle plantar flexors were normal, even in the most advanced cases. There was also weakness and atrophy of the anterior compartment muscles. Most cases had selective weakness of the long finger extensor muscles. None of the affected individuals had cardiomyopathy. Age at onset varied from 4 to 5 years to the early twenties. Muscle MRI showed atrophy of affected muscles, EMG gave a myopathic pattern, and muscle biopsy of 2 affected patients showed myopathic changes without rimmed vacuoles. Hedera et al. (2003) reported a large Italian American kindred in which at least 11 members spanning 3 generations were affected with an autosomal dominant distal myopathy. Clinical features included weakness of foot and toe extensor muscles, and some patients had proximal weakness. No patient had distal weakness of the upper extremities or neck muscles, even in advanced stages of the disease. The average age at symptom onset was 20 years. Two affected patients had signs of idiopathic dilated cardiomyopathy. Hedera et al. (2003) noted that their family differed from the family reported by Laing et al. (1995) by the absence of upper extremity weakness and neck muscle weakness. Darin et al. (2007) reported a Tanzanian boy with distal myopathy and mild dilated cardiomyopathy. He began walking on the toes at age 11 months and had Achilles tenotomy at age 6 years. Examination at age 7 showed weakness of the great toe and ankle dorsiflexors, atrophy of the anterior tibial muscles, weakness of the hip flexors, and decreased reflexes. Echocardiography showed mild left atrial enlargement and prolonged isovolumetric relaxation time. Skeletal muscle biopsy showed hypotrophy of type 1 fibers and apparent absence of type 2B fibers. Serum creatine kinase was mildly elevated. - Clinical Variability Muelas et al. (2010) identified the same mutation in the MYH7 gene (lys1729del; 160760.0044) in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. There was atrophy of the anterior lower leg compartment muscles, which contrasted with calf hypertrophy. Some had more widespread proximal muscle involvement, resembling that seen in the allelic disorder myosin storage myopathy (608358). Variable findings included quadriceps atrophy, ankle retraction, pes cavus, scoliosis, claw toes, and high-arched palate. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic as well as neurogenic features, and muscle biopsies yielded various findings, such as fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. Most patients had slow progression, but some were severely disabled, and many had myalgias. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy. Muelas et al. (2010) also noted that the variable features could lead to misdiagnosis of neurogenic atrophy, congenital myopathies, or even mitochondrial myopathies.
In affected members of 7 separate families with Laing distal myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see ... In affected members of 7 separate families with Laing distal myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see 160760.0029-160760.0030) and no mutations in the seventh family. The family reported by Hedera et al. (2003) had a deletion of lys1729 (160760.0044). In a Tanzanian boy with Laing myopathy and mild cardiac involvement, Darin et al. (2007) identified a heterozygous mutation in the MYH7 gene (160760.0036).
Meredith et al. (2004) identified a heterozygous mutation in the MYH7 gene (lys1729del; 160760.0044) in affected members of an Italian American family with Laing distal myopathy reported by Hedera et al. (2003). Muelas et al. (2010) identified the ... Meredith et al. (2004) identified a heterozygous mutation in the MYH7 gene (lys1729del; 160760.0044) in affected members of an Italian American family with Laing distal myopathy reported by Hedera et al. (2003). Muelas et al. (2010) identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. Muelas et al. (2012) demonstrated a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by Hedera et al. (2003), indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin.
Laing distal myopathy is diagnosed in individuals with the following [Hedera et al 2003, Lamont et al 2006]:...
