Tuesday, February 20, 2018

Beta-propeller protein-associated neurodegeneration

Stige KE, Gjerde IO, Houge G, Knappskog PM, Tzoulis C. Beta-propeller protein-associated neurodegeneration: a case report and review of the literature. Clin Case Rep. 2018 Jan 4;6(2):353-362.

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next-generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.
All patients had delayed psychomotor development and intellectual disability manifesting from infancy or early childhood characterized by pronounced loss of expressive language skills. In addition, 44 of 59 patients (74.6%) developed progressive cognitive decline upon reaching adolescence or early adulthood. The majority had epileptic seizures (42/62, 67.7%) and movement disorders including dystonia (44/60, 73.3%) and parkinsonism (35/58, 60.3%). Epileptic seizures started in early childhood and showed a spectrum ranging from focal to generalized seizures and epileptic spasms. Multiple seizure types were commonly seen in the same individuals. The epilepsy was generally most severe in childhood and improved with advancing age. Dystonia and parkinsonism developed in adolescence or early adulthood when the motor function started deteriorating and caused severe motor disability with many patients becoming wheelchair-dependent or bedridden.

From the article

Rett-like features, including developmental regression, loss of purposeful hand skills, stereotypic hand movements, and bruxism, were seen in 14 patients (14/50, 28%). All but one of these had atypical Rett syndrome or Rett-like features, meaning that they did not fulfill all formal diagnostic criteria for Rett syndrome.

Spasticity, sleep disturbances, and ocular/visual defects have been variably reported to be a part of the phenotype. A systematic statistical evaluation of these was not possible due to inconsistent reporting and incomplete descriptions in the literature. Limb spasticity of highly variable severity has been described in both children and adults. A wide range of sleep disturbances has been reported including REM sleep disorder, excessive movement during sleep, circadian rhythm sleep disorder, hypersomnolence with choreiform movements at onset of sleep, parasomnia with nocturnal screaming, and unspecified sleep disorders. Ocular/visual involvement has been reported in 17 patients and comprises myopia, astigmatism, strabismus, abnormal pupillary shade, spontaneous retinal detachment, bilateral partial retinal coloboma, patchy loss of pupillary ruff, difficulties with eyesight with intermittent double-vision, bilateral optic disk pallor, bilateral optic atrophy, increased visual evoked potential (VEP) latency, cortical blindness, and retinitis pigmentosa.

Dysmorphic features have not been systematically characterized in BPAN. Definite data were only available for 16 of 64 patients (25%) of whom 11 (68.8%) were reported to have dysmorphic features. These included microcephaly, abnormal nasal bridge (depressed, high, wide, and flat), a small mouth [, tented upper lip, hypertelorism, epicanthal folds, downslanting palpebral fissures, large ears, bilateral low-set ears, low hanging columella, short philtrum, high palate, downturned mouth and micrognathia , narrow face , narrow nose, thin upper lip, kyphosis, flat and almost rocker bottom feet, fingers tapered  with fifth finger clinodactyly, partial synophrys, and congenital talipes varus. Small cold hands and feet were also reported. It was not possible to identify any common dysmorphic features from this analysis.

Other clinical features of BPAN include neuropsychiatric symptoms, “happy demeanor”, and excessive drooling. Chorea has been reported in one patient. Bilateral sensory neural hearing loss has also been reported as well as auditory agnosia.

The vast majority of patients with BPAN (55/61, 90.2%) had MRI findings consistent with iron deposition in the basal ganglia. The two most typical findings were as follows:

Hypointense signal in the substantia nigra and globus pallidus on T2-weighted or iron-sensitive sequences such as SWI. This finding was more prominent in older individuals. The T2 hypointensity was generally more pronounced in the substantia nigra compared to the globus pallidus, a feature that may help distinguish BPAN from other forms of NBIA.

Hyperintense “halo” surrounding a band of central hypointensity in the substantia nigra and cerebral peduncles on T1-weighted images. This finding is generally regarded as pathognomonic for BPAN.

MRI findings in BPAN. Brain MRI of the Norwegian patient at the age of 33 years, showing typical findings for BPAN. (A) Axial T1-weighted image at the level of the midbrain shows symmetric hyperintense “halos” surrounding a band of central hypointensity in the substantia nigra (arrows). Axial T2-weighted and SWI image of the same area shows prominent hypointensities in the substantia nigra and cerebral peduncles (arrows). (B) Axial images at the level of the striatum show high T1 signal and low T2 and SWI signal in the globus pallidus. The low SWI signal corresponds to areas of increased iron deposition (arrowheads).

Takano K, Goto K, Motobayashi M, Wakui K, Kawamura R, Yamaguchi T, Fukushima Y, Kosho T. Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. Eur J Med Genet. 2017 Oct;60(10):521-526.

Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN.

Hattingen E, Handke N, Cremer K, Hoffjan S, Kukuk GM. Clinical and Imaging Presentation of a Patient with Beta-Propeller Protein-Associated Neurodegeneration, a Rare and Sporadic form of Neurodegeneration with Brain Iron Accumulation (NBIA). Clin Neuroradiol. 2017 Dec;27(4):481-483.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye-of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity.

Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron
accumulation. Handb Clin Neurol. 2018;147:293-305.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.

Inspired by a colleague's patient

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