Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distal most portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD.

FSH dystrophy 4q35 deletion in patients presenting with facial-sparing scapular myopathy.

OBJECTIVE: To evaluate the incidence of the facioscapulohumeral dystrophy (FSHD) 4q35 deletion in patients with facial-sparing scapular myopathy. BACKGROUND: Scapular winging is typical of FSHD but may also be prominent in other muscle disorders including scapuloperoneal syndromes. With DNA testing, it is possible to determine if patients with facial-sparing scapular myopathy have FSHD. METHODS: Fourteen of 17 unrelated patients with facial-sparing scapular myopathy, seen over a 7-year period at a regional neuromuscular center, agreed to have DNA testing for FSHD. The clinical and laboratory features of these patients were also noted. RESULTS: Of the 14 patients, 10 (71%) had restriction fragments consistent with the 4q35 deletion. The mean size of the smaller fragment following EcoRI digestion was 29.5 kb (range 20 to 39). The mean age at onset was 19.9 years; at presentation, 44.7 years. Except for the absence of facial weakness, most patients had clinical and laboratory features otherwise consistent with FSHD. Five patients (50%) had a positive family history of similar weakness. Following removal of outliers, the Pearson correlation coefficient (r) value between EcoRI fragment size and age at onset was 0.64, and between fragment size and limb muscle strength, 0.64. CONCLUSION: The FSHD 4q35 deletion was found in 71% of the facial-sparing scapular myopathy patients. They otherwise resemble typical FSHD patients in age at onset, physical characteristics, and association between fragment size and disease severity.

Linkage localization of Börjeson-Forssman-Lehmann syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a form of X-linked mental retardation (XLMR) with characteristic minor physical anomalies. It has no biochemical or cytogenetic markers. Heterozygous females may be entirely normal or may have mild-to-moderate manifestations. We studied 41 individuals from one family with BFLS for linkage on the X chromosome. The highest lod scores were 2.32 with DXS10 and 2.24 with DXS51, both at a theta = 0.0. A single recombinant was found between HPRT and BFLS. These results suggest that the BFLS locus is on the distal portion of Xq. Previously reported linkage studies in families with XLMR have not shown linkage with DXS10. This study suggests that one of the several X chromosome loci whose dysfunction is associated with mental retardation is located on distal Xq.

Hypertensive encephalopathy in childhood.

Hypertensive encephalopathy is an uncommon but recognized complication of malignant hypertension in children. We reviewed the clinical course, laboratory studies, and outcomes of 12 patients with hypertensive encephalopathy seen at the University of Iowa Hospitals and Clinics between 1979 and 1994. The most common presenting symptoms were seizures, headache, and vision changes. Laboratory studies were nonspecific and in some patients were normal. Hypertensive encephalopathy is a clinical diagnosis. Management consists of recognition of this syndrome and aggressive treatment of hypertension. The neurologic outcome in our series was good.

Autosomal recessive cerebellar hypoplasia.

Cerebellar hypoplasia is found in association with a variety of neurologic and systemic disorders. It is the primary finding in the uncommonly reported condition of autosomal recessive cerebellar hypoplasia. We describe two siblings with cerebellar hypoplasia documented in both by magnetic resonance imaging (MRI) and review the clinical features of previously reported cases of autosomal recessive cerebellar hypoplasia. The most common findings in this disorder are nonprogressive ataxia, strabismus, mental retardation, and speech delay with dysarthria. Previously reported cases have been confirmed by autopsy, pneumoencephalography, or computed tomographic (CT) scans. MRI clearly documents diffuse cerebellar hypoplasia and aids in distinguishing autosomal recessive cerebellar hypoplasia from other disorders. The pathophysiology of this disorder is uncertain, however, studies of the weaver mutant mouse (an animal model of autosomal recessive cerebellar hypoplasia) suggest that an abnormality of the Bergmann glia may lead to the observed granule cell layer deficiency in these patients. This diagnosis should be considered for children with nonprogressive ataxia and families should be made aware of the 25% recurrence risk.

Steroid therapy and cardiac function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy leads to progressive deterioration in skeletal and cardiac muscle function. Steroids prolong ambulation and improve respiratory muscle strength. The authors hypothesized that steroid treatment would stabilize cardiac muscle function. Echocardiograms performed from 1997 to 2004 for 111 subjects 21 years of age or younger with Duchenne muscular dystrophy were restrospectively reviewed. The medical record was reviewed for steroid treatment. Untreated and steroids-treated subjects did not differ in age, height, weight, body mass index, systolic and diastolic blood pressure, or left ventricular mass. The shortening fraction was lower in the untreated group. Of those treated, 29 received prednisone and 19 received deflazacort. There was no difference in the shortening fraction between the two treated subgroups. Treated subjects not receiving steroids still had a normal shortening fraction, which was no different from the shortening fraction of those still receiving treatment. As compared with the treated subjects, the untreated subjects 10 years of age or younger were 4.4 times more likely to have a shortening fraction less than< 28% (p = 0.03), and the untreated subjects older than 10 years were 15.2 times more likely to have a shortening fraction less than< 28% (p < 0.01). This retrospective study suggests that the progressive decline in cardiac function of patients with Duchenne muscular dystrophy can be altered by steroid treatment. The effect appears to be sustained beyond the duration of treatment and independent of steroid type.

