Various types of herediary inclusion body myopathies map to chromosome 9p1-q1

Hereditary inclusion body myopathies are a clinically heterogeneous group of disorders characterized by adult-onset, slowly progressive muscle weakness and typical histopathology: rimmed vacuoles and filamentous inclusions. The disorders are usually inherited as an autosomal recessive trait. The gene responsible for the disease found in Iranian Jews, who present wih quadriceps-sparing myopathy, maps to chromosome 9p1-q1. We address the question of whether hereditary inclusion myopathies are genetically as well as clinically heterogeneous disorders. We mapped the disease gene segregating in two families of Afghani-Jewish and one family of Iraqi-Jewish descent to the chromosome 9 locus. Similarly, the disease gene segregating in a non-Jewish family from India mapped to the same locus. By contrast, the disease gene segregating in a French-Canadian family in which affected individuals had central nervous system involvement as well as hereditary inclusion body myopathy, did not map to this locus. We conclude that many but not all forms of autosomal recessive hereditary inclusion body myopaty are caused by a gene defect that maps to chromosome 9p1-q1.     

Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus

In 1995 Laing et al. (Am J Hum Genet 56(1995)422) described a single family with nine members affected by an autosomal dominant infantile onset distal myopathy. This family generated a LOD score of 2.6 for a locus on chromosome 14. We describe two families with an infantile onset distal myopathy: a new family with four affected members and the family previously described by Scoppetta et al. (Acta Neurol Scand 92(1955)122) in both of which haplotype segregation was compatible with linkage to the same chromosome 14 locus, generating LOD scores of 0.9 at a penetrance of 100% for the markers D14S283 and D14S64 (theta=0) in both families. The loci for autosomal recessive hereditary inclusion body myopathy and Nonaka myopathy on chromosome 9 and for autosomal dominant distal myopathy of Markesberry-Griggs and Udd on chromosome 2q31-33 were excluded by linkage analysis. The disease followed a uniform course with selective wasting of the anterior tibial muscles, starting in infancy and recognizable by a characteristic clinical sign of the 'hanging big toe'. This was followed by slow progression, with involvement of the finger and wrist extensor muscles in the third decade and proximal limb muscles in the fourth decade. Interestingly, we also found evidence of an accompanying mild peripheral neuropathy in the oldest individual with hypomyelination of numerous large myelinated fibres. In addition, this patient's muscle biopsy also showed autophagic vacuoles and numerous intranuclear tubulo-filamentous inclusions of 15-20 nm diameter. Given that all three families with infantile onset distal myopathy are compatible with linkage to the same locus on chromosome 14, this study supports evidence for, and enlarges the clinical and neuropathological spectrum of the distal myopathy on chromosome 14.     

An Italian family with autosomal recessive quadriceps-sparing inclusion-body myopathy (ARQS-IBM) linked to chromosome 9p1

We report an Italian family with autosomal recessive quadriceps-sparing inclusion-body myopathy (ARQS-IBM). The patients (two second cousins) developed a slowly progressive distal and proximal myopathy with complete sparing of the quadriceps. Muscle biopsy showed rimmed vacuoles in numerous muscle fibers, and electron microscopy documented accumulation of 15–21 nm filaments, DNA analysis established linkage to 9p1 and haplotype analysis revealed that the patients shared a recombined common haplotype. The gene locus of ARQS-IBM was initially mapped to chromosome 9p1-q1 in families of Iranian-Jewish origin and later confirmed in a few other ethic groups. This is the first report of Italian patients with ARQS-IBM showing positive linkage to chromosome 9p1. Our data suggest that patients having distal and proximal myopathy with rimmed vacuoles and possible recessive inheritance, often classified as distal myopathies, should be thoroughly investigated according to the diagnostic criteria of h-IBM and, when positive, studied for linkage to chromosome 9p1. Received: 8 February 2000 / Accepted in revised form: 6 April 2000     

Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives

PURPOSE OF REVIEW: Distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy is an adult-onset autosomal recessive, slowly progressive and debilitating myopathy due to mutations in the gene that regulates the synthesis of sialic acid. This review aims to update our knowledge of this myopathy and to review studies about pathomechanism and therapeutic strategies. RECENT FINDINGS: Owing to the mutated gene, it was expected that the pathomechanism of this myopathy would be based on hyposialylation, a highly controversial phenomenon. This concept has been supported by findings in two recently generated animal models. In addition, the intracellular amyloid-beta accumulation in a distal myopathy with rimmed vacuole mouse model is relevant to similar findings in patients. SUMMARY: Clarifying the role of hyposialylation in distal myopathy with rimmed vacuole/hereditary inclusion body myopathy could potentially lead to a therapeutic strategy for this progressive myopathy. In addition, strategies aimed at preventing amyloid-beta deposition or enhancing its clearance could also be beneficial, as this epiphenomenon is now known to occur early in the course of the disease.     

