Late-onset camptocormia caused by a heterozygous in-frame CAPN3 deletion.

Camptocormia is defined by a pathological involuntary flexion of the thoracic and lumbar spine that is fully reducible in the supine position. Although originally described as a manifestation of conversion disorder, it is more commonly caused by a wide range of neurological diseases, in particular movement and neuromuscular disorders. We describe here a rare case of late onset camptocormia caused by autosomal dominant calpainopathy due to a heterozygous in-frame deletion in CAPN3 leading to loss of a single lysin amino acid in the catalytic domain of calpain-3. Creatine kinase levels, electromyography, and thigh muscle MRI were normal. Muscle biopsy did not show lobulated fibers and calpain-3 protein expression was not decreased, but in vitro functional assays showed impaired proteolytic function of. Lys254del CAPN3. Autosomal dominant calpainopathy should be considered in the differential diagnosis of late onset camptocormia and unexplained paravertebral myopathies even in presence of normal creatine kinase levels, and in absence of lobulated fibers, of decreased calpain-3 protein expression, and of muscle limb involvement.

Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis, and camptocormia.

INTRODUCTION: McArdle disease is a glycogen storage disease caused by mutations in the PYGM gene encoding myophosphorylase. It manifests classically with childhood-onset exercise-induced pain. METHODS: We report the characteristics of 2 unrelated patients with a new homozygous mutation of the PYGM gene. RESULTS: Two patients, aged 76 and 79 years, presented with severe upper and lower limb atrophy and weakness. Additionally, 1 patient presented with bilateral ptosis, and the other with camptocormia. In both patients, symptoms had developed progressively in the 2 preceding years, and there was no history of exercise intolerance. Both patients demonstrated myogenic abnormalities on electromyography, multiple glycogen-containing vacuoles and undetectable muscle myophosphorylase activity on muscle biopsy, and a novel homozygous frameshift p.Lys42Profs*48 PYGM mutation. CONCLUSIONS: This report expands the phenotype and genotype of McArdle disease and suggests that PYGM mutations should be looked for in patients with very late-onset myopathy with no previous history of exercise intolerance. Muscle Nerve 57: 157-160, 2018.

Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study.

Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T4 -T12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (ρˆG , -0.46; 95% CI, -0.67 to -0.26), vertebral fracture (ρˆG , 0.39; 95% CI, 0.18 to 0.61), vBMD (ρˆG , -0.23; 95% CI, -0.41 to -0.04), and paraspinal muscle density (ρˆG , -0.22; 95% CI, -0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (ρˆG , 0.17; 95% CI, -0.05 to 0.38) and facet joint OA (ρˆG , 0.05; 95% CI, -0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. © 2016 American Society for Bone and Mineral Research.

Identification of Quantitative Trait Loci Associated with the Skeletal Deformity LSK complex in Gilthead Seabream (Sparus aurata L.).

Morphological abnormalities, especially skeletal deformities, are some of the most important problems affecting gilthead seabream (Sparus aurata L.) aquaculture industry. In this study, a QTL analysis for LSK complex deformity in gilthead seabream is reported. LSK complex is a severe deformity consisting of a consecutive repetition of three vertebral deformities: lordosis, scoliosis, and kyphosis. Seventy-eight offspring from six breeders from a mass-spawning were analyzed: five full-sibling families, three maternal, and two paternal half-sibling families. They had shown a significant association with the LSK complex prevalence in a previous segregation analysis. Fish were genotyped using a set of multiplex PCRs (ReMsa1-13), which includes 106 microsatellite markers. Two methods were used to perform the QTL analysis: a linear regression with the GridQTL software and a linear mixed model with the Qxpak software. A total of 18 QTL were identified. Four of them (QTLSK3, 6, 12, and 14), located in LG5, 8, 17, and 20, respectively, were the most solid ones. These QTL were significant at genome level and showed an extremely large effect (>35%) with both methods. Markers close to the identified QTL showed a strong association with phenotype. Two of these molecular markers (DId-03-T and Bt-14-F) were considered as potential linked-to-this-deformity markers. The detection of these QTL supposes a critical step in the implementation of marker-assisted selection in this species, which could decrease the incidence of this deformity and other related deformities. The identification of these QTL also represents a major step towards the study of the etiology of skeletal deformities in this species.