DiagnosisClinical DiagnosisLaing distal myopathy is diagnosed in individuals with the following [Hedera et al 2003, Lamont et al 2006]:Initial weakness of the great toe and ankle dorsiflexors, eventually leading to a high-stepping gait and secondary tightening of the tendo Achillis Subsequent weakness of the finger extensors (within months to years) often accompanied by an action tremor of the hands Mild involvement of the facial musculature, particularly of the orbicularis oculi and oris muscles Early weakness of neck flexion in most families Note: In one family, weakness did not occur until the sixth decade. Very slow progression of weakness with gradual involvement of the proximal leg and trunk muscles. No affected individuals have been confined to a wheelchair for mobility. Age of onset ranging from the first year of life to the late teens, but most commonly before age five years. Family history consistent with autosomal dominant inheritance Note: Identification of mutations within MYH7 is the gold standard for diagnosis of Laing distal myopathy (see Molecular Genetic Testing). TestingSerum creatine kinase concentration, usually normal, may in rare cases be as high as eight times the upper limit of normal. Nerve conduction studies are normal. Electromyographic findings are nonspecific, with occasional fibrillation potentials but no prolonged or large motor unit potentials [Zimprich et al 2000]. Muscle biopsy is not diagnostic. Myopathic features inconsistently identified include the following: Excessive variation in fiber size, with small type I fibers in some and small type II fibers in others Inconsistent fiber predominance and excessive central nucleation Mild necrosis and regeneration; fatty replacement in "end-stage" muscles Rimmed vacuoles and filamentous inclusions are seen rarely, in contrast to other distal myopathies On immunohistochemical staining for slow and fast myosin in two individuals, coexpression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type I to fiber type II [Lamont et al 2006] Molecular Genetic TestingGene. MYH7, encoding the protein myosin heavy chain, cardiac muscle beta isoform, is the only gene known to be associated with Laing distal myopathy. Clinical testingSequence analysis/mutation scanning of the MYH7 coding region and associated splice junctions. Specific MYH7 mutations identified to date include missense mutations to proline, deletions of an amino acid, or charge reversal from Glu to Lys in exons 32-38 [Meredith et al 2004, Udd 2009]. MYH7 mutations have been identified in approximately 50% of individuals with early-onset distal myopathy [Author, personal observation]. Table 1. Summary of Molecular Genetic Testing Used in Laing Distal MyopathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMYH7Sequence analysis / mutation scanning 2Sequence variants 3, 4~95% 5Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. See Molecular Genetics.5. Sequence analysis of the exons identifies all mutations known to date; no gross deletions or deep intronic mutations have as yet been identified in this gene. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. The current protocol for searching for mutations causing Laing distal myopathy in persons with characteristic clinical findings is to sequence exons 30-40 of MYH7 from genomic DNA. This should detect the majority of mutations associated with this phenotype, though Darin et al [2007] identified a p.Thr441Met mutation in exon 14 associated with a Laing distal myopathy phenotype and additional cardiomyopathy. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersFamilial hypertrophic cardiomyopathy 1 (CMH1) (OMIM 160760). MYH7 mutations causing familial hypertrophic cardiomyopathy are spread along almost the entire length of the molecule, including both the head and the tail, overlapping the mutations causing Laing distal myopathy and myosin storage myopathy (see Familial Hypertrophic Cardiomyopathy Overview).Myosin storage myopathy (MSM, or hyaline body myopathy) (OMIM 608358). Myosin storage myopathy is genetically heterogeneous: autosomal recessive myosin storage myopathy has been linked to another chromosomal locus [Onengüt et al 2004].MSM that is caused by mutations of MYH7 is usually either congenital or early-onset and either non-progressive or very slowly progressive. The weakness tends to be more proximal than distal. Five published MYH7 mutations have now been identified in MSM (p.Leu1779Pro, p.Leu1793Pro, p.Arg1845Trp, p.Glu1883Lys, p.His1901Leu). These mutations are in the tail of the myosin molecule, including the region of titin binding and the assembly competent domain [Tajsharghi et al 2003, Bohlega et al 2004, Dye et al 2006, Chai et al 2007, Tajsharghi et al 2007]. The p.Leu1793Pro mutation has been linked with either myosin storage myopathy or pure cardiomyopathy in a mother and daughter in the same family [Uro-Coste et al 2009].The p.Arg1845Trp mutation is a recurrent mutation, described multiple times in unrelated affected individuals [Laing et al 2005, Shingde et al 2006, Pegoraro et al 2007]. The p.Glu1883Lys mutation is unusual in that it is associated with recessive myosin storage myopathy and cardiomyopathy [Tajsharghi et al 2007]. Scapuloperoneal myopathy. Pegoraro et al [2007] identified p.Arg1845Trp, the mutation most commonly associated with myosin storage myopathy, in two of 17 persons with a clinical diagnosis of scapuloperoneal myopathy.Hypertrophic distal myopathy and cardiomyopathy. One individual in a family with the p.Val606Met mutation had hypertrophic cardiomyopathy and hypertrophic distal myopathy, including gross hypertrophy of the tibialis anterior muscle, which is normally atrophic in Laing distal myopathy [Overeem et al 2007].