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.     

Distal myopathies

Among various previously described distal myopathies, several diseases have now been established as clinically and genetically distinct entities. The most representative diseases are dominantly inherited Welander distal myopathy and tibial muscular dystrophy, and the recessively inherited distal myopathy with rimmed vacuoles and distal muscular dystrophy (Miyoshi myopathy). Since the discovery of the gene loci for several distal myopathies, several diseases previously categorized as different disorders have now proven to be the same or allelic disorders (e.g. distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy, Miyoshi myopathy and limb-girdle muscular dystrophy with gene locus at 2p13). Except for Miyoshi myopathy, which has the typical findings of muscular dystrophy, most of the distal myopathies share the common pathologic features of myopathic changes with rimmed vacuoles. The pathologic changes are somewhat similar to those seen in chronic muscular dystrophy, but necrotic and regenerative processes are less prominent and creatine kinase levels are either normal or only mildly elevated. Further study is necessary to determine why rimmed vacuoles are so common in the distal myopathies, and what role they play in the pathogenesis of muscle fibre atrophy and loss, predominantly in the distal portions of the extremities.     

Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy

Distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (hIBM) share similar clinical features, including onset in young adulthood with preferential involvement of the anterior compartment of the lower legs and sparing of the quadriceps femoris muscles. The most significant muscle pathology is the presence of rimmed vacuoles, which appear to play a major role in muscle atrophy and weakness. After the discovery of the gene locus in both DMRV and hIBM on chromosome 9 and mutations in the gene encoding the enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), it became clear that they are allelic disorders. From gene analysis, it is evident that these diseases are not restricted to people of Japanese and Jewish ancestry, but that they are widely distributed throughout all ethnic groups. Although defective glycosylation to a muscle fiber has been suggested, the mechanism by which myofibrillar degeneration is followed by rimmed vacuole formation remains to be clarified.     

Distal myopathies

Distal myopathies are classified according to clinical, histopathological, and genetic patterns into the following: late adult onset type 1, or Welander myopathy, the first recognized distal myopathy with autosomal dominant inheritance and very recently linked to chromosome 2p; late adult onset type 2, or Markesbery-Griggs/Udd myopathy, autosomal dominant with linkage to chromosome 2q; early adult onset type 1, or Nonaka myopathy, an autosomal recessive disease linked to 9p1-q1 and considered indistinguishable from hereditary inclusion body myopathy; early adult onset type 2, or Miyoshi myopathy, with autosomal recessive inheritance linked to chromosome 2p12-p14; and early adult onset type 3, or Laing myopathy, autosomal dominant with linkage to chromosome 14. Very recently, dysferlin, a novel skeletal muscle gene, has been found mutated in Miyoshi myopathy and also in the limb girdle muscular dystrophy 2B, a disease with a completely different phenotype. This indicates that the classification of the distal and other genetically determined muscle diseases will probably change when these myopathies are understood at the molecular level. For example, it would be reasonable to use the term dysferlinopathies to describe all the diseases due to dysferlin mutations.     

Hereditary inclusion‐body myopathy: Clues on pathogenesis and possible therapy

Hereditary inclusion‐body myopathy (h‐IBM), or distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with onset in early adult life and a progressive course leading to severe disability. h‐IBM/DMRV is due to mutations of a gene (GNE) that codes for a rate‐limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been unambiguously clarified how GNE gene mutations impair muscle metabolism. Although numerous studies have indicated a key role of hyposialylation of glycoproteins in h‐IBM/DMRV pathogenesis, others have demonstrated new and unpredicted functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h‐IBM/DMRV and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of this disorder. Muscle Nerve, 2009     

Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the α1 subunit of a P/Q-type voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Z_max: 3.33 at = 0.05) and D1S2705 (Z_max: 3.64 at = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21–q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1–linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.     

Intranuclear and cytoplasmic filamentous inclusions in distal myopathy (Welander)

Summary Ultrastructural examination of anterior tibial muscle from four patients with late-onset autosomal dominant distal myopathy of Welander-type revealed intrasarcoplasmic filamentous inclusions in association with rimmed vacuoles. In one of the patients, identical intranuclear filamentous inclusions were also found. These filamentous inclusions are similar to those desxribed in inclusion body myositis (IBM). They have also been observed in hereditary neuromuscular disorders including autosomal recessive distal myopathy. Thus, the filamentous inclusions occur in different neuromuscular conditions with different etiologies. These findings further raise the question of the specificity of the filamentous inclusions in IBM.Supported by grants from the Swedish Medical Research Council (proj. 3875, visiting research grant K. Borg), the Swedish MS foundation, the Swedish Society of Medicine, the Swedish Society for Traffic and Polio Disabled, Erik and Edith Fernströms Foundation for Medical Research and from the Karolinska Institute     

