Autosomal dominant distal myopathy not linked to the known distal myopathy loci

The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected individuals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.     

Genetic linkage of Welander distal myopathy to chromosome 2p13.

Welander distal myopathy (WDM) is an autosomal dominant myopathy with late-adult onset characterized by slow progression of distal muscle weakness. The disorder is considered a model disease for hereditary distal myopathies and is almost only seen in Sweden and some parts of Finland. A genomewide screening has been performed in initially two Swedish families with 400 highly polymorphic microsatellite markers. We report here that the disease is linked to chromosome 2p13. Seven additional nonrelated families have subsequently been mapped to the same area where a maximum two-point LOD score of 17.97 was obtained with the marker D2S2113 at 0.0 recombination fraction. The region has been restricted by recombinations and the finding of a common shared haplotype through all analyzed families. This restricts the gene locus region to 2.4 cM. These findings provide evidence for the involvement of a single locus for WDM. The WDM region overlaps with the linkage region for Miyoshi myopathy and limb-girdle muscular dystrophy 2B. The dysferlin gene responsible for these disorders is considered a primary candidate gene for WDM.     

Infantile autosomal dominant distal myopathy.

Introduction – Distal myopathies are currently regarded as a non-homogeneous group of disorders including different autosomal dominant, recessive and sporadic forms. Material and methods - The cases of a mother and her son and daughter are described and compared to previously reported cases from 4 families. Despite minor differences, the clinical picture is remarkably homogeneous, both within the same family and among different families. Conclusion - A distinct clinical form can be identified including: a) autosomal dominant inheritance; b) onset in infancy or childhood with peroneal muscles weakness; c) not disabling evolution in spite of possible late involvement of muscles others than tibio-peroneal; d) usually normal serum CK and other muscle enzymes; e) EMG evidence of primary myogenic damage; f) morphological findings of non-specific myopathy. Because of the benign evolution and the absence of true dystrophic changes in most biopsies we suggest the term infantile autosomal dominant distal myopathy should be preferred to infantile autosomal dominant distal muscular dystrophy.     

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     

Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

Distal myopathy with rimmed vacuoles is an autosomal recessive muscular disorder, characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood. Recently, the gene locus for familial vacuolar myopathy with autosomal recessive inheritance (hereditary inclusion body myopathy) was mapped to chromosome 9 by genome-wide linkage analysis of nine Persian-Jewish families. Since both disease conditions share similar clinical, genetic, and histopathological features, we analyzed seven families with distal myopathy with rimmed vacuoles using ten microsatellite markers within the region of the hereditary inclusion body myopathy locus. Significantly high cumulative pairwise lod scores were obtained with three markers: D9S248 (Z_max = 5.90 at Θ = 0), D9S43 (Z_max = 5.25 at Θ = 0), and D9S50 (Z_max = 4.23 at Θ = 0). Detection of obligate recombination events as well as multipoint linkage analysis revealed that the most likely location of the distal myopathy with rimmed vacuoles gene is in a 23.3-cM interval defined by D9S319 and D9S276 on chromosome 9. The results raise the possibility that distal myopathy with rimmed vacuoles and hereditary inclusio body myopathy in Persian Jews are allelic diseases.     

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.     

Early onset chromosome 14-linked distal myopathy (Laing)

A dominantly inherited form of distal myopathy with onset in early childhood was first reported in a 4-generation Australian family in 1995. In the present report we provide further information on the clinical phenotype and natural history of this myopathy, and on the electromyogram and magnetic resonance imaging findings in affected individuals. The pattern of muscle involvement was similar to that in the 'tibial' forms of distal myopathy such as the Finnish (Udd) and Markesbery-Griggs types, with additional involvement of the finger extensors and of some more proximal limb and neck muscles. However, the age of onset was earlier than in these other myopathies and rimmed vacuoles were not found in biopsies from two affected individuals. Evidence of possible anticipation was found in one branch of the family. The gene locus for this myopathy had been mapped to 14q11.2-q13. The linkage region has been refined to a 24 cM region between D14S283 and D14S49 and mutations have been excluded in the PABP2 gene for oculopharyngeal muscular dystrophy which lies within this region.     

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene. Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.     

Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)

We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.     

