What are the common early symptoms or signs of Paget disease of bone, especially if I have a family history of the condition?

Early symptoms of Paget disease of bone can be subtle or absent. When present, they often include bone pain, which can be dull and persistent, particularly in the pelvis, spine, skull, or long bones of the legs. Other signs might include bone deformities (e.g., bowing of a leg, enlarged skull), nerve compression leading to hearing loss (if the skull is affected), or unexplained fractures. A family history significantly increases the risk, so monitoring for these signs is important.

How is Paget disease of bone typically diagnosed, and what specific tests are used?

Diagnosis of Paget disease of bone usually involves a combination of tests. Blood tests often show elevated levels of alkaline phosphatase, an enzyme that indicates increased bone turnover. X-rays are crucial for identifying characteristic changes in bone structure, such as enlarged, misshapen, or thickened bones. A bone scan (scintigraphy) can pinpoint all affected bones,

SQSTM1 gene

The SQSTM1 gene provides instructions for making the sequestosome-1 protein, which plays a critical role in bone remodeling, cell recycling, and immune responses.

Normal Function

The SQSTM1 gene provides instructions for making a protein called sequestosome-1. This protein helps regulate bone remodeling, a normal process in which old bone is broken down and replaced by new bone. Sequestosome-1 is involved in a chemical signaling pathway that promotes the formation and activity of bone cells called osteoclasts, which are specialized cells that break down bone tissue during bone remodeling.

In addition to its role in bone remodeling, sequestosome-1 may have other functions, although these are less well-defined. Sequestosome-1 may be involved in recycling worn-out cell parts and unneeded proteins (autophagy), the self-destruction of cells when they are no longer needed (apoptosis), and the body's immune responses and inflammatory reactions.

Health Conditions Related to Genetic Changes

Paget disease of bone

Variants (also called mutations) in the SQSTM1 gene have been associated with Paget disease of bone. This disorder causes one or more bones to be larger than normal, misshapen, and easily broken (fractured). Many SQSTM1 gene variants lead to the substitution of one protein building block (amino acid) for another in sequestosome-1.

Through a mechanism that is not well understood, SQSTM1 gene variants lead to an increase (overactivation) in the chemical signaling pathway that promotes osteoclast formation. This increase in signaling stimulates the production of too many osteoclasts and triggers the breakdown of bone. In people with Paget disease of bone, affected bone is broken down by osteoclasts and replaced by bone cells called osteoblasts much faster than usual. As a result, the new bone tissue is less organized and weaker than normal bone. These problems with bone remodeling cause certain bones to become unusually large, misshapen, and prone to fracture.

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis.

Other disorders

Frontotemporal dementia (FTD): Variants in the SQSTM1 gene can cause FTD, a progressive brain disorder that affects personality, behavior, and language. FTD is often considered to be part of the same disease spectrum as amyotrophic lateral sclerosis (ALS). These variants cause cells to produce a version of the sequestosome-1 protein that does not function properly, disrupting cellular processes such as autophagy and apoptosis.
Distal myopathy with rimmed vacuoles (DMRV): Variants in the SQSTM1 gene have been found in a few individuals with this muscle disorder. Affected individuals have muscle weakness (myopathy) that typically begins in adulthood, primarily affecting the shoulders and distal muscles, such as those in the hands and feet.
NADGP: This condition involves a decline in cognitive function (neurodegeneration), poor coordination and balance (ataxia), involuntary tensing of the muscles (dystonia), and difficulty following movements with the eyes (gaze palsy). The variants lead to impaired autophagy, resulting in the buildup of abnormal proteins in brain cells.

Other Names for This Gene

A170
autophagy receptor p62
OSIL
p60
p62
p62B
PDB3
ubiquitin-binding protein p62
ZIP3