|
Laminopathies
Laminopathies are the collective term for diseases caused by mutations in the lamin genes. The LMNA gene, and as recently discovered also the LMNB1 and LMNB2 genes, give rise to the most phenotypically diverse group of diseases of all the intermediate filament-induced pathologies. LMNA- and LMNB-encoded proteins are expressed in nearly all cell types and yet only some tissues are susceptible to pathogenic damage. The diversity appears to be unrelated to the location of mutations in the protein as pathogenic mutations have been found in many positions. Thus although the reasons for this extreme phenotypic diversity of disorders are not yet understood, the mechanisms underlying the laminopathies are the subject of much current research.
Clinical types of laminopathies
1. Lipodystrophy disorders
2. Muscle laminopathies (Muscular dystrophy disorders)
3. Neurological disorders
4. Systemic laminopathies: premature aging syndromes
5. Other phenotypes
1. Lipodystrophy disorders
Familial partial lipodystrophy (Dunnigan type) (FPLD2; OMIM #151660) The first identified disorder in this group was familial partial lipodystrophy (Dunnigan type, FPDL2), in which the distribution of body fat is abnormal: fat deposits are progressively lost from some areas such as limbs (giving hyperdefinition of muscle masses), abdomen and thorax, but accumulate excessively in others (e.g. "buffalo hump" deposits across the shoulders), giving very characteristic body morphology. Affected individuals are predisposed to insulin-resistant diabetes (type II diabetes). This type of FDLP is associated with mutations in LMNA. Associated type V intermediate filament proteins: lamin A [Refs] Acquired partial lipodystrophy (APL; OMIM #608709) Acquired partial lipodystrophy, also called "Barraquer-Simons syndrome", appears to behave like a complex trait with a component of genetic susceptibility, and has been associated with mutations in the LMNB2 gene. Patients with acquired partial lipodystrophy all share similar clinical phenotypes that included gradual onset of bilateral subcutaneous fat loss from the head, neck, upper extremities, and thorax but not the lower extremities. Renal dysfunction and glomerular nephritis have sometimes been reported with APL. Diagnostic criteria also included the absence of a clear family history of lipodystrophy and onset of lipodystrophy before adulthood. Associated type V intermediate filament proteins: lamin B2 [Refs] Type A insulin resistance syndrome Type A insulin resistance syndrome refers to a type of polycystic ovary syndrome with hyperandrogenism and acanthosis nigricans with pronounced insulin resistance, and is often connected with mutations in insulin receptor genes. A case of this syndrome, showing several defects in the insulin signal transduction pathway, has now been linked to a unique LMNA mutation. There was however no indication of abnormal adipose tissue distribution or obesity. Associated type V intermediate filament proteins: lamin A [Refs] Generalized lipoatrophy syndrome This rare syndrome has a phenotype characterized by atypical acquired generalized lipoatrophy with (as in many other lipodystrophies) insulin-resistant diabetes; also liver steatosis, hypertrophic cardiomyopathy, distinctive subcutaneous manifestations (scattered leukomelanodermic papules) and cardiac hypertrophic abnormalities involving thickness and calcification of the valves. There were also possible progeric features such as premature graying hair. Associated type V intermediate filament proteins: lamin A [Refs] Familial partial lipodystrophy (Köbberling) (FPLD1; OMIM %608600) Another type of familial partial lipodystrophy (FPLD1) has also been described as associated with a mutation in LMNA. The typical abnormalities of adipose tissue distribution that characterize FPLD1 are recognized as loss of fat deposits specifically from the extremities, increased fat deposits seen around the face, head and neck area, as well as around the trunk. Associated type V intermediate filament proteins: lamin A [Refs]
[Back to index]
2. Muscle laminopathies (Muscular dystrophy disorders)
Emery-Dreifuss muscular dystrophy
Emery-Dreifuss muscular dystrophy is a skeletal and cardiac muscle condition, involving muscle wasting, tendon contracture and later appearance of cardiomyopathy and conduction defects in the heart, which may be fatal. While classic (X-linked) Emery-Dreifuss is associated with emerin mutations, this autosomal form of the condition has been associated with mutations in the LMNA gene as a dominant or recessive disorder.
