Clinical Manifestations of BPAN in a patient with moderate learning disability

Oghenefejiro Ofovwe (Psychiatry Trainee)
Dr Mo Eyeoyibo (Consultant Psychiatrist)


This is a case report of a patient with complex psychiatric presentations with polymorphic symptoms that cut across mental health as well as neuropsychological specialties. We present the case history and diagnosis to highlight the neuropsychiatric manifestations of BPAN in a 26 year old female with moderate learning disability.

We highlight the importance of and need for early genetic testing in all patients presenting with challenging behaviour on a background of early developmental problems and learning disability. We also stress the requirement for mental health professionals to be conversant with neuropsychiatric conditions where diagnoses may be challenging to make while mainly focused on psychiatric presentations.


Neurodegeneration with brain iron accumulation (NBIA) is a genetically and clinically heterogeneous group of disorders with the common feature of iron accumulation in the basal ganglia and substantia nigra (1, 2). Beta-propeller protein-associated neurodegeneration (BPAN) is the most recently identified subtype of neurodegeneration with brain iron accumulation (NBIA), with X linked dominant inheritance (3, 4). It is an extremely rare disease typically characterized by early-onset seizures, infantile-onset global developmental delay, intellectual disability, absent to limited expressive language, disordered sleep, motor dysfunction (ataxia), and abnormal behaviours often similar to autism spectrum disorder in childhood, followed by a decline in adulthood with the development of parkinsonism, dystonia and dementia (5, 6). There are also characteristic MRI findings which are more specific in later childhood, adolescence or early adulthood (7).

The diagnosis of BPAN is established on molecular genetic testing by identifying de novo mutations in the WDR45 gene which plays a critical role in autophagy through a WD40 repeat protein with a beta-propeller platform structure (2, 3, 6, 8, 9). Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genome sequencing) depending on the phenotype. Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on the phenotype, whereas genomic testing may not. In some cases, the phenotype of BPAN may be distinctive enough to warrant single gene-targeted testing, whereas those with a phenotype that is indistinguishable from many other inherited disorders with intellectual disability and neurological findings (including seizures) are more likely to be diagnosed using genomic testing. In cases where a pathogenic variant of WDR45 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for BPAN is possible. (7)

Some individuals who have been diagnosed with intellectual disability or early-onset parkinsonism based on their signs and symptoms have later been found to have BPAN when genetic testing was done, suggesting a high frequency of BPAN among patients with intellectual disability and young onset parkinsonism (10).

Case History

The subject (Case X) is a 26 year old female with moderate learning disability who was referred to a Mental Health of Learning Disability Service at 20 years of age with worsening mood, unprovoked inconsolable crying for long periods with very few minutes of respite in between, and increasing challenging behaviour mainly consisting of shouting, screaming obscene and abusive words and throwing things or banging her head when distressed. The cause for this was unknown because the behaviour was mostly unprovoked and largely unpredictable.

Case X has one sibling, a sister who is four years older and without any learning disability. Neither parent has a learning disability however a paternal uncle has Down syndrome. There is no family history of psychiatric illness.

She had an extensive medical history. Antenatal and pregnancy history were unremarkable and she was born at term with polydactyly which was surgically corrected. She suffered significant developmental delay from six weeks. She sat at 16 months and did not walk until two years of age. She also started demonstrating challenging behaviour with temper tantrums at 33 months. She was diagnosed with sleep apnoea, epilepsy with focal seizures and hypokinetic disorder in childhood. Brain MRI was performed at the age of five years with non-specific findings, described in her records as a shadow on the left side of the brain. She attended special school and college for people with special needs and was studying living skills. Prior to her referral she was initially managed by Child and Adolescent Mental Health Services for depression and behavioural problems, and had been on high doses of antipsychotics and anxiolytics to manage challenging behaviour.

Following referral, she was initially diagnosed with a moderate depressive episode and subsequently recurrent depressive disorder with anxiety. She had various courses of treatment with antidepressants including Sertraline and Venlafaxine, mood stabilisers and low dose antipsychotics to manage arousal and challenging behaviour as described above. She was also supported with benzodiazepines for agitation with little effect.

