Pantothenate Kinase-associated Neurodegeneration

Definition

Pantothenate kinase-associated neurodegeneration (PKAN), long known as Hallervorden-Spatz syndrome (HSS), is a very rare childhood neurodegenerative disorder that is associated with the accumulation of iron in the brain, which causes progressively worsening abnormal movements and dementia.

Description

In addition to its original name, Hallervorden-Spatz syndrome, pantothenate kinase-associated neurodegeneration has also been called neurodegeneration with brain iron accumulation (NBIA). The name Hallervorden-Spatz is rapidly being discontinued by those who study and treat the disease, both because the new names indicate the nature of the underlying disorder, and because Julius Hallervorden, who described the syndrome, was involved in a "selective euthanasia" program in Nazi Germany to kill retarded children.

Demographics

PKAN is so rare that there is no reliable information on its prevalence. It affects boys and girls equally. Typical age of onset is in middle childhood to early adolescence, although onset in early adulthood may occur.

Causes and symptoms

PKAN occurs due to mutation in the gene for pantothenate kinase 2 (PANK2), which is an enzyme, a type of protein that regulates a reaction inside a cell. PANK2 helps regulates the production of coenzyme A, an important intermediate in the production of energy within all cells. Mutations in the gene for PANK2 lead to loss of function of this enzyme, the consequence of which is accumulation of iron and the amino acid cysteine within brain cells. It is not yet known how this leads to the disease, but it is possible that cysteine interacts with iron, leading to buildup of other molecules within brain cells that puts stress on the cells and causes them to degenerate.

PKAN causes dystonia, a sustained posturing of lower limbs due to excessive muscle contraction. Leg dystonia leads to gait difficulties and other limitations of movement. Dystonia may also affect the upper limbs and the muscles of the face and neck. Abnormal movements may also include writhing or tremor. Ability to walk is usually lost within 15 years. Dysarthria, or impairment of the ability to speak, is common, and is usually accompanied by swallowing difficulty. PKAN also causes progressive dementia, or impairment of normal intellectual function, although this is more variable among patients. PKAN may also cause a degenerative eye condition, retinitis pigmentosa.

An atypical form of PKAN has similar features, but with later age of onset and more variable and less severe symptoms. Speech difficulties tend to be more common in atypical patients. Atypical patients may or may not have a recognizable gene defect.

Diagnosis

Diagnosis of PKAN begins with a neurological exam, which is followed up by a magnetic resonance imaging (MRI) scan to reveal a characteristic signal from the affected portions of the brain. Genetic testing may be done to look for the mutation in the PKAN gene.

Treatment team

Treatment involves a pediatric neurologist, a speech-language pathologist, and physical and occupational therapists.

Treatment

There is no treatment that can halt or slow the degeneration of the brain that occurs in PKAN. The recent discovery of the gene defect may lead to a better understanding of the neurodegenerative process, and thereby to better treatments.

Drug therapy for the movement disorders of PKAN is variably successful, and becomes less so with time. Drugs used for Parkinson's disease such as levodopa may be beneficial in some patients. Trihexyphenidyl may be useful. Oral antispasticity medications, including diazepam and dantrolene, can help reduce muscle stiffness and spasticity. Intrathecal baclofen has been successful in several patients. A pallidotomy, a type of brain surgery that destroys part of the globus pallidus internus, a structure in the brain that regulates movements, has shown some success at relieving painful dystonia and returning some function to the affected limbs.

Speech impairment may be the most severe consequence of PKAN. Assistive communication devices such as computers or letter boards offer the possibility of continued communication even as the disease worsens.

Clinical trials

PKAN is so rare there are few clinical trials. Some effort is underway to determine whether supplements with PANK2's normal products or related molecules may be effective.

Prognosis

The average duration of disease is 11 years. Death is usually caused by aspiration pneumonia, brought on by food inhaled into the airways.

BOOKS

The Official Patient's Sourcebook on Hallervorden-Spatz Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Health Publications, 2002.

WEBSITES

NBIA Disorders Association. <http://www.hssa.org/> (April 27, 2004).

Richard Robinson