Novel GNE mutations in two phenotypically distinct HIBM2 patients

Homozygous mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene cause hereditary inclusion body myopathy type 2 (HIBM2). We describe two unrelated American patients with novel GNE mutations. While one patient followed a typical disease course for HIBM2 with an onset at age 25 and rimmed vacuole pathology on muscle biopsy, the second patient had several features atypical for HIBM2. This patient’s onset was at age 55, included distal weakness, quadriceps sparing and respiratory insufficiency. His muscle biopsy showed prominent necrosis without rimmed vacuoles. This study expands the phenotype and illustrates the clinical spectrum of HIBM2 identified in a U.S. based neuromuscular clinic.     

Distal myopathies

PURPOSE OF REVIEW: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. RECENT FINDINGS: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. SUMMARY: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders.     

Distal myopathy with rimmed vacuoles in a case of opercular syndrome

We report the case of a 30-year-old man with opercular syndrome who developed distal myopathy with rimmed vacuoles (DMRV). Muscle biopsy showed variation in fiber size and scattered fibers with rimmed vacuoles. The identification of a homozygous c. 1714G>C (p. V572L) mutation in the GNE gene genetically confirmed the diagnosis of DMRV, which is thought to be identical to hereditary inclusion body myopathy (HIBM). Our results indicate the possibility that other organs such as the central nervous system could be affected in DMRV/HIBM, although bilateral opercular lesions might have been caused by destructive events either in utero or in the perinatal period.     

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.     

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation.     

Autosomal recessive distal muscular dystrophy: a comparative study with distal myopathy with rimmed vacuole formation

To clarify the clinical and morphological characteristics of distal muscular dystrophy, clinical and pathological material from 4 affected persons was compared with similar studies in 4 patients with distal myopathy with rimmed vacuole formation. Although these two forms of autosomal recessive distal myopathy with onset in young adulthood were highly similar in their clinical symptoms, histochemical and electron microscopic findings of muscles subjected to biopsy were quite different. The muscle abnormalities in distal muscular dystrophy were almost the same as those in Duchenne muscular dystrophy, showing massive fiber necrosis followed by active fiber regeneration. In contrast, distal myopathy with rimmed vacuole formation showed a progressive muscle fiber atrophy and loss, rimmed vacuoles in the sarcoplasm, and no apparent fiber necrosis or regeneration.     

Distal myopathy with rimmed vacuoles: clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients

Abstract

Objectives: Distal myopathy with rimmed vacuoles (DMRV) is a typical autosomal recessive hereditary inclusion body myopathy, characterized by slowly progressive distal muscle weakness with relative sparing of the quadriceps. This study aimed to investigate the variability of clinical and morphological presentation and the spectrum of Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) mutations in Chinese DMRV patients.

Methods: We retrospectively reviewed the medical records of 37 patients with DMRV in PLA General Hospital from 1986 to 2011, and further conducted a review of 16 reported Chinese DMRV patients from other hospitals. We systematically analyzed the clinical, muscle morphological features and GNE gene mutation status of all DMRV patients.

Results: A total of 53 DMRV patients were studied. Fourteen cases had family history and other 39 cases were sporadic. Fifteen cases showed atypical pathological presentation as mononuclear cell invasion into necrotic or non-necrotic muscle fibers. Rare initial symptom, earlier age of onset and more dysmorphic presentations were shown in sporadic patients. Eighteen mutations in GNE gene were identified. c.317T>C (p.I106T) was a novel GNE gene mutation. c.1892C>T (p.A631V), c.527A>T (p.D176V) and c.1523T>C (p.L508S) were the common GNE mutations in Chinese DMRV patients.

Discussion: The clinical, pathological and genetic characteristics of DMRV are distinct in Chinese patients.     

Reducing bodies in distal myopathy with rimmed vacuole formation

A 42-year-old woman with distal myopathy with rimmed vacuoles had intracytoplasmic inclusion bodies similar to those described in reducing body myopathy. Since these inclusions were found in fibers with high acid phosphatase activity and occasional rimmed vacuoles, their formation appeared to correlate with active myofibrillar degeneration, but their origin remains unknown.     

Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant

Study of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) revealed that almost all cases of distal myopathy with rimmed vacuoles were caused by GNE mutations. Seven new mutations were identified, including M712T, which is the most common mutation in Jewish hereditary inclusion body myopathy. In addition, a splice-variant characteristic of the skeletal muscle was found, whereas the difference of the expression level between GNE-mutated and -nonmutated patients was not apparent.