Clinical Guidance

A clear genotype-phenotype correlation for PKAN has not been observed. However, individuals with two null variants (which predict no protein production) consistently have classic PKAN. Other combinations of pathogenic variants (i.e., null/missense, homozygous missense, or compound heterozygous missense) yield either classic or atypical phenotypes in no predictable pattern. Homozygosity for the pathogenic missense variant consistently presents as classic PKAN; however, the phenotype associated with homozygosity of other common alleles is unpredictable. Two thirds of individuals with PKAN are compound heterozygotes, with disease of unpredictable clinical course. Within families, the phenotype is fairly consistent among affected individuals.

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Diagnostic Criteria

Suggestive Findings

Pantothenate kinase-associated neurodegeneration (PKAN) should be suspected in individuals with the following clinical, radiographic, and laboratory features and family history.

Clinical features

• Dystonia

• Dysarthria

• Spasticity

• Choreoathetosis

• Parkinsonism

• Hyperreflexia

• Extensor toe signs

• Onset in first to third decade of life

• Gait change / loss of ambulation

• Pigmentary retinopathy

• Intellectual and developmental disabilities, mainly in children with very young onset

Radiographic features. "Eye of the tiger" sign on T2-weighted brain MRI (≥1.5 Tesla): a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. See .

Laboratory features

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Differential Diagnosis

Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation (NBIA). NBIA is defined as the group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Types of NBIA are included in . Neurodegeneration with brain iron accumulation multigene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time; a panel may not include a specific gene of interest.

Table 2.

Types of NBIA: Molecular Genetics

Gene | Disease Name | MOI | Progression

ATP13A2

| Kufor-Rakeb syndrome1 | AR | Later-onset, slowly pro...

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with pantothenate kinase-associated neurodegeneration (PKAN), the following are recommended if they have not already been completed:

• Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech

• Ophthalmologic assessment for evidence of retinopathy

• Screening developmental assessment, with referral for more formal testing if delay is indicated

• Assessment for physical therapy, occupational therapy, and/or speech therapy

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A consensus clinical management guideline for PKAN is available to provide management information at a detailed level . Pharmacologic and surgical interventions have focused on palliation of symptoms. Symptomatic treatment is aimed primarily at the dystonia, which can be profoundly debilitating and distressing to the affected individual and caregivers. Therapies to manage dystonia in affected individuals that have been used with varying success include the following:

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Clinical Guidance

Anecdotal reports of three sibs with atypical PKAN treated with alpha-tocopherol and idebenone indicated worsening of symptoms, with subsequent improvement once these compounds were stopped [JP Harpey, personal communication].

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Therapies Under Investigation

Iron chelation. Interest in iron chelation has reemerged as data on deferiprone (Ferriprox®) have accumulated in several populations of affected individuals. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes intracellular iron. One small Phase II pilot trial has been performed to assess deferiprone in the PKAN population. Deferiprone was tolerated well in the nine affected individuals who completed the study, and there was a statistically significant reduction of iron in the pallida by MRI evaluation. However, there was no change in their clinical status. The authors suggested that a longer trial period may be necessary to produce clinical amelioration .

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"

Surveillance Guidelines

As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for treatable causes of pain. These may include occult GI bleeding, urinary tract infections, mouth lacerations, and occult bone fractures. The combination of osteopenia in a nonambulatory individual with marked stress on long bones from dystonia places individuals with PKAN at especially high risk for fractures without apparent trauma. The following should be performed on a regular basis:

• Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status

• Ophthalmologic assessment

• Oral assessment for consequences of trauma

• Assessment of ambulation, environmental adaptations, speech abilities, and communication needs to help affected individuals to maintain independence

• Swallowing evaluation and regular dietary assessments to assure adequate nutrition

Source: GeneReviews — "Pantothenate Kinase-Associated Neurodegeneration"