Laing distal myopathy is characterized by muscle weakness and atrophy [Lamont et al 2006]. ...
Natural HistoryLaing distal myopathy is characterized by muscle weakness and atrophy [Lamont et al 2006]. Onset is usually before age five years. In a few children onset has been so early as to delay walking. In two families, weakness was not recognized until the teenage years [Zimprich et al 2000, Hedera et al 2003, Lamont et al 2006].Weakness follows a typical sequence in all affected children, initially affecting dorsiflexion of the ankle and great toe, leading to a high-stepping gait and secondary tightening of the tendo Achillis (see Figure 1).FigureFigure 1. Early development of anterior compartment weakness has led to marked tightening of the tendo Achillis bilaterally, with the affected individual unable to place his heels on the ground. Weakness of finger extensors develops shortly thereafter or over several years. The third and fourth fingers seem to be more severely affected than the other fingers (see Figure 2). Weakness of the finger extensors is often accompanied by a postural and action tremor of the hands. FigureFigure 2. Individual with Laing distal myopathy attempting to extend her second to fifth fingers. Note marked weakness of third and fourth finger extension. Mild facial weakness is often present, leading to inability to bury the eyelashes completely when closing the eyes tightly, and inability to keep the lips pursed against resistance. One affected individual has a mild Bell's phenomenon. Weakness of neck flexion, seen in all affected individuals, is usually early in onset, though weakness of neck flexion did not manifest in one family until the sixth decade. In most affected individuals and sites, the weakness is symmetric. After distal weakness has been present for more than ten years, mild proximal weakness occurs, with a slight Trendelenburg gait and mild scapular winging (see Figure 3). Axial musculature may be mildly weak as well, manifesting as, for example, inability to do a sit-up. FigureFigure 3. Mild scapular winging and weakness develops later. Progression is extremely slow and no affected adults have needed a wheelchair for mobility, even those in their seventh decade. Cardiac problems are not generally described in affected individuals. However, a father and son in one family developed a dilated cardiomyopathy for which no other cause was found [Hedera et al 2003] and certain specific mutations, notably the glutamate to lysine charge reversal mutations, do show an associated, in some cases severe cardiomyopathy [Udd 2009].Pathology. The muscle pathology in Laing distal myopathy is highly variable [Lamont et al 2006]. Type 1 slow muscle fibers (in which MYH7 is expressed) may be atrophic; there may be type 1 or type 2 fiber predominance; rimmed vacuoles, common in other distal myopathies, are rare [Lamont et al 2006]. Sural nerve biopsy in an older individual showed hypomyelination of large nerve fibers without onion bulb formation, and no degenerating or regenerating fibers [Voit et al 2001]. No other nerve biopsies have been reported.
No genotype-phenotype correlations for MYH7 have been identified to date....
Genotype-Phenotype CorrelationsNo genotype-phenotype correlations for MYH7 have been identified to date.Laing distal myopathy. All mutations known to be associated with Laing distal myopathy occur within exons 32-38 as missense mutations to proline, deletion of an amino acid, or a charge reversal mutation from glutamate to lysine in the tail of the encoded protein (myosin heavy chain, cardiac muscle beta isoform protein), including the region of the binding site for M protein and myomesin [Meredith et al 2004, Udd 2009]. The charge reversal mutations p.Glu1801Lys and p.Glu1856Lys [Udd 2009] are associated with a Laing distal myopathy phenotype combined with cardiomyopathy. Similarly, the p.Glu1883Lys recessive myosin storage myopathy mutation is also associated with cardiomyopathy [Tajsharghi et al 2007]. There thus appears to be a class of Glu>Lys charge reversal mutations associated with a skeletal muscle disease (either Laing distal myopathy or myosin storage myopathy) and cardiomyopathy. Some of the mutations are recurrent, notably the p.Lys1617del and the p.Lys1729del mutations [Meredith et al 2004, Lamont et al 2006, Udd 2009].Myosin storage myopathy. The mutations known to be associated with myosin storage myopathy cluster within exons 37-39.