Heritability of spinal curvature and its relationship to disc degeneration and bone mineral density in female adult twins.

PURPOSE: To determine the heritability of spine curve using plain radiographs and to identify risk factors for spine curvature including age, body mass index, smoking, bone mineral density (BMD), and lumbar disc degeneration (LDD). METHODS: A classical twin study of 110 MZ and 136 DZ adult female twins. Demographic and clinical information obtained from long spine radiographs, lumbar spine degeneration on spine MR scan, and BMD assessed by DEXA at hip and lumbar spine were included in multiple logistic regression models to determine risk factors for spine curvature. RESULTS: Heritability estimates ranged between 41 (19-59) % for pelvic incidence to 61 (46-72) % for thoracic kyphosis; with lumbar lordosis and cervical lordosis having 59 (42-71) % and 43 (23-59) % heritability, respectively. For each spine curve, the model showing the best fit contained additive genetic and shared environmental components with no contribution from the unique environment. Significant risk factors for increased thoracic kyphosis were lumbar spine BMD, age, and cervical lordosis; for pelvic incidence were lumbar spine BMD and lumbar lordosis; for lumbar lordosis were cervical lordosis, pelvic incidence and LDD; and age alone predicted cervical lordosis (p = 0.001). CONCLUSION: In this sample of middle-aged and elderly women, there were significant genetic influences on all spine curves but particularly thoracic kyphosis and lumbar lordosis. The strongest predictor for lumbar lordosis was LDD (p < 0.0001) which is itself genetically determined in part. For thoracic kyphosis, BMD was strongly associated and remained so (for lumbar BMD) with the inclusion of age, showing BMD to be an independent risk factor. This work highlights the genetic factors influencing normal spine curvature in women.

Unusual case of levodopa-responsive camptocormia in a patient with negative dopamine transporter scan and normal DYT 5 gene.

OBJECTIVE: To describe an unusual case of camptocormia responding to levodopa. METHODS: We present a case of camptocormia with a sustained excellent response to levodopa in a patient with negative dopamine transporter and no DYT 5 genetic mutations. RESULTS: We present a 52-year-old man with 2 years' history of progressive camptocormia, with nearly normal posture while standing and forward trunk flexion close to 90 degrees after walking for less than a minute. His posture completely resolved in the supine position. There were no pyramidal or extrapyramidal signs or dystonia in other locations. Family history was noncontributory except 1 paternal aunt with Parkinson disease. There was no history of antidopaminergic exposure. Workup, including brain, cervical, thoracic, and lumbar spine magnetic resonance imaging and paraspinal muscle electromyography, was unremarkable. Serum ceruloplasmin level was normal. Genetic testing for dopa-responsive dystonia, including GTP cyclohydrolase 1 (GCH 1) and tyrosine hydroxylase (TH) gene mutations (sequencing and deletion), was negative. DYT 6 (THAP1) gene mutation was not found, and dopamine transporter scan imaging obtained 4 years after onset of symptoms was normal. The patient has had an excellent response to levodopa sustained for the past 2 years. CONCLUSIONS: Levodopa should be considered in camptocormia even when not associated with neurodegenerative parkinsonism or DYT 5 gene mutation.

Characterization of two ENU-induced mutations affecting mouse skeletal morphology.

Using the N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we have identified two skeletal morphology mutants, Skm1 and Skm2. Positional cloning and candidate gene sequencing localized the causative point mutations within the genes coding for natriuretic peptide receptor C (NPR-C) and filamin b (FLNB), respectively. Mice that carry a mutation in Npr3 exhibit a skeletal overgrowth phenotype, resulting in an elongated body and kyphosis. Skm2 mice, carrying a mutation in Flnb, present with scoliosis and lordosis. These mutant mice will serve as useful models for the study of vertebral malformations.

Sagittal spinal profile and spinopelvic balance in parents of scoliotic children.

