Pathology
Progeria is one type of laminopathy

Dystrophies and Connective Tissue Disorders



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Progeria is one type of laminopathy
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"Dystrophies and Connective Tissue Disorders"
Caption: Progeria is one type of laminopathy
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Image by: Scaffidi P, Gordon L, Misteli T. PLoS Biology Vol. 3/11/2005
© Creative Commons http://commons.wikimedia.org/wiki/File:Progeria.png

The laminopathies are genetic conditions caused by mutations that affect the lamins, particularly lamin A/C, which is encoded by the LMNA gene. The lamins make up the protein matrix adjacent to the inner nuclear membrane in the nuclear envelope. Mutations in the LMNA gene destabilize the nuclear envelope, disrupt chromatin structure, and interrupt gene expression. LMNA encodes three protein isoforms, so mutations can have a broad range of effects, in specific tissues or more generalized, depending on the exact mutation. There are several types of laminopathy:

Restrictive dermopathy

Restrictive dermopathy is a rare, autosomal recessive laminopathy that causes skin and bone dysplasia. The disorder is lethal in infancy due to respiratory complications. It can be caused not only by mutations in LMNA, but also an associated gene (secondary laminopathy).

Muscular dystrophy

Muscular dystrophy is a progressive loss of muscle tissue and strength (atrophy). Mutation of lamin A/C is involved in at least two forms of this genetic disease: Emery-Dreifuss type 2 and limb girdle type 1B.

Emery-Dreifuss muscular dystrophy type 2 is an inherited condition (X-linked recessive according to Cleveland Clinic though other reports indicate a dominant form, type 3) that affects both skeletal and cardiac muscle. The earliest symptom is joint contractures, which restrict movement and often appear during childhood. Heart rhythm problems become apparent in adulthood. The other forms of Emery-Dreifuss muscular dystrophy are related to the emerin (EMD) gene (emerinopathy) and more common than those related to the LMNA gene. Studies have spent considerable effort in differentiating these forms of the disease.

Limb girdle muscular dystrophy affects the proximal muscles of the body, those closest to the center: the shoulders and hips. Only one of the 19 known forms of this disorder is a laminopathy according to the Muscular Dystrophy Association, and it is autosomal dominant. Age of onset can vary, as can the speed and course of progression.

Progeria

Progeria is a premature aging syndrome, and it can manifest in either childhood or adulthood depending on the mutation that causes it.

Known as Hutchinson-Gilford syndrome, children with progeria begin to rapidly age shortly after birth and have a risk of early stroke and other heart problems. This form of progeria was first recognized as a laminopathy in 2003. It is a dominant disorder, occurring with a new mutation in lamin A in 90 percent of cases according to Pubmed Health. Patients rarely survive into their teens.

Werner syndrome is known as adult-onset progeria. When individuals with the disorder hit puberty, they start aging at a rapid pace. The syndrome is most often associated with mutations in the WRN gene, but cases with LMNA mutations have been identified, dubbed atypical Werner's syndrome. Diabetes, heart disease, and other aging-related problems are often seen in these patients. Atypical Werner’s also has features of lipodystrophy.

Lipodystrophy

Lipodystrophy is atrophy of adipose tissue, resulting in abnormal fat redistribution. Familial partial lipodystrophy is characterized by a loss of subcutaneous fat in one area of the body and redistribution in another. In the most common form of the disorder, type 2, fat loss occurs in the torso and limbs with redistribution to the face and neck. Type 2, or Dunnigan-type, familial partial lipodystrophy is caused by a defect in the LMNA gene and associated with metabolic disorders like diabetes. An associated disorder is mandibuloacral dysplasia, a rare autosomal recessive disorder caused by defects in lamin A/C that causes lipodystrophy as well as aberrant skeletal development, particularly in the face and jaw.

Charcot-Marie-Tooth disorder

Charcot-Marie-Tooth disorder is considered the most common inherited nerve condition. The peripheral nerves are affected, resulting in foot deformities, weakness, and numbness with leg muscle atrophy. The disease is progressive but ranges from mild to severe, eventually leading to an inability to walk in those who are most severely affected. The defects appear in adolescence or early adulthood. The various types of Charcot-Marie-Tooth are caused by defects in different genes. Type 2B1 is a non-demyelinating form caused by mutations in LMNA. In 2009, this laminopathy was also associated with concurrent dilated cardiomyopathy when a new mutation was identified.

Heart manifestations

The manifestation of cardiac-specific laminopathy manifests as dilated cardiomyopathy with associated conduction issues and heart failure. As with other forms of the disorder, diabetes and metabolic disturbances (particularly insulin resistance) may be present. The disorder takes time to develop because dilated cardiomyopathy is a progressive weakening of the heart muscle. Another manifestation is heart-hand syndrome. It is characterized by congenital heart disease and limb deformities. In recent years, new mutations were discovered that put individuals at risk of sudden cardiac death.

As research continues into these conditions and more mutations are identified, new types of laminopathy will likely be named. The involvement of other genes is also becoming evident.

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