Congenital myopathy. The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis, such as central core disease (CCD) or centronuclear myopathy. Sometimes clinical manifestations can give a clue. For instance, the weakness in CCD is more proximal than distal, affecting the hip girdle in particular. In centronuclear myopathy, ptosis and restriction of eye movements are common. However, the overlap in phenotype between the milder congenital myopathies and Laing distal myopathy can be considerable. In these situations, muscle biopsy should show characteristic structural changes in the congenital myopathies, such as central cores in CCD, whereas it does not in individuals with Laing distal myopathy. ...
Differential DiagnosisCongenital myopathy. The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis, such as central core disease (CCD) or centronuclear myopathy. Sometimes clinical manifestations can give a clue. For instance, the weakness in CCD is more proximal than distal, affecting the hip girdle in particular. In centronuclear myopathy, ptosis and restriction of eye movements are common. However, the overlap in phenotype between the milder congenital myopathies and Laing distal myopathy can be considerable. In these situations, muscle biopsy should show characteristic structural changes in the congenital myopathies, such as central cores in CCD, whereas it does not in individuals with Laing distal myopathy. Distal myopathies. The other major group in the differential diagnosis is distal myopathy (see Table 2). Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after the age of 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long-toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. Udd distal myopathy is caused by mutations in TTN, the gene encoding titin [Hackman et al 2002].Nonaka early-adult-onset distal myopathy with rimmed vacuoles usually begins in the second or third decade in the anterior compartment of the legs and in the toe extensors. Foot drop and a steppage gait are present with progression to loss of ambulation after 12 to 15 years. This is the same condition as quadriceps-sparing myopathy and is caused by mutation of GNE [Nishino et al 2002].Markesbery-Griggs late-onset distal myopathy is characterized by weakness of ankle dorsiflexion usually beginning in the late 40s, followed later by slow progression to the finger and wrist extensor muscles and to the intrinsic muscles of the hand. Eventually the proximal leg muscles become involved. This disease is caused by a mutation in ZASP (LDB3) [Griggs et al 2007]. MPD3, a dominant distal myopathy, was described in Finland in a single family in which some affected individuals had onset in the upper limbs and others in the lower limbs; later, both upper and lower limbs are involved [Haravuori et al 2004]. Miyoshi early-adult-onset myopathy begins in the posterior compartment of the legs, manifests as difficulty climbing stairs and walking on toes and progresses to other distal and proximal muscles as with LGMD2B (see Dysferlinopathy). The serum CK concentration is usually more than 50 times normal. Welander distal myopathy may sometimes have onset in the anterior compartment muscles of the lower legs, instead of the usual onset in the hand and finger extensors [von Tell et al 2002]. Typically, affected individuals experience weakness of the extensor of the index finger after age 40 years, followed by slow progression to the other finger extensors and to the anterior and posterior leg muscles. Table 2. Distal MyopathiesView in own windowDisease NameMean Age at Onset (Years)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene Symbol (Locus) 1Autosomal dominantWelander distal myopathy>40Distal upper limbs (finger and wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN Markesbery-Griggs late-onset distal myopathy>40Vacuolar and myofibrillar myopathyZASP (LDB3) Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar and myofibrillarMYOT Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsNormal to (rarely) moderately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7 Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands; dysphonia1-8 timesRimmed vacuolesMATR3Distal myopathy with pes cavus and areflexia15-50Anterior and posterior lower leg; dysphonia and dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13)New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22)Autosomal recessiveNonaka early-adult-onset distal myopathy15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE Miyoshi early-adult-onset myopathy Posterior compartment in legs>10 timesMyopathic changesDYSF Udd & Griggs [2001]1. Locus given only if the gene is not knownNote: Of the distal myopathies presented in Table 2, those most likely to be considered in the differential diagnosis for Laing distal myopathy include Udd distal myopathy (tibial muscular dystrophy), Nonaka distal myopathy, Markesbury-Griggs distal myopathy, and MPD3 [Mastaglia et al 2005]. The major feature differentiating Laing distal myopathy from these entities is age of onset (see Table 2). Another distinguishing feature is the weakness of neck flexion, which although mild, does present early in most individuals with Laing distal myopathy.Distal myopathies less likely to be considered in the differential diagnosis are Miyoshi distal myopathy (predominantly affecting the posterior compartment of the leg and much more rapidly progressive) and Welander distal myopathy (predominantly affecting the hands).Charcot-Marie-Tooth Hereditary Neuropathy also commonly features foot drop and thus may be considered in the differential diagnosis. Evidence of sensory involvement, namely reduction in pinprick appreciation in the toes, is usually seen in Charcot-Marie-Tooth neuropathy.