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q

Twenty-one members of a Swedish family suffering from myopathy and cardiomyopathy underwent neurological and cardiological investigations. Medical charts of 2 affected deceased patients were reviewed. Twelve patients had myopathy. The distribution of weakness was axial in mildly affected, axial and predominantly distal in moderately affected, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy revealed granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic right ventribular cardiomyopathy. Nonsustained ventribular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of them had a pacemaker implanted because of atrioventricular block and sick sinus syndrome. Inheritance is autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. Linkage analysis of candidate chromosomal regions showed a maximum 2-point LOD score of 2.76 for marker locus D10S1752 on chromosome 10q. A multipoint peak LOD score of 3.06 between markers D10S605 and D10S215 suggests linkage to chromosome 10q22.3, and this region may harbor a genetic defect for myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopahty.     

Distal myopathies

Distal myopathies are a heterogeneous group of genetic disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet, and pathologically by myopathic changes in skeletal muscles. Five distinct distal myopathies are identified, among them four have been recently defined by their gene and causative mutations. They are classified according to age at onset, mode of inheritance, and muscle groups initially involved into the following: Laing myopathy (infancy onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in a myosin gene (MYH7) on chromosome 14q; Nonaka myopathy (early adult onset, autosomal recessive inheritance, onset in anterior compartment of legs), identical to quadriceps-sparing familial inclusion myopathy, caused by mutations in the GNE gene on chromosome 9p-q; Miyoshi myopathy (early adult onset, autosomal recessive inheritance, onset in posterior compartment of legs) caused by mutations in the dysferlin gene on chromosome 2p; Welander myopathy (late adult onset, autosomal dominant inheritance, onset in hands) linked to chromosome 2p; Udd/Markesbery-Griggs myopathy (late adult onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in the titin gene on chromosome 2q. Except for Miyoshi myopathy, which has a striking elevated serum creatine kinase level and the typical findings of muscular dystrophy, most of the distal myopathies have normal or midly elevated creatine kinase levels and share the common pathologic feature of rimmed vacuoles.     

PARK6-linked parkinsonism occurs in several European families.

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson's disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.     

Phenotypic features and genetic findings in 2 chinese families with Miyoshi distal myopathy

BACKGROUND: Miyoshi distal myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) were found to map to the same mutant gene encoding for dysferlin on chromosome 2p13. Most reported cases were large inbred kindreds whose members demonstrated both MM and LGMD2B phenotypes. OBJECTIVE: To investigate the clinical, neurophysiological, histopathological, and genetic features in 4 patients with MM from 2 unrelated Chinese families demonstrating linkage to the dysferlin locus. RESULTS: All patients were characterized by early adult onset, preferential atrophy, and weakness of calf muscles, marked elevation of serum creatine kinase levels, and absence of dysferlin staining. Magnetic resonance imaging showed fatty and fibrotic tissue signals in the affected muscles. Genetic analysis revealed novel compound heterozygous mutations, 1310+1G to A and GGG to GTC transition at nucleotide 1650 (G426V ) in one family and another novel compound heterozygous mutation, a deletion of C at nucleotide 477 and a CCG to CTG transition at nucleotide 6576 (P2068L), in the other family. CONCLUSION: Miyoshi distal myopathy in these 2 Chinese families demonstrated a homogenous phenotype and compound heterozygous mutations. Among the 4 mutations, 3 were novel mutations that, to our knowledge, have not been reported previously.     

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies

OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.     

Proof of genetic heterogeneity in the proximal myotonic myopathy syndrome (PROMM) and its relationship to myotonic dystrophy type 2 (DM2)

Recently, myotonic dystrophy type 2 has been described as a separate disease entity that is distinctive from classical Steinert's disease since it lacks a CTG repeat expansion on chromosome 19q. A gene locus for myotonic dystrophy type 2 has been mapped to chromosome 3q. Independently, proximal myotonic myopathy has been recognized as yet another form of a multisystem myotonic disorder. Its relationship to myotonic dystrophy type 2 remains to be clarified. In our linkage study of 17 German proximal myotonic myopathy families nine of them mapped to the myotonic dystrophy type 2 locus (LOD score 18.9). However, two families with a typical proximal myotonic myopathy phenotype were excluded from this locus (LOD score -7.4). These results confirm genetic heterogeneity in the proximal myotonic myopathy syndrome. Furthermore, in the majority of the proximal myotonic myopathy families the disease phenotype may be caused by allelic mutations in the putative myotonic dystrophy type 2 gene.     

Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24

Hereditary motor and sensory neuropathy type IIC (HMSN IIC) is an autosomal dominant axonal neuropathy. The cardinal features include distal muscle wasting and weakness, vocal cord paralysis, and mild sensory impairment. Recently, HMSN IIC locus was mapped to chromosome 12q23-24. Two families affected by HMSN IIC were identified and evaluated for linkage to this region. Segregation analysis in both families was consistent with linkage to chromosome 12q23-24. Combined analysis generated a multipoint LOD score of 2.1 at marker D12S1583 and refined the HMSN IIC gene interval to The clinical and molecular findings are discussed.     

Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q

OBJECTIVE: To investigate anticipation in proximal myotonic myopathy (PROMM). BACKGROUND: PROMM is a recently described autosomal dominantly inherited disorder similar to but distinct from myotonic dystrophy (DM). DM belongs to the group of inherited disorders with anticipation caused by an unstable trinucleotide repeat expansion. In PROMM, no mutation has been identified, although PROMM has recently been mapped to a gene locus on chromosome 3q. METHODS: We investigated 10 German families with the PROMM phenotype and linkage to chromosome 3q. We based our analysis of anticipation on the age of disease onset. Anticipation was assumed if the offspring had first symptoms earlier in life than his or her affected parent. For statistical analysis Independence Estimating Equations (IEE) and a Monte-Carlo bootstrap were used. RESULTS: In 27 affected living parent-offspring pairs from these 10 families, the mean difference of disease onset was 18.8 years with either statistical analysis (p < 10-14 and p < 10-15). The mean disease onset interval in years was greater in father-offspring as compared to the mother-offspring pairs (p < 0.05; IEE). CONCLUSION: Our findings suggest the occurrence of anticipation in parent-offspring pairs from families with the PROMM phenotype and linkage to chromosome 3q. The different disease onset intervals in mother-offspring and father-offspring pairs could indicate a mild parent-of-origin effect. These observations are compatible with the suggestion that PROMM, like DM, may be a trinucleotide repeat associated disorder. In contrast to DM, anticipation in PROMM is milder, a congenital form does not seem to occur, and fertility does not appear to be affected.     

Paroxysmal kinesigenic dyskinesia and generalized seizures: clinical and genetic analysis in a Spanish pedigree

Familial paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder featuring brief, dystonic or choreoathetotic attacks, typically triggered by sudden movements. Symptoms usually start in mid-childhood, although in several pedigrees infantile convulsions have been reported as the presenting sign. Previous linkage studies have identified two PKD loci on 16 p12.1-q21. We report here the clinical features of a Spanish kindred with autosomal dominant PKD, in which haplotype data are compatible with linkage to the pericentromeric region of chromosome 16 and exclude linkage to the locus for Paroxysmal Non Kinesigenic Dyskinesia (PNKD) on chromosome 2 q35. In this family, the conservative candidate region for the disease lies between markers D16S3145 and GATA140E03 on 16 p12.1-q21 and partially overlaps with both the Paroxysmal Kinesigenic Dyskinesia - Infantile Convulsions (PKD-IC) critical interval and the Episodic Kinesigenic Dyskinesia 2 (EKD2) locus. Unusual findings in our pedigree were early infantile onset of the dyskinesias in one patient and generalized seizures as adults in two, adding to previous observations of phenotypic overlap between epileptic and non-epileptic paroxysmal disorders. Further clinical and genetic studies are needed to elucidate whether PKD and PKD-IC are allelic disorders with age-dependent phenotypic expression.     

A recessive form of central core disease,transiently presenting as multi-minicore disease,is associated with a homozygous mutation in the ryanodine receptor type 1 gene

Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.     

Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity

OBJECTIVE: To map the gene responsible for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) in a large affected family. BACKGROUND: Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically heterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8). METHODS: The authors carried out a genomewide linkage screen on a large family with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci was excluded. RESULTS: Analysis of markers on chromosome 8q24 gave a peak two-point lod score of 4.49 at marker D8S1799. Analysis of recombination events in this family and in the previously published SPG8-linked family narrowed the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci was excluded. The SPG8-linked family had a significantly older mean age at onset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families. CONCLUSIONS: These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHSP) locus at chromosome 8q24 and strongly suggest that there are at least five ADPHSP loci. The data provide additional evidence for locus-phenotype correlations in ADPHSP.