Beta-Propeller Protein-Associated Neurodegeneration

Alternate names

BPAN; NBIA5; Neurodegeneration with brain iron accumulation type 5; SENDA; Static encephalopathy of childhood with neurdegeneration in adulthood; Neurodegeneration with brain iron accululation 5 ; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5; BETA-PROPELLER PROTEIN-ASSOCIATED NEURODEGENERATION; STATIC ENCEPHALOPATHY OF CHILDHOOD WITH NEURODEGENERATION IN ADULTHOOD

Definition

Beta-propeller protein-associated neurodegeneration (BPAN) is a disorder that damages the nervous system and is progressive, which means that it gradually gets worse.

Summary

• It is part of the group of disorders known as neurodegeneration with brain iron accumulation.
• This disorder presents with global developmental delay in childhood which becomes progressive in early adulthood.

Epidemiology

• BPAN is a rare disorder. Its prevalence is unknown, but it is thought to account for between 35 and 40 percent of all cases of NBIA disorders.
• 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.

Cause

• BPAN is caused by mutations in the WDR45 gene.
• This gene provides instructions for making the WIPI4 protein.
• WIPI4 has a characteristic structure resembling a seven-bladed propeller, from which the name of the disorder is derived.
• The WIPI4 protein is involved in a process called autophagy, which helps clear unneeded materials from cells, including excess amounts of an iron storage protein called ferritin.

Gene mutations

• Most of the WDR45 gene mutations identified in people with BPAN result in the absence of functioning WIPI4 protein.
• As a result, the process of autophagy is impaired, making cells less efficient at removing damaged cell structures and waste materials. Researchers suggest that nerve cells (neurons) may be particularly vulnerable to impaired autophagy because they have long extensions (axons and dendrites), making it even more difficult to transport the waste materials from these structures to the compartments in the cell body where recycling takes place (the lysosomes).
• The waste materials can build up in these areas and damage them.
• Damage to neurons results in the neurological problems that occur in BPAN.

Inheritance

X-linked dominant inheritance

• This condition is inherited in an X-linked dominant pattern.
• The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes.
• In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder.
• A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
• In most X-linked dominant disorders, males experience more severe symptoms than females.
• While this is not always the case in BPAN, most individuals with the disorder are females, likely because a smaller number of affected males survive until birth.
• Almost all cases of BPAN result from new mutations in the gene and occur in people with no history of the disorder in their family. Rarely, an affected person inherits the mutation from a mildly affected mother.
• Among reported cases, males with BPAN and most females with BPAN have not had children.

Signs and symptoms

Symptoms include dystonia (a movement disorder resulting in muscular spasms, twisting and repetitive movements) spasticity, parkinsonism (slurred or slow speech, stiffness of the muscles, slow movement, and visible tremors), and cognitive decline.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Abnormal autonomic nervous system physiology
• Abnormality of eye movement(Abnormal eye movement)
• Bradykinesia(Slow movements)
• Cerebellar atrophy(Degeneration of cerebellum)
• Cerebral atrophy(Degeneration of cerebrum)
• Dementia(Dementia, progressive)
• Dystonia
• Frontal release signs
• Global developmental delay
• Intellectual disability(Mental deficiency)
• Iron accumulation in substantia nigra
• Parkinsonism
• Poor speech
• Progressive encephalopathy
• Rigidity(Muscle rigidity)
• Sleep disturbance(Difficulty sleeping)
• Spastic paraparesis
• Tremor

5%-29% of people have these symptoms

• Aggressive behavior(Aggressiveness)
• Optic atrophy
• Seizure

Diagnosis

• The quality of the neuroimaging, including magnet strength and spacing of image slices, can limit the ability to accurately identify abnormal brain iron. <ref>Gregory A, Hayflick S. Neurodegeneration with Brain Iron Accumulation Disorders Overview. 2013 Feb 28 [Updated 2019 Oct 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121988/</ref>[1].
• Iron-sensitive sequences, such as SWI, GRE, and T2*, should be used as a first-line diagnostic investigation to identify the characteristic changes in NBIA.
• By the time clear neurologic features are present, the brain MRI almost always shows characteristic changes, although iron may be visible only later in the disease course.
• Neuropathologic findings include axonal spheroids in the CNS and, in some types, in peripheral nerves.

Treatment

• Treatment is aimed at addressing the symptoms found in each individual.<ref>Gregory A, Hayflick S. Neurodegeneration with Brain Iron Accumulation Disorders Overview. 2013 Feb 28 [Updated 2019 Oct 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121988/</ref>[2].
• Pharmacologic treatment of spasticity and seizures
• Trial of oral or intrathecal baclofen for those with significant dystonia
• Botulinum toxin for those with focal dystonia
• L-DOPA treatment, which is beneficial in rare cases.
• Deep brain stimulation, used clinically for dystonia with increasing frequency, shows some evidence of benefit.
• Psychiatric treatment for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms

References

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NIH genetic and rare disease info

• NIH info on Beta-Propeller Protein-Associated Neurodegeneration

Beta-Propeller Protein-Associated Neurodegeneration is a rare disease.

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