To establish the extent of disease in an individual diagnosed with Laing distal myopathy, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Laing distal myopathy, the following evaluations are recommended:A full neurologic history and examination at presentation, with particular reference to early gross motor milestones. The examination should particularly note tightening of the tendo Achillis (Figure 1) and the pattern of muscle weakness. Although it does not appear that cardiac manifestations are a prominent feature in most cases, an electrocardiogram and echocardiogram should be performed as a baseline. Treatment of ManifestationsPhysiotherapy assessment with particular reference to preventing or treating tightening of the tendo Achillis is very useful. In more advanced cases, lightweight splinting of the ankle (e.g., with an ankle-foot orthosis) may be recommended. SurveillanceAfter establishing the diagnosis and instituting the indicated therapies (see Treatment of Manifestations), annual review is recommended.Electrocardiogram and echocardiogram should be repeated if symptoms of cardiac insufficiency occur.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Laing Distal Myopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMYH714q11.2Myosin-7MYH7 homepage - Leiden Muscular Dystrophy pagesMYH7Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Laing Distal Myopathy (View All in OMIM) View in own window 160500MYOPATHY, DISTAL, 1; MPD1 160760MYOSIN, HEAVY CHAIN 7, CARDIAC MUSCLE, BETA; MYH7Normal allelic variants. MYH7 comprises 40 exons. Exonic normal allelic variants (exons 30-40):p.Ser1491Cys p.Thr1522Thr p.Val1691Metp.Ala1702Ala p.Glu1799Glu p.Arg1846Gly p.Lys1919Asn Non-coding normal allelic variants (exons 30-40):Intron 31: +112G>C Intron 32: +37A>C Intron 38: +31G>A Intron 39: –63G>A 3'UTR G>A +112 Pathologic allelic variants. All MYH7 pathologic allelic variants identified to date are in exons 32-38. p.Arg1500Pro (exon 32) p.Glu1508del (exon 33)p.Ala1603Pro (exon 34)p.Lys1617del (exon 34) p.Ala1663Pro (exon 35) p.Leu1706Pro (exon 35) p.Lys1729del (exon 36) p.Glu1801Lys (exon 37)p.Glu1856Lys (exon 38)Normal gene product. The normal gene product is the myosin heavy chain of slow skeletal muscle fibers that is also expressed in the heart. Abnormal gene product. All published mutations causing Laing distal myopathy are missense mutations to proline, deletion of an amino acid, or conversion of glutamate to lysine within exons 32-38. The missense mutations to proline and amino-acid deletions should disrupt the ability of the myosin tail to form a coiled coil [Meredith et al 2004]. The effect of the glutamate to lysine mutations is uncertain. Using biophysical analysis of the p.Arg1500Pro mutant protein, Armel & Leinwand [2010] demonstrated reduced thermodynamic stability and reduced thick filament stability. Similarly, the most frequently found mutation in myosin storage myopathy, p.Arg1845Trp, is predicted by silico analysis to cause disruption of the ability of the myosin tail to form a coiled coil [Laing et al 2005], and myosin storage myopathy mutations overlap the position of Laing distal myopathy mutations. Armel & Leinwand [2009] show that the myosin storage myopathy mutations may either reduce thermodynamic stability or affect thick filament assembly.