The molecular genetics of human facioscapulohumeral muscular dystrophy and the myodystrophy mouse model.

Facioscapulohumeral dystrophy is an autosomal dominant muscular dystrophy, the gene for which is localized to 4q35. It appears to be caused by deletion of tandem repeats that do not contain an expressed sequence. One current hypothesis is that the deletion affects expression of a centromeric gene (not yet identified) through a position effect. The mouse mutant, myodystrophy (myd), is a candidate model for facioscapulohumeral dystrophy. Myd has a progressive muscular dystrophy and maps to a segment of mouse chromosome 8 that is syntenic with human 4q31-4q35.

Reflex sympathetic dystrophy in children.

Reflex sympathetic dystrophy (RSD) is an uncommonly reported entity in children. This paper reports five cases of RSD in children and summarizes 80 cases of pediatric RSD reported in the literature. The diagnosis is based on the clinical findings of pain, dysesthesia, and autonomic instability. Tache cérébrale, not previously described in the diagnosis of RSD, is a helpful sign of vasomotor dysfunction. RSD in childhood frequently affects the lower extremities, in contrast to the adult localization around the shoulders and hands. Noninvasive, nonpharmacologic management is generally successful. A simple outpatient program of massage and mobilization was beneficial in four of the five patients treated in this study.

Mouse myodystrophy (myd) mutation: refined mapping in an interval flanked by homology with distal human 4q.

Myodystrophy (myd) is an autosomal-recessive mouse mutation with dystrophic skeletal muscle. We propose that myd may be a model of the human disorder facioscapulohumeral dystrophy (FSHD) on the basis of clinical features and homologous genetic map locations. FSHD maps to human 4q35, while myd maps to mouse chromosome 8. To explore the relationship between FSHD and myd, it is necessary to define the homologous regions of human chromosome 4 and mouse chromosome 8, and ultimately, identify the genes underlying both disorders. A kallikrein gene (KaL3) was previously mapped by in situ hybridization to mouse chromosome 8 and human 4q35. We report the genetic map location of Kal3, bringing to 4 the number of genes with homologues on human 4q31-35 placed on the genetic map of mouse chromosome 8. As a first step in gene isolation, we have narrowed the interval containing myd by typing 125 affected mice with microsatellite markers. Analysis of recombinants placed myd in an interval that is flanked by genes with homologues in human 4q.

Mouse myodystrophy (myd) mutation: refined mapping in an interval flanked by homology with distal human 4q.

Myodystrophy (myd) is an autosomal-recessive mouse mutation with dystrophic skeletal muscle. We propose that myd may be a model of the human disorder facioscapulohumeral dystrophy (FSHD) on the basis of clinical features and homologous genetic map locations. FSHD maps to human 4q35, while myd maps to mouse chromosome 8. To explore the relationship between FSHD and myd, it is necessary to define the homologous regions of human chromosome 4 and mouse chromosome 8, and ultimately, identify the genes underlying both disorders. A kallikrein gene (Kal3) was previously mapped by in situ hybridization to mouse chromosome 8 and human 4q35. We report the genetic map location of Kal3, bringing to 4 the number of genes with homologues on human 4q31-35 placed on the genetic map of mouse chromosome 8. As a first step in gene isolation, we have narrowed the interval containing myd by typing 125 affected mice with microsatellite markers. Analysis of recombinants placed myd in an interval that is flanked by genes with homologues in human 4q.

The mouse homolog of FRG1, a candidate gene for FSHD, maps proximal to the myodystrophy mutation on chromosome 8.

The human autosomal dominant neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD) is associated with deletions within a complex tandem DNA repeat (D4Z4) on Chromosome (Chr) 4q35. The molecular mechanism underlying this association of FSHD with DNA rearrangements is unknown, and, thus far, no gene has been identified within the repeat. We isolated a gene mapping 100 kb proximal to D4Z4 (FSHD Region Gene 1:FRG1), but were unable to detect any alterations in total or allele-specific mRNA levels of FRG1 in FSHD patients. Human Chr 4q35 exhibits synteny homology with the region of mouse Chr 8 containing the gene for the myodystrophy mutation (myd), a possible mouse homolog of FSHD. We report the cloning of the mouse gene (Frg1) and show that it maps to mouse Chr 8. Using a cross segregating the myd mutation and the European Collaborative Interspecific Backcross, we showed that Frg1 maps proximal to the myd locus and to the Clc3 and Ant1 genes.

Linkage localization of facioscapulohumeral muscular dystrophy (FSHD) in 4q35.

Fasioscapulohumeral muscular dystrophy (FSHD) has recently been localized to 4q35. We have studied four families with FSHD. Linkage to the 4q35 probes D4S163, D4S139, and D4S171 was confirmed. We found no recombinants helpful in detailed localization of the FSHD gene. Two of our families include males with a rapidly progressive muscle disease that had been diagnosed, on the basis of clinical features, as Duchenne muscular dystrophy. One of these males is available for linkage study and shares the haplotype of his FSHD-affected aunt and cousin.

