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* OSTEOPETROSIS IS A RARE GENETIC DISORDER WHICH CAUSES BONES TO BECOME DENSE * RESEARCHERS EXAMINED THE REMAINS WHICH WERE UNEARTHED FROM MALIQ IN 1963 * THEY FOUND CLASSIC SIGNS OF 

OSTEOPETROSIS INCLUDING BONE STIFFENING AND FRACTURE * THE MAN'S PRESENTATION OF THE DISEASE IS IDENTICAL TO SIMILAR SEEN IN THE PRESENT * THE FINDINGS SUGGEST THAT OSTEOPETROSIS IS

STABLE AND UNLIKELY TO CHANGE IN FUTURE By IAN RANDALL FOR MAILONLINE Published: 11:42 EDT, 23 October 2020 | Updated: 13:30 EDT, 23 October 2020 An Iron Age man who died some 6,600 years

ago in what is today Albania had the oldest-known case of osteopetrosis — or 'stone bone disease' — a study has found. Osteopetrosis is a rare genetic disorder which results in a

person's bones hardening and becoming denser — making them more susceptible to fracture. It can be classified into different types, depending on the pattern of inheritance — with the

genetically dominant version being more mild and the recessive one severe. The former occurs today in one–nine of every 100,000 births, and the latter in out of of every 200,000 children

born. Researchers from Germany analysed the 5 feet (1.5 metres) -tall remains of a man, who died in his twenties, which were unearthed in the town of Maliq in 1963. They found classic signs

of the disorder — specifically a version of the genetically dominant type — with bone stiffening and evidence of a fracture and deformity. It is unclear exactly how the man's condition

would have affected his life — although the team said that is was possible it may have restricted his physical abilities. The Maliq skeleton — which has been radiocarbon dated to around 

4,620–4,456 BC — predates the next oldest-known case of osteopetrosis by some 4,800 years. Furthermore, the team found that the man's condition is exactly the same as cases of autosomal

dominant osteopetrosis seen today. This stability in the disease suggests it is also unlikely to change in the future.  The study was conducted by palaeopathologist Julia Gresky of the 

German Archaeological Institute and colleagues. 'A largely unknown element of rare diseases is their history: when did these diseases first emerge and have they undergone any changes

with time?' the team wrote. 'Palaeopathological studies of human remains from archaeological contexts can provide objective, nonbiased evidence of the origins and development of

rare diseases by studying the traces of disease directly on the bones,' they added.  The team analysed the man's remains — which included both humerus (upper arm) bones, part of

the radius (one of the two lower arm bones) and femur (thigh bone) — under X-rays and computed tomography (CT) scans as well as down a microscope. All analyses revealed the characteristic

signs of osteopetrosis — with the bones all being unusually heavy and featuring evidence of tissue stiffening, obliteration of the marrow cavity and distinct flaring of the 'neck

sections' of the long bones. The team also found evidence in one of the humeri of what they suspect was either a fracture caused by the bone bending and cracking, or possibly

malformation as a more direct result of osteopetrosis. 'In our case we have evidence for one healed fracture of the radius (lower left arm) and we have have a distortion of the right

humerus,' Dr Gresky told MailOnline. 'He might have been slightly restricted in severe physical work, but this cannot be entirely proven.' As to the exact type of

osteopetrosis, the researchers were able —based on the man's estimated age — to rule out 'autosomal recessive osteopetrosis', which typically leads to death in the first

decade of life if untreated. Instead — based on the rigid bands in parts of the long bones and the increased fracture risk — the team have concluded that the man was afflicted with type 2 

autosomal dominant osteopetrosis. 'Genetic analysis of this individual could narrow the diagnosis down to a particular mutation if DNA preservation was sufficient,' the researchers

noted. The findings also provide experts with insight to how little this type of osteopetrosis has changed over the millennia — suggesting it will remain stable in future as well. 'The

pathognomonic features described for patients with autosomal dominant osteopetrosis are identical to those described for this 6000-year-old skeleton,' the researchers explained. The 

morphology was identical at the macroscopic, radiographical and microscopic level — indicating that the expression of autosomal dominant osteopetrosis has not changed for thousands of

years.' 'Rare diseases are still underrepresented in current medical research,' the team said. 'Adding ancient cases, while respecting the ethical limits for exploring

human remains, can provide different data to those that can be taken from a living patient.' For example, they explained, ancient remains can be subjected to more intensive radiological

scans that would be safe to use on a living patients — and they also offer the opportunity to undertake more extensive sampling for analysis than a biopsy. In future studies, the team hope

to be able to assess whether osteopetrosis was more or less common millennia ago.  The full findings of the study were published in the journal The Lancet Diabetes and Endocrinology. 

OSTEOPETROSIS: THE BASICS  Osteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage.  Researchers have described several major types of osteopetrosis, which

are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked.  The different types of the disorder can also be distinguished by the

severity of their signs and symptoms. Autosomal dominant osteopetrosis  Autosomal dominant osteopetrosis , which is also called Albers-Schönberg disease, is typically the mildest type of the

disorder.  Some affected individuals have no symptoms.  In these people, the unusually dense bones may be discovered by accident when an x-ray is done for another reason.  In affected

individuals who develop signs and symptoms, the major features of the condition include multiple bone fractures, abnormal side-to-side curvature of the spine (scoliosis) or other spinal

abnormalities, arthritis in the hips, and a bone infection called osteomyelitis.  These problems usually become apparent in late childhood or adolescence. Autosomal recessive osteopetrosis

Autosomal recessive osteopetrosis is a more severe form of the disorder that becomes apparent in early infancy.  Affected individuals have a high risk of bone fracture resulting from

seemingly minor bumps and falls.  Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial

muscles.  Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells.  As a result, people with severe osteopetrosis are

at risk of abnormal bleeding, a shortage of red blood cells (anaemia), and recurrent infections.  In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy

or early childhood. Other features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen

(hepatosplenomegaly).  Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures

(epilepsy). Intermediate autosomal osteopetrosis A few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an

autosomal dominant or an autosomal recessive pattern of inheritance.  The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture

and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities.  However, some affected individuals have had abnormal calcium deposits

(calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis. X-linked  Rarely, osteopetrosis can have an X-linked pattern of

inheritance.  In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a build-up of fluid (lymphedema) and a condition called

anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands.  Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe,

recurrent infections to develop. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder.  SOURCE: US National Library of

Medicine