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Beta-Propeller Protein-Associated Neurodegeneration

SENDA


Presentation

  • A female patient presented with significant developmental delay in early childhood and subsequently demonstrated neurodegeneration with progressive dystonia and dementia in her third decade.[ncbi.nlm.nih.gov]
Wheelchair Bound
  • […] of global developmental delay and generalized seizures in childhood presented at the age of 21 with parkinsonian symptoms, including unsteady gait, frequent falls, and rigidity in all extremities, which steadily progressed over 4 years to leave her wheelchair-bound[ajnr.org]
Feeding Difficulties
  • For those with feeding difficulties, feeding therapy may be considered.[ncbi.nlm.nih.gov]
Hirsutism
  • At 14 years of age, she was noted to have limited elbow extension, mild hirsutism and tapering of her fingers ( Figure 1 ; Supplementary Video ). A brain MRI at that time revealed iron deposition in the basal ganglia.[nature.com]
Large Ears
  • Note the high nasal bridge, downslanted palpebral fissures and large ears with prominent inferior crus of the antihelix. Bottom: patient 2 at 13 years of age. Note high nasal bridge and low hanging columella.[nature.com]
Hip Dislocation
  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).[ncbi.nlm.nih.gov]
Abnormal Eye Movement
  • She developed abnormal eye movements and auditory inattention. There were no seizures. There was no family history of neurological disease. On examination, her head circumference was normal and she did not have any dysmorphic features.[annalsofian.org]
  • Symptoms include juvenile parkinsonism, dementia, abnormal eye movements and involuntary jerking of facial and finger muscles. Neuroferritinopathy is the only genetically dominant form of NBIA identified so far.[nbiaalliance.org]
Generalized Seizure
  • seizures in childhood presented at the age of 21 with parkinsonian symptoms, including unsteady gait, frequent falls, and rigidity in all extremities, which steadily progressed over 4 years to leave her wheelchair-bound.[ajnr.org]
  • Seizures are frequently multiform and include focal seizures with impaired consciousness, epileptic spasms [Hogarth, personal communication], and generalized seizures, including absence, atonic, myoclonic, and tonic-clonic [ Hayflick et al 2013 ].[ncbi.nlm.nih.gov]
Clumsiness
  • Most children are described as clumsy with an ataxic gait — unsteady, staggering movements while walking. Generally, the individuals are healthy, but they may exhibit other problems. Seizures are common, as are sleep disorders.[nbiadisorders.org]
  • Children are typically clumsy and have a broad-based or ataxic gait. Some never learn to walk; others who achieve walking eventually become non-ambulatory. Some have mild spasticity that generally does not require treatment.[ncbi.nlm.nih.gov]
Spastic Quadriplegia
  • Other clinical features include: spastic cerebral palsy spastic quadriplegia Iron accumulation in the brain specifically in globus pallidus and substantia nigra. This disorder is thought to be genetically determined with defective iron metabolism.[radiopaedia.org]
  • Its clinical course is described as biphasic with an initial presentation during childhood, as spastic quadriplegia or static encephalopathy with early developmental delay with or without seizures, followed by dementia in adulthood and the development[nature.com]
Muscle Tone Abnormalities
  • ., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox anti-parkinsonian medications, or orthopedic[ncbi.nlm.nih.gov]
Cognitive Deficit
  • As cognitive deficits progress in those with advanced disease, carbidopa/levodopa formulations may carry a lower risk of adverse neuropsychiatric effects than dopamine agonists.[ncbi.nlm.nih.gov]

Workup

  • The youngest patient reported with these MRI findings is a 6-year-old girl with Rett syndrome–like features diagnosed by whole exome sequencing. 8 In contrast, although our patient underwent her first brain MRI as part of a diagnostic workup for cognitive[pediatrics.aappublications.org]
  • (See Presentation and Workup.) [4, 5, 6] PKAN is relentlessly progressive. The clinical course is characterized by progressive dementia, spasticity, rigidity, dystonia, and choreoathetosis.[emedicine.medscape.com]
Hypsarrhythmia
  • Her infantile spasms and hypsarrhythmia disappeared promptly by adrenocorticotropic hormone therapy (CORTROSYN Z, 0.0125mg/kg/day daily for 2weeks intramuscularly), though the administration of pyridoxal phosphate and valproic acid had poor efficacy.[readbyqxmd.com]
  • Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG.[ncbi.nlm.nih.gov]
Amyloid Plaque
  • Numerous tau-positive neurofibrillary tangles were seen in several regions; no beta-amyloid plaques or Lewy bodies were observed [ Hayflick et al 2013 ].[ncbi.nlm.nih.gov]