• Emery-Dreifuss muscular dystrophy, autosomal dominant (EDMD2; OMIM #181350)
Associated type V intermediate filament proteins: lamin A
[Refs] • Emery-Dreifuss muscular dystrophy, autosomal recessive (EDMD3; OMIM #604929)
Associated type V intermediate filament proteins: lamin A
[Refs]
Limb-girdle muscular dystrophy type 1B (LGMD1B; OMIM #159001) This disorder is characterized by proximal muscle weakness and wasting. Many of the clinical features overlap with EDMD. The following features distinguish this disorder from EDMD: absence of rigid spine, minimal or late elbow and Achilles tendon contractures and calf hypertrophy occasionally present. Associated type V intermediate filament proteins: lamin A [Refs] Congenital muscular dystrophy (CMD) Congenital muscular dystrophy (CMD) is a heterogeneous group of autosomal recessively inherited diseases; present with hypotonia, muscle weakness and the variable appearance of contractures characterized by dystrophic changes on skeletal-muscle biopsy at birth or within the first 6 months of life. The heterogeneous nature of CMD is reflected by differing degrees of motor developmental delay, physical disability, muscle pathology, elevation of serum creatine kinase and a variable presence of mental retardation and structural brain defects. CMD is among the most frequent autosomal recessively inherited neuromuscular disorders. Associated type V intermediate filament proteins: lamin A [Refs]
Multisystem dystrophy syndrome
The discovery of patients with combinations of the various defects described above (lipodystrophy, cardiac anomalies and muscular dystrophy) confirms that these laminopathy disorders are closely related and are probably part of an extended phenotypic spectrum.
Dilated cardiomyopathy 1A (CMD1A; OMIM #115200) Dilated cardiomyopathy is a heart muscle disease characterized by ventricular dilatation and reduced systolic function. It represents an outcome of a heterogeneous group of inherited and acquired disorders. It is resulting in high mortality due to sudden death or heart failure. The mode of the disease manifestation is age-dependent without peripheral muscle involvement. Associated type V intermediate filament proteins: lamin A, lamin C1 Other associated intermediate filament proteins: desmin [Refs] Dilated cardiomyopathy with conduction system defects (DCM-CD) This disorder is characterized by conduction system defects including sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias. This group of disorders is highly heterogeneous with numerous loci and 21 different genes linked to DCM to date. LMNA mutations have been associated with autosomal dominant DCM-CD. Associated type V intermediate filament proteins: lamin A Other associated intermediate filament proteins: desmin [Refs]
[Back to index]
3. Neurological disorders
Charcot-Marie-Tooth disease type 2B1 (CMT2B1; OMIM #605588) Charcot-Marie Tooth (CMT) disease is a group of motor and sensory neurodegenerative disorders and subtypes have been associated with a number of genes. By measuring the conduction velocity in the median nerve, CMT can be classified as one of two main forms, i.e. type 1, demyelinating neuropathy (conductance velocity <38 m/s), or type 2, axonal neuropathy (CMT2, conductance velocity >38 m/s). Type 2 CMT can be recessive or dominant. There are many loci for AR-CMT2, but at least one form can be caused by mutation of the LMNA gene. The range of observed phenotypic severity suggests the action of modifier genes. Associated type V intermediate filament proteins: lamin A [Refs]
Autosomal dominant leukodystrophy (ADLD; OMIM %169500) Adult-onset autosomal dominant leukodystrophy is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system. Associated type V intermediate filament proteins: lamin B1 [Refs] Axonal neuropathy, muscular dystrophy, cardiac disease This term has been used to describe a laminopathy with overlapping phenotypes. Associated type V intermediate filament proteins: lamin A [Refs] Axonal neuropathy, muscular dystrophy, cardiac disease, leuconychia This family presents with a number of overlapping phenotypes extending the range of laminopathy disorders. Associated type V intermediate filament proteins: lamin A [Refs] Autosomal dominant spinal muscular dystrophy (AD-SMA; OMIM #182980) Spinal muscular atrophy is characterized by the degeneration of the anterior horn cells in the spinal cord, leading to symmetrical muscle weakness and wasting. Autosomal dominant transmission is seen in about two-thirds of hereditary adult-onset proximal SMA. Some cases of autosomal dominant proximal spinal muscular atrophy now appear to be attributable to mutations in the LMNA gene. Associated type V intermediate filament proteins: lamin A [Refs]
[Back to index]
4. Systemic laminopathies: premature aging syndromes