BACKGROUND CONTEXT: It is well known that spinal biomechanics and familial predisposition play an important role in the onset and evolution of idiopathic scoliosis. The relationship between the sagittal profile of the spine and spinal biomechanics has also been established in a number of studies. It has been suggested previously that a certain sagittal spinal configuration with implications for spinal rotational stiffness is inherited, thus providing a possible explanation for the well-known hereditary component in adolescent idiopathic scoliosis (AIS). PURPOSE: To test the hypothesis that the familial trend in AIS may be partially explained by the inheritance of a sagittal spinal profile, which has been shown to make the spine less resistant to rotatory decompensation. STUDY DESIGN: A prospective case controlled radiographic analysis of the sagittal profile of the spine and spinopelvic alignment. PATIENT SAMPLE: One hundred two parents of scoliotic children, compared with 102 age-matched controls (parents of nonscoliotic children). OUTCOME MEASURES: Physiologic measures: sagittal profile of the spine and spinopelvic alignment. METHODS: Freestanding lateral radiographs of 51 parent couples of girls with severe (Cobb angle >30°) progressive AIS (AIS group) and 102 age-matched controls (control group) were taken. Parents with manifest spinal deformities or spinal pathology of any kind were excluded based on history or spinal X-ray to avoid distorted sagittal images with unreliable measurements. Values were calculated for thoracic kyphosis (T4-T12), lumbar lordosis (L1-L5), spinal balance (sagittal plumb line of C7 and T4, T1-L5 sagittal spinal inclination, T9 sagittal offset), curvature parameters (expressed in the area under the curve [AUC]), and pelvic parameters (pelvic tilt, pelvic incidence, and sacral slope). In addition, the height, offset, and length of the posteriorly inclined spinal segment, inclination of each vertebra, and normalized sagittal spinal profile were calculated. Differences in spinopelvic alignment between fathers and mothers of both groups were analyzed. RESULTS: In the fathers of the AIS group, the plumb line of T4 was significantly less posteriorly positioned relative to the hip axis (79 mm vs. 92 mm; p=.009); the overall AUC and the lumbar AUC were significantly smaller (p=.002 and p=.008, respectively) as compared with the fathers in the control group. Vertebrae T11-L2 were significantly less backwardly inclined in the fathers of the AIS group (T11, L2: p<.05 and T12-L1: p<.01). An analysis of sagittal spinal profile showed a significantly flatter spine in the fathers of the AIS group (p=.01). No significant differences were observed in height, offset, and length of the backwardly inclined spinal segment. In the mothers of the AIS group, no statistically significant differences were observed in the spinopelvic parameters, spinal curvature, inclination of the vertebrae, and declive spinal segment parameters or sagittal spinal profile as compared with the mothers in the control group. CONCLUSIONS: The sagittal spinal profile of the fathers of scoliotic children was significantly flatter than the sagittal spinal profile of fathers of nonscoliotic children. No difference was found in the sagittal spinal profile of the mothers of scoliotic children as compared with mothers of nonscoliotic children. Although it is well known that scoliotic mothers have an increased risk of having a scoliotic offspring, this study indicates that fathers may possibly contribute as well through their sagittal spinal profile to the inheritance of idiopathic scoliosis.

Orthogenomics: an update.

The study of genomics in orthopaedics has considerably lagged behind such study in other medical disciplines. Seminal work from other lines of medical research demonstrates the importance of genomic information in the evolution of personalized medicine. Common techniques for studying genome-phenotype associations include single nucleotide polymorphism, haplotype, and quantitative trait loci analysis. The few genome-based studies in major orthopaedic and related conditions have focused on osteoporosis, osteoarthritis, neuropathy and nerve compression, spinal deformity, trauma and inflammatory response, and pain and analgesia. The nascent field of orthogenomics, newly defined here as the application of genomic study to orthopaedic practice, has produced findings that could affect the practice of orthopaedics. However, more work is required, and the findings must be distilled and harnessed into applicable and achievable steps to improve clinical orthopaedic practice.