Physical health issues that may be contributing to the presentation were investigated for, including urinary tract infections and ear infections. She also received hormonal treatments as early menopause was considered a possible cause. She had assessments for hearing and visual impairments and hearing aids were prescribed, as well as pain relief for dysmenorrhea as this was thought to be possibly contributing to her distress. However, there was little improvement despite these interventions. She had brief periods of stability in terms of mood and behaviour which seemed to be as a result of alterations to her medication but her behaviour and mental state continued to decline steadily. She had no acute admissions and was referred for psychological support but disengaged after a short while.

Over the last two years, Case X suffered fluctuating deterioration developing new vision, speech and swallowing difficulties as well as tongue atrophy on the left side. Her mobility also worsened and she was diagnosed with arthritis, which was considered to be a cause for her limping and leaning to one side, and she was treated with two foot surgeries. Her mobility and speech progressively worsened alongside worsening tremors and she increasingly needed to hold on to objects to walk. She now manifests with progressive cognitive decline, becoming increasingly dependent on her mother for activities of daily living and social functioning. Brain MRI showed evidence of mineral deposition in the basal ganglia, which is suggestive of beta-propeller protein associated neurodegeneration (BPAN). Results of confirmatory genetic testing are pending. The goals of treatment are to manage her symptoms by optimising her medication while offering psychological support to her and her family.


Beta-propeller protein-associated neurodegeneration is an extremely rare disease with a variable phenotype. Neurodegeneration with brain iron accumulation disorders have a prevalence of 1/1,000,000 and, of these, BPAN constitutes only 7% (11). It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition. This report further expands the body of knowledge of the phenotype of BPAN highlighting potential neuropsychiatric manifestations (see Table).

The case demonstrates the classical presentation of BPAN as described in the literature (12). The typical two fold manifestation of symptoms was observed, with delayed psychomotor development and intellectual disability first manifesting in infancy, pronounced loss of expressive language skills and development of parkinsonism, dystonia and progressive cognitive decline in early adulthood. There were also comorbid features such as seizures and sleep disorder. This presentation is seen in the majority of cases, as described in several studies. There is, however, not a great deal of emphasis on the psychiatric symptoms of BPAN in previous reports. This report provides a more detailed picture of these especially in the context of learning disability.

The most common manifestation of psychiatric symptoms in learning disability is challenging behaviour and is often proportional to the severity of learning disability. It can be challenging to delineate and describe psychiatric symptoms in learning disability. This could be the reason why there are several incomplete and inconsistent reports of neuropsychiatric symptoms in BPAN. One case described yelling (8) while several others mention Rett-like stereotypic behaviours such as hand wringing and bruxism (11). This emphasises the need for early genetic testing in those presenting with such neuropsychiatric features in the context of learning disability. Accordingly, there is a growing consensus that genomic testing should be routinely performed for all people with a learning disability.

Table: Clinical features of Beta-propeller protein-associated neurodegeneration (BPAN) as seen in Case X

Neuropsychiatric features
Mood instability
Anxiety symptoms
Pathological crying or laughing
Self-harming behaviour

Neurological features
Neurological symptoms
Global developmental delay
Limited speech

Other features
Sleep disturbance
Swallowing difficulties with tongue atrophy
Deteriorating vision

Early genetic testing is vital because, as highlighted in Case X, early brain MRI may be normal in BPAN, with iron accumulation not producing changes detectable on neuroimaging until later in life and, as such, may not be helpful in diagnosing young patients (3, 8, 11, 12). Earlier diagnosis of BPAN will mean that affected families have earlier intervention and access to extra support to manage this severe condition which would likely foster better multidisciplinary management strategies as well as accurate assessment of recurrence risk and proper genetic counselling.


Management of BPAN is mainly symptomatic especially at the stage of decline in motor function. However, early diagnosis and regular clinical follow‐up will enable appropriate therapeutic intervention for patients with subtle early symptoms of parkinsonism (12). For example, studies have reported substantial initial benefit with the use of oral levodopa in BPAN (13). Management of neuropsychiatric complications at a late stage is particularly challenging as antipsychotic medications can exacerbate movement problems as side effects as demonstrated in this case. This further emphasises the importance of early diagnosis, which also enables timely psychological support for patients and their families.


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