Genetic and physical mapping on chromosome 4 narrows the localization of the gene for facioscapulohumeral muscular dystrophy (FSHD).

We have used a combination of classical RFLPs and PCR-based polymorphisms including CA repeats and single-strand conformation polymorphisms to generate a fine-structure genetic map of the distal long arm of chromosome 4q. This map is now genetically linked to the pre-existing anchor map of 4pter-4q31 and generates, for the first time, a complete linkage map of this chromosome. The map consists of 32 anchor loci placed with odds of greater than 1,000:1. The high-resolution map in the cytogenetic region surrounding 4q35 provides the order 4cen-D4S171-F11-D4S187-D4S163-D4S139-4q ter. When we used somatic cell hybrids from a t(X;4)(p21;q35) translocation, these five markers fell into three groups consistent with the genetic map-D4S171 and F11 in 4pter-4q35, D4S163 and D4S139 in 4q35-4qter, and D4S187 as a junction fragment between these two regions. These markers are in tight linkage to the gene for facioscapulo-humeral muscular dystrophy (FSHD) mapped to this region by several collaborating investigators and provide a framework for further detailed analysis of this region.

The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant form of muscular dystrophy. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. Recently, a probe was identified that detects an EcoRI fragment length polymorphism which segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. In several familial cases and four independent sporadic FSHD mutations, the variation in size of the EcoRI fragment was due to a decrease in copy number of the 3.2 kb repeats. To gain further insight into the relationship between the tandem array and FSHD, a single 3.2 kb repeat unit was characterized. Fluorescence in situ hybridization (FISH) demonstrates that the 3.2 kb repeat cross-hybridizes to several regions of heterochromatin in the human genome. In addition, DNA sequence analysis of the repeat reveals a region which is highly homologous to a previously identified family of heterochromatic repeats, LSau. FISH on interphase chromosomes demonstrates that the tandem array of 3.2 kb repeats lies within 215 kb of the 4q telomere. Together, these results suggest that the tandem array of 3.2 kb repeats, tightly linked to the FSHD locus, is contained in heterochromatin adjacent to the telomere. In addition, they are consistent with the hypothesis that the gene responsible for FSHD may be subjected to position effect variegation because of its proximity to telomeric heterochromatin.

Genetic mapping near the myd locus on mouse chromosome 8.

Myodystrophy (myd), an autosomal recessive mutation of the mouse characterized by progressive weakness and dystrophic muscle histology, maps to the central portion of Chromosome (Chr) 8 (Lane et al. J. Hered 67, 135, 1976). This portion of Chr 8 contains the genes for a mitochondrial uncoupling protein (Ucp) and kallikrein (Kal3), which map to distal 4q in the human, providing evidence for a segment of homology. Characteristics of the myd phenotype coupled with this homology suggest that myd may be a mouse homolog of facioscapulohumeral muscular dystrophy (FSHD), which maps to human 4q35. We have confirmed and expanded the region of mouse 8-human 4 homology by generating a map of Chr 8 in an interspecific backcross of C57BL/6J and a partially inbred strain derived from M. spretus. The map is comprised of the genes for Ucp, coagulation factor XI (Cfl1), and chloride channel 5 (Clc5), all of which have homologs on distal human 4q, 15 microsatellite loci, and the membrane cofactor protein pseudogene (Mcp-ps). To place myd in the genetic map, 75 affected progeny from an intersubspecific backcross of animals heterozygous for myd with Mus musculus castaneus were genotyped with Chr 8 microsatellite loci. The mutation maps between D8Mit30 and D8Mit75, an interval that is flanked by genes with human homologs at distal 4q. These results are consistent with the possibility that myd is the mouse homolog of FSHD.

Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by short episodes of involuntary movement attacks triggered by sudden voluntary movements. Although a genetic basis is suspected in idiopathic cases, the gene has not been discovered. Establishing strict diagnostic criteria will help genetic studies. METHODS: The authors reviewed the clinical features of 121 affected individuals, who were referred for genetic study with a presumptive diagnosis of idiopathic PKD. RESULTS: The majority (79%) of affected subjects had a distinctive homogeneous phenotype. The authors propose the following diagnostic criteria for idiopathic PKD based on this phenotype: identified trigger for the attacks (sudden movements), short duration of attacks (<1 minute), lack of loss of consciousness or pain during attacks, antiepileptic drug responsiveness, exclusion of other organic diseases, and age at onset between 1 and 20 years if there is no family history (age at onset may be applied less stringently in those with family history). In comparing familial and sporadic cases, sporadic cases were more frequently male, and infantile convulsions were more common in the familial kindreds. Females had a higher remission rate than males. An infantile-onset group with a different set of characteristics was identified. A clear kinesigenic trigger was not elicited in all cases, antiepileptic response was not universal, and some infants had attacks while asleep. CONCLUSIONS: The diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) can be made based on historical features. The correct diagnosis has implications for treatment and prognosis, and the diagnostic scheme may allow better focus in the search for the PKD gene(s).