Camptocormia as presenting sign in myofibrillar myopathy.

Camptocormia, due to paraspinal muscle weakness, is seen in several types of myopathy. Myofibrillar myopathies (MFM) are histopathologically characterized by desmin-positive protein aggregates and myofibrillar disintegration. Camptocormia can be seen in the late stages of the known MFM diseases. We present a case of MFM with progressive camptocormia since the age of 64, isolated for 6years, followed later by upper and lower limb weakness. Camptocormia has never been described as the presenting clinical sign of MFM. MFM joins the growing number of myopathies potentially presenting with camptocormia.

Late-onset axial myopathy and camptocormia in a calpainopathy carrier.

Camptocormia is a debilitating gait disorder characterized by the hyperflexion of the thoracolumbar spine during the upright position. Its etiologies are heterogenous, including parkinsonism and various neuromuscular disorders. Here, we report a camptocormia patient due to a late-onset axial myopathy with numerous lobulated fibers. The patient's father reportedly had similar symptoms. Myriad lobulated fibers are common among patients with an autosomal recessive muscular dystrophy due to calpain-3 gene (CAPN3) mutations or calpainopathy. CAPN3 sequencing revealed a single c.759-761delGAA mutation. Calpainopathy carriers are generally asymptomatic. The presence of lobulated fibers in this patient suggests that camptocormia could be a manifestation of calpainopathy carrier, although the possibility of a coexisting undiagnosed myopathy cannot be excluded. The current patient should spur the evaluation of camptocormia among calpainopathy carriers.

Mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy facial asymmetry psychomotor retardation kyphoscoliosis dermatofibrosarcoma and multiple exostoses.

We report molecular cytogenetic characterization of mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy, facial asymmetry, psychomotor retardation, kyphoscoliosis, dermatofibrosarcoma and multiple exostoses. The supernumerary r(1) is associated with gene dosage increase of CHRNB2, ADAR and KCNJ10 in the pericentromeric area of 1q, and a breakpoint within CTTNBP2NL at 1p13.2. We speculate that the gene dosage increase of CHRNB2, ADAR and KCNJ10 is most likely responsible for epilepsy, and the breakpoint at 1p13.2 in the supernumerary r(1) is most likely responsible for the development of multiple exostoses and osteochondroma in this patient.

A major QTL controls susceptibility to spinal curvature in the curveback guppy.

BACKGROUND: Understanding the genetic basis of heritable spinal curvature would benefit medicine and aquaculture. Heritable spinal curvature among otherwise healthy children (i.e. Idiopathic Scoliosis and Scheuermann kyphosis) accounts for more than 80% of all spinal curvatures and imposes a substantial healthcare cost through bracing, hospitalizations, surgery, and chronic back pain. In aquaculture, the prevalence of heritable spinal curvature can reach as high as 80% of a stock, and thus imposes a substantial cost through production losses. The genetic basis of heritable spinal curvature is unknown and so the objective of this work is to identify quantitative trait loci (QTL) affecting heritable spinal curvature in the curveback guppy. Prior work with curveback has demonstrated phenotypic parallels to human idiopathic-type scoliosis, suggesting shared biological pathways for the deformity. RESULTS: A major effect QTL that acts in a recessive manner and accounts for curve susceptibility was detected in an initial mapping cross on LG 14. In a second cross, we confirmed this susceptibility locus and fine mapped it to a 5 cM region that explains 82.6% of the total phenotypic variance. CONCLUSIONS: We identify a major QTL that controls susceptibility to curvature. This locus contains over 100 genes, including MTNR1B, a candidate gene for human idiopathic scoliosis. The identification of genes associated with heritable spinal curvature in the curveback guppy has the potential to elucidate the biological basis of spinal curvature among humans and economically important teleosts.

Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome.

Several subtypes of facioscapulohumeral muscular dystrophy (FSHD) with atypical clinical presentation have been described. We report a new, distinct phenotype with progressive bent spine syndrome solely affecting the paraspinal muscles. Magnetic resonance imaging study of the lumbar spine revealed marked atrophy of the paraspinal muscles. The diagnosis was confirmed by DNA testing, which revealed shortened restriction fragments of the D4Z4 repeat on haplotype A in connection with a positive family history.

