[Skip to Content]
Research team members are shown in Cabral, Dominican Republic, where they are studying clusters of the rare disease PKAN. (provided photo)
Research team members are shown in Cabral, Dominican Republic, where they are studying clusters of the rare disease PKAN. (provided photo)

Investigating a rare disease

Scientists explore cluster of cases of inherited condition; it has no cure and few treatments

Above: Associate professor Frank Middleton, PhD, medical student Alfred “AJ” Espinoza, and clinical research associate Rhianna Ericson, all from Upstate, are part of a group studying the rare illness PKAN in the Dominican Republic. From left are Carlos Muniz, MD; Middleton; Craig Bass and his wife, Susan Baser, MD; Ericson; Madeline Santana, MD; and Espinoza. Santana is Dominican; the others are from the United States.



In a remote corner of the Caribbean, Upstate researchers are taking part

in an international effort to study and perhaps alleviate a rare degenerative disease.

This inherited condition, known by its initials as PKAN (pronounced PEA-kan), has an unexplained cluster of cases in a poor provincial town in the Dominican Republic, where affected children and teens gradually lose control of their muscles, similar in some ways to Parkinson’s disease.

Symptoms and their intensity vary from person to person and can include:

-- frequent falls, leading to broken teeth and other injuries;

-- tongues hanging uncontrollably out of mouths and often getting bitten;

-- bodies becoming clumsy, spastic or tightly twisted;

-- trouble speaking or swallowing, which can lead to problems of getting sufficient nutrition;

-- tremors and involuntary movements;

-- eventually needing help with everyday tasks like combing hair, using the bathroom or walking;

-- vision problems;

-- death in childhood or early adulthood.

The condition stems from a genetic mutation that causes iron to accumulate in the basal ganglia, a part of the brain associated with movement. PKAN, which stands for pantothenate kinase-associated neurodegeneration, has no known cure and few available treatments, which typically offer only limited, temporary relief.

“As iron accumulates in the basal ganglia, patients slowly lose their ability to control their movements. Their ability to think, however, remains unaffected. They are prisoners in a body which refuses to obey their commands,” is how a video documenting PKAN, titled “Tough as Iron,” sums up its effects (see below).

This young Dominican man appears in “Tough as Iron,” a short documentary on PKAN. People with PKAN can often fall, leading to broken teeth.

This young Dominican man appears in “Tough as Iron,” a short video about PKAN. People with PKAN can often fall, leading to broken teeth.

In most of the world, PKAN occurs in about one to three people per million. But in the dusty, sun-bleached Dominican town of Cabral, with a population of about 16,000, the rate is at least a thousand times above the world average. Cabral has at least 40 known cases, and likely more undiscovered cases. A few other rural Dominican towns also show dramatically elevated rates of PKAN.

Upstate’s Frank Middleton, PhD, is among an international team of researchers studying the disease, to seek ways to halt or reverse its effects and to help families who have a member with PKAN. This team, working under the PELICAN Study (see below), has been interviewing affected families, obtaining DNA samples for gene sequencing studies and supplying clothing, gifts and food, since those with PKAN can have a high metabolism and need extra calories. The team hopes eventually to establish more and faster DNA testing and genetic counseling for carriers of the mutation. 

To get the disease, both parents must be carriers — people who carry the genetic mutation but do not have the disease. If two carriers have children, each of their children has a 25% chance of having the disease, a 50% chance of being a carrier and a 25% chance of neither having the disease nor being a carrier. The town has an estimated 2,500 carriers, about 15% of the population, so the chances of two carriers mating in a town like Cabral is relatively high.

“What is unique about this situation is that because the prevalence is so high, there are opportunities to understand precisely how it starts and develop treatments that you simply could not do anywhere else in the world,” says Middleton, an associate professor with appointments in neuroscience and physiology, biochemistry and molecular biology, pediatrics and psychiatry and behavioral science.

Calling PKAN “an emerging pediatric health crisis” in the Dominican Republic, he notes that certain factors of life in Cabral and other affected towns probably contribute to the high incidence, such as:

-- frequent intermarriage among cousins in a relatively isolated town, some of whom are not aware of the familial relationship;

-- a lack of awareness that one is a carrier and a general lack of understanding of genetics;

-- beliefs and superstitions that reject scientific explanations for PKAN, instead thinking it is a curse or that it is spread by infection;

-- lack of funding for and availability of genetic testing, analysis and research.

-- difficulty in getting to Cabral — three hours over bad roads from the capital — let alone transporting sensitive medical equipment there that might allow, for example, brain scans for early detection of the telltale iron accumulation.

Middleton’s research into PKAN included the use of saliva samples as an additional tool for screening, as well as identifying subgroups of PKAN by their particular symptoms.

By studying the underlying mechanisms of PKAN, the scientists may also discover connections to other neurodegenerative movement disorders, including Parkinson’s disease.

A quick look at a rare disease

PKAN: The initials stand for pantothenate kinase-associated neurodegeneration. This rare, inherited disorder stems from a mutation of the PANK2 gene, which leads to abnormal iron accumulation in the brain and progressively affects muscles and movement, resembling Parkinson’s disease in some ways. It is found in unexplained clusters in a few towns in the Dominican Republic, which allows for in-depth study. Symptoms can show up in early childhood and vary widely in severity and form. There is no cure. Current treatments — such as physical therapy, chelation to extract excess iron and Botox injections to relieve muscle spasms — usually offer at most limited, temporary relief.

NBIA: PKAN is the most common type of this group of disorders. The initials stand for neurodegeneration with brain iron accumulation. As the name states, NBIA disorders are characterized by an abnormal accumulation of iron in the brain and progressive degeneration of the nervous system. Click here for more details about PKAN and related disorders from the NBIA Diseases Foundation.

FIRSTHAND REPORT: Click here to hear a "HealthLink on Air" interview with Upstate medical student Alfred "AJ" Espinoza, who explains the disorder and describes people with the condition whom he met on a research trip to the Dominican Republic.

PELICAN Study: Starting in 2011, a team of doctors and scientists began studying the disease and providing medical care and family support, including gifts and food supplements. The name stands for PKAN Evaluation in Cabral Natives, Cabral being a Dominican town with a high incidence of the disease.

INFORMATIONAL VIDEO: “Tough as Iron” shows how PKAN affects people who have it and their families and talks with experts about efforts to alleviate it, in layman’s terms. It’s about five minutes long. Click here to view it.

Upstate Health magazine's fall 2020 cover

This article appears in the fall 2020 issue of Upstate Health magazine.

Read the full issue online at issuu.com.

Subscribe to our printed publication in the mail or to receive an emailed electronic version.