Clinical Guidance

Germline nonsense variants are predicted to lead to non-viable males. The vast majority of pathogenic variants are de novo and private.

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"

Diagnostic Criteria

No formal diagnostic criteria for beta-propeller protein-associated neurodegeneration (BPAN) have been published.

Suggestive Findings

BPAN should be suspected in an individual with the following and findings.

Clinical Findings

Seizures characterized by the following:

• Features

• Onset in early childhood

• Development of multiple seizure types

• Seizures worse in early childhood, lessening with age

• Types

• Generalized (absence, tonic, atonic, tonic-clonic and myoclonic)

• Focal seizures with impaired consciousness

• Epileptic spasms

• Syndromes

• West syndrome

• Lennox-Gastaut syndrome

• Early-onset epilepsy with intellectual disability

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"

Differential Diagnosis

In childhood, the core clinical features of BPAN – seizures, developmental delay / intellectual disability, movement disorders, and behavioral abnormalities – are highly variable between individuals and lack specificity, overlapping with many other genetic and sporadic (non-genetic) disorders. Early in the disease course, imaging abnormalities are similarly nonspecific, particularly if iron-sensitive sequences are not employed. The differential diagnosis at this stage is therefore broad, and includes Rett syndrome, Angelman syndrome, alpha-fucosidosis, and the epileptic encephalopathies of infancy and childhood:

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with beta-propeller protein-associated neurodegeneration (BPAN), the following evaluations are recommended:

• Complete neurologic examination and developmental assessment including evaluation of motor function, speech/language, swallowing, and sleep

• EEG monitoring, including sleep EEG, for any child with features (by history or observation) to suggest overt or occult seizures. Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG.

• Assessments by specialists in physical, occupational, and/or speech therapy

• Ophthalmologic examination

• Assessment of nutrition by a nutritionist or dietician

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Seizures. As seizure severity and complexity varies widely, management should be tailored to the individual. Some children with BPAN may have no evidence of seizures or experience only rare febrile events and require no ongoing pharmacologic intervention. Others have severe, refractory epilepsy with multiple seizure types warranting the involvement of specialists in pediatric epilepsy and consideration of multiple therapeutic modalities, including anti-seizure medication, ketogenic diet, and/or vagus nerve stimulation.

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"

Therapies Under Investigation

Because BPAN falls in the category of NBIA and because individuals with BPAN have high brain iron, the possibility of chelation therapy is sometimes raised. The chelator deferiprone is currently under investigation for treatment of another NBIA disorder, PKAN. However, to date there is no evidence that iron chelation initiated early in the disease course prevents or delays the parkinsonian degeneration in adulthood or otherwise alters the course of PKAN. Nonetheless, results of these studies may inform its use in BPAN and/or lead to additional clinical trials. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"

Surveillance Guidelines

The following are appropriate:

• Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and swallowing. Often done every three to six months, follow up may be annual for those who are more stable.

• For those receiving dopaminergic drugs (for parkinsonism), monitoring for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias

• Follow-up ophthalmologic examination every one to two years

Source: GeneReviews — "Beta-Propeller Protein-Associated Neurodegeneration"