Orthopaedic manifestations of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disease that affects 1 in 3,000 persons worldwide. Café-au-lait macules and peripheral nerve sheath tumors (ie, neurofibromas) are the most commonly recognized manifestations of NF-1. However, NF-1 affects multiple organ systems, and a multidisciplinary approach to treatment is required. Management of the orthopaedic manifestations of NF-1 is often difficult. The most complex manifestations are scoliosis (dystrophic and nondystrophic), congenital pseudarthrosis of the tibia, and problems related to soft-tissue tumors. Metabolic bone disease is common; many patients are frankly osteopenic, which further complicates treatment. Dystrophic scoliosis, which may be caused by either bony dysplasia or intraspinal pathology, is characterized by early presentation and rapid progression. Pseudarthrosis is common even after instrumented fusion. Nondystrophic scoliosis tends to behave like adolescent idiopathic scoliosis, although it may present earlier and is associated with a higher rate of pseudarthrosis. Congenital pseudarthrosis of the tibia is a long-bone dysplasia that afflicts patients with NF-1. Management of this osseous deformity is challenging. Failure to achieve union and refracture are common.

Disproportionate body lengths correlate with idiopathic-type curvature in the curveback guppy.

STUDY DESIGN: A comparative allometric study of body lengths in an animal model for human idiopathic-type scoliosis. OBJECTIVE: To compare body length variation among adult curved and noncurved curveback female guppies. SUMMARY OF BACKGROUND DATA: Tallness and/or abnormal anthropometric parameters have been correlated to idiopathic-type scoliosis (IS) in numerous studies. Heritable curvature in curveback has demonstrated morphologic and developmental similarities to human IS. Because control of body length in the guppy is heritable and variable, we investigated whether length might also be correlated to curvature in the curveback population. METHODS: Component body lengths were measured from digital photographs for 321 (246 curved and 75 noncurved) females. Sources of experimental variation were omitted by only measuring 2-dimensional curves in mature females all from the same pedigree, and raised under controlled conditions of diet and environment. Body length was divided into 2 component parts (precaudal and caudal). Body lengths were tested statistically for correlation to curvature and curve magnitude. RESULTS: Although absolute length does not correlate to curvature, this survey of length in the curveback model reveals 2 important similarities to anthropometric studies of IS: that there are disproportionate body lengths among females with curvature, and the suggestion of an underlying growth abnormality among curved individuals. CONCLUSION: In order to better characterize the relationship between growth, length disproportion, and curvature in the guppy, further studies are warranted. However, this inquiry further supports the usefulness of curveback as a model for understanding the basic biology of idiopathic-type scoliosis and encourages study of growth-related factors.

Myopathy causing camptocormia in idiopathic Parkinson's disease: a multidisciplinary approach.

Extreme forward flexion of the spine, named camptocormia (CC), and head drop syndrome (HD) may be among the most disabling symptoms in Parkinson's disease (PD). This study aims to eludicate the etiology of PD-associated CC and HD via a multidisciplinary approach (clinical examination, electromyography, MRI, genetic analysis, muscle morphology) centering on the histology of the paraspinal muscles. We studied 17 patients with the clinical diagnosis of PD and CC or head drop syndrome and six controls. We performed muscle biopsies of paraspinal muscles and deep neck extensor muscles. Mean age at onset of postural abnormality was 66 years and mean latency between onset of parkinsonian symptoms to first signs of CC or head drop was 7 years. The electromyogram of paraspinal muscles was abnormal in 13-14 patients. Histopathology revealed chronic myopathic changes in 14 of 17 biopsies, consisting of abnormal variation in fiber size, increase in internal nuclei, and increase in connective tissue, myofibrillar disarray and similarities to protein surplus myopathies. Interestingly, heterozygous variants in the Parkin gene were found in 2 of 9 investigated patients. We conclude that CC and HD in PD are predominantly myopathic. Aberrant protein aggregation may link PD and CC.