Treatment

  • Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease.[ncbi.nlm.nih.gov]
  • : Dopamine agonists Levodopa Deep brain stimulation Symptomatic treatment for dystonia and seizures A 33-year-old woman with a history of global developmental delay and generalized seizures in childhood presented at the age of 21 with parkinsonian symptoms[ajnr.org]
  • There is currently no specific treatment for BPAN. To delay the onset of her condition, Heidi takes medication for those with Parkinson’s disease.[today.mims.com]

Prognosis

  • The specific course and prognosis should implicate restrained psychopharmacological interventions. The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder.[ncbi.nlm.nih.gov]
  • Early diagnosis of BPAN is of utmost importance, providing families with a direction for possible management and prognosis and preventing further unnecessary diagnostic testing.[pediatrics.aappublications.org]
  • (See Presentation and Prognosis.) [7, 8] The disease can be familial or sporadic.[emedicine.medscape.com]

Etiology

  • Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet. PubMed PMID: 24973356 Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease. N Engl J Med.[books.google.de]
  • Etiology The exact etiology of PKAN is not known. One proposed hypothesis is that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain.[emedicine.medscape.com]
  • Note that specific eponyms are applied to a particular clinical and electrographic profile and do not imply a specific etiology: many genetic and non-genetic etiologies can result in a given epilepsy syndrome.[ncbi.nlm.nih.gov]

Epidemiology

  • […] with brain iron accumulation type 4 - SENDA - Static encephalopathy of childhood with neurdegeneration in adulthood Classification (Orphanet): - Rare genetic disease - Rare neurologic disease Classification (ICD10): - Diseases of the nervous system - Epidemiological[csbg.cnb.csic.es]
  • […] definition according to the specific consensus conference or to The Diseases Database based on the Unified Medical Language System (NLM) and a link to: a) Wikipedia definition b) The Diseases Database Also the Mesh corresponding term has to be chosen EPIDEMIOLOGY[flipper.diff.org]
  • Epidemiology • Estimated prevalence of 1-3/ million population has been suggested based on observed cases in a population. • PKAN: highest prevalence & founder mutation in Central Europe • Neuroferritinopathy is classically seen in patients from the Cumbrian[slideshare.net]
Sex distribution
Age distribution

Pathophysiology

  • In addition, early identification of WDR45 mutation may lead to a better understanding of the pathophysiology of BPAN and result in the development of novel therapeutic interventions for preventing or delaying the onset of neurodegeneration for pediatric[pediatrics.aappublications.org]
  • Beta-Propeller Protein-Associated Neurodegeneration (BPAN) •Beta-propeller protein-associated neurodegeneration is unique among the NBIAs in its mode of inheritance, its presumed pathophysiology.[slideshare.net]
  • Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP : Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA). Curr Neuropharmacol 2013; 11 : 59–79. 12.[nature.com]
  • The reason why our patient did not respond positively is not clear, it may depend on unexplained individual characteristics, nevertheless not excluding the intervention of other specific pathophysiological mechanisms in this form of disease.[journal.frontiersin.org]
  • Our research unit “Molecular Pathophysiology of Neurodegenerative Disorders” has investigated the molecular pathogenesis of abnormal protein accumulation in the nervous system in neurodegenerative diseases to facilitate the analyses of pathogenic substances[ura.sec.tsukuba.ac.jp]

Prevention

  • Currently, there is no known effective prevention or treatment of neurologic decline in BPAN.[pediatrics.aappublications.org]
  • Basically, without evolution, the fledgling field of precision medicine would wither and die, and we would lose our opportunity to prevent, diagnose, and treat the diseases that account for the bulk of morbidity and mortality in humans and in animals.This[medworm.com]
  • To prevent him from regressing, his parents regularly work out with him. Elijah, who also helps clean at Berkshire Nautilus through his high school internship program, also exercises there.[berkshireeagle.com]
  • […] dopaminergic drugs for parkinsonism for: Adverse neuropsychiatric effects Psychiatric symptoms Worsening of parkinsonism Nutrition Monitoring of height and weight in children Swallowing evaluation and regular dietary assessments Assure adequate nutrition Prevent[nbiacure.org]
  • It has been demonstrated that A2AR is able to prevent amyloid--induced synaptotoxicity in animal models and cell cultures. Moreover A2AR has been shown to control NMDA currents and glutamate outflow in the hippocampus.[oatd.org]

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