Beta-Propeller Protein-Associated Neurodegeneration

CLINICAL CHARACTERISTICS

Beta-propeller protein-associated neurodegeneration (BPAN) is typically characterized by early-onset seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, motor dysfunction (ataxia), and abnormal behaviors often similar to autism spectrum disorder. Seizure types including generalized (absence, tonic, atonic, tonic-clonic and myoclonic), focal with impaired consciousness, and epileptic spasms, as well as epileptic syndromes (West syndrome and Lennox-Gastaut syndrome) can be seen. With age seizures tend to resolve or become less prominent, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings.

DIAGNOSIS/TESTING: The diagnosis of BPAN is established by identifying on molecular genetic testing: In females. A heterozygous germline pathogenic variant; In males. Either a hemizygous pathogenic variant or partial deletion of . Somatic mosaicism has been reported in rare females (and possibly in 1 male).

MANAGEMENT

Seizure management, tailored to the individual, may include anti-seizure (ASM), ketogenic diet, and/or vagus nerve stimulation. Developmental delays and intellectual disability are managed in infancy and early childhood with early intervention programs and in school-age children with individual education programs. Consultation with a developmental pediatrician to ensure appropriate services is recommended. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Consider alternative means of communication, such as an Augmentative and Alternative Communication (AAC) program, for individuals who have expressive language difficulties. Motor dysfunction in childhood is managed with physical therapy to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Occupational therapy may aid in writing, feeding, grooming, and dressing. For those with feeding difficulties, feeding therapy may be considered. For individuals with social/behavioral difficulties, consider applied behavior analysis (ABA) therapy, medical management strategies in conjunction with a developmental specialist, and pediatric psychiatry consultation to address aggressive or destructive behaviors. In adolescents/adults with parkinsonism, dystonia, and spasticity, the usual pharmacologic agents can be considered with the caveat that these therapies could exacerbate the cognitive deficits that also occur in this age group. Children with abnormal behaviors may qualify for and benefit from interventions used in treatment of autism spectrum disorder. Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and evidence of swallowing dysfunction. For those receiving dopaminergic drugs (for parkinsonism), monitor for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias. Use of ASM during pregnancy for women with a seizure disorder is generally recommended, despite an increased risk for adverse fetal outcome associated with some ASMs. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy ideally should take place prior to conception. Transitioning to a lower-risk medication may be possible.

GENETIC COUNSELING

BPAN is inherited in an X-linked manner; to date, most affected individuals have been female, and the vast majority are simplex cases (i.e., a single occurrence in a family) resulting from a pathogenic variant. The exceptions include two familial cases, one with presumed maternal germline mosaicism and one with transmission of a pathogenic variant by a phenotypically normal mother who demonstrated significantly skewed X-chromosome inactivation. Females with the typical BPAN phenotype do not reproduce. In rare instances, a female who is mildly affected may reproduce. Affected males do not reproduce. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPAN are possible.