Atypical Werner syndrome (WRN; OMIM #277700) The most extreme group of the laminopathies are probably the progeria disorders, which are usually lethal early in the second decade of life due to atherosclerosis. Clinical hallmarks include premature ageing, short stature, and tight atrophied or ulcerated skin. The patients also have "birdlike" faces and high, squeaky or hoarse voice, premature greying and thinning hair and early onset of cataracts. Many other additional symptoms have also been described. Associated type V intermediate filament proteins: lamin A [Refs] Hutchinson-Gilford progeria syndrome (HGPS; OMIM #176670) Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder that is estimated to have an incidence of one in eight million. Children are healthy at birth with clinical features that appear within the first few years of life, including growth retardation with short stature, incomplete sexual maturation and low weight for height ratio. Patients also suffer widespread atherosclerosis, skin wrinkling, loss of subcutaneous fat, alopecia and various skeletal abnormalities including craniofacial alterations. Mental and emotional development is normal. The disorder is lethal, with affected individuals dying between 7 and 27 years (average of 13 years) from cardiovascular disease. Associated type V intermediate filament proteins: lamin A [Refs] Restrictive dermopathy (RD; OMIM #275210) Restrictive dermopathy or tight skin contracture syndrome is characterised by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis. Patients also have abnormal facial features, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures. The disorder is lethal soon after birth. As well as mutations in the LMNA gene, mutations have also been reported in the ZMPSTE24 gene encoding one of the lamin processing enzymes. Associated type V intermediate filament proteins: lamin A [Refs] Mandibuloacral dysplasia with type A lipodystrophy (MADA; OMIM #248370) Mandibuloacral dysplasia (MAD) is a rare autosomal recessive developmental disorder characterised by postnatal growth retardation, mandibular and clavicular acroosteolysis, delayed closure of the cranial suture, joint contractures, lipodystrophy and mottled cutaneous pigmentation. Like familial partial lipodystrophy, MAD is also associated with diabetes. Associated type V intermediate filament proteins: lamin A [Refs]
[Back to index]
5. Other phenotypes
Cardiac arrhythmia A fatal or near-fatal cardiac arrhythmia can be the first clinical manifestation. Replacement of cardiac myocytes by fibrosis seems to be the predominant pathologic-anatomic finding. Associated type V intermediate filament proteins: lamin A [Refs] Cardiac conduction defect (CCD; OMIM #115080) Cardiac conduction defect and familial sudden death have been demonstrated to have various genetic and nongenetic causes. Associated type V intermediate filament proteins: lamin A [Refs] Lamin-related rigid spine muscular dystrophy Rigid spine syndrome is characterized by marked limitation in flexion of the whole dorsolumbar and cervical spine, owing to contracture of the spinal extensors and leading to loss of movement of the spine and the thoracic cage. There may be limitation of other joints, especially a limited extension of the elbows and the ankles. Although the condition is not progressive, the development of scoliosis and associated deformities often lead to respiratory failure. Associated type V intermediate filament proteins: lamin A [Refs] Metabolic syndrome Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. The symptoms and features are
fasting hyperglycemia, high blood pressure, central obesity (also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist; decreased HDL cholesterol; elevated triglycerides.
Associated diseases and signs are elevated uric acid levels, fatty liver (especially in concurrent obesity), progressing to non-alcoholic fatty liver disease, polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (a skin condition featuring dark patches). Associated type V intermediate filament proteins: lamin A [Refs] Muscular dystrophy Unclassified generalized muscular dystrophy Associated type V intermediate filament proteins: lamin A [Refs] Muscular dystrophy and lipodystrophy Unclassified generalized muscular dystrophy, with fat accumulation in the neck, back and abdominal region; sometimes with a mild myopathy and/or dilated cardiomyopathy. Associated type V intermediate filament proteins: lamin A [Refs] Dropped head syndrome Dropped head syndrome is characterized by gradual forward sagging of the head due to weakness of the neck extensor muscles. Associated type V intermediate filament proteins: lamin A [Refs] Muscular dystrophy and axonal neuropathy Laminopathy with overlapping phenotypes. Associated type V intermediate filament proteins: lamin C1 [Refs]
[Back to index]
Last modified: September 21 2007 13:48:17. |
