** TODO Utiliser chèque énergie
SCHEDULED: <2022-04-10 Sun>

* Outline
** NBIA

* NBIA

** Beta-propeller protein associated neurodegeneration
*** Phenotype [cite:@hayflick2013]
- All subjects had been diagnosed with global developmental delay in infancy or early childhood and carried a diagnosis of in- tellectual disability into adulthood.
- Most children made slow developmental gains over time. Developmental quotients ranged from 30–50, with severely limited expressive language in childood.
- As children, most subjects were described as clumsy with a broad-based or ataxic gait but were generally healthy.
- Six were noted to have spasticity.
  Thirteen subjects had epilepsy in childhood requiring treatment with anti-epileptic medication.

BPAN = first X-linked, WDR45 and distinc phenotype
- suspicion : 7 patients in [cite:@gregory2009]
- confirmed + molecular basis in [cite:@haack2012] [cite:@hayflick2013]
* Beta-propeller protein associated neurodegeneration
** Phenotype [cite:@hayflick2013]
*** Clinical
- All (23): global developmental delay in infancy/early childhood + ID as adult
- Most children : made slow developmental gains over time. Developmental quotients ranged from 30–50, with severely limited expressive language in childood.
- Most : clumsy children (broad-based or ataxic gait) but generally healthy.
- 6: spasticity.
- 13: epilepsy in childhood requiring treatment

- comorbid features in childhood include seizures, spasticity, disordered sleep and stereotypies that further define the BPAN phenotype.
- Although, L-DOPA provides substan- tial initial benefit in BPAN, the benefit is short-lived and its use limited by dyskinesias.

- comorbid features in childhood : seizures, spasticity, disordered sleep and stereotypies that further define the BPAN phenotype.

- all subjects exhibited neurological deterioration in adolescence or early adulthood with the onset of dystonia, parkinsonism, and new cognitive decline.
  - The mean age at deterioration was 25.3 years (range 15–37 years).
    The parkinsonism was characterized by prominent bradykinesia, rigidity and freezing of gait; however, tremor was noted in only two subjects.
  - Dystonia was a common feature beginning in adolescence

- all : neurological deterioration in adolescence/early adulthood: dystonia, parkinsonism, and new cognitive decline.
  - mean age 25.3 years (range 15–37 years).
  - parkinsonism = prominent bradykinesia, rigidity and freezing of gait; however, tremor was noted in only two subjects.
  - Dystonia common in adolescence

  - deterioration of cognition concomitant with onset of the movement disorder, with progres- sive loss of limited expressive language skills advancing to severe dementia in end stages.
- Eighteen subjects are living, and their current ages range from 16 to 44 years. Five female subjects died during their third to fifth decades of life; one died with severe parkinsonism and dysphagia at 48 years of age, which was 11 years after her neurological deterioration reportedly began. Two died from aspiration pneumonia, and two died from unknown causes

  - deterioration of cognition concomitant with onset of the movement disorder, with progressive loss of limited expressive language skills advancing to severe dementia in end stages.
- life expectancy :
  - 18 living (16 to 44 years)
  - 5 female died during 30-50 years
    - 1 ; severe parkinsonism and dysphagia at 48 years of age (11 years after neurological deterioration)
    - 2 aspiration pneumonia
    - 2 unknown causes

  - Additional phenotypic features reported in only a subset of patients included disordered sleep, ocular defects and Rett-like hand stereotypies (Table 1).
*** Phenotype described in Gregory2002, Gregory2019.
*** Genetic basis in Haack2012

  - Subset : disordered sleep, ocular defects and Rett-like hand stereotypies (Table 1).
*** MRI
- all = increased iron deposit in substantia nigra and globus pallidus (reports not seens)
- 13 MRI from 11 patients seen
  - T2 hypointense : substantia nigra and globus pallidus
  - all 13 : substantia nigra : more hypointense
  - 6/10 global pallidus hypointensity variable
  - T1: **halo** in substantia nigra and cerebral pedoncule (center = dark, hyperintensite haloi)
    -> unique to BPAN ?
  - 19/23 : generalized cerebral atrophy
  - 6/23 cerebellar atrophy
*** Neuropatho : 1 patient
- gross: mild cerebellar atrophy, thinned cerebral peduncles, dark/grey brown in substantia nigra
- microscopic (globus pallidus, substantia nigra)
  - iron
  - numerous large axonal spheroids, siderophages, reactive astrocytes
  - severe neuronal loss
  - putamen, thalamus, granular cell layer also affected
  -  tau-positive neurofibrillary tangles in hippocampus, neocortex, putamen, hypothalamus
** Genetic basis in Haack2012

** References

* References

- [ ] [cite:@haylick2013] phenotype details of the cohort in [cite:@haack2012]

- [X] [cite:@haylick2013] phenotype details of the cohort in [cite:@haack2012]

  - exomes in 14 unrelated patients found mutations in 13.  +7 patients : so 20 patients in total
  - phenotype
    - global developmental delay in early childhood and slow motor and cognitive gains until adolescence or early adulthood, when dystonia, parkinsonism, and dementia would manifest
    - IRM:
      - a markedly hypointense signal on T2- weighted sequences in the substantia nigra and globus pallidus
      - A unique feature of this form of NBIA was T1 hyperintensity surrounding a central linear region of sig- nal hypointensity within the substantia nigra and cerebral peduncles

  MRI with arrows :)

- [X] Gregory2009
  7 patients: new phenotype

@article {gregory2009,
	author = {Gregory, A and Polster, B J and Hayflick, S J},
	title = {Clinical and genetic delineation of neurodegeneration with brain iron accumulation},
	volume = {46},
	number = {2},
	pages = {73--80},
	year = {2009},
	doi = {10.1136/jmg.2008.061929},
	publisher = {BMJ Publishing Group Ltd},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.},
	issn = {0022-2593},
	URL = {https://jmg.bmj.com/content/46/2/73},
	eprint = {https://jmg.bmj.com/content/46/2/73.full.pdf},
	journal = {Journal of Medical Genetics}
}